Miracle-dz/UniFAR-FTUs huggingface dataset:
Cardiovascular and kidney outcomes with finerenone in patients with type 2 diabetes and chronic kidney disease: the FIDELITY pooled analysis

Abstract Aims The complementary studies FIDELIO-DKD and FIGARO-DKD in patients with type 2 diabetes and chronic kidney disease (CKD) examined cardiovascular and kidney outcomes in different, overlapping stages of CKD. The purpose of the FIDELITY analysis was to perform an individual patient-level prespecified pooled efficacy and safety analysis across a broad spectrum of CKD to provide more robust estimates of safety and efficacy of finerenone compared with placebo. Methods and results For this prespecified analysis, two phase III, multicentre, double-blind trials involving patients with CKD and type 2 diabetes, randomized 1:1 to finerenone or placebo, were combined. Main time-to-event efficacy outcomes were a composite of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, or hospitalization for heart failure, and a composite of kidney failure, a sustained ≥57% decrease in estimated glomerular filtration rate from baseline over ≥4 weeks, or renal death. Among 13 026 patients with a median follow-up of 3.0 years (interquartile range 2.3–3.8 years), the composite cardiovascular outcome occurred in 825 (12.7%) patients receiving finerenone and 939 (14.4%) receiving placebo [hazard ratio (HR), 0.86; 95% confidence interval (CI), 0.78–0.95; P = 0.0018]. The composite kidney outcome occurred in 360 (5.5%) patients receiving finerenone and 465 (7.1%) receiving placebo (HR, 0.77; 95% CI, 0.67–0.88; P = 0.0002). Overall safety outcomes were generally similar between treatment arms. Hyperkalaemia leading to permanent treatment discontinuation occurred more frequently in patients receiving finerenone (1.7%) than placebo (0.6%). Conclusion Finerenone reduced the risk of clinically important cardiovascular and kidney outcomes vs. placebo across the spectrum of CKD in patients with type 2 diabetes. Key Question Does finerenone, a novel selective, nonsteroidal mineralocorticoid receptor antagonist, added to maximum tolerated renin–angiotensin system inhibition reduce cardiovascular disease and kidney disease progression over a broad range of chronic kidney disease in patients with type 2 diabetes? Key Finding In a prespecified, pooled individual-level analysis from two randomized trials, we found reductions both in cardiovascular events and kidney failure outcomes with finerenone. Because 40% of the patients had an estimated glomerular filtration rate of >60 mL/min/1.73m2 they were identified solely on the basis of albuminuria. Take Home Message Finerenone reduces the risk of clinical cardiovascular outcomes and kidney disease progression in a broad range of patients with chronic kidney disease and type 2 diabetes. Screening for albuminuria to identify at-risk patients among patients with type 2 diabetes facilitates reduction of both cardiovascular and kidney disease burden.
Sources of Occupational Stress among Office Workers—A Focus Group Study

Workplace stress remains a major interest of occupational health research, usually based on theoretical models and quantitative large-scale studies. Office workers are especially exposed to stressors such as high workload and time pressure. The aim of this qualitative research was to follow a phenomenological approach to identify work stressors as they are perceived by office workers. Six focus groups with office workers of different occupations were conducted in Belgium and Slovenia. A total of 39 participants were included in the study. We used the RQDA software for data processing and analysis and the seven job-quality indices of the European Working Conditions Survey (EWCS) to structure our findings. The results show that work intensity and social environment proved to be main stress categories, followed by skills and discretion, prospects, and working time quality. The physical environment and earnings were not covered in our results. We created organisational (structural/process-oriented and financial) stressors and office workers’ physical health as two additional categories since these topics did not fit into the EWCS. While our findings mainly confirm data from existing occupational stress literature and emphasise the multi-level complexity of work stress experiences, this paper suggests that there are relevant stressors experienced by office workers beyond existing quantitative frameworks.
Normal Retinotopy in Primary Visual Cortex in a Congenital Complete Unilateral Lesion of Lateral Geniculate Nucleus in Human: A Case Study

