bluuebunny/crossref_metadata_2025_split huggingface dataset:
Concomitant inhibition of hedgehog signalling and activation of retinoid receptors abolishes bleomycin‐induced lung fibrosis
Authors: Eleraky Ahmed Fawzy , Helal Gouda Kamel , Elshafie Mohamed F. , Ismail Raed S. 
Published: February 2021

AbstractPulmonary fibrosis is a devastating disease with unknown treatment. All‐trans retinoic acid (ATRA) attenuates bleomycin‐induced lung fibrosis by different mechanistic pathways. However, the role of retinoid receptors in lung fibrosis is still unclear. Forskolin (FSK), a potent inhibitor for the revolutionary hedgehog (Hh) signalling pathway, has a promising antifibrotic effect on other organs such as the liver. This study investigates the interplay between the retinoid receptors modulation and the Hh signalling pathway in bleomycin (BLM)‐induced pulmonary fibrosis. Rats were randomised and administrated a single dose of 7.5 mg/kg of BLM alone and with ATRA, FSK and both of them. The effects of FSK and ATRA on lung functions, oxidative stress markers (malondialdehyde [MDA], glutathione [GSH], superoxide dismutase [SOD] and catalase [CAT]), retinoid markers (retinoic acid receptors [RAR] and rexinoid X receptors [RXR]) and Hh signalling markers (patched homolog 1 [Ptch‐1], Smoothened [Smo] and glioblastoma‐2 [Gli‐2]) were assessed. In single therapies, ATRA and FSK ameliorated BLM‐induced lung fibrosis. On the contrary, a combination of both drugs synergistically reversed the effect of BLM‐induced lung fibrosis, as indicated by the enhancement of lung functions and the decrease of the α‐smooth muscle actin (α‐SMA) expression and collagen deposition. Additionally, FSK and ATRA ameliorated oxidative stress and inflammation, reduced transforming growth factor β1 (TGF‐β1) levels and reversed the effect of BLM on the mRNA expression of Ptch‐1, Smo and Gli‐2. FSK inhibited the Hh pathway and also activated protein kinase A (PKA) that is, in part, involved in phosphorylation of RAR/RXR heterodimer (a key step in retinoid receptor activation). The present results suggest that a combination of FSK and ATRA has a promising therapeutic value for lung fibrosis management.
A randomized controlled trial of oxycodone/acetaminophen versus acetaminophen alone for emergency department patients with musculoskeletal pain refractory to ibuprofen
Authors: Friedman Benjamin W. , Irizarry Eddie , Feliciano Carmen , Izzo Albert J. , Borrayes Lester , Restivo Andrew , Costa Vincent , Bijur Polly E. 
Published: February 2021

AbstractBackgroundUse of oral opioids does not result in more pain relief than nonopioid alternatives when administered to patients as first‐line treatment for acute musculoskeletal pain. This study compared the efficacy of oxycodone/acetaminophen to that of acetaminophen alone as second‐line treatment for patients with acute musculoskeletal pain who were administered prescription‐strength ibuprofen and reported insufficient relief 1 h later.MethodsA randomized, double‐blind study was conducted in two urban emergency departments. Opioid‐naïve patients ≥ 18 years with an acute musculoskeletal injury were administered ibuprofen 600 mg as part of the study protocol. Those who reported insufficient relief 1 h later were randomized (1:1 ratio) to oxycodone 10 mg/acetaminophen 650 mg or acetaminophen 650 mg. The primary outcome was improvement in 0 to 10 pain scale between randomization and 2 h later. We also assessed medication‐associated adverse events. A sample size calculation, built around a minimum clinically important difference of 1.3 units, determined the need for 154 patients.ResultsWe screened 924 patients and enrolled 393. All 393 received ibuprofen. A total of 159 (40%) patients reported inadequate relief after 1 h had elapsed. A total of 154 of these were randomized, 77 to oxycodone/acetaminophen and 77 to acetaminophen. Baseline characteristics were comparable. Among patients randomized to oxycodone/acetaminophen, mean (±SD) improvement in 0 to 10 pain scale was 4.0 (±2.6) versus 2.9 (±2.4) in the acetaminophen arm. The 95% confidence interval (CI) for the mean difference of 1.1 was 0.3 to 1.9. Among patients who received oxycodone/acetaminophen, 26 of 76 (34%) reported any medication‐related adverse event versus seven of 74 (9%) participants who received acetaminophen. The 95% CI for the between‐group difference of 25% was 12% to 37%).ConclusionAmong patients with acute musculoskeletal pain refractory to oral ibuprofen, oxycodone/acetaminophen resulted in slightly greater pain relief than acetaminophen, but this was associated with more medication‐related adverse events.
Evaluation of repeat testing of a non‐sequencing based NIPT test on a Finnish general‐risk population
Authors: Karlsson Filip , Ahola Tarja , Dahlberg Jenny , Prensky Lawrence , Moilanen Helena , Spalding Heli 
Published: February 2021

