Miracle-dz/UniFAR-FTUs huggingface dataset:
Role of matrix metalloproteinases in multi-system inflammatory syndrome and acute COVID-19 in children

Introduction Multisystem Inflammatory Syndrome in children (MIS-C) is a serious inflammatory sequela of SARS-CoV2 infection. The pathogenesis of MIS-C is vague and matrix metalloproteinases (MMPs) may have an important role. Matrix metalloproteinases (MMPs) are known drivers of lung pathology in many diseases. Methods To elucidate the role of MMPs in pathogenesis of pediatric COVID-19, we examined their plasma levels in MIS-C and acute COVID-19 children and compared them to convalescent COVID-19 and children with other common tropical diseases (with overlapping clinical manifestations). Results Children with MIS-C had elevated levels of MMPs (P < 0.005 statistically significant) in comparison to acute COVID-19, other tropical diseases (Dengue fever, typhoid fever, and scrub typhus fever) and convalescent COVID-19 children. PCA and ROC analysis (sensitivity 84–100% and specificity 80–100%) showed that MMP-8, 12, 13 could help distinguish MIS-C from acute COVID-19 and other tropical diseases with high sensitivity and specificity. Among MIS-C children, elevated levels of MMPs were seen in children requiring intensive care unit admission as compared to children not needing intensive care. Similar findings were noted when children with severe/moderate COVID-19 were compared to children with mild COVID-19. Finally, MMP levels exhibited significant correlation with laboratory parameters, including lymphocyte counts, CRP, D-dimer, Ferritin and Sodium levels. Discussion Our findings suggest that MMPs play a pivotal role in the pathogenesis of MIS-C and COVID-19 in children and may help distinguish MIS-C from other conditions with overlapping clinical presentation.
The longitudinal association between possible new sarcopenia and the depression trajectory of individuals and their intimate partners

Background It is currently unknown whether the dynamic nature of depression affects the development of sarcopenia. Herein, this study aims to assess the association between possible new sarcopenia and the depression trajectory of individuals and their intimate partners through a 4-year longitudinal cohort study. Methods Our study included 784 pairs of individuals without possible sarcopenia and their spouses from the China Health and Retirement Longitudinal Study (CHARLS) 2011. All individuals and their spouses received three assessments of the Center for Epidemiologic Studies Depression 10-item (CESD-10) scale in 2011, 2013, and 2015. According to the diagnostic algorithm recommended by the Asian Working Group for Sarcopenia (AWGS) 2019, we evaluated the incidence of possible sarcopenia in individuals in 2015. Latent class analysis (LCA) was used to identify a longitudinal depression trajectory of individuals and their spouses during a 4-year follow-up. Subsequently, we assessed the relationship between possible sarcopenia and depression trajectory using three generalized additive models. Results In 2015, 24.87% (195/784) of individuals were diagnosed with possible sarcopenia. LCA identified five depression trajectories: a persistently high risk of depression in individuals and their spouses (reference; class 1 = 34 [4.3%]); a persistently low risk of depression in individuals and their spouses (class 2 = 526 [67.1%]); a high risk of depression in individuals and a low risk of depression in spouses (class 3 = 46 [5.9%]); a low risk of depression in individuals and a high risk of depression in spouses (class 4 = 116 [14.8%]); and a reduced risk of depression in individuals and their spouses (class 5 = 62 [7.9%]). The highest incidence of possible sarcopenia was shown in class 1, followed by classes 3 and 5. Classes 2 (adjusted relative risk (RR) = 0.44, 95% confidence interval (CI): 0.20–0.97) and 4 (adjusted RR = 0.40, 95%CI: 0.17–0.96) had a significantly lower incidence of possible sarcopenia than class 1. Subgroup analysis demonstrated that the incidence of possible sarcopenia in class 4 was obviously higher in women (38.89%) than in men (18.4%). Conclusions Our study indicates a persistently high risk of depression in individuals to develop possible sarcopenia. In addition, a persistently high risk of depression in intimate partners potentially increases the risk of possible new sarcopenia, especially in female individuals who are at low risk of depression.
Short-term effect of sacubitril/valsartan on endothelial dysfunction and arterial stiffness in patients with chronic heart failure

