Miracle-dz/UniFAR-FTUs huggingface dataset:
Pharmacokinetics of toltrazuril and its metabolites in pregnant and nonpregnant ewes and determination of their concentrations in milk, allantoic fluid, and newborn plasma.

The objectives of this study were to determine the pharmacokinetics of toltrazuril and its metabolites in pregnant and nonpregnant ewes following a single oral dose and to determine the plasma concentrations of these compounds in milk, allantoic fluid, and newborn plasma. Eighteen healthy ewes were randomly divided into three groups (n = 6 each): pregnant ewes at 12-13 weeks of gestation (group A), nonpregnant ewes (group B), and pregnant ewes at 1-2 weeks before expected lambing date (group C). Ewes in all groups received a single oral dose of toltrazuril at 20 mg/kg body weight. In groups A and B, blood samples were collected at 1, 3, 5, 7, 9, 12, 15, 18 hr, every 6 hr to day 3, every 12 hr to day 7 and thereafter every 24 hr to day 14 post-toltrazuril administration. In group C, parturition was induced 24-36 hr after toltrazuril administration then milk, allantoic fluid, and newborn plasma samples were collected immediately after birth. Drug metabolites were assayed using ultra high-performance liquid chromatography-ultraviolet detection method (UHPLC-UV). The maximum concentration (Cmax ), area under the plasma concentration-time curve (AUC0-t) , AUC to 24 and 48 hr (AUC0-24 ), and (AUC0-48 ) were significantly higher in pregnant ewes. Longer apparent half-life (T1/2 ), significantly higher apparent volume of distribution (Vd/F) and total clearance (Cl/F) were observed in nonpregnant ewes. The time to maximum plasma concentration (Tmax ), mean residence time (MRT) and elimination rate constant (Kel ) were similar in both groups. The AUC0-24 and AUC0-48 were significantly higher in nonpregnant ewes. The AUC0-t was significantly higher in pregnant ones. The ratio of plasma toltrazuril concentrations in ewes and toltrazuril concentrations in newborn lambs' plasma, allantoic fluid, and milk were 68%, 2.3%, and 5.3%, respectively. Results of this study showed that toltrazuril is well absorbed after a single oral dose in ewes with widespread distribution in different body tissues.
Rising Pneumococcal Antibiotic Resistance in the Post 13-valent Pneumococcal Conjugate Vaccine Era in Pediatric Isolates from a Primary Care Setting.

IMPORTANCE Antibiotic-resistant S. pneumoniae strains may cause infections that fail to respond to antimicrobial-therapy. Results reported from hospitalized patients with invasive, bacteremic infections may not be the same as those observed in a primary-care setting where young children receive care for non-invasive infections. Young children experience the highest burden of pneumococcal disease. OBJECTIVES To determine the antibiotic susceptibility of S. pneumoniae strains isolated from children in a primary-care setting in the post-13-valent pneumococcal conjugate vaccine (PCV-13) era. DESIGN, SETTING, AND PARTICIPANTS Prospective collection of 1201 isolates of S. pneumoniae from 2006-2016 in a primary-care setting. Antibiotic susceptibility testing to 16 different antibiotics of ten classes performed. Participants were children age 6 to 36 months old. Nasopharyngeal swabs were obtained from patients during acute otitis media (AOM) visits and routine healthy visits. Middle ear fluid obtained by tympanocentesis. RESULTS After introduction of PCV-13, antibiotic susceptibility of pneumococci, especially to penicillin, initially improved largely due to disappearance of serotype 19A, included in PCV-13. However, beginning in 2013, antibiotic susceptibility among pneumococcal strains began decreasing due to new serotypes not included in PCV-13. In addition to reduced susceptibility to penicillin, the most recent isolates show reduced susceptibility to third generation cephalosporins, fluoroquinolones and carbapenems, antibiotics commonly used to treat life-threatening, invasive pneumococcal diseases. CONCLUSIONS AND RELEVANCE In recent years, pneumococcal nasopharyngeal and AOM isolates from children exhibit reduced susceptibility to penicillin, third generation cephalosporin, fluoroquinolone and carbapenem antibiotics. The new strains have a different profile of resistance compared to the pre-PCV-13 era.
DPEP1 expression promotes proliferation and survival of leukaemia cells and correlates with relapse in adults with common B cell acute lymphoblastic leukaemia