AbstractIntroductionTo evaluate the effect of repeating test failures using an automated, non‐sequencing based non‐invasive prenatal testing test on a general‐risk population in Finland.Material and MethodsA total of 545 samples from women who represent the average‐risk population in Oulu, Finland were analyzed with Vanadis® non‐invasive prenatal testing. Repeat testing of test failures was performed using a second sample. Results before and after repeat testing were compared with the reference outcome, as determined by clinical examination of neonates.ResultsThere were eight test failures after first‐pass analysis, representing 1.5% of samples (95% CI 0.6%‐2.9%). Seven out of eight failures could be resolved by analysis of a second sample, thereby reducing the test failure rate from 1.5% to 0.2% (95% CI 0.0%‐1.0%).ConclusionsRepeating test failures with a second plasma sample could significantly reduce the effective failure rate, thereby providing a way to effectively minimize test failures and further improving clinical utility and test performance.
Population pharmacokinetics and pharmacodynamics of Tranexamic acid in women undergoing caesarean delivery
Authors: Li Shuhui , Ahmadzia Homa K. , Guo Dong , Dahmane Elyes , Miszta Adam , Luban Naomi L.C. , Berger Jeffrey S. , James Andra H. , Wolberg Alisa S. , van den Anker John N. , Gobburu Jogarao V.S. 
Published: February 2021

AimsThe population pharmacokinetics (PK) and pharmacodynamics (PD) of tranexamic acid (TXA) have not been studied to prevent postpartum haemorrhage (PPH) in pregnant women. It is unclear which TXA dose assures sufficient PPH prevention. This study investigated population PK/PD of TXA in pregnant women who underwent caesarean delivery to determine the optimal prophylactic doses of TXA for future studies.MethodsWe analysed concentration (PK) and maximum lysis (PD) data from 30 pregnant women scheduled for caesarean delivery who received 5, 10 or 15 mg/kg of TXA intravenously using population approach.ResultsTXA PK was best described by a two‐compartment model with first‐order elimination and the following parameters: clearance (between‐subject variability) of 9.4 L/h (27.7%), central volume of 10.1 L (47.4%), intercompartmental clearance of 22.4 L/h (66.7%), peripheral volume of 14.0 L (13.1%) and additive error of 1.4 mg/L. The relationship between TXA concentration and maximum lysis was characterized by a sigmoid Emax model with baseline lysis of 97%, maximum inhibition of 89%, IC50 of 6.0 mg/L (65.3%), hill factor of 8.5 (86.3%) and additive error of 7.3%. Simulations demonstrated that 500 and 650 mg of TXA maintained therapeutic targets for 30 minutes and 1 hour, respectively, in 90% of patients.ConclusionThis is the first population PK and PD study of TXA in pregnant women undergoing caesarean delivery. Our analysis suggests that a 650 mg dose provides adequate PPH prophylaxis up to 1 hour, which is less than the currently used 1000 mg of TXA in pregnant women.
Implications of a defined daily dose fixed database for drug utilization research studies: The case of statins in Portugal
Authors: Abrantes Catarina , Tonin Fernanda S. , Reis‐Pardal Joana , Castel‐Branco Margarida , Furtado Claudia , Figueiredo Isabel V. , Fernandez‐Llimos Fernando 
Published: February 2021

