Miracle-dz/UniFAR-FTUs huggingface dataset:
Fischer rats exhibit maladaptive structural and molecular right ventricular remodelling in severe pulmonary hypertension: a genetically prone model for right heart failure

AIMS The ability of the right ventricle (RV) to adapt to increased afterload is the major determinant of survival in patients with pulmonary hypertension (PH). In this study, we explored the effect of genetic background on RV adaptation and survival in a rat model of severe pulmonary arterial hypertension (PAH). METHODS AND RESULTS PH was induced by a single injection of SU5416 (SU) in age-matched Sprague Dawley (SD) or Fischer rats, followed by a 3-week exposure to chronic hypoxia (SUHx). SD and Fischer rats exhibited similar elevations in RV systolic pressure, number of occlusive pulmonary vascular lesions, and RV hypertrophy (RV/LV+S) in response to SUHx. However, no Fischer rats survived beyond 7 weeks compared with complete survival for SD rats. This high early mortality of Fischer rats was associated with significantly greater RV dilatation and reduced ejection fraction, cardiac output, and exercise capacity at 4 weeks post-SU. Moreover, microarray analysis revealed that over 300 genes were uniquely regulated in the RV in the severe PAH model in the Fischer compared with SD rats, mainly related to angiogenesis and vascular homoeostasis, fatty acid metabolism, and innate immunity. A focused polymerase chain reaction array confirmed down-regulation of angiogenic genes in the Fischer compared with SD RV. Furthermore, Fischer rats demonstrated significantly lower RV capillary density compared with SD rats in response to SUHx. CONCLUSION Fischer rats are prone to develop RV failure in response to increased afterload. Moreover, the high mortality in the SUHx model of severe PAH was caused by a failure of RV adaptation associated with lack of adequate microvascular angiogenesis, together with metabolic and immunological responses in the hypertrophied RV.
Modelling Palaeoecological Time Series Using Generalised Additive Models

In the absence of annual laminations, time series generated from lake sediments or other similar stratigraphic sequences are irregularly spaced in time, which complicates formal analysis using classical statistical time series models. In lieu, statistical analyses of trends in palaeoenvironmental time series, if done at all, have typically used simpler linear regressions or (non-) parametric correlations with little regard for the violation of assumptions that almost surely occurs due to temporal dependencies in the data or that correlations do not provide estimates of the magnitude of change, just whether or not there is a linear or monotonic trend. Alternative approaches have used LOESS-estimated trends to justify data interpretations or test hypotheses as to the causal factors without considering the inherent subjectivity of the choice of parameters used to achieve the LOESS fit (e.g. span width, degree of polynomial). Generalized additive models (GAMs) are statistical models that can be used to estimate trends as smooth functions of time. Unlike LOESS, GAMs use automatic smoothness selection methods to objectively determine the complexity of the fitted trend, and as formal statistical models, GAMs, allow for potentially complex, non-linear trends, a proper accounting of model uncertainty, and the identification of periods of significant temporal change. Here, I present a consistent and modern approach to the estimation of trends in palaeoenvironmental time series using GAMs, illustrating features of the methodology with two example time series of contrasting complexity; a 150-year bulk organic matter δ15N time series from Small Water, UK, and a 3000-year alkenone record from Braya-So, Greenland. I discuss the underlying mechanics of GAMs that allow them to learn the shape of the trend from the data themselves and how simultaneous confidence intervals and the first derivatives of the trend are used to properly account for model uncertainty and identify periods of change. It is hoped that by using GAMs greater attention is paid to the statistical estimation of trends in palaeoenvironmental time series leading to more a robust and reproducible palaeoscience.
Discordant roles for FGF ligands in lung branching morphogenesis between human and mouse

