Miracle-dz/UniFAR-FTUs huggingface dataset:
Islet Autoantibody Standardization Program 2018 Workshop: Interlaboratory Comparison of Glutamic Acid Decarboxylase Autoantibody Assay Performance.

BACKGROUND The Islet Autoantibody Standardization Program (IASP) aims to improve the performance of immunoassays measuring type 1 diabetes (T1D)-associated autoantibodies and the concordance of results among laboratories. IASP organizes international interlaboratory assay comparison studies in which blinded serum samples are distributed to participating laboratories, followed by centralized collection and analysis of results, providing participants with an unbiased comparative assessment. In this report, we describe the results of glutamic acid decarboxylase autoantibody (GADA) assays presented in the IASP 2018 workshop. METHODS In May 2018, IASP distributed to participants uniquely coded sera from 43 new-onset T1D patients, 7 multiple autoantibody-positive nondiabetic individuals, and 90 blood donors. Results were analyzed for the following metrics: sensitivity, specificity, accuracy, area under the ROC curve (ROC-AUC), partial ROC-AUC at 95% specificity (pAUC95), and concordance of qualitative and quantitative results. RESULTS Thirty-seven laboratories submitted results from a total of 48 different GADA assays adopting 9 different formats. The median ROC-AUC and pAUC95 of all assays were 0.87 [interquartile range (IQR), 0.83-0.89] and 0.036 (IQR, 0.032-0.039), respectively. Large differences in pAUC95 (range, 0.001-0.0411) were observed across assays. Of formats widely adopted, bridge ELISAs showed the best median pAUC95 (0.039; range, 0.036-0.041). CONCLUSIONS Several novel assay formats submitted to this study showed heterogeneous performance. In 2018, the majority of the best performing GADA immunoassays consisted of novel or established nonradioactive tests that proved on a par or superior to the radiobinding assay, the previous gold standard assay format for GADA measurement.
LncRNA MEG3 inhibits rheumatoid arthritis through miR‐141 and inactivation of AKT/mTOR signalling pathway

Rheumatoid arthritis (RA) is a chronic inflammation mediated by autoimmune responses. MEG3, a kind of long noncoding RNA (lncRNA), participates in cell proliferation in cancer tissues. However, the correlation between MEG3 and RA is yet unclear. Therefore, to clarify how MEG3 works in RA, we performed a series of experiments using RA samples. We found that MEG3 was downregulated in the fibroblast‐like synoviocytes of RA patients (RA‐FLS), in comparison with healthy subjects. MEG3 was also down‐regulated evidently in lipopolysaccharide (LPS)‐treated chondrocyte. As part of our experiments, MEG3 was overexpressed in chondrocyte by transfection with lentivirus containing sequences encoding MEG3. In addition, in presence of LPS, reductions were identified not only in the cell proliferation, but also in the generation of interleukin‐23 (IL‐23), which, however were reversed in the lentivirus (containing MEG3‐encoding sequences)‐transfected chondrocytes. Up‐regulated MEG3 resulted in an increase the level of Ki67. Moreover, MEG3 was negatively correlated with miR‐141, and miR‐141 was up‐regulated in LPS‐treated chondrocyte. Inhibitory effects of MEG3 overexpression, mentioned above, were partially abolished by overexpressed miR‐141. Further, animal experiment also showed the inhibitory effect of MEG3 in overexpression on the AKT/mTOR signaling pathway. In‐vivoexperiments also showed that cell proliferation was facilitated by MEG3 overexpression with inhibited inflammation. In summary, the protective role of MEG3 in RA was proved to be exerted by the increase in the rate of proliferation, which might correlate to the regulatory role of miR‐141 and AKT/mTOR signal pathway, suggesting that MEG3 holds great promise as a therapeutic strategy for RA.
‘Stealth trauma’ in the young and the old: the next challenge for major trauma networks?