AimsGiven the discrepancies between PDDs (prescribed daily doses) and DDDs (defined daily doses), we aimed to assess the extent of error in the results of an 18‐year population‐level study on statin utilization in Portugal.MethodsThe Portuguese regulatory agency provided data for the period 2000–2018 on statin dispensing (C10AA). The DDDs were gathered from the ATC/DDD database. DDDs were calculated by the DDD year‐by‐year approach (DDDYEAR) and by the DDD last‐year approach (DDDLAST). PDDs were calculated according to the year‐by‐year approach (PDDYEAR). Statin annual utilization rates per 1000 inhabitants per day were also calculated. Percent errors were calculated for PDDYEAR and DDDYEAR units.ResultsThe DDDYEAR approach revealed decreases in the consumption of atorvastatin, fluvastatin, lovastatin, pravastatin and simvastatin in 2009, when their DDD was modified. Conversely, the results from both DDDLAST and PDDYEAR approaches indicated gradual changes in the actual consumption of all statins in Portugal. Before 2009, atorvastatin, pravastatin and simvastatin utilization was greatly overestimated by DDDYEAR/1000 inhabitants/day. The average dose of lovastatin prescribed in the past 18 years (20 mg) was below the assigned DDDs during the study period, varying from 30 mg to 45 mg. Conversely, the PDD for fluvastatin was above the DDD values (ranging from 40 mg in 2000 to 70 mg in 2016). For atorvastatin, pravastatin and simvastatin, national PDDs were above the assigned DDD until the DDD modification in 2009.ConclusionsA more dynamic system, based on national and annually updated DDDs, should be able to reduce discrepancies between DDDs and PDDs and the bias in utilization studies.
Population pharmacokinetic analysis of RO5459072, a low water‐soluble drug exhibiting complex food–drug interactions
Authors: Kratochwil Nicole A. , Stillhart Cordula , Diack Cheikh , Nagel Sandra , Al Kotbi Nada , Frey Nicolas 
Published: February 2021

AimsRO5459072, a cathepsin‐S inhibitor, Biopharmaceutics Classification System class 2 and P‐glycoprotein substrate, exhibited complex, nonlinear pharmacokinetics (PK) while fasted that seemed to impact both the absorption and the disposition phases. When given with food, all nonlinearities disappeared. Physiologically based PK (PBPK) modelling attributed those nonlinearities to dose‐dependent solubilisation and colonic absorption. The objective of this population PK analysis was to complement the PBPK analysis.MethodsPK profiles in 39 healthy volunteers after first oral dosing (1–600 mg) while fasted or fed in single and multiple ascending dose studies were analysed using population compartmental modelling.ResultsThe PK of RO5459072 while fed was characterized by a 1‐compartmental PK model with linear absorption and elimination. The nonlinearities while fasted were captured using dose dependent bioavailability and 2 sequential first‐order absorption phases: one following drug administration and one occurring 11 hours later and only for doses >10 mg. The bioavailability in the first absorption phase increased between 1 and 10 mg and then decreased with dose, in agreement with in vitro dissolution and solubility studies. The remaining fraction of doses to be absorbed by the second absorption phase was found to have a bioavailability similar to that in the first absorption phase.ConclusionThe population PK model supported that dissolution‐ and solubility‐limited absorption from the proximal and distal intestine alone explains the nonlinear PK of RO5459072 in fasted state and the linear PK in fed state. This work, together with the PBPK analysis, raised our confidence in the understanding of this complex PK.
Arthritis in systemic lupus erythematosus is characterized by local IL-17A and IL-6 expression in synovial fluid
Authors: Sippl N , Faustini F , Rönnelid J , Turcinov S , Chemin K , Gunnarsson I , Malmström V 
Published: February 2021

Summary
Arthritis is a common clinical feature of systemic lupus erythematosus (SLE) and is usually non-erosive, as opposed to rheumatoid arthritis (RA). While RA synovial pathology has been extensively studied, little is known about the pathophysiology of lupus arthritis. Here, we aimed to explore the cytokine and cellular compartments in synovial fluids of SLE patients with arthritic manifestations. Acellular synovial fluid and paired serum samples from SLE patients (n = 17) were analyzed with cytokine bead array for T helper-associated cytokines. From two SLE patients, synovial fluid mononuclear cells (SFMC) could also be captured and were analyzed by multiparameter flow cytometry to dissect T cell, B cell, monocyte and dendritic cell phenotypes. SLE-derived SFMC were further stimulated in vitro to measure their capacity for producing interferon (IFN)-γ and interleukin (IL)-17A. All patients fulfilled the ACR 1982 classification criteria for SLE. Clinical records were reviewed to exclude the presence of co-morbidities such as osteoarthritis or overlap with RA. IL-17A and IL-6 levels were high in SLE synovial fluid. A clear subset of the synovial CD4+ T cells expressed CCR6+, a marker associated with T helper type 17 (Th17) cells. IL-17A-production was validated among CD4+CCR6+ T cells following in-vitro stimulation. Furthermore, a strong IFN-γ production was observed in both CD4+ and CD8+ cells. Our study shows high IL-17A and IL-6 levels in synovial fluids of patients with lupus arthritis. The Th17 pathway has been implicated in several aspects of SLE disease pathogenesis and our data also point to Th17 involvement for lupus arthritis.
Skin exposure to scented products used in daily life and fragrance contact allergy in the European general population ‐ The EDEN Fragrance Study
Authors: van Amerongen Cynthia C.A. , Ofenloch Robert F. , Cazzaniga Simone , Elsner Peter , Gonçalo Margarida , Naldi Luigi , Svensson Åke , Bruze Magnus , Schuttelaar Marie L.A. 
Published: February 2021