Fibroblast growth factor (FGF) signaling plays an important role in lung organogenesis. Over recent decades, FGF signaling in lung development has been extensively studied in animal models. However, little is known about the expression, localization, and functional roles of FGF ligands during human fetal lung development. Therefore, we aimed to determine the expression and function of several FGF ligands and receptors in human lung development. Using in situ hybridization (ISH) and RNA sequencing, we assessed their expression and distribution in native human fetal lung. Human fetal lung explants were treated with recombinant FGF7, FGF9, or FGF10 in air–liquid interface culture. Explants were analyzed grossly to observe differences in branching pattern as well as at the cellular and molecular level. ISH demonstrated that FGF7 is expressed in both the epithelium and mesenchyme; FGF9 is mainly localized in the distal epithelium, whereas FGF10 demonstrated diffuse expression throughout the parenchyma, with some expression in the smooth muscle cells (SMCs). FGFR2 expression was high in both proximal and distal epithelial cells as well as the SMCs. FGFR3 was expressed mostly in the epithelial cells, with lower expression in the mesenchyme, while FGFR4 was highly expressed throughout the mesenchyme and in the distal epithelium. Using recombinant FGFs, we demonstrated that FGF7 and FGF9 had similar effects on human fetal lung as on mouse fetal lung; however, FGF10 caused the human explants to expand and form cysts as opposed to inducing epithelial branching as seen in the mouse. In conjunction with decreased branching, treatment with recombinant FGF7, FGF9, and FGF10 also resulted in decreased double‐positive SOX2/SOX9 progenitor cells, which are exclusively present in the distal epithelial tips in early human fetal lung. Although FGF ligand localization may be somewhat comparable between developing mouse and human lungs, their functional roles may differ substantially. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Intravenous tPA (Tissue-Type Plasminogen Activator) in Patients With Acute Ischemic Stroke Taking Non–Vitamin K Antagonist Oral Anticoagulants Preceding Stroke

Background and Purpose— Although there are no trials or large cohorts to inform clinical care, current guidelines caution against giving intravenous tPA (tissue-type plasminogen activator) to patients with acute ischemic stroke who are taking non–vitamin K antagonist oral anticoagulants (NOACs). We performed a literature review of intravenous tPA in patients treated with NOACs preceding stroke. Methods— A literature search of PubMed was performed encompassing January 2010 to March 2018. Patient characteristics, timing of last medication intake, laboratory testing, use of reversal, and outcomes ⩽3 months after discharge were summarized. Results— We identified 55 studies with 492 NOAC patients receiving tPA (dabigatran, 181; rivaroxaban, 215; apixaban, 40; and unspecified NOAC, 56). Among patients with complete data, the median time from the last NOAC intake to symptom onset was 8 hours (interquartile range, 2.5–14.5), with 55.2% (80/145) within 12 hours. Few patients underwent sensitive laboratory tests, such as thrombin time, diluted thrombin time, or anti-Xa assays before tPA administration. The overall observed rates of symptomatic intracranial hemorrhage, mortality, and favorable outcomes (National Institutes of Health Stroke Scale score, ⩽1; modified Rankin Scale score, 0–2; or neurological improvement in the National Institutes of Health Stroke Scale score, ≥8 points) were 4.3% (20/462), 11.3% (48/423), and 43.7% (164/375), respectively. Among dabigatran-treated patients, reversal with idarucizumab was associated with fewer symptomatic intracranial hemorrhage (4.5% [2/44] versus 7.4% [8/108]; unadjusted odds ratio, 0.60; 95% CI, 0.12–2.92), death (4.5% [2/44] versus 12.0% [13/108]; unadjusted odds ratio, 0.35; 95% CI, 0.08–1.61), and more favorable outcomes (79.1% [34/43] versus 39.2% [29/74]; unadjusted odds ratio, 5.86; 95% CI, 2.45–14.00), although the differences were not statistically significant for symptomatic intracranial hemorrhage and death. Conclusions— These preliminary observations suggest that tPA may be reasonably well tolerated without prohibitive risks of bleeding complications in selected patients on NOACs. Reversal of anticoagulant effects by idarucizumab for dabigatran-treated patients before tPA is an emerging strategy that was associated with more favorable outcomes.
Cost-effectiveness of interventions for medically unexplained symptoms: A systematic review

