Miracle-dz/UniFAR-FTUs huggingface dataset:
Skew‐normal random‐effects model for meta‐analysis of diagnostic test accuracy (DTA) studies

Hierarchical models are recommended for meta‐analyzing diagnostic test accuracy (DTA) studies. The bivariate random‐effects model is currently widely used to synthesize a pair of test sensitivity and specificity using logit transformation across studies. This model assumes a bivariate normal distribution for the random‐effects. However, this assumption is restrictive and can be violated. When the assumption fails, inferences could be misleading. In this paper, we extended the current bivariate random‐effects model by assuming a flexible bivariate skew‐normal distribution for the random‐effects in order to robustly model logit sensitivities and logit specificities. The marginal distribution of the proposed model is analytically derived so that parameter estimation can be performed using standard likelihood methods. The method of weighted‐average is adopted to estimate the overall logit‐transformed sensitivity and specificity. An extensive simulation study is carried out to investigate the performance of the proposed model compared to other standard models. Overall, the proposed model performs better in terms of confidence interval width of the average logit‐transformed sensitivity and specificity compared to the standard bivariate linear mixed model and bivariate generalized linear mixed model. Simulations have also shown that the proposed model performed better than the well‐established bivariate linear mixed model in terms of bias and comparable with regards to the root mean squared error (RMSE) of the between‐study (co)variances. The proposed method is also illustrated using a published meta‐analysis data.
Cognition and benefit obtained with hearing aids: a study in elderly people.

PURPOSE To verify the effects of cognition on the benefit obtained with the use of hearing aids and on the quality of life of elderly people with hearing loss. METHODS 17 elderly people with moderate sensorineural hearing loss (SNHL) bilateral were evaluated. The elderly people were divided into two groups according to the results of 10-point cognitive screening 10-CS: G1- seven elderly people without change and G2-10 elderly people with a suggestive result of cognitive alteration. Study protocol: self-evaluation questionnaire - (Hearing Handicap Inventory for the Elderly (HHIE)), geriatric depression scale (GDS), quality of life questionnaire - (Short-Form 36 (SF36)) and evaluation of the listening effort through the Visual Analogue Scale (VAS). After the evaluation, the elderly people received hearing aids. After three months of effective amplification, the protocol was reapplied with the inclusion of the International Questionnaire for the Evaluation of Hearing Aids - (IOI-HA). RESULTS The sample was characterized according to age, schooling, Critério de Classificação Econômico Brasil Associação Brasileira das Empresas de Pesquisa (ABEP), degree of loss, Índice Percentual de Reconhecimento da Fala (IPRF) and Speech Intelligibility Index (SII) of the ear with better audibility. The statistical study revealed that there was significant difference only in relation to age. The comparative study before and after the intervention revealed a significant improvement in the 10-CS scores in the group G2, in the participation restriction - HHIE, in the listening effort and in some areas of the SF36. There was no difference in QI-AASI between groups second the factor 1, factor 2 and Total Score. CONCLUSION There was improvement of the quality of life after three months of amplification use. There was no effect of cognition on the benefit obtained with the use of hearing aids.
β‐Catenin Preserves the Stem State of Murine Bone Marrow Stromal Cells Through Activation of EZH2

During bone marrow stromal cell (BMSC) differentiation, both Wnt signaling and the development of a rigid cytoskeleton promote commitment to the osteoblastic over adipogenic lineage. β‐catenin plays a critical role in the Wnt signaling pathway to facilitate downstream effects on gene expression. We show that β‐catenin was additive with cytoskeletal signals to prevent adipogenesis, and β‐catenin knockdown promoted adipogenesis even when the actin cytoskeleton was depolymerized. β‐catenin also prevented osteoblast commitment in a cytoskeletal‐independent manner, with β‐catenin knockdown enhancing lineage commitment. Chromatin immunoprecipitation (ChIP)‐sequencing demonstrated binding of β‐catenin to the promoter of enhancer of zeste homolog 2 (EZH2), a key component of the polycomb repressive complex 2 (PRC2) complex that catalyzes histone methylation. Knockdown of β‐catenin reduced EZH2 protein levels and decreased methylated histone 3 (H3K27me3) at osteogenic loci. Further, when EZH2 was inhibited, β‐catenin's anti‐differentiation effects were lost. These results indicate that regulating EZH2 activity is key to β‐catenin's effects on BMSCs to preserve multipotentiality. © 2020 American Society for Bone and Mineral Research.
Management of mild cognitive impairment (MCI): The need for national and international guidelines

