Miracle-dz/UniFAR-FTUs huggingface dataset:
A novel SCN9A splicing mutation in a compound heterozygous girl with congenital insensitivity to pain, hyposmia and hypogeusia

Congenital insensitivity to pain (CIP) is a rare autosomal recessive disorder presenting with a spectrum of clinical features caused by mutations in different genes. A 10‐year‐old girl with CIP, hyposmia and hypogeusia, and her unaffected twin and parents underwent next generation sequencing of SCN9A exons and flanking splice sites. Transcript analysis from whole blood successfully assayed the effect of the mutation on the mRNA splicing by polymerase chain reaction amplification on cDNA and Sanger sequencing. We identified the novel splicing variant c.1108‐2A>G compound with the p.Arg896Gln (c.2687G>A) missense mutation previously described in a homozygous patient. The new intronic variant was predicted to induce exon 10 skipping. Conversely, SCN9A mRNA assay demonstrated its partial deletion with a loss of 46 nucleotides causing a premature stop codon in position p.Gln369 (NP_002968). Genetic analysis showed that the two variants were biallelic, being the mother and brother heterozygous carriers of the missense mutation, and the father heterozygous for the splicing mutation. Skin biopsy showed lack of Meissner's corpuscles, loss of epidermal nociceptors and normal autonomic organ innervation. We report a novel splicing mutation and provide clues on its pathogenic effect, broadening the spectrum of genotypes and phenotypes associated to CIP.
Modelling the cost-effectiveness of tofacitinib for the treatment of rheumatoid arthritis in the United States

Abstract Background and objectives: Rheumatoid arthritis (RA) is a chronic, debilitating disease affecting an estimated 1.5 million patients in the US. The condition is associated with a substantial health and economic burden. An economic model was developed to evaluate the cost-effectiveness of tofacitinib (a novel oral Janus kinase inhibitor) versus biologic therapies commonly prescribed in the US for the treatment of RA. Methods: A cost–utility model was developed whereby sequences of treatments were evaluated. Response to treatment was modeled by HAQ change, and informed by a network meta-analysis. Mortality, resource use and quality of life were captured in the model using published regression analyses based on HAQ score. Treatment discontinuation was linked to response to treatment and to adverse events. Patients were modeled as having had an inadequate response to methotrexate (MTX-IR), or to a first biologic therapy (TNFi-IR). Results: The tofacitinib strategy was associated with cost savings compared with alternative treatment sequences across all modeled scenarios (i.e. in both the MTX-IR and TNFi-IR scenarios), with lifetime cost savings per patient ranging from $65,205 to $93,959 (2015 costs). Cost savings arose due to improved functioning and the resulting savings in healthcare expenditure, and lower drug and administration costs. The tofacitinib strategies all resulted in an increase in quality-adjusted life years (QALYs), with additional QALYs per patient ranging from 0.01 to 0.22. Conclusions: Tofacitinib as a second-line therapy following methotrexate failure and as a third-line therapy following a biologic failure produces lower costs and improved quality of life compared with the current pathway of care.
Potentiating Response to Drop-Jump Protocols on Sprint Acceleration: Drop-Jump Volume and Intrarepetition Recovery Duration.