Background In primary and secondary care medically unexplained symptoms (MUS) or functional somatic syndromes (FSS) constitute a major burden for patients and society with high healthcare costs and societal costs. Objectives were to provide an overview of the evidence regarding the cost-effectiveness of interventions for MUS or FSS, and to assess the quality of these studies. Methods We searched the databases PubMed, PsycINFO, the National Health Service Economic Evaluation Database (NHS-EED) and the CEA registry to conduct a systematic review. Articles with full economic evaluations on interventions focusing on adult patients with undifferentiated MUS or fibromyalgia (FM), irritable bowel syndrome (IBS) and chronic fatigue syndrome (CFS), with no restrictions on comparators, published until 15 June 2018, were included. We excluded preventive interventions. Two reviewers independently extracted study characteristics and cost-effectiveness data and used the Consensus on Health Economic Criteria Checklist to appraise the methodological quality. Results A total of 39 studies out of 1,613 articles met the inclusion criteria. Twenty-two studies reported costs per quality-adjusted life year (QALY) gained and cost-utility analyses (CUAs). In 13 CUAs the intervention conditions dominated the control conditions or had an incremental cost-effectiveness ratio below the willingness-to-pay threshold of € 50,000 per QALY, meaning that the interventions were (on average) cost-effective in comparison with the control condition. Group interventions focusing on MUS (n = 3) or FM (n = 4) might be more cost-effective than individual interventions. The included studies were heterogeneous with regard to the included patients, interventions, study design, and outcomes. Conclusion This review provides an overview of 39 included studies of interventions for patients with MUS and FSS and the methodological quality of these studies. Considering the limited comparability due to the heterogeneity of the studies, group interventions might be more cost-effective than individual interventions. Registration Study methods were documented in an international prospective register of systematic reviews (PROSPERO) protocol, registration number: CRD42017060424.
Metabarcoding of shrimp stomach content: Harnessing a natural sampler for fish biodiversity monitoring

Given their positioning and biological productivity, estuaries have long represented key providers of ecosystem services and consequently remain under remarkable pressure from numerous forms of anthropogenic impact. The monitoring of fish communities in space and time is one of the most widespread and established approaches to assess the ecological status of estuaries and other coastal habitats, but traditional fish surveys are invasive, costly, labour intensive and highly selective. Recently, the application of metabarcoding techniques, on either sediment or aqueous environmental DNA, has rapidly gained popularity. Here, we evaluate the application of a novel, high‐throughput DNA‐based monitoring tool to assess fish diversity, based on the analysis of the gut contents of a generalist predator/scavenger, the European brown shrimp, Crangon crangon. Sediment and shrimp samples were collected from eight European estuaries, and DNA metabarcoding (using both 12S and COI markers) was carried out to infer fish assemblage composition. We detected 32 teleost species (16 and 20, for 12S and COI, respectively). Twice as many species were recovered using metabarcoding than by traditional net surveys. By comparing and interweaving trophic, environmental DNA and traditional survey‐based techniques, we show that the DNA‐assisted gut content analysis of a ubiquitous, easily accessible, generalist species may serve as a powerful, rapid and cost‐effective tool for large‐scale, routine estuarine biodiversity monitoring.
Solving Poisson's Equation using Deep Learning in Particle Simulation of PN Junction

Simulating the dynamic characteristics of a PN junction at the microscopic level requires solving the Poisson's equation at every time step. Solving at every time step is a necessary but time-consuming process when using the traditional finite difference (FDM) approach. Deep learning is a powerful technique to fit complex functions. In this work, deep learning is utilized to accelerate solving Poisson's equation in a PN junction. The role of the boundary condition is emphasized in the loss function to ensure a better fitting. The resulting I-V curve for the PN junction, using the deep learning solver presented in this work, shows a perfect match to the I-V curve obtained using the finite difference method, with the advantage of being 10 times faster at every time step.
LGR5 promotes tumorigenicity and invasion of glioblastoma stem‐like cells and is a potential therapeutic target for a subset of glioblastoma patients