In the UK, reports from the Trauma Audit Research Network (TARN)1 2 have shown that the very young and the very old now outnumber higher profile trauma groups, such as road accidents and stabbings. Other countries have seen similar demographic shifts. The very young and the very old share many societal and medical traits, including late diagnosis of severe injuries that may not be apparent on initial presentation.3 This could be described as ‘stealth trauma’. Many countries have established major trauma networks,4 5 with the English system showing incremental improvements in patient outcomes.6 However, these systems rely on early identification by prehospital services of the ‘major trauma patient’ (usually by application of a trauma triage tool by ambulance staff). This identifies patients for immediate transfer to a major trauma centre (MTC), however this system does not work at the extremes of age. The TARN reports show that the old and the very young have a delayed process of care. The mechanism of injury …
Diagnosis and management of sepsis‐induced coagulopathy and disseminated intravascular coagulation

1Department of Emergency and Disaster Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan 2Department of Anesthesiology, Critical Care, and Surgery, Duke University School of Medicine, Durham, NC, USA 3Department of Pathology and Molecular Medicine, and Department of Medicine, McMaster University, Hamilton, Ontario, Canada 4Department of Haematology, Manchester Royal Infirmary, Manchester, UK 5Amsterdam University Medical Centers, Location Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands 6University College London Hospitals NHS Foundation Trust, London, UK
BET Inhibition as a Rational Therapeutic Strategy for Invasive Lobular Breast Cancer

Purpose: Invasive lobular carcinoma (ILC) is a subtype of breast cancer accounting for 10% of breast tumors. The majority of patients are treated with endocrine therapy; however, endocrine resistance is common in estrogen receptor–positive breast cancer and new therapeutic strategies are needed. Bromodomain and extraterminal inhibitors (BETi) are effective in diverse types of breast cancer but they have not yet been assessed in ILC. Experimental Design: We assessed whether targeting the BET proteins with JQ1 could serve as an effective therapeutic strategy in ILC in both 2D and 3D models. We used dynamic BH3 profiling and RNA-sequencing (RNA-seq) to identify transcriptional reprograming enabling resistance to JQ1-induced apoptosis. As part of the RATHER study, we obtained copy-number alterations and RNA-seq on 61 ILC patient samples. Results: Certain ILC cell lines were sensitive to JQ1, while others were intrinsically resistant to JQ1-induced apoptosis. JQ1 treatment led to an enhanced dependence on antiapoptotic proteins and a transcriptional rewiring inducing fibroblast growth factor receptor 1 (FGFR1). This increase in FGFR1 was also evident in invasive ductal carcinoma (IDC) cell lines. The combination of JQ1 and FGFR1 inhibitors was highly effective at inhibiting growth in both 2D and 3D models of ILC and IDC. Interestingly, we found in the RATHER cohort of 61 ILC patients that 20% had FGFR1 amplification and we showed that high BRD3 mRNA expression was associated with poor survival specifically in ILC. Conclusions: We provide evidence that BETi either alone or in combination with FGFR1 inhibitors or BH3 mimetics may be a useful therapeutic strategy for recurrent ILC patients.
Longitudinal changes in axial length in high myopia: a 4-year prospective study

Aim To determine the longitudinal changes in the axial length (AL) in patients with high myopia without any other ophthalmic disease Methods Participants were divided into two groups: a high myopia group (60 eyes) without myopic degeneration, such as chorioretinal atrophy or posterior staphyloma, and a control group (60 eyes). Both groups were further divided into subgroups according to the AL: subgroup 1 (≥27.5 mm), subgroup 2 (26.0–27.5 mm), subgroup 3 (24.5–26.0 mm) and subgroup 4 (<24.5 mm). The ALs were measured five times at 1-year interval using an IOL master, and the AL was fitted with linear mixed models. Results In the high myopia group, the AL showed a relatively constant increase at each visit, and they were significantly different with previous measurements at most visits, whereas the control group showed no significant change of AL. Subgroups 1,2 and 3 showed significant changes in AL over time (0.064, 0.032 and 0.012 mm/y, respectively). In univariate analyses, age, best-corrected visual acuity, baseline AL and anterior chamber depth were significantly correlated with changes in the AL in the high myopia group. In multivariate analysis, only baseline AL remained significant (p<0.001). Conclusions Myopic eyes, including moderately myopic eyes, showed a consistent increase in AL over 4 years, and eyes with a longer baseline AL showed a greater increase in AL than eyes with a shorter AL.
Gait and Computerized Dynamic Posturography (CDP) Aspects in Early Progressive Supranuclear Palsy (PSP) - A Case Report