Dehydropeptidase‐1 (DPEP1) is a zinc‐dependent metalloproteinase abnormally expressed in many cancers. However, its potential role in adults with B cell acute lymphoblastic leukaemia (ALL) is unknown. We found that in adults with common B cell ALL high DPEP1, transcript levels at diagnosis were independently associated with an increased cumulative incidence of relapse (CIR) and worse relapse‐free survival (RFS) compared with subjects with low transcript levels. We show an increased proliferation and prosurvival role of DPEP1 in B cell ALL cells via regulation of phosphCREB and p53, which may be the biological basis of the clinical correlation we report. Our data implicate DPEP1 expression in the biology of common B cell ALL in adults. We report clinical correlates and provide a potential biological basis for these correlations. If confirmed, analysing DPEP1 transcript levels at diagnosis could help predict therapy outcomes. Moreover, regulation of DPEP1 expression could be a therapy target in B cell ALL.
Cancer stem cell-specific expression profiles reveal emerging bladder cancer biomarkers and identify circRNA_103809 as an important regulator in bladder cancer

Bladder cancer stem cells (BCSCs), exhibiting self-renewal and differentiation capacities, may contribute to the tumor initiation, metastasis, recurrence and drug resistance of bladder cancer. However, the underlying functional mechanisms of BCSCs remain to be clarified. In this study, we describe the differentially-expressed mRNAs, lncRNAs, and circRNAs in BCSCs compared with that in bladder cancer non-stem cells (BCNSCs) through the transcriptome microarray data analysis using bladder cancer patients’ specimens. CircRNA_103809, the top one among the highly expressed circRNA identified in BCSCs, promotes the self-renewal, migration and invasion capabilities of bladder cancer by acting as a miR-511 sponge. Additionally, GO and KEGG pathway analysis suggest the differentially expressed genes identified may be involved in the cellular metabolism, differentiation and metastasis regulation of the cancer cells. Co-expression networks of lncRNAs/mRNAs and circRNAs/mRNAs constructed by WGCNA give a picture of the non-coding/coding RNAs regulating patterns in BCSCs. Notably, as core genes in the networks, AHCY, C6orf136 and LRIG1 show high potential to be prognosticators for bladder cancer. Therefore, further studies of non-coding RNA functional mechanisms in BCSCs is valuable for detecting the pathogenic mechanisms and discovering novel biomarkers in bladder cancer.
Dietary daidzein decreases food intake accompanied with delayed gastric emptying in ovariectomized rats

ABSTRACT We previously found that equol, a metabolite of intestinal bacterial conversion from soy isoflavone daidzein, has female-specific anorectic effects. In the present study, we used seven-week-old female ovariectomized (OVX) Sprague Dawley rats to test the hypothesis that the anorectic effect of dietary daidzein may be attributed to delayed gastric emptying. Results suggest that dietary daidzein delays gastric emptying and that it has an anorectic effect with residual gastric contents, but not without gastric contents. Dietary equol significantly decreased daily food intake in the OVX rats without sleeve gastrectomy, but not in those with sleeve gastrectomy, suggesting that the accumulation of food in the stomach is required for the anorectic effect of equol to occur. These results support the hypothesis that the anorectic effect of dietary daidzein is attributed to delayed gastric emptying. GRAPHICAL ABSTRACT Dietary daidzein delays gastric emptying, and has an anorectic effect with residual gastric contents, but not without gastric contents.
Effect of Intravenous Interferon β-1a on Death and Days Free From Mechanical Ventilation Among Patients With Moderate to Severe Acute Respiratory Distress Syndrome: A Randomized Clinical Trial.

