bluuebunny/crossref_metadata_2025_split huggingface dataset:
Serum transferrin as a biomarker of hepatocyte nuclear factor 4 alpha activity and hepatocyte function in liver diseases
Authors: Guldiken Nurdan , Argemi Josepmaria , Gurbuz Berivan , Atkinson Stephen R. , Oliverius Martin , Fila Petr , Hamesch Karim , Bruns Tony , Cabezas Joaquín , Lozano Juan J. , Mann Jelena , Cao Sheng , Mathurin Philippe , Shah Vijay H. , Trautwein Christian , Thursz Mark R. , Bataller Ramon , Strnad Pavel 
Published: February 2021

Abstract
Background
Serum transferrin levels represent an independent predictor of mortality in patients with liver failure. Hepatocyte nuclear factor 4 alpha (HNF4α) is a master regulator of hepatocyte functions. The aim of this study was to explore whether serum transferrin reflects HNF4α activity.

Methods
Factors regulating transferrin expression in alcoholic hepatitis (AH) were assessed via transcriptomic/methylomic analysis as well as chromatin immunoprecipitation coupled to DNA sequencing. The findings were corroborated in primary hepatocytes. Serum and liver samples from 40 patients with advanced liver disease of multiple etiologies were also studied.

Results
In patients with advanced liver disease, serum transferrin levels correlated with hepatic transferrin expression (r = 0.51, p = 0.01). Immunohistochemical and biochemical tests confirmed reduced HNF4α and transferrin protein levels in individuals with cirrhosis. In AH, hepatic gene-gene correlation analysis in liver transcriptome revealed an enrichment of HNF4α signature in transferrin-correlated transcriptome while transforming growth factor beta 1 (TGFβ1), tumor necrosis factor α (TNFα), interleukin 1 beta (IL-1β), and interleukin 6 (IL-6) negatively associated with transferrin signature. A key regulatory region in transferrin promoter was hypermethylated in patients with AH. In primary hepatocytes, treatment with TGFβ1 or the HNF4α inhibitor BI6015 suppressed transferrin production, while exposure to TNFα, IL-1β, and IL-6 had no effect. The correlation between hepatic HNF4A and transferrin mRNA levels was also seen in advanced liver disease.

Conclusions
Serum transferrin levels constitute a prognostic and mechanistic biomarker. Consequently, they may serve as a surrogate of impaired hepatic HNF4α signaling and liver failure.
Lower iodine storage in the placenta is associated with gestational diabetes mellitus
Authors: Neven Kristof Y. , Cox Bianca , Cosemans Charlotte , Gyselaers Wilfried , Penders Joris , Plusquin Michelle , Roels Harry A. , Vrijens Karen , Ruttens Ann , Nawrot Tim S. 
Published: February 2021

Abstract
Background
The micronutrient iodine is essential for a healthy intrauterine environment and is required for optimal fetal growth and neurodevelopment. Evidence linking urinary iodine concentrations, which mainly reflects short-term iodine intake, to gestational diabetes mellitus (GDM) is inconclusive. Although the placental concentrations would better reflect the long-term gestational iodine status, no studies to date have investigated the association between the placental iodine load and the risk at GDM. Moreover, evidence is lacking whether placental iodine could play a role in biomarkers of insulin resistance and β-cell activity.

Methods
We assessed the incidence of GDM between weeks 24 and 28 of gestation for 471 mother-neonate pairs from the ENVIRONAGE birth cohort. In placentas, we determined the iodine concentrations. In maternal and cord blood, we measured the insulin concentrations, the Homeostasis Model Assessment (HOMA) for insulin resistance (IR) index, and β-cell activity. Logistic regression was used to estimate the odds ratios (OR) of GDM, and the population attributable factor (PAF) was calculated. Generalized linear models estimated the changes in insulin, HOMA-IR, and β-cell activity for a 5 μg/kg increase in placental iodine.

Results
Higher placental iodine concentrations decreased the risk at GDM (OR = 0.82; 95%CI 0.72 to 0.93; p = 0.003). According to the PAF, 54.2% (95%CI 11.4 to 82.3%; p = 0.0006) of the GDM cases could be prevented if the mothers of the lowest tertile of placental iodine would have placental iodine levels as those belonging to the highest tertile. In cord blood, the plasma insulin concentration was inversely associated with the placental iodine load (β = − 4.8%; 95%CI − 8.9 to − 0.6%; p = 0.026).