Impairment of the geniculostriate pathway results in scotomas in the corresponding part of the visual field. Here, we present a case of patient IB with left eye microphthalmia and with lesions in most of the left geniculostriate pathway, including the Lateral Geniculate Nucleus (LGN). Despite the severe lesions, the patient has a very narrow scotoma in the peripheral part of the lower-right-hemifield only (beyond 15° of eccentricity) and complete visual field representation in the primary visual cortex. Population receptive field mapping (pRF) of the patient’s visual field reveals orderly eccentricity maps together with contralateral activation in both hemispheres. With diffusion tractography, we revealed connections between superior colliculus (SC) and cortical structures in the hemisphere affected by the lesions, which could mediate the retinotopic reorganization at the cortical level. Our results indicate an astonishing case for the flexibility of the developing retinotopic maps where the contralateral thalamus receives fibers from both the nasal and temporal retinae.
EVI1 Promotes the Proliferation and Invasive Properties of Human Head and Neck Squamous Cell Carcinoma Cells

Head and neck squamous cell carcinoma (HNSCC) is a frequent malignancy with a poor prognosis. So far, the EGFR inhibitor cetuximab is the only approved targeted therapy. A deeper understanding of the molecular and genetic basis of HNSCC is needed to identify additional targets for rationally designed, personalized therapeutics. The transcription factor EVI1, the major product of the MECOM locus, is an oncoprotein with roles in both hematological and solid tumors. In HNSCC, high EVI1 expression was associated with an increased propensity to form lymph node metastases, but its effects in this tumor entity have not yet been determined experimentally. We therefore overexpressed or knocked down EVI1 in several HNSCC cell lines and determined the impact of these manipulations on parameters relevant to tumor growth and invasiveness, and on gene expression patterns. Our results revealed that EVI1 promoted the proliferation and migration of HNSCC cells. Furthermore, it augmented tumor spheroid formation and the ability of tumor spheroids to displace an endothelial cell layer. Finally, EVI1 altered the expression of numerous genes in HNSCC cells, which were enriched for Gene Ontology terms related to its cellular functions. In summary, EVI1 represents a novel oncogene in HNSCC that contributes to cellular proliferation and invasiveness.
Anatabine, Nornicotine, and Anabasine Reduce Weight Gain and Body Fat through Decreases in Food Intake and Increases in Physical Activity

Obesity is a leading cause of preventable death in the United States. Currently approved pharmacotherapies for the treatment of obesity are associated with rebound weight gain, negative side effects, and the potential for abuse. There is a need for new treatments with fewer side effects. Minor tobacco alkaloids (MTAs) are potential candidates for novel obesity pharmacotherapies. These alkaloids are structurally related to nicotine, which can help reduce body weight, but without the same addictive potential. The purpose of the current study was to examine the effects of three MTAs (nornicotine, anatabine, and anabasine) and nicotine on weight gain, body composition, chow intake, and physical activity. We hypothesized that the MTAs and nicotine would reduce weight gain through reductions in chow intake and increases in physical activity. To test this, male Sprague Dawley rats were housed in metabolic phenotyping chambers. Following acclimation to these chambers and to (subcutaneous (sc)) injections of saline, animals received daily injections (sc) of nornicotine, anabasine, anatabine, or nicotine for one week. Compared to saline-injected animals that gained body weight and body fat during the treatment phase, injections of nornicotine and anatabine prevented additional weight gain, alongside reductions in body fat. Rats receiving anabasine and nicotine gained body weight at a slower rate relative to rats receiving saline injections, and body fat remained unchanged. All compounds reduced the intake of chow pellets. Nornicotine and nicotine produced consistent increases in physical activity 6 h post-injection, whereas anabasine’s and anatabine’s effects on physical activity were more transient. These results show that short-term, daily administration of nornicotine, anabasine, and anatabine has positive effects on weight loss, through reductions in body fat and food intake and increases in physical activity. Together, these findings suggest that MTAs are worthy of further investigations as anti-obesity pharmacotherapies.
Sedation with Propofol plus Paracetamol in External Cephalic Version: An Observational Study