Byrne, PJ, Moody, JA, Cooper, SM, Callanan, D, and Kinsella, S. Potentiating response to drop-jump protocols on sprint acceleration: drop-jump volume and intrarepetition recovery duration. J Strength Cond Res XX(X): 000-000, 2018-The purpose of this study was to investigate the postactivation potentiation response first to bounce drop jump (BDJ) volume; second, BDJ intrarepetition recovery duration and recovery duration between BDJs and 20-meter (including 5- and 10-m split times) sprint performance. The study was undertaken in 2 parts, the first part compared different volumes of BDJs and the second part compared different BDJ intrarepetition recovery periods. The effect of recovery periods between the BDJs and the subsequent 20-m sprints was examined in both parts 1 and 2 (15 seconds, 4, 8, and 12 minutes). Fourteen (mean ± SD: age = 20.83 ± 1.26 years; height = 1.77 ± 0.04 m; and mass = 74.89 ± 6.07 kg) (part 1) and 15 (mean ± SD: age = 20.64 ± 1.00 years; height = 1.78 ± 0.06 m; and mass = 75.67 ± 6.28 kg) (part 2) male collegiate and club hurling players volunteered to participate. A randomized cross-over design was used to compare BDJ volumes (1, 2, and 3 sets of 3 repetitions) and BDJ intrarepetition recovery time (15 vs. 60 seconds) after a warm-up followed by 2 baseline 20-m sprints. The results in part 1 reported a significant improvement in 5- and 10-m sprint time for 1 set of 3 BDJs between baseline and 4 minutes (5 m: -2.34%, p = 0.04, effect size [ES] = -0.043; 10 m: -1.42%, p = 0.03, ES = -0.35), and baseline and 12 minutes (5 m: -3.33%, p = 0.03, ES = -0.57; 10 m: -2.13%, p = 0.01, ES = -0.52). Part 2 reported a significant improvement in 5-m sprint time between baseline and 15 seconds (5 m: -3.38%, p = 0.01, ES = -0.83; 10 m: -2.07%, p = 0.02, ES = -0.58) after the BDJs. The findings support the use of 1 set of 3 BDJs using a 15-second intrarepetition recovery period to maximize 5-, 10-, and 20-m sprint performance after 15 seconds of recovery after the final BDJ in hurling players. The acute response to this BDJ protocol proves to be time efficient and effective in acutely improving sprint acceleration.
Subclinical Hypothyroidism and the Risk of Cardiovascular Disease and All-Cause Mortality: A Meta-Analysis of Prospective Cohort Studies.

OBJECTIVES To determine the impact of subclinical hypothyroidism (SCH) on the risk of cardiovascular disease (CVD) and all-cause mortality, a comprehensive meta-analysis was performed according to the age or coexisting CVD risk status of the participants. METHODS Studies regarding the association of SCH with all-cause mortality from PubMed and Embase databases were included. The pooled relative risk (RR) of CVD and all-cause mortality was calculated using the Mantel-Haenszel method. A subgroup analysis of participants with high CVD risk was conducted, including history of coronary, cerebral, or peripheral artery disease; dilated cardiomyopathy; heart failure; atrial fibrillation; venous thromboembolism; diabetes mellitus; or chronic kidney disease. RESULTS In total, 35 eligible articles incorporating 555,530 participants were included. SCH was modestly associated with CVD and all-cause mortality (RR for CVD = 1.33 [confidence interval (CI) 1.14-1.54]; RR for all-cause mortality = 1.20 [CI 1.07-1.34]). However, the association was not observed in participants aged ≥65 years. Subgroup analysis showed that participants with SCH and high CVD risk showed a significantly higher risk of all-cause mortality (RR for CVD = 2.20 [CI 1.28-3.77]; RR for all-cause mortality = 1.66 [CI 1.41-1.94]), whereas those with SCH and low CVD risk did not. Additional subgroup analysis of six studies with a mean participant age of ≥65 years and high CVD risk showed a significant high risk of all-cause mortality in the SCH group (RR = 1.41 [CI 1.08-1.85]; I2 = 0%). CONCLUSIONS SCH is associated with an increased CVD risk and all-cause mortality, particularly in participants with high CVD risk.
Customizing a Research‐Based Reading Practice

Teachers are often asked to implement research-based instructional programs with fidelity and to ensure that all students reach high academic standards. These requests sometimes conflict when teachers find that not all their students are benefiting from the research-backed programs. In this article, we suggest that researchers and teachers can work together to balance the importance of both program fidelity and instructional flexibility, based on findings from recent research on Peer-Assisted Learning Strategies (PALS) for Reading in Grades 2-6. We detail how teachers can learn to implement research-based practices with fidelity, as well as customize these practices to fit their own purposes. We end with general recommendations for customizing research-based practices.
MicroRNA-155 Amplifies Nitric Oxide/cGMP Signaling and Impairs Vascular Angiotensin II Reactivity in Septic Shock