Conclusions
Higher concentrations of placental iodine are linked with a lower incidence of GDM. Moreover, a lower placental iodine load is associated with an altered plasma insulin concentration, HOMA-IR index, and β-cell activity. These findings postulate that a mild-to-moderate iodine deficiency could be linked with subclinical and early-onset alterations in the normal insulin homeostasis in healthy pregnant women. Nevertheless, the functional link between gestational iodine status and GDM warrants further research.
Prevalence of commonly diagnosed disorders in UK dogs under primary veterinary care: results and applications
Authors: O’Neill Dan G. , James Hannah , Brodbelt Dave C. , Church David B. , Pegram Camilla 
Published: February 2021

Abstract
Background
Although dogs are a commonly owned companion animal in the UK, the species experiences many health problems that are predictable from demographic information. This study aimed to use anonymised veterinary clinical data from the VetCompass™ Programme to report the frequency of common disorders of dogs under primary veterinary care in the UK during 2016 and to explore effects associated with age, sex and neuter status.

Results
From an available population of 905,543 dogs under veterinary care at 886 veterinary clinics during 2016, the current study included a random sample of 22,333 (2.47 %) dogs from 784 clinics. Prevalence for each disorder was calculated at the most refined level of diagnostic certainty (precise-level precision) and after grouping to a more general level of diagnostic precision (grouped-level precision). The most prevalent precise-level precision disorders recorded were periodontal disease (prevalence 12.52 %, 95 % CI: 12.09–12.97), otitis externa (7.30 %, 95 % CI: 6.97–7.65) and obesity (7.07 %, 95 % CI: 6.74–7.42). The most prevalent grouped-level disorders were dental disorder (14.10 %, 95 % CI: 13.64–14.56), skin disorder (12.58 %, 95 % CI: 12.15–13.02) and enteropathy (10.43 %, 95 % CI: 10.04–10.84). Associations were identified for many common disorders with age, sex and neuter.

Conclusions
The overall findings can assist veterinarians and owners to prioritise preventive care and to understand demographic risk factors in order to facilitate earlier diagnosis of common disorders in dogs. The information on associations with age, sex and neuter status provides additional contextual background to the complexity of disorder occurrence and supports targeted health controls for demographic subsets of dogs.
Use of immune repertoire sequencing to resolve discordant microscopic and immunochemical findings in a case of T cell-rich large B cell lymphoma in a young dog
Authors: Lee Gary Kwok Cheong , Bienzle Dorothee , Keller Stefan Matthias , Hwang Mei-Hua , Darzentas Nikos , Chang Haiyang , Rätsep Emily , Egan Rebecca , Beeler-Marfisi Janet 
Published: February 2021

Abstract
Background
Lymphocytic neoplasms with frequent reactive lymphocytes are uncommonly reported in dogs, and can pose a diagnostic challenge. Different diagnostic modalities such as cytology, flow cytometry, histopathology, immunohistochemistry, and clonality testing, are sometimes required for a diagnosis. This report illustrates the value of using a multi-modal diagnostic approach to decipher a complex lymphocytic tumor, and introduces immune repertoire sequencing as a diagnostic adjunct.

Case presentation
A 10-month-old Great Dane was referred for marked ascites. Cytologic analysis of abdominal fluid and hepatic aspirates revealed a mixed lymphocyte population including numerous large lymphocytes, yielding a diagnosis of lymphoma. Flow cytometrically, abdominal fluid lymphocytes were highly positive for CD4, CD5, CD18, CD45, and MHC II, consistent with T cell lymphoma. Due to a rapidly deteriorating clinical condition, the dog was euthanized. Post mortem histologic evaluation showed effacement of the liver by aggregates of B cells surrounded by T cells, suggestive of hepatic T cell-rich large B cell lymphoma. Immune repertoire sequencing confirmed the presence of clonal B cells in the liver but not the abdominal fluid, whereas reactive T cells with shared, polyclonal immune repertoires were found in both locations.