Importance Acute respiratory distress syndrome (ARDS) is associated with high mortality. Interferon (IFN) β-1a may prevent the underlying event of vascular leakage. Objective To determine the efficacy and adverse events of IFN-β-1a in patients with moderate to severe ARDS. Design, Setting, and Participants Multicenter, randomized, double-blind, parallel-group trial conducted at 74 intensive care units in 8 European countries (December 2015-December 2017) that included 301 adults with moderate to severe ARDS according to the Berlin definition. The radiological and partial pressure of oxygen, arterial (Pao2)/fraction of inspired oxygen (Fio2) criteria for ARDS had to be met within a 24-hour period, and the administration of the first dose of the study drug had to occur within 48 hours of the diagnosis of ARDS. The last patient visit was on March 6, 2018. Interventions Patients were randomized to receive an intravenous injection of 10 μg of IFN-β-1a (144 patients) or placebo (152 patients) once daily for 6 days. Main Outcomes and Measures The primary outcome was a score combining death and number of ventilator-free days at day 28 (score ranged from -1 for death to 27 if the patient was off ventilator on the first day). There were 16 secondary outcomes, including 28-day mortality, which were tested hierarchically to control type I error. Results Among 301 patients who were randomized (mean age, 58 years; 103 women [34.2%]), 296 (98.3%) completed the trial and were included in the primary analysis. At 28 days, the median composite score of death and number of ventilator-free days at day 28 was 10 days (interquartile range, -1 to 20) in the IFN-β-1a group and 8.5 days (interquartile range, 0 to 20) in the placebo group (P = .82). There was no significant difference in 28-day mortality between the IFN-β-1a vs placebo groups (26.4% vs 23.0%; difference, 3.4% [95% CI, -8.1% to 14.8%]; P = .53). Seventy-four patients (25.0%) experienced adverse events considered to be related to treatment during the study (41 patients [28.5%] in the IFN-β-1a group and 33 [21.7%] in the placebo group). Conclusions and Relevance Among adults with moderate or severe ARDS, intravenous IFN-β-1a administered for 6 days, compared with placebo, resulted in no significant difference in a composite score that included death and number of ventilator-free days over 28 days. These results do not support the use of IFN-β-1a in the management of ARDS. Trial Registration ClinicalTrials.gov Identifier: NCT02622724.
Evapotranspiration of the Vetiver and Tifton 85 grasses grown in horizontal subsurface flow constructed wetlands

Abstract Estimation of the Crop Evapotranspiration (ETC) in Horizontal Subsurface Flow Constructed Wetlands (HSSF-CWs) is of great importance for hydrological modeling of these systems. The objective of this work was to obtain the Crop Coefficient (KC) values of Vetiver (Chrysopogon zizanioides) and Tifton 85 (Cynodon spp.) grasses when grown in HSSF-CWs whose porous medium was saturated with solutions containing different nutrients concentrations. The water balance was performed every day in order to determine the KC of the grasses. It was verified that the KC values of the Vetiver grass were independent of the nutrient availability, expressed in terms of Electrical Conductivity (EC) of the nutrient solution. The KC value in the initial growth phase (Phase I) was 0.99, independent of the seasons. In Phase II, the KC were 0.95 and 1.36 for autumn and spring, respectively, and for Phase III were 1.12 in autumn and 1.60 in spring. In relation to the Tifton 85 grass, the KC values showed a quadratic behavior as a function of the EC, where the KC estimation models were obtained by the cluster analysis in Phase II and III. For Phase I, the KC value was 1.17, independent of the EC and the time of year.
Exploring scoring methods for research studies: Accuracy and variability of visual and automated sleep scoring

Sleep studies face new challenges in terms of data, objectives and metrics. This requires reappraising the adequacy of existing analysis methods, including scoring methods. Visual and automatic sleep scoring of healthy individuals were compared in terms of reliability (i.e., accuracy and stability) to find a scoring method capable of giving access to the actual data variability without adding exogenous variability. A first dataset (DS1, four recordings) scored by six experts plus an autoscoring algorithm was used to characterize inter‐scoring variability. A second dataset (DS2, 88 recordings) scored a few weeks later was used to explore intra‐expert variability. Percentage agreements and Conger's kappa were derived from epoch‐by‐epoch comparisons on pairwise and consensus scorings. On DS1 the number of epochs of agreement decreased when the number of experts increased, ranging from 86% (pairwise) to 69% (all experts). Adding autoscoring to visual scorings changed the kappa value from 0.81 to 0.79. Agreement between expert consensus and autoscoring was 93%. On DS2 the hypothesis of intra‐expert variability was supported by a systematic decrease in kappa scores between autoscoring used as reference and each single expert between datasets (.75–.70). Although visual scoring induces inter‐ and intra‐expert variability, autoscoring methods can cope with intra‐scorer variability, making them a sensible option to reduce exogenous variability and give access to the endogenous variability in the data.
Reply to Letter to the Editor: Perfusion controls muscle glucose uptake by altering the rate of glucose dispersion in vivo.