Abstract Objectives: To review available evidence of pharmacological and non-pharmacological treatment for MCI and analyse information and limitations in national and international guidelines. Methods: Experts from several European countries conducted a qualitative review of the literature on MCI and treatments for MCI, as well as respective chapters in national and international guidelines on dementia/MCI. Psychotherapeutic/psychosocial treatments were excluded from the review. Results: Consensus diagnostic criteria for MCI are available, making early recognition and accurate classification of MCI subtypes possible. MCI can be identified in a primary care setting. Further corroboration and differential diagnosis should be done at specialist level. Mixed pathologies are the rule in MCI, thus a multi-target treatment approach is a rational strategy. Promising evidence has been generated for multi-domain interventions. Limited evidence is available for different pharmacological classes that have been investigated in MCI clinical trials (e.g. acetylcholinesterase inhibitors). EGb 761® improved symptoms in some clinical trials; it is the only pharmacological treatment recommended in existing guidelines for the symptomatic treatment of MCI. Conclusions: MCI is recognised as an important treatment target and some recent national guidelines have considered symptomatic treatment recommendations for MCI. However, more needs to be done, especially at an international level.
Epidermal Delivery of Retinyl Palmitate Loaded Transfersomes: Penetration and Biodistribution Studies

The alteration of retinoids levels in the skin can cause different disorders in the maturation of epithelial skin cells. Topical administration of these lipophilic molecules is a challenge that can be addressed by encapsulation into drug delivery systems. In this study, retinyl palmitate transferosomes formulated in cream were developed and the increases in the penetration of the active ingredients as well as the biodistribution were evaluated in vitro and in vivo. Transfersomes demonstrated a significant increase in the administration of retinyl palmitate to the epidermis by quantification of the active ingredients in the different layers of the skin, as well as by fluorescence microscopy of biopsies of non-dermatomized pig-ear skin. These results suggest that transfersomes may be an efficient vehicle for the delivery of retinoids to inner layers of the skin, such as the epidermis.
Identification of dysregulated genes and pathways of different brain regions in Alzheimer’s disease

Abstract Background: Alzheimer’s disease (AD) is a degenerative neurologic disease. The study aimed to identify the key differentially expressed genes (DEGs) and pathways in AD pathogenesis and obtain potential biomarkers in AD diagnosis. Methods: An integrated analysis of publicly available Gene Expression Omnibus datasets of AD was performed. DEGs in hippocampus tissue (HIP), temporal gyrus tissue (TG), frontal gyrus tissue (FG) and whole blood (WB) were identified. Bioinformatics analyses were used to insight into the functions of DEGs. The expression levels of candidate DEGs were preliminarily validated in GSE1297. The discriminatory ability of candidate DEGs in WB samples of AD patients and healthy individuals was evaluated in GSE63060 and GSE63061 datasets through receiver operating characteristic (ROC) analysis. Results: The DEGs in HIP, TG and FG tissues of AD were identified. Functions involved in regulation of apoptotic process, apoptotic process and cell death were significantly enriched from DEGs in AD. MAPK signaling pathway and Wnt signaling pathway were significantly enriched. YAP1, MAPK9 and GJA1 were the hub proteins in protein–protein interaction network in HIP, TG and FG. The expression levels of 14 DEGs in GSE1297 dataset were consistent with our integrated analysis. Moreover, 7 out of 14 DEGs had the diagnostic value in distinguishing AD patients from healthy controls in both GSE630060 and GSE630061 datasets. Conclusion: The DEGs including YAP1, MAPK1, GJA1 and pathways including MAPK signaling pathway and Wnt signaling pathway may be related to AD progression. RAD51C, SAFB2, SSH3 and TXNDC9 might be potential biomarkers in AD diagnosis.
PIK3CA mutations, PTEN, and pHER2 expression and impact on outcome in HER2-positive early-stage breast cancer patients treated with adjuvant chemotherapy and trastuzumab.