Heart failure (HF) is associated to endothelial dysfunction that promotes the increase of arterial stiffness thus augmenting myocardial damage. Sacubitril/Valsartan is used in the treatment of HF reduced ejection fraction (HFrEF) and has been proven effective in reducing cardiovascular disease (CVD) progression and all-cause mortality. The aim of this study was to evaluate the effect of Sacubitril/Valsartan on endothelial dysfunction, arterial stiffness, oxidative stress levels and platelets activation in patients with HFrEF, at baseline and after 6 months of treatment. We enrolled 100 Caucasian patients. Endothelial function was evaluated by the reactive hyperemia index (RHI) and arterial stiffness (AS) by the measurement of carotid-femoral pulse wave velocity (PWV), augmentation pressure (AP) and augmentation index (AI). At baseline, among enrolled outpatients, 43% showed a NYHA class II and 57% a NYHA class III. At 6 months, there was a significant improvement of several hemodynamic, clinical and metabolic parameters with a significant reduction in oxidative stress indices such as 8-isoprostane (p < 0.0001) and Nox-2 (p < 0.0001), platelets activity biomarkers such as sP-selectin (p < 0.0001) and Glycoprotein-VI (p < 0.0001), and inflammatory indices. Moreover, we observed a significant improvement in arterial stiffness parameters and in endothelial function indices. Our study demonstrated that 6 months treatment with Sacubitril/Valsartan, in patients with HFrEF, improves endothelial dysfunction and arterial stiffness, by reducing oxidative stress, platelet activation and inflammation circulating biomarkers, without adverse effects.
Warming offsets the benefits of elevated CO2 in water relations while amplifies elevated CO2-induced reduction in forage nutritional value in the C4 grass Megathyrsus maximus

Tropical grasslands are very important to global carbon and water cycles. C4 plants have increased heat tolerance and a CO2 concentrating mechanism that often reduces responses to elevated concentrations of CO2 ([CO2]). Despite the importance of tropical grasslands, there is a scarcity of studies that elucidate how managed tropical grasslands will be affected by elevated [CO2] and warming. In our study, we used a combination of a temperature-free air-controlled enhancement (T-FACE) and a free-air carbon dioxide enrichment (FACE) systems to increase canopy temperature and [CO2] under field conditions, respectively. We warmed a field-grown pasture dominated by the C4 tropical forage grass Megathyrsus maximus by 2°C above ambient under two levels of [CO2] (ambient (aC) and elevated (eC - 600 ppm) to investigate how these two factors isolated or combined regulate water relations through stomatal regulation, and how this combination affects PSII functioning, biochemistry, forage nutritive value, and digestibility. We demonstrated that the effects of warming negated the effects of eC in plant transpiration, water potential, proline content, and soil moisture conservation, resulting in warming canceling the eCO2-induced improvement in these parameters. Furthermore, there were additive effects between eC and warming for chlorophyll fluorescence parameters and aboveground nutritive value. Warming sharply intensified the eCO2-induced decrease in crude protein content and increases in forage fibrous fraction and lignin, resulting in a smaller forage digestibility under a warmer CO2-enriched atmosphere. Our results highlight the importance of multifactorial studies when investigating global change impacts on managed ecosystems and the potential consequences for the global carbon cycle like amplification in methane emissions by ruminants and feeding a positive climate feedback system.
Citrullinated glucose-regulated protein 78 is a candidate target for melanoma immunotherapy