AbstractBackgroundFragrances are widely used in scented products used in daily life with the potential to induce skin sensitization.ObjectiveTo evaluate exposure to scented products and to explore associations between exposure and fragrance contact allergy.MethodsA cross‐sectional study on individuals from 18 to 74 years of age, who were randomly selected from the general population in five European countries. A random sample (N = 3119) was patch tested and interviewed on exposure to scented products.ResultsFemale participants were strongly associated with exposure to scented products relative to male participants. Participants age 40 years and older showed an inverse association with exposure to scented products. Compared to Sweden, The Netherlands followed by Germany showed the highest overall exposure to scented products. Sensitive skin was associated with exposure to scented products and with fragrance allergy. In univariable regression analysis, exposure to leave‐on products and to specific scented product subgroups was significantly associated with fragrance allergy.ConclusionExposure to scented products depends primarily on sex and age. Female sex and sensitive skin are relevant indicators for developing fragrance allergy. Because aggregate exposure, especially to scented leave‐on products, may enhance the prevalence of contact allergy to fragrances, further investigations into exposure amounts and frequencies is warranted.
Effects of sorghum biomass quality on ensilability and methane yield
Authors: Pasteris Andrea M. , Zapka Oliver , Plogsties Vincent , Herrmann Christiane , Heiermann Monika 
Published: February 2021

AbstractSorghum is currently being introduced in the temperate regions of Europe. It is characterized by good digestibility and high biomass yields, which make it a useful crop for anaerobic digestion. In this study, six commercial sorghum varieties comprising four different cultivars of Sorghum bicolorL. Moench and two interspecific sorghum hybrids (Sorghum sudanenseL. × S. bicolorL. Moench) were harvested on two different dates during the years 2016 and 2017 at two diverse soil‐climate sites in Germany. The fresh harvested material and silages were analyzed to examine the ensilability of the different varieties with contrasting maturity characteristics. Subsequently, methane production experiments were performed to determine the specific methane yield (SMY) of the samples. The sorghum fresh matter (FM) varied among the sorghum types, including the parameters total solids (TS; 22.69%–46.93%FM), water‐soluble carbohydrates (2.68%–11.38%TS), and nitrates (0%–0.35%TS). The excellent ensiling ability of all the sorghum types analyzed was confirmed by evaluating the fermentation profile (pH range of 3.7–4.6; dominant presence of lactic acid [LA]; acetic acid [AA] in the range of 0.70%–2.38%TS; insignificant amount of butyric acid). The SMY ranged between 231.25 and 321.31 Ln kg−1 VS and tended to decrease with the increasing harvest time and maturity. LA and AA were positively correlated with the SMY, while the neutral detergent fiber content was negatively correlated with it. The SMY—a key parameter reflecting the crop biomass quality for biogas production—was slightly higher for S. bicolorthan for the sorghum hybrids. However, the results of this study confirmed that if the final purpose is biomethanation, the ensilability of different sorghum types imposes no restriction. Furthermore, different sorghum types offer a wide harvest window, which can be useful for cropping schemes, ensiling, and methane production.
The toll of success: Female leaders in the “women‐friendly” Greek advertising agencies
Authors: Miliopoulou Georgia‐Zozeta , Kapareliotis Ilias 
Published: February 2021