Glioblastoma (GBM) is the most common and lethal primary malignant brain tumor which lacks efficient treatment and predictive biomarkers. Expression of the epithelial stem cell marker Leucine‐rich repeat‐containing G‐protein coupled receptor 5 (LGR5) has been described in GBM, but its functional role has not been conclusively elucidated. Here, we have investigated the role of LGR5 in a large repository of patient‐derived GBM stem cell (GSC) cultures. The consequences of LGR5 overexpression or depletion have been analyzed using in vitro and in vivo methods, which showed that, among those with highest LGR5 expression (LGR5high), there were two phenotypically distinct groups: one that was dependent on LGR5 for its malignant properties and another that was unaffected by changes in LGR5 expression. The LGR5‐responding cultures could be identified by their significantly higher self‐renewal capacity as measured by extreme limiting dilution assay (ELDA), and these LGR5high‐ELDAhigh cultures were also significantly more malignant and invasive compared to the LGR5high‐ELDAlow cultures. This showed that LGR5 expression alone would not be a strict marker of LGR5 responsiveness. In a search for additional biomarkers, we identified LPAR4, CCND2, and OLIG2 that were significantly upregulated in LGR5‐responsive GSC cultures, and we found that OLIG2 together with LGR5 were predictive of GSC radiation and drug response. Overall, we show that LGR5 regulates the malignant phenotype in a subset of patient‐derived GSC cultures, which supports its potential as a predictive GBM biomarker. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Chronic Pain, Sleep, and Cognition in Older Adults With Insomnia: A Daily Multilevel Analysis.

STUDY OBJECTIVES The goal of this study was to examine daily associations between sleep and cognition in older adults suffering from insomnia, with or without a history of chronic pain. METHODS Sixty older adults with insomnia and a history of chronic pain (HxCP; n = 33, mean age = 69.5 years, standard deviation = 7.8) or no history of chronic pain (NCP; n = 27, mean age = 69.7 years, standard deviation = 7.9) completed 14 days of diaries and actigraphy, measuring sleep onset latency (SOL), wake after sleep onset (WASO), sleep efficiency (SE), and sleep quality. Participants completed daily cognitive measures of processing speed (ie, symbol digit modalities test, SDMT), reasoning (ie, letter series), and verbal memory (ie, word list delayed recall). For HxCP and NCP, associations between sleep parameters, daily pain, depressive symptoms (ie, Beck Depression Inventory, Second Edition scores), and daily cognition, controlling for age, and global cognition were examined through multilevel modeling. RESULTS For HxCP, greater self-reported WASO was associated with worse next-day SDMT performance, whereas greater actigraphic WASO was associated with better next-day SDMT performance. Greater depression was associated with worse daily letter series performance. Greater self-reported WASO and SE were associated with better next-day delayed recall. For NCP, greater self-reported WASO and depression were associated with better daily SDMT performance, whereas worse daily pain was associated with worse SDMT and delayed recall performance. CONCLUSIONS In older adults with HxCP, improving sleep may benefit lower level cognition, whereas reducing depression may affect higher level cognition. Discrepancies in sleep parameters promote assessment of objective and subjective sleep outcomes when investigating effects of insomnia on cognition. CLINICAL TRIAL REGISTRATION Title: Intraindividual Variability in Sleep and Cognitive Performance in Older Adults (REST), Registry: ClinicalTrials.gov, Identifier: NCT02967185, URL: https://clinicaltrials.gov/ct2/show/NCT02967185.
[The prevalence of human papillomaviruses in patients with colon polyps].

INTRODUCTION Potential role of HPV infection in pathogenesis of colon polyps and cancer remains undetermined. The aim of the study was to investigate the prevalence of DNA of HPV- 6, -11, -16 and -18 in the biopsies from colon polyps. MATERIAL AND METHODS We investigated the biopsies from 24 patients (23 from colon polyps and I from colon cancer) of Department of Gastroenterology Medical University of Warsaw using Real time PCR HPV-6/11. Real-TM (Sacace Biotechnologies) was performed on termocycler Smart Cycler Dx. RESULTS We didn't detect oncogenic HPV16 and HPV18 in any of the investigated specimens, HPV-11 was present in 11 patients including all patients with adenoma tubule-villosum. We detect HPV6 in 5 samples from polyps and 1 from colon cancer. CONCLUSIONS HPV 6 and HPV 11 could play a role in pathogenesis some colon polyps but the final conclusions demand further investigations. Oncogenic HPV 16 and 18 probably don't play any role in colon polyps pathogenesis.
Comparative Antiviral Efficacy of Generic Sofosbuvir versus Brand Name Sofosbuvir with Ribavirin for the Treatment of Hepatitis C