Conclusions
T cell-rich large B cell lymphoma is a rare neoplasm in dogs that may be challenging to diagnose and classify due to mixed lymphocyte populations. In this case, the results of histopathology, immunohistochemistry and immune repertoire sequencing were most consistent with a hepatic B cell neoplasm and reactive T cells exfoliating into the abdominal fluid. Immune repertoire sequencing was helpful in delineating neoplastic from reactive lymphocytes and characterizing repertoire overlap in both compartments. The potential pitfalls of equating atypical cytomorphology and monotypic marker expression in neoplasia are highlighted.
A CTSA One Health Alliance guidance on institutional review of veterinary clinical studies
Authors:   CTSA One Health Alliance, Moore S. A. , O’Kell A. , Borghese H. , Garabed R. , O’Meara H. , Baneux P. 
Published: February 2021

AbstractHarmonized institutional processes and reviewer training are vital to maintain integrity and ethical rigor of the veterinary clinical research pipeline and are a prerequisite to future work that might establish centralized or single-site ethical and regulatory review to ease initiation of multi-center studies. Funded by a CTSA One Health Alliance (COHA) pilot award, a diverse working group of veterinary clinicians and institutional representatives was convened in February 2020 to develop a guidance document detailing broadly agreed upon practices for ethical review and approval of veterinary clinical studies conducted in the United States.The working group defined key areas of need for consensus, developed a set of associated guidelines, and circulated these for review by COHA’s fifteen member institutions. Six focus areas were identified by the working group and included vital items of protocol review, composition of the review committee, post-approval monitoring and adverse event reporting, consideration of special circumstances such as satellite sites and the use of healthy veterinary subjects in research, and the informed consent process.This document outlines a broadly agreed-upon framework through which to approach vital items associated with veterinary clinical study protocol review and approval. These approaches represent current best practice in the review and approval of veterinary clinical studies, and can serve as a guidance for veterinary clinician-scientists and regulatory experts, to ensure robust and ethically conducted studies that can contribute to the advancement of both animal and human health.
MicroRNA 219-5p inhibits alveolarization by reducing platelet derived growth factor receptor-alpha
Authors: Freeman Amelia , Qiao Luhua , Olave Nelida , Rezonzew Gabriel , Gentle Samuel , Halloran Brian , Pryhuber Gloria S. , Gaggar Amit , Tipple Trent E. , Ambalavanan Namasivayam , Lal Charitharth Vivek 
Published: February 2021

AbstractBackgroundMicroRNA (miR) are small conserved RNA that regulate gene expression post-transcription. Previous genome-wide analysis studies in preterm infants indicate that pathways of miR 219-5p are important in infants with Bronchopulmonary Dysplasia (BPD).MethodsHere we report a prospective cohort study of extremely preterm neonates wherein infants diagnosed with severe BPD expressed increased airway miR-219-5p and decreased platelet derived growth factor receptor alpha (PDGFR-α), a target of mir-219-5p and a key regulator of alveolarization, compared to post-conception age-matched term infants.ResultsmiR-219-5p was highly expressed in the pulmonary epithelial lining in lungs of infants with BPD by in situhybridizationof human infant lungs. In both in vitro and in vivo (mouse) models of BPD, miR-219-5p was increased on exposure to hyperoxia compared with the normoxia control, with a complementary decrease of PDGFR-α. To further confirm the target relationship between miR‐219 and PDGFR-α, pulmonary epithelial cells (MLE12) and lung primary fibroblasts were treated with a mimic of miR-219-5p and a locked nucleic acid (LNA) based inhibitor of miR-219-5p. In comparison with the control group, the level of miR‐219 increased significantly after miR‐219 mimic treatment, while the level of PDGFR-α declined markedly. LNA exposure increased PDGFR-α. Moreover, in BPD mouse model, over-expression of miR-219-5p inhibited alveolar development, indicated by larger alveolar spaces accompanied by reduced septation.ConclusionsTaken together, our results demonstrate that increased miR-219-5p contributes to the pathogenesis of BPD by targeting and reducing PDGFR-α. The use of specific miRNA antagonists may be a therapeutic strategy for preventing the development of BPD.
The association between hospital length of stay before rapid response system activation and clinical outcomes: a retrospective multicenter cohort study
Authors: Park Jimyung , Lee Yeon Joo , Hong Sang-Bum , Jeon Kyeongman , Moon Jae Young , Kim Jung Soo , Kang Byung Ju , Ahn Jong-Joon , Lee Dong-Hyun , Park Jisoo , Cho Jae Hwa , Lee Sang-Min 
Published: February 2021

Abstract
Background
Rapid response system (RRS) is being increasingly adopted to improve patient safety in hospitals worldwide. However, predictors of survival outcome after RRS activation because of unexpected clinical deterioration are not well defined. We investigated whether hospital length of stay (LOS) before RRS activation can predict the clinical outcomes.