Objectives: Septic shock is a life-threatening clinical situation associated with acute myocardial and vascular dysfunction, whose pathophysiology is still poorly understood. Herein, we investigated microRNA-155–dependent mechanisms of myocardial and vascular dysfunction in septic shock. Design: Prospective, randomized controlled experimental murine study and clinical cohort analysis. Setting: University research laboratory and ICU at a tertiary-care center. Patients: Septic patients, ICU controls, and healthy controls. Postmortem myocardial samples from septic and nonseptic patients. Ex vivo evaluation of arterial rings from patients undergoing coronary artery bypass grafting. Subjects: C57Bl/6J and genetic background–matched microRNA-155 knockout mice. Interventions: Two mouse models of septic shock were used. Genetic deletion and pharmacologic inhibition of microRNA-155 were performed. Ex vivo myographic studies were performed using mouse and human arterial rings. Measurements and Main Results: We identified microRNA-155 as a highly up-regulated multifunctional mediator of sepsis-associated cardiovascular dysfunction. In humans, plasma and myocardial microRNA-155 levels correlate with sepsis-related mortality and cardiac injury, respectively, whereas in murine models, microRNA-155 deletion and pharmacologic inhibition attenuate sepsis-associated cardiovascular dysfunction and mortality. MicroRNA-155 up-regulation in septic myocardium was found to be mostly supported by microvascular endothelial cells. This promoted myocardial microvascular permeability and edema, bioenergetic deterioration, contractile dysfunction, proinflammatory, and nitric oxide-cGMP-protein kinase G signaling overactivation. In isolate cardiac microvascular endothelial cells, microRNA-155 up-regulation significantly contributes to LPS-induced proinflammatory cytokine up-regulation, leukocyte adhesion, and nitric oxide overproduction. Furthermore, we identified direct targeting of CD47 by microRNA-155 as a novel mechanism of myocardial and vascular contractile depression in sepsis, promoting microvascular endothelial cell and vascular insensitivity to thrombospondin-1–mediated inhibition of nitric oxide production and nitric oxide–mediated vasorelaxation, respectively. Additionally, microRNA-155 directly targets angiotensin type 1 receptor, decreasing vascular angiotensin II reactivity. Deletion of microRNA-155 restored angiotensin II and thrombospondin-1 vascular reactivity in LPS-exposed arterial rings. Conclusions: Our study demonstrates multiple new microRNA-155–mediated mechanisms of sepsis-associated cardiovascular dysfunction, supporting the translational potential of microRNA-155 inhibition in human septic shock.
Improving the Antimicrobial Power of Low-Effective Antimicrobial Molecules Through Nanotechnology.

The objective of this work was on the one hand to assess the antibacterial activity of amines anchored to the external surface of mesoporous silica particles against Listeria monocytogenes in comparison with the same dose of free amines as well. It was also our aim to elucidate the mechanism of action of the new antimicrobial device. The suitability of silica nanoparticles to anchor, concentrate and improve the antimicrobial power of polyamines against L. monocytogenes has been demonstrated in a saline solution and in a food matrix. Moreover, through microscope observations it has been possible to determine that the attractive binding forces between the positive amine corona on the surface of nanoparticles and the negatively charged bacteria membrane provoke a disruption of the cell membrane. The surface concentration of amines on the surface of the nanoparticles is so effective that immobilized-amines were 100 times more effective in killing L. monocytogenes bacteria than the same amount of free polyamines. This novel approach for the creation of antimicrobial nanodevices opens the possibility to put in value the antimicrobial power of natural molecules that have been discarded because of its low antimicrobial power. PRACTICAL APPLICATION Consumers demand for high-quality products, free from chemical preservatives, with an extended shelf-life. In this study, a really powerful antimicrobial agent based on a nanomaterial functionalized with a non-antimicrobial organic molecule was developed as a proof of concept. Following this approach it could be possible to develop a new generation of natural and removable antimicrobials based on their anchoring to functional surfaces for food, agricultural or medical purposes.
Comparison of single- and multi-strain probiotics effects on broiler breeder performance, egg production, egg quality and hatchability