BACKGROUND This study was conducted to determine the frequency of PIK3CA mutations and human epidermal growth factor receptor-2 (HER2) phosphorylation status (pHER2-Tyr1221/1222) and if PIK3CA, phosphatase and tensin homolog (PTEN), or pHER2 has an impact on outcome in HER2-positive early-stage breast cancer patients treated with adjuvant chemotherapy and trastuzumab. PATIENTS AND METHODS Two hundred and forty HER2-positive early-stage breast cancer patients receiving adjuvant treatment (cyclophosphamide 600 mg/m2, epirubicin 60 mg/m2, and fluorouracil 600 mg/m2) before administration of 1 year trastuzumab were assessable. PTEN and pHER2 expression were assessed by immunohistochemistry. PIK3CA mutations (exons 9 and 20) were determined by pyrosequencing. RESULTS Five-year overall survival (OS) and invasive disease-free survival were 87.8% and 81.0%, respectively. Twenty-six percent of patients had a PIK3CA mutation, 24% were PTEN low, 45% pHER2 high, and 47% patients had increased PI3K pathway activation (PTEN low and/or PIK3CA mutation). No significant correlations were observed between the clinicopathological variables and PIK3CA, PTEN, and pHER2 status. In both univariate and multivariate analyses, patients with PIK3CA mutations or high PI3K pathway activity had a significant worse OS [multivariate: hazard ratio (HR) 2.14, 95% confidence interval (CI) 1.01-4.51, P = 0.046; and HR 2.35, 95% CI 1.10-5.04, P = 0.03]. CONCLUSION Patients with PIK3CA mutations or increased PI3K pathway activity had a significantly poorer survival despite adequate treatment with adjuvant chemotherapy and trastuzumab.
Differential Impact of Weight Loss and Glycemic Control on Inflammasome Signaling

Interleukin (IL)‐1β is involved in obesity‐associated inflammation and in the pathogenesis of type 2 diabetes (T2D) mellitus. Our aim was to correlate serum IL‐1β and caspase‐1 levels with weight loss, glucose metabolism, and insulin resistance (IR) after bariatric surgery.
Prevalence and Correlates of Bullying Behavior Among Nigerian Middle School Students

School bullying has received considerable criminological, psychological, educational, and governmental attention. However, much of the attention is focused on bullying in western, Asian, and Scandinavian countries. There appears to be scant, if any, attention paid to this problem on the African continent. Using cross-sectional data from a sample of 1,192 junior secondary school (middle school) students in Nigeria, this study examines the prevalence and correlates of bullying in this sample of secondary school students in Nigeria. Bullying prevalence rate in this sample was 59.9%. The study finds that males were more likely to bully than females, and the most prevalent form of bullying behavior for both genders was making fun of someone. Correlates for bullying perpetration were association with delinquent friends, negative school climate, attending a private school, and ethnicity.
Genetic heterogeneity in Leigh syndrome: Highlighting treatable and novel genetic causes

Leigh syndrome (LS), the most common childhood mitochondrial disorder, has characteristic clinical and neuroradiologic features. Mutations in more than 75 genes have been identified in both the mitochondrial and nuclear genome, implicating a high degree of genetic heterogeneity in LS. To profile these genetic signatures and understand the pathophysiology of LS, we recruited 64 patients from 62 families who were clinically diagnosed with LS at Seoul National University Children's Hospital. Mitochondrial genetic analysis followed by whole‐exome sequencing was performed on 61 patients. Pathogenic variants in mitochondrial DNA were identified in 18 families and nuclear DNA mutations in 22. The following 17 genes analyzed in 40 families were found to have genetic complexity: MTATP6, MTND1, MTND3, MTND5, MTND6, MTTK, NDUFS1, NDUFV1, NDUFAF6, SURF1, SLC19A3, ECHS1, PNPT1, IARS2, NARS2, VPS13D, and NAXE. Two treatable cases had biotin‐thiamine responsive basal ganglia disease, and another three were identified as having defects in the newly recognized genes (VPS13D or NAXE). Variants in the nuclear genes that encoded mitochondrial aminoacyl tRNA synthetases were present in 27.3% of cases. Our findings expand the genetic and clinical spectrum of LS, showing genetic heterogeneity and highlighting treatable cases and those with novel genetic causes.
DNA methylation changes on immune cells in Systemic Lupus Erythematosus