Abstract BACKGROUND: Posture and gait instability may cause of morbidity in individuals with progressive supranuclear palsy (PSP). OBJECTIVE: To quantitatively measure balance control by using computerized dynamic posturography (CDP) and to assess gait analysis in early PSP. CASE REPORT: She was evaluated for Berge balance scale, Functional Independence Measure (FIM) and postural stability using CDP device in early PSP with still able to walk or stand unassisted. Also, Gait analysis was conducted using an 8 M-camera Vicon 612 data capturing system set. Berge balance scale improved from 41/56 to 48/56. The score of FIM improved from 71/126 points to 95/126 points in early PSP. In CDP analysis, there was a decrease of composite equilibrium score (38 %). There was an increase of composite equilibrium score (59%) after three months of treatment. In gait analysis, there was no difference of gait parameters after three months of treatment in early PSP. CONCLUSIONS: Both CDP and gait analysis are important quantitative tools in the assessment of posture and gait instability as well as allow for early disclosure of the failure of the postural control system in early PSP.
Effective classification for unbalanced bank direct marketing data with over-sampling

Direct marketing is an effective tool used by financial institutions such as banks to promote products and services. This study began with analyzing an unbalanced direct marketing data set and subsequently discovered the rare class problem. The problem has prompted unsatisfactory classification rate for an important minority class in the data set. The analysis shows that the problem is caused by the small size of the minority class, overlapping of classes, and noisy data. Further, the incapability of classification algorithms in handling unbalanced data sets has also contributed to the problem. Data-level approaches are normally used to solve or mitigate the problem. The authors evaluated various data-level approaches using the data set and identified SMOTE (an over-sampling technique) as the effective approach to the problem. The authors also managed to identify a set of useful features for classification, instead of using all the features in the data set.
Sacral nerve stimulation with appropriate parameters improves constipation in rats by enhancing colon motility mediated via the autonomic-cholinergic mechanisms.

BACKGROUND While sacral nerve stimulation (SNS) has been applied for treating constipation, its parameters were adopted from SNS for fecal incontinence, its effects are limited and mechanisms are largely unknown. AIM To investigate the effects and mechanism of SNS with appropriate parameters on constipation in rats treated with loperamide. METHODS First, using rectal compliance as an outcome measure, an experiment was performed to derive effective SNS parameters. Then a 7-day SNS was performed in rats with constipation induced by loperamide. Autonomic function were assessed by the spectral analysis of the heart rate variability (HRV) derived from the electrocardiogram. Serum levels of pancreatic polypeptide (PP), and norepinephrine (NE). Acetylcholine (Ach) in colon was assessed. RESULTS 1) Acute SNS at 5Hz , 100µs was found effective in enhancing rectal compliance and accelerating distal colon transit (p＜0.05 vs. sham SNS). 2) The 7-day SNS normalized loperamide-induced constipation, assessed by the number, weight and water content of fecal pellets and accelerated the distal colon transit (29.4 ± 3.7 min with sham-SNS vs. 16.4 ± 5.3 min with SNS but not gastric emptying or intestinal transit. 4) SNS significantly increased vagal activity (p=0.035) and decreased sympathetic activity (p=0.012) assessed by the spectral analysis of HRV as well as by the serum PP. 5) SNS increased ACh in the colon tissue; atropine blocked the accelerative effect of SNS on distal colon transit. CONCLUSIONS SNS with appropriate parameters improves constipation induced by loperamide by accelerating distal colon motility, mediated via the autonomic-cholinergic function.
Natural History of Atherosclerosis and Abdominal Aortic Intima-Media Thickness: Rationale, Evidence, and Best Practice for Detection of Atherosclerosis in the Young