ABSTRACT 1. This study was conducted to investigate the effect of multi-strain probiotic (containing Lactobacillus acidophilus 2.5 × 107 cfu/g, Lactobacillus casei 2.5 × 107 cfu/g, Bifidobacterium thermophilum 2.5 × 107 cfu/g and Enterococcus faecium 2.5 × 107 cfu/g) and single-strain probiotic (Pediococcus acidilactici 1 × 1010 cfu/g) on broiler breeder performance and gastrointestinal health. 2. A completely randomised trial was conducted using 300 broiler breeder hens (Ross 308) aged 51 weeks old which were randomly allocated to 1 of 5 dietary treatments with 6 replicates per treatment in a 10 week trial. Treatments included (1) the basal diet a negative control, (2) basal diet supplemented with 0.1 g/kg multi-strain probiotic (MS), (3) basal diet supplemented with 0.1 g/kg single-strain probiotic (SS), (4) basal diet supplemented with 0.1 g/kg of both of probiotics (MS+ SS) and (5) positive control basal diet supplemented with 0.5 g/kg oxytetracycline antibiotic (OX). 3. Body weight, egg production, yolk weight, eggshell thickness and weight, Haugh unit, fertility and hatchability were determined. Results showed that dietary treatments had no significant effect on total hen house or total hatching egg production, egg weight, yolk colour index, shell weight, mortality, body weight, fertility, hatchability, oviduct and stroma weight or number of large and small yellow follicles (P > 0.05). None of the jejunum morphological parameters, apparent ileal digestibility of protein and ileal Lactobacillus population were influenced by supplemental probiotics (P > 0.05), although ileum Escherichia coli count was reduced by inclusion of dietary probiotics (P < 0.05). 4. It was concluded that although both probiotic treatments reduced coliforms, they did not improve broiler breeder performance or gastrointestinal tract (GIT) function.
Low serum vitamin D level is associated with intrahepatic cholestasis of pregnancy

Intrahepatic cholestasis of pregnancy (ICP) is a unique hepatic disorder of pregnancy and is related to adverse maternal and perinatal outcomes. The pathogenesis of the disease is not clear and appears to be multifactorial. There is increasing evidence that vitamin D (Vit D) plays a role in hepatobiliary homeostasis and in various liver diseases. We aimed to investigate the association between serum Vit D level and ICP.
Using Farm Animal Welfare Protocols as a Base to Assess the Welfare of Wild Animals in Captivity—Case Study: Dorcas Gazelles (Gazella dorcas)

Simple Summary Animal welfare is gaining attention regarding the conservation of species not only due to ethical and legal reasons but also because optimal welfare can ensure stable and healthy populations. Currently, there is a lack of protocols that help to objectively assess welfare of wild animals in captivity. In this study, we have developed and applied a protocol for the assessment of welfare in captive dorcas gazelles (Gazella dorcas). We have gathered information from existing literature about the biology of this species in wild conditions, as well as in zoo husbandry, breeding, management and care guidelines developed for this species. We took a protocol developed for the on-farm welfare assessment in cattle as a reference and suggested 23 indicators that we considered useful to assess welfare in captive dorcas gazelles. To test the utility of this protocol, we then applied it in five groups of dorcas gazelles from three different zoos and we detected areas for improvement in all of the groups assessed. Abstract There is a lack of protocols specifically developed for the assessment of welfare of wild animals in captivity, even when it is known that providing good standards of welfare is important. The aim of this study was the development and the application of a protocol for the assessment of welfare in captive dorcas gazelles. The protocol was mainly developed taking into account the protocol for the assessment of welfare in cattle from the Welfare Quality® project, the available literature of the biology of this species and the Husbandry Guidelines developed for captive breeding and management of this species. The protocol was specifically developed for dorcas gazelles and included four principles, 10 criteria and 23 animal and environmental-based indicators. To test its utility, this protocol was applied to five different groups of gazelles from three different zoos. Its application made possible to detect areas for improvement in all groups assessed.
Double Conjunction Fallacies in Physicians’ Probability Judgment

We report the first empirical data showing a significant amount of double conjunction fallacies in physicians’ probability judgments concerning prognosis and diagnosis. Our results support the hypothesis that physicians’ probability judgments are guided by assessments of evidential impact between diagnostic conditions and clinical signs. Moreover, we show that, contrary to some influential views, double conjunction fallacies represent an experimentally replicable reasoning bias. We discuss how the phenomenon eludes major current accounts of uncertain reasoning in medicine and beyond and how it relates to clinical practice.
Magnetic Resonance Imaging of Shear Stress and Wall Thickness in Tissue-Engineered Vascular Grafts.