Introduction Post translational modification of proteins plays a significant role in immune recognition. In particular the modification of arginine to citrulline which is mediated by PAD enzymes is increased during cellular stress (autophagy) which permits the presentation of modified epitopes upon MHC class II molecules for recognition by CD4 T cells. Citrullination also occurs in tumour cells as a result of continuous environmental stresses and increased autophagy. We have shown in animal models the efficient stimulation of citrullinated epitope specific CD4 T cells resulting in dramatic elimination/regression of tumours. The ER chaperone glucose-regulated protein 78 (GRP78) is known to also be required for stress-induced autophagy and is directly linked to autophagosome formation. GRP78 is known to be highly expressed by many tumour types. In this study we investigate the potential of targeting citrullinated GRP78 for cancer therapy. Methods A citrullinated GRP78 specific antibody was used to assess citrullinated GRP78 expression in murine and human tumour cells by flow cytometry. Five peptides were selected and used to vaccinate HLA transgenic mice and immune responses were characterised by ex vivo cytokine ELISpot assay. T cell repertoire in humans was assessed through proliferation assays and cytokine ELISpot assay. Citrullinated peptide was identified in murine B16 melanoma by mass spectrometry and the peptide vaccine was assessed for tumour therapy in a mouse melanoma model. Results We show the identification CD4 T cell responses to one citrullinated GRP78 epitope that are restricted through HLA DP*0401 and HLA-DR*0101 alleles. This peptide is detected by mass spectrometry in B16 melanoma grown in vivo and citrulline specific CD4 responses to two peptides spanning this epitope mediate efficient therapy of established B16 melanoma tumours in HHDII/DP4 (p<0.0001) transgenic mouse model. Finally, we demonstrate the existence of a repertoire of responses to the citrullinated GRP78 peptide in healthy individuals (p=0.0023) with 13/17 (76%) individuals showing a response to this peptide. Conclusion We propose that citrullinated GRP78 is a candidate tumour antigen and vaccination against citrullinated GRP78 may provide a promising tumour therapy approach.
A robust multiple heartbeats classification with weight-based loss based on convolutional neural network and bidirectional long short-term memory

Background: Analysis of electrocardiogram (ECG) provides a straightforward and non-invasive approach for cardiologists to diagnose and classify the nature and severity of variant cardiac diseases including cardiac arrhythmia. However, the interpretation and analysis of ECG are highly working-load demanding, and the subjective may lead to false diagnoses and heartbeats classification. In recent years, many deep learning works showed an excellent role in accurate heartbeats classification. However, the imbalance of heartbeat classes is universal in most of the available ECG databases since abnormal heartbeats are always relatively rare in real life scenarios. In addition, many existing approaches achieved prominent results by removing noise and extracting features in data preprocessing, which relies heavily on powerful computers. It is a pressing need to develop efficient and automatic light weighted algorithms for accurate heartbeats classification that can be used in portable ECG sensors. Objective: This study aims at developing a robust and efficient deep learning method, which can be embedded into wearable or portable ECG monitors for classifying heartbeats. Methods: We proposed a novel and light weighted deep learning architecture with weight-based loss based on a convolutional neural network (CNN) and bidirectional long short-term memory (Bi-LSTM) that can automatically identify five types of ECG heartbeats according to the AAMI EC57 standard. It was also true that the raw ECG signals were simply segmented without noise removal and other feature extraction processing. Moreover, to tackle the challenge of classification bias due to imbalanced ECG datasets for different types of arrhythmias, we introduced a weight-based loss function to reduce the influence of over-weighted categories in the ECG dataset. For avoiding the influence of the division of validation dataset, k-fold method was adopted to improve the reliability of the model. Results: The proposed algorithm is trained and tested on MIT-BIH Arrhythmia Database, and achieves an average of 99.33% accuracy, 93.67% sensitivity, 99.18% specificity, 89.85% positive prediction, and 91.65% F1 score.
Cardiovascular outcomes in patients treated with sodium-glucose transport protein 2 inhibitors, a network meta-analysis of randomized trials