P. Mason McClatchey, Ian M. Williams, Zhengeng Xu, Nicholas A. Mignemi, Curtis C. Hughey, Owen P. McGuinness, Joshua A. Beckman, David H. Wasserman, David C. Poole, Thorbjorn Akerstrom, Daniel Goldman, Graham M. Fraser, and X Christopher G. Ellis Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee; Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee; Departments of Anatomy & Physiology and Kinesiology, Kansas State University, Manhattan, Kansas; Department of Nutrition, Exercise and Sports, Section of Integrative Physiology, University of Copenhagen, Copenhagen, Denmark; Department of Medical Biophysics, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Canada; and Division of BioMedical Sciences, Faculty of Medicine, Memorial University of Newfoundland St. John’s, Newfoundland, Canada
Impact of individual and neighborhood dimensions of socioeconomic status on the prevalence of mild cognitive impairment over seven-year follow-up

Abstract Objectives: There is strong evidence about the association between low socioeconomic status (SES) and higher risk of dementia. However, it has not been conveniently addressed so far the role of SES on the incidence of mild cognitive impairment (MCI). This study examines the impact of individual and neighbourhood dimensions of SES, as well as their interaction, on the risk of developing MCI in a sample of older adults. Method: Data from the Vallecas Project cohort, an ongoing community-based longitudinal study for early detection of cognitive impairment and dementia, were used to build two indices of SES namely individual and neighbourhood, as well as a global SES as a combination of both, and to investigate their effects on MCI conversion by means of a multivariate-adjusted Cox proportional hazard model. Results: A total of 1180 participants aged 70 years and older were enrolled in this study. Of these, 199 cases of MCI (16.9%) were diagnosed at any point of the follow-up. The individual and neighbourhood dimensions of SES played different roles in the dynamics of the MCI occurrence through aging. Most importantly, the risk of developing MCI was almost double for lower SES quartiles when compared to the highest one. Conclusion: The incidence of MCI in older adults was related to both individual characteristics and socioeconomic context. Public health strategies should be holistic and focus not only on promoting the classical individual preventive measures, but also on reducing social inequalities to foster healthy aging and reduce dementia burden.
Determination of hazard ratio for progression‐free survival considering the tumor assessment schedule in sample size calculation

Progression‐free survival is recognized as an important endpoint in oncology clinical trials. In clinical trials aimed at new drug development, the target population often comprises patients that are refractory to standard therapy with a tumor that shows rapid progression. This situation would increase the bias of the hazard ratio calculated for progression‐free survival, resulting in decreased power for such patients. Therefore, new measures are needed to prevent decreasing the power in advance when estimating the sample size. Here, I propose a novel calculation procedure to assume the hazard ratio for progression‐free survival using the Cox proportional hazards model, which can be applied in sample size calculation. The hazard ratios derived by the proposed procedure were almost identical to those obtained by simulation. The hazard ratio calculated by the proposed procedure is applicable to sample size calculation and coincides with the nominal power. Methods that compensate for the lack of power due to biases in the hazard ratio are also discussed from a practical point of view.
Propensity score–weighted analysis of chemotherapy after PD-1 inhibitors versus chemotherapy alone in patients with non–small cell lung cancer (WJOG10217L)

Background Studies have suggested that chemotherapy after immune checkpoint inhibitors may confer an improved response for non–small cell lung cancer (NSCLC). However, potential selection bias in such studies has not been addressed. We therefore applied propensity score analysis to investigate the efficacy of chemotherapy after PD-1 inhibitor treatment (CAP) compared with chemotherapy alone. Methods We conducted a retrospective observational cohort study for patients treated at 47 institutions across Japan between April 1, 2014 and July 31, 2017. Eligible patients had advanced or recurrent NSCLC who have undergone chemotherapy. Patients subsequently treated with chemotherapy (docetaxel with or without ramucirumab, S-1 or pemetrexed) either after PD-1 inhibitor therapy (CAP cohort) or alone (control cohort) were included. The primary end point was objective response rate (ORR). Inverse probability weighting (IPW) was applied to adjust for potential confounding factors. Results A total of 1439 patients (243 and 1196 in the CAP and control cohorts, respectively) was available for unadjusted analysis. Several baseline characteristics—including age, histology, EGFR or ALK genetic alterations, and brain metastasis—differed significantly between the two cohorts. After adjustment for patient characteristics with the IPW method, ORR was 18.9% for the CAP cohort and 11.0% for the control cohort (ORR ratio 1.71; 95% CI 1.19 to 2.46; p=0.004). IPW-adjusted Kaplan-Meier curves showed that median progression-free survival (PFS) for the CAP and control cohorts was 2.8 and 2.7 months (IPW-adjusted HR 0.95; 95% CI 0.80 to 1.12; p=0.55), and median overall survival (OS) was 9.2 and 10.4 months (IPW-adjusted HR 1.05; 95% CI 0.86 to 1.28; p=0.63), respectively. Conclusions After accounting for selection bias by propensity score analysis, CAP showed a significantly higher ORR compared with chemotherapy alone, with the primary end point of ORR being achieved. However, these results did not translate into a PFS or OS advantage, suggesting that prior administration of PD-1 inhibitors may result in a synergistic antitumor effect with subsequent chemotherapy, but that such an effect is transient. CAP therefore does not appear to achieve durable tumor control or confer a lasting survival benefit.
Impact of milk and nutrient intake of piglets and sow milk composition on piglet growth and body composition at weaning.