OBJECTIVES Tissue-engineered vascular grafts (TEVGs) have demonstrated potential for treating congenital heart disease (CHD); however, quantitative imaging for tracking functional and structural remodeling of TEVGs has not been applied. Therefore, we evaluated the potential of magnetic resonance (MR) imaging for assessing TEVG wall shear stress (WSS) and wall thickness in a large animal model. METHODS Cell-seeded (n = 3) or unseeded (n = 3) TEVGs were implanted as inferior vena cava interposition grafts in juvenile lambs. Six months following implantation, two-dimensional phase-contrast MR imaging was performed at 3 slice locations (proximal, middle, and distal) to assess normalized WSS (i.e., WSS-to-cross sectional area). T2-weighted MR imaging was performed to assess TEVG wall thickness. Histology was qualitatively assessed, whereas immunohistochemistry was semiquantitatively assessed for smooth muscle cells (αSMA), macrophage lineage cells (CD11b), and matrix metalloproteinase activity (MMP-2 and MMP-9). Picrosirius Red staining was performed to quantify collagen content. RESULTS TEVG wall thickness was significantly higher for proximal, middle, and distal slices in unseeded versus cell-seeded grafts. Significantly higher WSS values existed for proximal versus distal slice locations for cell-seeded TEVGs, whereas no differences in WSS existed between slices for unseeded TEVGs. Additionally, no differences in WSS existed between cell-seeded and unseeded groups. Both groups demonstrated elastin formation, without vascular calcification. Unseeded TEVGs possessed greater content of smooth muscle cells when compared with cell-seeded TEVGs. No differences in macrophage, MMP activity, or collagen content existed between groups. CONCLUSION MR imaging allows for in vivo assessment of functional and anatomical characteristics of TEVGs and may provide a nonionizing approach that is clinically translatable to children undergoing treatment for CHD.
Personalized disease signatures through information-theoretic compaction of big cancer data

Significance Accurate cancer diagnostics is a prerequisite for optimal personalized cancer medicine. We propose an information-theoretic cancer diagnosis that identifies signatures comprising patient-specific oncogenic processes rather than cancer type-specific biomarkers. Such comprehensive transcriptional signatures should allow for more accurate classification of cancer patients and better patient-specific diagnostics. The approach that we describe herein allows decoding of large-scale molecular-level information and elucidating patient-specific transcriptional altered network structures. Thereby, we move from cancer type-associated biomarkers to unbiased patient-specific unbalanced oncogenic processes. Every individual cancer develops and grows in its own specific way, giving rise to a recognized need for the development of personalized cancer diagnostics. This suggested that the identification of patient-specific oncogene markers would be an effective diagnostics approach. However, tumors that are classified as similar according to the expression levels of certain oncogenes can eventually demonstrate divergent responses to treatment. This implies that the information gained from the identification of tumor-specific biomarkers is still not sufficient. We present a method to quantitatively transform heterogeneous big cancer data to patient-specific transcription networks. These networks characterize the unbalanced molecular processes that deviate the tissue from the normal state. We study a number of datasets spanning five different cancer types, aiming to capture the extensive interpatient heterogeneity that exists within a specific cancer type as well as between cancers of different origins. We show that a relatively small number of altered molecular processes suffices to accurately characterize over 500 tumors, showing extreme compaction of the data. Every patient is characterized by a small specific subset of unbalanced processes. We validate the result by verifying that the processes identified characterize other cancer patients as well. We show that different patients may display similar oncogene expression levels, albeit carrying biologically distinct tumors that harbor different sets of unbalanced molecular processes. Thus, tumors may be inaccurately classified and addressed as similar. These findings highlight the need to expand the notion of tumor-specific oncogenic biomarkers to patient-specific, comprehensive transcriptional networks for improved patient-tailored diagnostics.
Moving Object Detection Using a Parallax Shift Vector Algorithm

There are various algorithms currently in use to detect asteroids from ground-based observatories, but they are generally restricted to linear or mildly curved movement of the target object across the field of view. Space-based sensors in high inclination, low Earth orbits can induce significant parallax in a collected sequence of images, especially for objects at the typical distances of asteroids in the inner solar system. This results in a highly nonlinear motion pattern of the asteroid across the sensor, which requires a more sophisticated search pattern for detection processing. Both the classical pattern matching used in ground-based asteroid search and the more sensitive matched filtering and synthetic tracking techniques, can be adapted to account for highly complex parallax motion. A new shift vector generation methodology is discussed along with its impacts on commonly used detection algorithms, processing load, and responsiveness to asteroid track reporting. The matched filter, template generator, and pattern matcher source code for the software described herein are available via GitHub.