Abstract DNA methylation as a process that regulates gene expression is crucial in immune cells biology. Global and gene specific methylation changes have been described in autoimmunity, especially in Systemic Lupus Erythematosus. These changes not only contribute to the understanding of the disease, but also some have been proposed as diagnostic or disease activity biomarkers. The present review compiles the most recent discoveries on this field on each type of immune cells, including specific changes in signalling pathways, genes of interest and its possible applications on diagnosis or treatment.
Left ventricular response after cardiac resynchronization therapy is related to early left atrial volume reduction

Background/Aims The current study aimed to elucidate a time-course change in left atrial volume after cardiac resynchronization therapy (CRT) and to verify factors associated with left atrial volume reduction (LAVR) and its prognostic implications. Methods The records of 97 patients were retrospectively reviewed after CRT. Echocardiographic data were analyzed at baseline before CRT, at early follow-up (FU) (≤ 1 year, median 6 months), and at late FU (median 30 months). Left ventricular volume response (LVVR) was defined as 15% reduction in left ventricular (LV) end-systolic volume (ESV). LAVR was classified into two groups by the median value at early FU: LAVR (≥ 7.5%) and no LAVR (< 7.5%). Results LV ESV index continuously decreased from baseline to early FU and from early FU to late FU (106.1 ± 47.4 mL/m2 vs. 87.6 ± 51.6 mL/m2 vs. 72.5 ± 57.1 mL/m2). LA volume index decreased from baseline to early FU, but there were no reductions thereafter (51.8 ± 21.9 mL/m2 vs. 45.1 ± 19.6 mL/m2 vs. 44.9 ± 23.0 mL/m2). The only echocardiographic factor associated with LAVR was change in E velocity (odds ratio [OR], 1.04; p = 0.002). Early LAVR (OR, 10.05; p = 0.002) was an independent predictor for late LVVR. Conclusions LAVR was related to reduction in E velocity, suggesting its relation with optimization of LV filling pressure. Early LAVR was a predictor for LVVR to CRT in long-term FU.
Frequency of tuberculosis in cervical lymphadenopathy: our experience

Objective: To observe the frequency of tuberculosis in patients with cervical Lymphadenopathy. Study design: Prospective descriptive study. Sett ing& duration: At Hamdard University Hospital Karachi from January 2008 to January 2009. Methodology: All Patients with cervical Lymphadenopathy were included who presented in outpatient department. Detailed history, clinical examination, Complete blood picture, Erythrocyte sedimentation rate (ESR), Mantoux test (MT) and X-ray chest were done in all patients . Diagnosis was confi rmed either by Fine Needle Aspiration Cytology (FNAC), incisional or excisional biopsy . Data was collected on a predesigned Performa. Results: Sixty patients were included in study, female to male ratio was 1:0.7. Most common clinical presentation was multiple painless neck swellings (80%), others were abscess, discharging sinus, pyrexia & weight loss. Tuberculosis was confi rmed in 42 patients (70%), squamous cell carcinoma in 02(3.33%), Lymphoproliferative disorders 03 (05%), Kikuchi disease o1 (1.66%) and Non-specifi c infl ammation in 12 (20%) patients. Conclusion: Tuberculosis is commonest cause of cervical Lymphadenopathy in our clinical practice.
Andrographolide mitigates cardiac apoptosis to provide cardio‐protection in high‐fat‐diet‐induced obese mice

Excessive intake of high fat diet (HFD) and associated obese conditions are critical contributors of cardiac diseases. In this study, an active metabolite andrographolide from Andrographis paniculata was found to ameliorate HFD‐induced cardiac apoptosis. C57/BL6 mouse were grouped as control (n = 9), obese (n = 8), low dose (25 mg/kg/d) andrographolide treatment (n = 9), and high dose (50 mg/kg/d) andrographolide treatment (n = 9). The control group was provided with standard laboratory chow and the other groups were fed with HFD. Andrographolide was administered through oral gavage for 1 week. Histopathological analysis showed increase in apoptotic nuclei and considerable cardiac‐damages in the obese group signifying cardiac remodeling effects. Further, Western blot results showed increase in pro‐apoptotic proteins and decrease in the proteins of IGF‐1R‐survival signaling. However, feeding of andrographolide significantly reduced the cardiac effects of HFD. The results strongly suggest that andrographolide supplementation can be used for prevention and treatment of cardiovascular disease in obese patients.
The NRF2 Signaling Network Defines Clinical Biomarkers and Therapeutic Opportunity in Friedreich’s Ataxia