Methods
Using a nationwide multicenter RRS database, we identified patients for whom RRS was activated during hospitalization at 9 tertiary referral hospitals in South Korea between January 1, 2016, and December 31, 2017. All information on patient characteristics, RRS activation, and clinical outcomes were retrospectively collected by reviewing patient medical records at each center. Patients were categorized into two groups according to their hospital LOS before RRS activation: early deterioration (LOS < 5 days) and late deterioration (LOS ≥ 5 days). The primary outcome was 28-day mortality and multivariable logistic regression was used to compare the two groups. In addition, propensity score-matched analysis was used to minimize the effects of confounding factors.

Results
Among 11,612 patients, 5779 and 5883 patients belonged to the early and late deterioration groups, respectively. Patients in the late deterioration group were more likely to have malignant disease and to be more severely ill at the time of RRS activation. After adjusting for confounding factors, the late deterioration group had higher 28-day mortality (aOR 1.60, 95% CI 1.44–1.77). Other clinical outcomes (in-hospital mortality and hospital LOS after RRS activation) were worse in the late deterioration group as well, and similar results were found in the propensity score-matched analysis (aOR for 28-day mortality 1.66, 95% CI 1.45–1.91).

Conclusions
Patients who stayed longer in the hospital before RRS activation had worse clinical outcomes. During the RRS team review of patients, hospital LOS before RRS activation should be considered as a predictor of future outcome.
Diabetic phenotype and prognosis of patients with heart failure and preserved ejection fraction in a real life cohort
Authors: Lejeune Sibille , Roy Clotilde , Slimani Alisson , Pasquet Agnès , Vancraeynest David , Vanoverschelde Jean-Louis , Gerber Bernhard L. , Beauloye Christophe , Pouleur Anne-Catherine 
Published: February 2021

Abstract
Background
Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome, with several underlying etiologic and pathophysiologic factors. The presence of diabetes might identify an important phenotype, with implications for therapeutic strategies. While diabetes is associated with worse prognosis in HFpEF, the prognostic impact of glycemic control is yet unknown. Hence, we investigated phenotypic differences between diabetic and non-diabetic HFpEF patients (pts), and the prognostic impact of glycated hemoglobin (HbA1C).

Methods
We prospectively enrolled 183 pts with HFpEF (78 ± 9 years, 38% men), including 70 (38%) diabetics (type 2 diabetes only). They underwent 2D echocardiography (n = 183), cardiac magnetic resonance (CMR) (n = 150), and were followed for a combined outcome of all-cause mortality and first HF hospitalization. The prognostic impact of diabetes and glycemic control were determined with Cox proportional hazard models, and illustrated by adjusted Kaplan Meier curves.

Results
Diabetic HFpEF pts were younger (76 ± 9 vs 80 ± 8 years, p = 0.002), more obese (BMI 31 ± 6 vs 27 ± 6 kg/m2, p = 0.001) and suffered more frequently from sleep apnea (18% vs 7%, p = 0.032). Atrial fibrillation, however, was more frequent in non-diabetic pts (69% vs 53%, p = 0.028). Although no echocardiographic difference could be detected, CMR analysis revealed a trend towards higher LV mass (66 ± 18 vs 71 ± 14 g/m2, p = 0.07) and higher levels of fibrosis (53% vs 36% of patients had ECV by T1 mapping > 33%, p = 0.05) in diabetic patients.
Over 25 ± 12 months, 111 HFpEF pts (63%) reached the combined outcome (24 deaths and 87 HF hospitalizations). Diabetes was a significant predictor of mortality and hospitalization for heart failure (HR: 1.72 [1.1–2.6], p = 0.011, adjusted for age, BMI, NYHA class and renal function). In diabetic patients, lower levels of glycated hemoglobin (HbA1C < 7%) were associated with worse prognosis (HR: 2.07 [1.1–4.0], p = 0.028 adjusted for age, BMI, hemoglobin and NT-proBNP levels).