Background Chronic hepatitis C infection is a major cause for liver failure and liver cancer and can be treated with highly effective all oral directly acting antiviral (DAA) drugs. Generic versions of these DAAs are available in India. Method This was an open-label, single-center, prospective, nonrandomized observational study for the comparative safety and efficacy of generic versus brand name sofosbuvir with ribavirin therapy for chronic hepatitis C infection (all genotypes). Between December 2014 and December 2015, 66 patients received either generic sofosbuvir (400mg) or brand name SOLVALDI (400mg) with weight based ribavirin for 24 weeks in a single multispecialty hospital in Mumbai. Monitoring viral loads and safety labs was performed as per national guidelines. Results Sustained virologic response was 72.4% versus 75.7% (p=0.78) among patients treated with generics and SOVALDI, respectively. At 4 weeks on-treatment, approximately 90% of patients from both groups had undetectable or below the lower limit of quantification. Change in hemoglobin was comparable in both groups (p=0.26). Conclusion Generic versions of sofosbuvir reported in this study are safe and efficacious to treat hepatitis C. However, bioequivalency studies of all generic DAAs need to be performed before wider use of such drugs for the treatment of hepatitis C.
Clostridial Butyrate Biosynthesis Enzymes Are Significantly Depleted in the Gut Microbiota of Nonobese Diabetic Mice

Alterations of the gut microbiota early in age have been hypothesized to impact T1D autoimmune pathogenesis. In the NOD mouse model, protection from T1D has been found to operate via modulation of the composition of the intestinal microbiota during a critical early window of ontogeny, although little is known about microbiota functions related to T1D development. Here, we show which gut microbial functions are specifically associated with protection from T1D in the time window between insulitis development and T1D onset. In particular, we describe that production of butyrate biosynthesis enzymes is significantly reduced in NOD mice, supporting the hypothesis that modulating the gut microbiota butyrate production may influence T1D development. ABSTRACT Increasing evidence suggests that the intestinal microbiota is involved in the pathogenesis of type 1 diabetes (T1D). Here we sought to determine which gut microbial taxa and functions vary between nonobese diabetic (NOD) mice and genetically modified NOD mice protected from T1D (Eα16/NOD) at 10 weeks of age in the time window between insulitis development and T1D onset. The gut microbiota of NOD mice were investigated by analyzing stool samples with a metaproteogenomic approach, comprising both 16S rRNA gene sequencing and microbial proteome profiling through high-resolution mass spectrometry. A depletion of Firmicutes (particularly, several members of Lachnospiraceae) in the NOD gut microbiota was observed compared to the level in the Eα16/NOD mice microbiota. Moreover, the analysis of proteins actively produced by the gut microbiota revealed different profiles between NOD and Eα16/NOD mice, with the production of butyrate biosynthesis enzymes being significantly reduced in diabetic mice. Our results support a model for gut microbiota influence on T1D development involving bacterium-produced metabolites as butyrate. IMPORTANCE Alterations of the gut microbiota early in age have been hypothesized to impact T1D autoimmune pathogenesis. In the NOD mouse model, protection from T1D has been found to operate via modulation of the composition of the intestinal microbiota during a critical early window of ontogeny, although little is known about microbiota functions related to T1D development. Here, we show which gut microbial functions are specifically associated with protection from T1D in the time window between insulitis development and T1D onset. In particular, we describe that production of butyrate biosynthesis enzymes is significantly reduced in NOD mice, supporting the hypothesis that modulating the gut microbiota butyrate production may influence T1D development.