Atherosclerosis underlies most myocardial infarctions and ischemic strokes. The timing of onset and the rate of progression of atherosclerosis differ between individuals and among arterial sites. Physical manifestations of atherosclerosis may begin in early life, particularly in the abdominal aorta. Measurement of the abdominal aortic intima-media thickness by external ultrasound is a non-invasive methodology for quantifying the extent and severity of early atherosclerosis in children, adolescents, and young adults. This review provides an evidence-based rationale for the assessment of abdominal aortic intima-media thickness—particularly as an age-appropriate methodology for studying the natural history of atherosclerosis in the young in comparison to other methodologies—establishes best practice methods for assessing abdominal aortic intima-media thickness, and identifies key gaps in the literature, including those that will identify the clinical relevance of this measure.
Pregnancy rate after fixed-time transfer of cryopreserved embryos collected by non-surgical route in Lacaune sheep.

This study investigated the feasibility of applying fixed-time (cryopreserved) embryo transfer in ewes. Embryos (n=106) were non-surgically recovered from superovulated donors (n=39) on day 6-7 after estrus. Straws containing one or two embryos (morulae and/or blastocysts) subjected to either slow freezing (SF, n=62) or vitrification (VT, n=44) were randomly used within fixed-time embryo transfer on Day 8.5. Recipient ewes were nulliparous (n=58) bearing corpora lutea after synchronous estrus induction protocol. The pregnancy rate was higher (p = .03) in SF (39.4%) than VT (16.9%) and survival rate tended (p = .08) to be higher in SF than in VT (25.8 vs 15.9%). Lambing rates were similar (p = .13) between SF (20.9%) and VT (15.9%). Embryos recovered by non-surgical route after cervical dilation treatment and later cryopreserved by either slow freezing or vitrification produced reasonable pregnancy rates after FTET.
Adult Neurogenesis in the Development of Epilepsy

Compelling evidence indicates that hippocampal dentate granule cells are generated throughout human life and into old age. While animal studies demonstrate that these new neurons are important for memory function, animal research also implicates these cells in the pathogenesis of temporal lobe epilepsy. Several recent preclinical studies in rodents now suggest that targeting these new neurons can have disease-modifying effects in epilepsy.
Training in improvisation techniques helps reduce caregiver burden and depression: Innovative Practice

This study measured outcomes of a novel pilot program designed to teach improvisation skills to caregivers of family members with dementia. Fifteen caregivers completed questionnaires measuring changes in their perception of burden (Zarit Burden Interview), depression (Beck Depression Inventory), their cared-for person’s neuropsychiatric symptoms (Neuropsychiatric Inventory Questionnaire), and experiences related to caregiving. Caregivers’ depressive symptoms and sense of burden significantly decreased after completing the six-week program. Caregivers reported that their loved ones’ neuropsychiatric symptoms increased during the course of the intervention, though associated distress did not also increase. The Improv for Care program shows promise as an intervention for caregivers to improve stress, mood, and coping skills.
Lifestyle factors and high-risk atherosclerosis: Pathways and mechanisms beyond traditional risk factors