Background Gliflozins altering the sodium-glucose transport protein 2 (SGLT2) in the nephron, represent alone or in combination a promising treatment option for patients with type II diabetes mellitus. In addition to glucose control, these drugs provide benefits including reduced risk of long-term cardiovascular (CV) and renal complications. Several trials evaluated gliflozins in patients with various degrees of cardiac dysfunction with heterogeneous results. Objectives We aimed to perform a comprehensive analysis of the effect of gliflozins on CV outcomes. Methods Systematic searches of electronic databases were conducted until September 2022. Multiple treatment network meta-analysis was performed in R. Random-effects model was used to combine risk estimates across trials calculating risk ratio (RR) with 95% confidence intervals as summary statistics. The primary endpoint of interest was the rate of heart failure-related hospitalization (HHF) and the composite of HHF with CV mortality (HHF + CVD). Secondary outcomes included major adverse cardiac events (MACE), CV- and overall mortality, myocardial infarction (MI), and stroke. Results Twenty-nine studies randomizing 88,418 patients were identified. Gliflozins reduced the risk of HHF (RR: 0.72 [0.69; 0.76]) and HHF + CVD (RR: 0.78 [0.75; 0.82]). The risk of MACE and its component also improved significantly except for stroke. The network analyses did not explore major differences among the individual substances. The only exception was sotagliflozin which appeared to be more effective regarding HHF + CVD, stroke, and MI compared to ertugliflozin, in HHF + CVD and stroke compared to dapagliflozin, and in stroke endpoint compared to empagliflozin. Conclusion Our meta-analysis supports a group effect of gliflozins beneficial in a wide spectrum of patients with a risk of heart failure (HF) development. In addition to the improvement of HF-related outcomes, the risk of major adverse events is also reduced with SGLT2 inhibition. Systematic review registration [www.ClinicalTrials. gov], identifier [CRD42022358078].
Bidirectional association between functional disability and multimorbidity among middle-aged and older adults in Thailand

Objectives The purpose of this study was to assess the bidirectional association between multimorbidity (MM) and functional disability among middle-aged and older adults in a longitudinal study in Thailand. Methods We analyzed longitudinal data of participants aged 45 years and older from two consecutive waves (in 2015 and 2017) of the Health, Aging, and Retirement in Thailand (HART). Functional disability was assessed with a 4-item activity of daily living (ADL) scale. Logistic regression analysis was conducted to assess the association between baseline functional disability and incident MM (≥2), and baseline morbidity and incident functional disability. Results The results indicate that a total of 1,716 individuals without morbidity at baseline and 3,529 without functional disability at baseline were included. At follow-up, 16.7 and 20.0% of functional disability cases and 7.1 and 3.6% of nonfunctional disability cases developed 2 morbidities and 3 or more morbidities, respectively, and 6.6% of MM cases and 4.0% of non-MM cases developed a functional disability. In the final logistic regression model adjusted for education, income, age, marital status, sex, smoking tobacco, body mass index (BMI), alcohol use, physical activity, and social engagement, functional disability at baseline was positively associated with incident MM (≥2) (adjusted odds ratio [aOR]: 2.58, 95% CI: 1.42–4.72), and MM (≥3) at baseline was positively associated with incident functional disability (aOR: 1.97, 95% CI: 1.13–3.43). Conclusion Multimorbidity and functional disability were bidirectionally associated.
With a little help from our pediatrician: An intervention to promote mathematics-related home activities through regular well-child visits

Introduction Children’s involvement in mathematics-related activities in the home environment is associated with the development of their early numeracy over the preschool years. Intervention studies to promote parents’ awareness and provision of mathematics-related home activities are however scant. In this study we developed and tested the effectiveness of a non-intensive intervention program delivered by community pediatricians to promote mathematics-related activities in the home environment. Methods Parents of 204 Italian children were invited to report on the frequency of mathematics-related home activities when children attended the first preschool year (3 years, 8 months of age on average) and, subsequently, the third preschool year (5 years, 6 months of age on average). At both waves, children were also assessed on their early numeracy. In occasion of the routine well-child visit at age 5, parents who were randomly allocated to the intervention condition (vs. a business-as-usual control condition) received guidance on age-appropriate home mathematics-related practices to sustain children’s numerical development. Results Results revealed that parents in the intervention group improved their provision of home mathematics-related activities at the post-intervention assessment (relative to baseline) to a greater extent than parents in the control condition. No effect was observed on children’s early numeracy. Discussion Overall, results are promising in suggesting that community pediatricians may be a resource to promote home mathematics-related activities though non-intensive low-cost interventions.
Cell type-specific changes in Wnt signaling and neuronal differentiation in the developing mouse cortex after prenatal alcohol exposure during neurogenesis