Although the influence of neuraxial anesthesia or sedation with remifentanil in external cephalic version (ECV) is widely known, ECV results using propofol have not been previously analyzed. This study aimed to evaluate ECV outcomes when propofol was used. An observational analysis of ECV was performed between 1 January 2018 and 31 December 2020. ECV was accomplished with tocolysis and propofol. One hundred and thirty-one pregnant women were recruited. The propofol mean dose was 156.1 mg (SD 6.1). A cephalic presentation was achieved in 61.1% (80/131) of the pregnant women. In total, 56.7% (38/67) of pregnant women with cephalic presentation at labor had a spontaneous delivery, 26.9% (18/67) had an operative delivery, and an intrapartum urgent cesarean section was performed in 16.4% (11/67). In total, 46 pregnant women (35.9%) were scheduled for an elective cesarean section due to non-cephalic presentation. The emergency cesarean section rate during the following 24 h was 10.7% (14/131). A major ECV complication arose in 15 cases (11.5%). ECV outcomes when propofol was used seems to be similar to those with other anesthetic adjunct, so sedation with propofol could be an adequate option for ECV. More studies are needed to compare its effectiveness with neuraxial techniques.
Bias-free estimation of information content in temporally sparse neuronal activity

Applying information theoretic measures to neuronal activity data enables the quantification of neuronal encoding quality. However, when the sample size is limited, a naïve estimation of the information content typically contains a systematic overestimation (upward bias), which may lead to misinterpretation of coding characteristics. This bias is exacerbated in Ca2+ imaging because of the temporal sparsity of elevated Ca2+ signals. Here, we introduce methods to correct for the bias in the naïve estimation of information content from limited sample sizes and temporally sparse neuronal activity. We demonstrate the higher accuracy of our methods over previous ones, when applied to Ca2+ imaging data recorded from the mouse hippocampus and primary visual cortex, as well as to simulated data with matching tuning properties and firing statistics. Our bias-correction methods allowed an accurate estimation of the information place cells carry about the animal’s position (spatial information) and uncovered the spatial resolution of hippocampal coding. Furthermore, using our methods, we found that cells with higher peak firing rates carry higher spatial information per spike and exposed differences between distinct hippocampal subfields in the long-term evolution of the spatial code. These results could be masked by the bias when applying the commonly used naïve calculation of information content. Thus, a bias-free estimation of information content can uncover otherwise overlooked properties of the neural code.
Functional Characterization of an In-Frame Deletion in the Basic Domain of the Retinal Transcription Factor ATOH7

Basic helix–loop–helix (bHLH) transcription factors are evolutionarily conserved and structurally similar proteins important in development. The temporospatial expression of atonal bHLH transcription factor 7 (ATOH7) directs the differentiation of retinal ganglion cells and mutations in the human gene lead to vitreoretinal and/or optic nerve abnormalities. Characterization of pathogenic ATOH7 mutations is needed to understand the functions of the conserved bHLH motif. The published ATOH7 in-frame deletion p.(Arg41_Arg48del) removes eight highly conserved amino acids in the basic domain. We functionally characterized the mutant protein by expressing V5-tagged ATOH7 constructs in human embryonic kidney 293T (HEK293T) cells for subsequent protein analyses, including Western blot, cycloheximide chase assays, Förster resonance energy transfer fluorescence lifetime imaging, enzyme-linked immunosorbent assays and dual-luciferase assays. Our results indicate that the in-frame deletion in the basic domain causes mislocalization of the protein, which can be rescued by a putative dimerization partner transcription factor 3 isoform E47 (E47), suggesting synergistic nuclear import. Furthermore, we observed (i) increased proteasomal degradation of the mutant protein, (ii) reduced protein heterodimerization, (iii) decreased DNA-binding and transcriptional activation of a reporter gene, as well as (iv) inhibited E47 activity. Altogether our observations suggest that the DNA-binding basic domain of ATOH7 has additional roles in regulating the nuclear import, dimerization, and protein stability.
Murine Beta-Amyloid (1–42) Oligomers Disrupt Endothelial Barrier Integrity and VEGFR Signaling via Activating Astrocytes to Release Deleterious Soluble Factors