The main objective of this study was to evaluate the impact of milk intake, milk composition and nutrient intake on piglet growth in lactation and body composition at weaning. To evaluate the body composition of piglets, data from one experiment (44 Danish Landrace × Yorkshire × Duroc piglets) were used to develop prediction equations for body pools of fat, protein, ash, and water based on live weight and deuterium dilution space (Exp.1). Furthermore, a total of 294 piglets (Danish Landrace × Yorkshire × Duroc) from 21 sows of second parity were included in a second experiment (Exp. 2). In Exp. 2, piglet live weight was recorded on days 3, 10, 17, and 25 of lactation. On the same days, the milk intake and body composition were measured, using the deuterium oxide (D2O) dilution technique. Piglet weight gain was highly positively correlated with the intake of milk and the intake of milk constituents in each week and on an overall basis having r values ranging from 0.65 to 0.93 (P < 0.001). When evaluating regressions for piglet growth, the milk intake in combination with the milk protein concentration explained 85% and 87% of the total variation in piglet gain in the second and third week of lactation, respectively, whereas milk intake was the only predictor of piglet gain in the first week of lactation explaining 81% of the variation. Fat, protein, and energy retention rates were all highly positively correlated with the daily intake of milk and intake of milk nutrients with r values ranging from 0.76 to 0.94 (P < 0.001). Piglet gain and retention rates were rather weakly correlated with the milk composition with r values ranging from 0.01 to 0.50 (being either negative or positive). Curvilinear response curves were fitted for live weight gain and body fat content at weaning in response to milk protein concentration, showing that live weight gain was slightly greater and body fat content was slightly lower at 4.9% milk protein, but it should be emphasized that the quadratic effects did not reach significance. Body fat content at weaning was positively related with intake of milk (R2 = 0.44, P < 0.001) and milk fat (R2 = 0.46, P < 0.01). In conclusion, milk intake had a major impact on piglet growth rate, and milk fat intake greatly influenced the body fat percentage at weaning, whereas milk composition per se only played a minor role for these traits.
Epicardial cell lineages and the origin of the coronary endothelium

The embryonic epicardium generates a population of epicardial‐derived mesenchymal cells (EPDC) whose contribution to the coronary endothelium is minor or, according to some reports, negligible. We have compared four murine cell‐tracing models related to the EPDC in order to elucidate this contribution. Cre recombinase was expressed under control of the promoters of the Wilms' tumor suppressor (Wt1), the cardiac troponin (cTnT), and the GATA5 genes, activating expression of the R26REYFP reporter. We have also used the G2 enhancer of the GATA4 gene as a driver due to its activation in the proepicardium. Recombination was found in most of the epicardium/EPDC in all cases. The contribution of these lineages to the cardiac endothelium was analyzed using confocal microscopy and flow cytometry. G2‐GATA4 lineage cells are the most frequent in the endothelium, probably due to the recruitment of circulating endothelial progenitors. The contribution of the WT1 cell lineage increases along gestation due to further endothelial expression of WT1. GATA5 and cTnT lineages represent 4% of the cardiac endothelial cells throughout the gestation, probably standing for the actual EPDC contribution to the coronary endothelium. These results suggest caution when using a sole cell‐tracing model to study the fate of the EPDC.