AbstractThis paper examines the views and attitudes of senior female executives in Greek advertising agencies. Using intersectionality as a theoretic lens, the authors study the intersection of sex, age, profession, and ethnicity, within a patriarchal, Southern European society and a male dominated industry. Research findings from 12 interviews reaffirm the motherhood penalty but also demonstrate how successful women refuse to be part of the boys' club, deconstruct the male stereotype, and engage in fierce counter‐stereotyping while showing lack of solidarity and empathy toward other women. After years at the intersection of two male‐dominated cultural contexts, these women have limited visibility of the barriers they encounter and see themselves as an embodied exception proving the rule, not as agents of change. Thus, individual success leads to collective defeat and to the prevalence of male dominance. This research contributes by presenting the view of successful women in adverse intersections, who demonstrate accumulated frustration, lack of collective gender consciousness, and lack of a sense of self‐fulfillment. The paper calls for further research that combines intersectionality with emotional transfers and defense mechanisms; research that explores the influence of intersectional conscientiousness, especially in the southern context.
Heating stability, physical and chemical analysis of calcium silicate‐based endodontic sealers
Authors: Antunes T. B. M. , Janini A. C. P. , Pelepenko L. E. , Abuna G. F. , Paiva E. M. , Sinhoreti M. A. C. , Raimundo I. M. , Gomes B. P. F. A. , de‐Jesus‐Soares A. , Marciano M. A. 
Published: February 2021

AbstractAimTo evaluate possible modifications in root canal sealers subjected to a variety of heating conditions using vibrational spectroscopy and analysis of physical and chemical properties.MethodologyEndoSequence BC Sealer HiFlow, Bio‐C Sealer, BioRoot RCS and AH Plus were analysed chemically using Raman spectroscopy (25–220 °C) and Fourier‐transform infrared spectroscopy (FT‐IR) (37–100 °C ). For FT‐IR, the materials were tested individually and mixed with root dentine powder. Scanning electron microscopy (SEM) and coupled energy dispersive spectroscopy (EDS) were used to evaluate surface and chemical elements. ISO 6876‐2012 and ASTM‐C266‐07 specifications were followed to evaluate flow, setting time (moist and dry), solubility and radiopacity. Also, pH analysis at 37 and 100 °C was performed. Shapiro–Wilk and Mixed ANOVA (within and between the effects of the subjects), Levene, and a post hoc analyses with Bonferroni correction were performed (P < 0.05).ResultsVibrational spectroscopy revealed peaks of tricalcium silicate, dicalcium silicate and zirconium dioxide. Chemical changes in the Raman spectra during heating were discrete, as the inorganic content predominated the signalling for all root canal sealers. FT‐IR analysis exhibited spectral changes in water absorption for EndoSequence BC Sealer HiFlow and Bio‐C Sealer, probably related to dehydration. For BioRoot RCS and AH Plus, no significant chemical changes were observed. Bio‐C Sealer exhibited a band of polyethylene glycol only after heating to 100 °C, probably related to its thermal decomposition. SEM/EDS analysis corroborated the composition results observed in vibrational spectroscopy for all materials. Heating to 100 °C significantly changed the flowability of all calcium silicate‐based sealers with a wide variation in setting times at both temperatures, along with solubility levels above ISO standards. For all tested sealers, radiopacity fulfilled the requirements, and pH exhibited alkaline values.ConclusionsThe tested calcium silicate‐based sealers were affected by heating. Calcium silicate‐based root canal sealers had high solubility which is a concern for their clinical use. AH Plus was the only root canal sealer that was stable after heating.
Female awareness about the preconception use of folic acid supplements in childbearing age: A cross‐sectional study
Authors: Raad Sarah Emad , AbuAlhommos Amal Khaleel 
Published: February 2021

AbstractAimsFolic acid is required for the growth and development of the fetus. There is strong evidence that taking folic acid before pregnancy and during the first trimester reduces the risk of neural tube defects (NTDs). This study aimed to assess women's awareness of preconception folic acid supplementation and its importance to the mother and the fetus.MethodsThis was a cross‐sectional questionnaire study conducted in Saudi Arabia between January and April 2019. An electronic questionnaire tool was designed and distributed using Google Forms through social media (Facebook and WhatsApp) websites. Binary logistics regression was used to estimate odds ratios (ORs), with 95% confidence intervals (CIs) for predictors of poor levels of awareness about folic acid.ResultsA total of 514 women participated in this study. The age range for the study participants was 18‐45 years. Only 24.1% of the participants reported that they routinely took folic acid. The most commonly reported source of information about folic acid use was the doctor. The majority of the participants had poor awareness of folic acid use. Older age (30 years and above) and not taking regular folic acid supplements were important predictors of poor awareness of folic acid. Having a university degree or higher education was an important predictor of increased awareness about folic acid.ConclusionOur study found that the awareness of the Saudi women was poor in identifying the generic name of folic acid, recognising the sources of folic acid, the correct dose of folic acid, and the side effects of high doses of folic acid and that there was good knowledge about the importance of folic acid, the consequences of folic acid deficiency, and the belief that even non‐pregnant women and girls of childbearing age should take folic acid.