Transgenic mouse models of Alzheimer’s disease (AD) overexpress mutations of the human amyloid protein precursor (APP) and presenilin-1 (PSEN1) genes, which are known causes of amyloid pathology in familial AD. However, animal models for studying AD in the context of aging and age-related co-morbidities, such as blood–brain barrier (BBB) disruptions, are lacking. More recently, aged and progeroid mouse models have been proposed as alternatives to study aging-related AD, but the toxicity of murine amyloid-beta protein (Aβ) is not well defined. In this study, we aimed to study the potential toxicity of murine Aβ on brain endothelial cells and astrocytes, which are important components of the BBB, using mouse brain endothelial cells (bEnd.3) and astrocytes (C8-D1A). Murine-soluble Aβ (1–42) oligomers (sAβO42) (10 µM) induced negligible injuries in an endothelial monolayer but induced significant barrier disruptions in a bEnd.3 and C8-D1A co-culture. Similar results of endothelial perturbation were observed in a bEnd.3 monolayer treated with astrocyte-conditioned medium (ACM) generated by astrocytes exposed to sAβO42 (ACM-sAβO42), while additional exogenous sAβO42 did not cause further damage. Western blot analysis showed that ACM-sAβO42 altered the basal activities of vascular endothelial growth factor receptor 2 (VEGFR2), eNOS, and the signaling of the MEK/ERK and Akt pathways in bEnd.3. Our results showed that murine sAβO42 was moderately toxic to an endothelial and astrocyte co-culture. These damaging effects on the endothelial barrier were induced by deleterious soluble factors released from astrocytes, which disrupted endothelial VEGFR2 signaling and perturbed cell survival and barrier stabilization.
Effects of Chemotherapy on Hematological Parameters and CD4+/CD8+ Ratio in Cats with Mediastinal Lymphoma and Seropositive to Feline Leukemia Virus

Simple Summary Mediastinal lymphoma is the most commonly diagnosed tumor in cats with feline leukemia virus infection (FeLV). The cyclophosphamide, vincristine, and prednisolone (COP) chemotherapeutic protocol is widely used and has achieved high complete-response (CR) rates with a long disease-free interval (DFI), and a long median survival time (MST), with low toxicity. The CD4+/CD8+ ratio is used to assess immunity in retroviral infected cats. This study was performed on 18 FeLV-infected cats with mediastinal lymphoma. The complete blood count, creatinine, alanine aminotransferase, and CD4+/CD8+ ratio were measured four times before treating with chemotherapy in the 1st, 2nd, 3rd, and 4th weeks. The white blood cell (WBC) counts, neutrophils, packed cell volume (PCV), and mean corpuscular volume (MCV) changed, while the CD4+/CD8+ ratio was not found to be significantly different. These results suggested that COP chemotherapy is safe as a treatment for FeLV-infected cats with mediastinal lymphoma. Abstract The objective of this study was to evaluate the effect of the COP chemotherapeutic protocol on hematological parameters, CD4+/CD8+ ratio, and the mortality of 18 client-owned FeLV-infected cats with mediastinal lymphoma. The complete blood count, creatinine, alanine aminotransferase, and CD4+/CD8+ ratio were measured four times before treating with chemotherapy in the 1st, 2nd, 3rd, and 4th weeks. The white blood cell (WBC) counts at the 1st week were significantly different from the 2nd, 3rd, and 4th inductions (p = 0.0075, p = <0.0001, and p = 0.0271, respectively). The neutrophils at the 1st week were significantly different from the 2nd and 3rd inductions (p = 0.0179, and p < 0.0001, respectively). The packed cell volume (PCV) at the 1st week was significantly differed from the 2nd, 3rd, and 4th induction times (p = 0.0029, p = 0.0006, and p = 0.0029, respectively. The mean corpuscular volume (MCV) at the 1st week was significantly different from the 4th week (p = 0.0145). We found that chemotherapy did not cause any significant change in the CD4+/CD8+ ratio (p-value 0.7407). The Kaplan–Meier curves showed the median survival time (MST) for the cats with a CD4+/CD8 ratio of less than 1 after the 1st week of chemotherapy was 134 days. This suggested that COP chemotherapy was a safe treatment for FeLV-infected cats with mediastinal lymphoma.
Experimental Investigations on Dry Sliding Wear Behavior of Kevlar and Natural Fiber-Reinforced Hybrid Composites through an RSM–GRA Hybrid Approach