Fetal Alcohol Spectrum Disorder (FASD) encompasses an array of effects of prenatal alcohol exposure (PAE), including physical abnormalities and cognitive and behavioral deficits. Disruptions of cortical development have been implicated in multiple PAE studies, with deficits including decreased progenitor proliferation, disrupted neuronal differentiation, aberrant radial migration of pyramidal neurons, and decreased cortical thickness. While several mechanisms of alcohol teratogenicity have been explored, how specific cell types in the brain at different developmental time points may be differentially affected by PAE is still poorly understood. In this study, we used single nucleus RNA sequencing (snRNAseq) to investigate whether moderate PAE from neurulation through peak cortical neurogenesis induces cell type-specific transcriptomic changes in the developing murine brain. Cluster analysis identified 25 neuronal cell types, including subtypes of radial glial cells (RGCs), intermediate progenitor cells (IPCs), projection neurons, and interneurons. Only Wnt-expressing cortical hem RGCs showed a significant decrease in the percentage of cells after PAE, with no cell types showing PAE-induced apoptosis as measured by caspase expression. Cell cycle analysis revealed only a subtype of RGCs expressing the downstream Wnt signaling transcription factor Tcf7l2 had a decreased percentage of cells in the G2/M phase of the cell cycle, suggesting decreased proliferation in this RGC subtype and further implicating disrupted Wnt signaling after PAE at this early developmental timepoint. An increased pseudotime score in IPC and projection neuron cell types indicated that PAE led to increased or premature differentiation of these cells. Biological processes affected by PAE included the upregulation of pathways related to synaptic activity and neuronal differentiation and downregulation of pathways related to chromosome structure and the cell cycle. Several cell types showed a decrease in Wnt signaling pathways, with several genes related to Wnt signaling altered by PAE in multiple cell types. As Wnt has been shown to promote proliferation and inhibit differentiation at earlier stages in development, the downregulation of Wnt signaling may have resulted in premature neuronal maturation of projection neurons and their intermediate progenitors. Overall, these findings provide further insight into the cell type-specific effects of PAE during early corticogenesis.
Environmental DNA: State-of-the-art of its application for fisheries assessment in marine environments

Fisheries management involves a broad and complex set of tasks that are necessary to prevent overfishing and to help the recovery of overfished stock. Monitoring fishing activities based on two main sources, landings data and scientific surveys, is a challenging task. Fisheries collection data is often limited, which compromises the accuracy of the results obtained. Therefore, several emerging applications of molecular methods have the potential to provide unique understanding of ecological processes in marine environments and to build stronger empirical underpinnings for the Ecosystem-Based Fisheries Management. Environmental DNA (eDNA) is a complex mixture of genetic material shed by those organisms that inhabit a given environment, whereby DNA is extracted from an environmental sample without accessing the target organism. eDNA studies can be categorized into two main approaches, i) eDNA metabarcoding or semi-targeted (community) approaches and ii) species-specific or targeted approaches (single). Although both categories are often discussed, they differ drastically in their methodology, interpretations and accuracy. Both approaches involve a series of steps that include eDNA capture, preservation, extraction and amplification. This detection will depend on the affinity to the targeted taxa sequences and completeness and accuracy of DNA reference collection databases. The eDNA method applied in marine environments are probably the most challenging aquatic environments for applying this technique. This is because of the extreme relationship between water-volume to biomass, dynamics and the physical and chemical properties of seawater that affect dispersion, dilution and preservation. Here, we review the present application of this novel method in fishery assessment in marine environments. To date, many studies suggest that this method offers the potential to revolutionize fisheries monitoring, which will contribute to improving the range of tasks involved in fisheries management. The compelling conclusion is that the methodological steps including in eDNA surveys should be standardized and that research efforts should focus on developing appropriately validated tests to address environmental and sampling factors that may affect eDNA detection in marine environments in order to draw reliable conclusions. This bioassessment tool can assist fisheries professionals in achieve their research, management, and conservation objectives, but not as a replacement for time-proven assessment methods.