Conclusion
Our study highlights phenotypic features characterizing diabetic patients with HFpEF. Notably, they are younger and more obese than their non-diabetic counterpart, but suffer less from atrial fibrillation. Although diabetes is a predictor of poor outcome in HFpEF, intensive glycemic control (HbA1C < 7%) in diabetic patients is associated with worse prognosis.
Prognostic value of soluble suppression of tumorigenesis-2 (sST2) for cardiovascular events in coronary artery disease patients with and without diabetes mellitus
Authors: Li Man , Duan Lei , Cai Yulun , Hao Benchuan , Chen Jianqiao , Li Huiying , Liu Hongbin 
Published: February 2021

Abstract
Background
Soluble suppression of tumorigenesis-2 (sST2) is implicated in myocardial overload and has long been recognized as an inflammatory marker related to heart failure and acute coronary syndrome, but data on the prognostic value of sST2 in patients with coronary artery disease (CAD) remain limited. This study sought to investigate the prognostic value of sST2 in patients with established CAD and its predictive value in CAD patients with and without type 2 diabetes mellitus (T2DM).

Methods
A total of 3641 consecutive patients were included in this prospective cohort study. The primary end point was major adverse cardiovascular events (MACEs). The secondary end point was all-cause death. The association between sST2 and outcomes was investigated using multivariable Cox regression.

Results
During a median follow-up of 6.4 years, MACEs occurred in 775 patients, and 275 patients died. Multiple Cox regression models showed that a higher level of sST2 was an independent predictor of MACEs development (HR = 1.36, 95% CI 1.17–1.56, p < 0.001) and all-cause death (HR = 2.01, 95% CI 1.56–2.59, p < 0.001). The addition of sST2 to established risk factors significantly improved risk prediction of the composite outcome of MACEs and all-cause death (C-index, net reclassification index, and integrated discrimination improvement, all p < 0.05). In subgroup analysis depending on diabetes status, the diabetes group had a significantly higher level of sST2, which remained a significant predictor of MACEs and all-cause death in patients with and without T2DM in multivariable models. The area under the curve (AUC) of CAD patients with diabetes mellitus was significantly higher than that of those without T2DM. For MACEs, the AUC was 0.737 (patients with T2DM) vs 0.620 (patients without T2DM). For all-cause death, the AUC was 0.923 (patients with T2DM) vs 0.789 (patients without T2DM).

Conclusions
A higher level of sST2 is significantly associated with long-term MACEs and all-cause death in CAD patients with and without T2DM. sST2 has strong predictive value for cardiovascular adverse events in CAD patients with T2DM, and these results provide new evidence for the role of sST2.
Bacillus aryabhattai TFG5-mediated synthesis of humic substances from coir pith wastes
Authors: Muniraj Iniyakumar , Shameer Syed , Ramachandran Priyadharshini , Uthandi Sivakumar 
Published: February 2021

Abstract
Background
Humic substances (HS) form the largest proportion among all the constituents of soil organic matter and are a key component of the terrestrial ecosystem. HS plays a multifunctional role in the environment by controlling the biogeochemical carbon cycle, providing nutrients and bio-stimulants for plant growth, and interacting with inorganic and organic pollutants. The rate of formation of HS in soils determines its productivity and carbon sequestration capacity. Enhancement of HS synthesis in the soil through the microbial route not only increases CO2 sequestration but also mitigates the greenhouse gas emissions in the environment.

Result
In this study, we attempted to understand the mechanism of formation and enhancement of HS from coir pith wastes using the tyrosinase produced by Bacillus aryabhattai TFG5. The bacterium TFG5 isolated from the termite garden produced the tyrosinase (1.34 U mL−1) and laccase (2.1 U mL−1) at 48 h and 60 h of fermentation, respectively. The extracellular tyrosinase from B. aryabhattai TFG5 was designated as TyrB. Homology modeling of TyrB revealed a structure with a predicted molecular mass of 35.23 kDa and two copper ions in the active center with its conserved residues required for the tyrosinase activity. TyrB efficiently transformed and polymerized standard phenols, such as p-cresol, p-hydroxyl benzoic acid, Levo DOPA, and 2,6 DMP, besides transforming free phenols in coir pith wash water (CWW). Additionally, UV–Vis and FT-IR spectra of the degradation products of the coir pith treated with TyrB revealed the formation of HS within 3 days of incubation. Furthermore, the E472/664 ratio of the degradation products revealed a higher degree of condensation of the aromatic carbons and the presence of more aliphatic structures in the HS.

Conclusion
The results confirmed the influence of TyrB for the effective synthesis of HS from coir pith wastes. The results of the present study also confirm the recently accepted theory of humification proposed by the International Humic Substances Society.