The present work aimed to investigate the dry sliding wear behaviors of hybrid polymer matrix composites made up of Kevlar, bamboo, palm, and Aloe vera as reinforcement materials of varying stacking sequences, along with epoxy as the matrix material. Three combinations of composite laminates with different stacking sequences such as AB, BC, and CA were fabricated by a vacuum-assisted compression molding process. The influence of composite laminates fabricated through various stacking sequences and dry sliding wear test variables such as load, sliding distance, and sliding velocity on the specific wear rate and co-efficient of friction were investigated. Experiments were designed and statistical validation was performed through response surface methodology-based D-optimal design and analysis of variance. The optimization was performed using grey relational analysis (GRA) to identify the optimal parameters to enhance the wear resistance of hybrid polymer composites under dry sliding conditions. The optimal parameters, such as composite combinations of CA, a load of 5 N, a sliding velocity of 3 m/s, and a sliding distance of 1500 m, were obtained. Furthermore, the morphologies of worn-out surfaces were investigated using SEM analysis.
Decreasing Pasteurization Treatment Efficiency against Amoeba-Grown Legionella pneumophila—Recognized Public Health Risk Factor

Legionellae are gram-negative bacteria most commonly found in freshwater ecosystems and purpose-built water systems. In humans, the bacterium causes Legionnaires’ disease (LD) or a Pontiac fever. In this study, the different waters (drinking water, pool water, cooling towers) in which Legionella pneumophila has been isolated were studied to assess the possible risk of bacterial spreading in the population. The influence of physical and chemical parameters, and interactions with Acanthamoeba castellanii on L. pneumophila, were analyzed by Heterotrophic Plate Count, the Colony-forming units (CFU) methods, transmission electron microscopy (TEM), and Sequence-Based Typing (SBT) analysis. During the study period (2013–2019), a total of 1932 water samples were analyzed, with the average annual rate of Legionella-positive water samples of 8.9%, showing an increasing trend. The largest proportion of Legionella-positive samples was found in cooling towers and rehabilitation centers (33.9% and 33.3%, respectively). Among the isolates, L. pneumophila SGs 2–14 was the most commonly identified strain (76%). The survival of Legionella was enhanced in the samples with higher pH values, while higher electrical conductivity, nitrate, and free residual chlorine concentration significantly reduced the survival of Legionella. Our results show that growth in amoeba does not affect the allelic profile, phenotype, and morphology of the bacterium but environmental L. pneumophila becomes more resistant to pasteurization treatment.
Gut microbiota, angiotensin-converting enzyme, celiac disease, and risk of COVID-19 infection: a review

Celiac disease (CD) is an autoimmune disorder of the gastrointestinal tract in a genetically susceptible person. Gluten is the most crucial trigger factor for CD, and environmental factors such as microbiota and opportunistic infection risk its pathogenesis. Coronavirus disease 19 (COVID-19) spread rapidly and became a problem for healthcare systems worldwide. Little is known about the risk of severe COVID-19 and the role of dysbiosis among patients with CD. There is also a lack of knowledge about the effects of CD gut microbiota on COVID-19 infection. Therefore, the current review discusses the relationship between CD and risk factors such as microbiota for susceptibility to COVID-19.
Cerebrospinal Fluid Metabolome in Parkinson’s Disease and Multiple System Atrophy

Parkinson’s disease (PD) and multiple system atrophy (MSA) belong to the neurodegenerative group of synucleinopathies; differential diagnosis between PD and MSA is difficult, especially at early stages, owing to their clinical and biological similarities. Thus, there is a pressing need to identify metabolic biomarkers for these diseases. The metabolic profile of the cerebrospinal fluid (CSF) is reported to be altered in PD and MSA; however, the altered metabolites remain unclear. We created a single network with altered metabolites in PD and MSA based on the literature and assessed biological functions, including metabolic disorders of the nervous system, inflammation, concentration of ATP, and neurological disorder, through bioinformatics methods. Our in-silico prediction-based metabolic networks are consistent with Parkinsonism events. Although metabolomics approaches provide a more quantitative understanding of biochemical events underlying the symptoms of PD and MSA, limitations persist in covering molecules related to neurodegenerative disease pathways. Thus, omics data, such as proteomics and microRNA, help understand the altered metabolomes mechanism. In particular, integrated omics and machine learning approaches will be helpful to elucidate the pathological mechanisms of PD and MSA. This review discusses the altered metabolites between PD and MSA in the CSF and omics approaches to discover diagnostic biomarkers.