Despite major efforts to reduce atherosclerotic cardiovascular disease (ASCVD) burden with conventional risk factor control, significant residual risk remains. Recent evidence on non-traditional determinants of cardiometabolic health has advanced our understanding of lifestyle–disease interactions. Chronic exposure to environmental stressors like poor diet quality, sedentarism, ambient air pollution and noise, sleep deprivation and psychosocial stress affect numerous traditional and non-traditional intermediary pathways related to ASCVD. These include body composition, cardiorespiratory fitness, muscle strength and functionality and the intestinal microbiome, which are increasingly recognized as major determinants of cardiovascular health. Evidence points to partially overlapping mechanisms, including effects on inflammatory and nutrient sensing pathways, endocrine signalling, autonomic function and autophagy. Of particular relevance is the potential of low-risk lifestyle factors to impact on plaque vulnerability through altered adipose tissue and skeletal muscle phenotype and secretome. Collectively, low-risk lifestyle factors cause a set of phenotypic adaptations shifting tissue cross-talk from a proinflammatory milieu conducive for high-risk atherosclerosis to an anti-atherogenic milieu. The ketone body ß-hydroxybutyrate, through inhibition of the NLRP-3 inflammasome, is likely to be an intermediary for many of these observed benefits. Adhering to low-risk lifestyle factors adds to the prognostic value of optimal risk factor management, and benefit occurs even when the impact on conventional risk markers is discouragingly minimal or not present. The aims of this review are (a) to discuss novel lifestyle risk factors and their underlying biochemical principles and (b) to provide new perspectives on potentially more feasible recommendations to improve long-term adherence to low-risk lifestyle factors.
Increased whitening efficacy and reduced cytotoxicity are achieved by the chemical activation of a highly concentrated hydrogen peroxide bleaching gel

Abstract Objective This study was designed for the chemical activation of a 35% hydrogen peroxide (H2O2) bleaching gel to increase its whitening effectiveness and reduce its toxicity. Methodology First, the bleaching gel - associated or not with ferrous sulfate (FS), manganese chloride (MC), peroxidase (PR), or catalase (CT) - was applied (3x 15 min) to enamel/dentin discs adapted to artificial pulp chambers. Then, odontoblast-like MDPC-23 cells were exposed for 1 h to the extracts (culture medium + components released from the product), for the assessment of viability (MTT assay) and oxidative stress (H2DCFDA). Residual H2O2 and bleaching effectiveness (DE) were also evaluated. Data were analyzed with one-way ANOVA complemented with Tukey’s test (n=8. p<0.05). Results All chemically activated groups minimized MDPC-23 oxidative stress generation; however, significantly higher cell viability was detected for MC, PR, and CT than for plain 35% H2O2 gel. Nevertheless, FS, MC, PR, and CT reduced the amount of residual H2O2 and increased bleaching effectiveness. Conclusion Chemical activation of 35% H2O2 gel with MC, PR, and CT minimized residual H2O2 and pulp cell toxicity; but PR duplicated the whitening potential of the bleaching gel after a single 45-minute session.
Cellular and Molecular Mechanisms in the Pathogenesis of Classical, Vascular, and Hypermobile Ehlers‒Danlos Syndromes

The Ehlers‒Danlos syndromes (EDS) constitute a heterogenous group of connective tissue disorders characterized by joint hypermobility, skin abnormalities, and vascular fragility. The latest nosology recognizes 13 types caused by pathogenic variants in genes encoding collagens and other molecules involved in collagen processing and extracellular matrix (ECM) biology. Classical (cEDS), vascular (vEDS), and hypermobile (hEDS) EDS are the most frequent types. cEDS and vEDS are caused respectively by defects in collagen V and collagen III, whereas the molecular basis of hEDS is unknown. For these disorders, the molecular pathology remains poorly studied. Herein, we review, expand, and compare our previous transcriptome and protein studies on dermal fibroblasts from cEDS, vEDS, and hEDS patients, offering insights and perspectives in their molecular mechanisms. These cells, though sharing a pathological ECM remodeling, show differences in the underlying pathomechanisms. In cEDS and vEDS fibroblasts, key processes such as collagen biosynthesis/processing, protein folding quality control, endoplasmic reticulum homeostasis, autophagy, and wound healing are perturbed. In hEDS cells, gene expression changes related to cell-matrix interactions, inflammatory/pain responses, and acquisition of an in vitro pro-inflammatory myofibroblast-like phenotype may contribute to the complex pathogenesis of the disorder. Finally, emerging findings from miRNA profiling of hEDS fibroblasts are discussed to add some novel biological aspects about hEDS etiopathogenesis.