Friedreich’s ataxia (FA) is a trinucleotide repeats expansion neurodegenerative disorder, for which no cure or approved therapies are present. In most cases, GAA trinucleotide repetitions in the first intron of the FXN gene are the genetic trigger of FA, determining a strong reduction of frataxin, a mitochondrial protein involved in iron homeostasis. Frataxin depletion impairs iron–sulfur cluster biosynthesis and determines iron accumulation in the mitochondria. Mounting evidence suggests that these defects increase oxidative stress susceptibility and reactive oxygen species production in FA, where the pathologic picture is worsened by a defective regulation of the expression and signaling pathway modulation of the transcription factor NF-E2 p45-related factor 2 (NRF2), one of the fundamental mediators of the cellular antioxidant response. NRF2 protein downregulation and impairment of its nuclear translocation can compromise the adequate cellular response to the frataxin depletion-dependent redox imbalance. As NRF2 stability, expression, and activation can be modulated by diverse natural and synthetic compounds, efforts have been made in recent years to understand if regulating NRF2 signaling might ameliorate the pathologic defects in FA. Here we provide an analysis of the pharmaceutical interventions aimed at restoring the NRF2 signaling network in FA, elucidating specific biomarkers useful for monitoring therapeutic effectiveness, and developing new therapeutic tools.
Direct Activation of Primary Motor Cortex during Subthalamic But Not Pallidal Deep Brain Stimulation

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) and globus pallidus internus (GPi) is an effective treatment for parkinsonian motor signs. Though its therapeutic mechanisms remain unclear, it has been suggested that antidromic activation of the primary motor cortex (M1) plays a significant role in mediating its therapeutic effects. This study tested the hypothesis that antidromic activation of M1 is a prominent feature underlying the therapeutic effect of STN and GPi DBS. Deep brain stimulation (DBS) of the subthalamic nucleus (STN) and globus pallidus internus (GPi) is an effective treatment for parkinsonian motor signs. Though its therapeutic mechanisms remain unclear, it has been suggested that antidromic activation of the primary motor cortex (M1) plays a significant role in mediating its therapeutic effects. This study tested the hypothesis that antidromic activation of M1 is a prominent feature underlying the therapeutic effect of STN and GPi DBS. Single-unit activity in M1 was recorded using high-density microelectrode arrays in two parkinsonian nonhuman primates each implanted with DBS leads targeting the STN and GPi. Stimulation in each DBS target had similar therapeutic effects, however, antidromic activation of M1 was only observed during STN DBS. Although both animals undergoing STN DBS had similar beneficial effects, the proportion of antidromic-classified cells in each differed, 30 versus 6%. Over 4 h of continuous STN DBS, antidromic activation became less robust, whereas therapeutic benefits were maintained. Although antidromic activation waned over time, synchronization of spontaneous spiking in M1 was significantly reduced throughout the 4 h. Although we cannot discount the potential therapeutic role of antidromic M1 activation at least in the acute phase of STN DBS, the difference in observed antidromic activation between animals, and target sites, raise questions about its hypothesized role as the primary mechanism underlying the therapeutic effect of DBS. These results lend further support that reductions in synchronization at the level of M1 are an important factor in the therapeutic effects of DBS. SIGNIFICANCE STATEMENT Recently there has been great interest and debate regarding the potential role of motor cortical activation in the therapeutic mechanisms of deep brain stimulation (DBS) for Parkinson's disease. In this study we used chronically implanted high density microelectrode arrays in primary motor cortex (M1) to record neuronal population responses in parkinsonian nonhuman primates during subthalamic nucleus (STN) DBS and globus pallidus internus (GPi) DBS. Our results suggest a contribution of antidromic activation of M1 during STN DBS in disrupting synchronization in cortical neuronal populations; however, diminishing antidromic activity over time, and differences in observed antidromic activation between animals and target sites with antidromic activation not observed during GPi DBS, raise questions about its role as the primary mechanism underlying the therapeutic effect of DBS.
Arterial anatomy of the anterior abdominal wall: Ultrasound evaluation as a real‐time guide to percutaneous instrumentation

Instrumenting the anterior abdominal wall carries a potential for vascular trauma. We previously assessed the presence, position, and size of the anterior abdominal wall superior and inferior (deep) epigastric arteries with computed tomography (CT). We now present a study using ultrasound (US) assessment of these arteries, to evaluate its use for real time guidance of percutaneous procedures involving the rectus sheath.