Miracle-dz/UniFAR-FTUs huggingface dataset:
Nonparametric estimation in an illness‐death model with component‐wise censoring

In disease settings where study participants are at risk for death and a serious nonfatal event, composite endpoints defined as the time until the earliest of death or the nonfatal event are often used as the primary endpoint in clinical trials. In practice, if the nonfatal event can only be detected at clinic visits and the death time is known exactly, the resulting composite endpoint exhibits “component‐wise censoring. ” The standard method used to estimate event‐free survival in this setting fails to account for component‐wise censoring. We apply a kernel smoothing method previously proposed for a marker process in a novel way to produce a nonparametric estimator for event‐free survival that accounts for component‐wise censoring. The key insight that allows us to apply this kernel method is thinking of nonfatal event status as an intermittently observed binary time‐dependent variable rather than thinking of time to the nonfatal event as interval‐censored. We also propose estimators for the probability in state and restricted mean time in state for reversible or irreversible illness‐death models, under component‐wise censoring, and derive their large‐sample properties. We perform a simulation study to compare our method to existing multistate survival methods and apply the methods on data from a large randomized trial studying a multifactor intervention for reducing morbidity and mortality among men at above average risk of coronary heart disease.
Comprehensive Transcriptome Analysis of mRNA Expression Patterns of Early Embryo Development in Goat under Hypoxic and Normoxic Conditions

Simple Summary Oxygen plays a vital role in the development of early embryos, no matter whether it is too high or low, it will adversely affect the early embryo development, but the mechanisms involved in these effects are still unclear. RNA-seq was performed to compare 8-cell-stage and blastocyst-stage goat embryos under hypoxic and normoxic conditions, the mRNA expression mechanisms of 8-cell- and blastocyst-stage embryos were systematically analyzed under hypoxic and normoxic conditions. Functional enrichment analysis indicated that these differentially expressed genes (DEGs) were mainly related to biological processes and function regulation. In conclusion, we can infer that oxidative stress regulates early embryo development by affecting the expression of zygotic genes and transcription factors, and those stress genes play a potential role in adaptation to normoxic environments in goat embryos. Abstract It has been reported that hypoxic environments were more suitable for the in vitro development of mammalian embryos, but the underlying mechanisms were still unclear. In the present study, RNA-seq was performed to compare 8-cell-stage and blastocyst-stage goat embryos under hypoxic and normoxic conditions; zygotes were checked at 72 and 168 h to 8-cell stage (L8C) and blastocyst stage (LM) in hypoxic conditions and 8-cell stage (H8C) and blastocyst stage (HM) in normoxic conditions. In the H8C and L8C groups, 399 DEGs were identified, including 348 up- and 51 down-regulated DEGs. In the HM and LM groups, 1710 DEGs were identified, including 1516 up- and 194 down-regulated DEGs. The expression levels of zygotic genes, transcription factors, and maternal genes, such as WEE2, GDF9, HSP70.1, BTG4, and UBE2S showed significant changes. Functional enrichment analysis indicated that these DEGs were mainly related to biological processes and function regulation. In addition, combined with the pathway–gene interaction network and protein–protein interaction network, twenty-two of the hub genes were identified and they are mainly involved in energy metabolism, immune stress response, cell cycle, receptor binding, and signal transduction pathways. The present study provides comprehensive insights into the effects of oxidative stress on early embryo development in goats.
Artemisia abrotanum L. (Southern Wormwood)—History, Current Knowledge on the Chemistry, Biological Activity, Traditional Use and Possible New Pharmaceutical and Cosmetological Applications

Artemisia abrotanum L. (southern wormwood) is a plant species with an important position in the history of European and Asian medicine. It is a species famous as a medicinal plant in Central Asia, Asia Minor, and in South-East and Central Europe. The raw materials obtained from this species are Abrotani herba and Abrotani folium. In the traditional European medicine, they have been used successfully most of all in liver and biliary tract diseases, in parasitic diseases in children and as antipyretic medication. In the official European medicine, this plant species is recommended by the French Pharmacopoeia for use in homeopathy. In many European countries, it is used traditionally in allopathy. The latest studies on the biological activity of extracts from the aboveground parts of the plant and/or the leaves, and/or the essential oil have provided evidence of other possible applications related to their antibacterial, antifungal, antioxidant, anticancer, and antiallergic properties. The latest studies have also focused on the repellent activity of the essential oil of this species and the possibility to use it in the prevention of diseases in which insects are the vectors. The main substances obtained from the plant that are responsible for this activity are: the essential oil, coumarins, phenolic acids, and flavonoids. Some of the latest investigations emphasize the large differences in the composition of the essential oil, determined by the geographical (climatic) origin of the plant. A. abrotanum is recommended by the European Cosmetic Ingredients Database (CosIng) as a source of valuable cosmetic ingredients. Additionally, the leaves of this species possess a well-established position in the food industry. This plant species is also the object of biotechnological studies.
Back to the Origins: Background and Perspectives of Grapevine Domestication

Domestication is a process of selection driven by humans, transforming wild progenitors into domesticated crops. The grapevine (Vitis vinifera L.), besides being one of the most extensively cultivated fruit trees in the world, is also a fascinating subject for evolutionary studies. The domestication process started in the Near East and the varieties obtained were successively spread and cultivated in different areas. Whether the domestication occurred only once, or whether successive domestication events occurred independently, is a highly debated mystery. Moreover, introgression events, breeding and intense trade in the Mediterranean basin have followed, in the last thousands of years, obfuscating the genetic relationships. Although a succession of studies has been carried out to explore grapevine origin and different evolution models are proposed, an overview of the topic remains pending. We review here the findings obtained in the main phylogenetic and genomic studies proposed in the last two decades, to clarify the fundamental questions regarding where, when and how many times grapevine domestication took place. Finally, we argue that the realization of the pan-genome of grapes could be a useful resource to discover and track the changes which have occurred in the genomes and to improve our understanding about the domestication.
Food Industry By-Products as Raw Materials in the Production of Value-Added Corn Snack Products

The addition of brewer’s spent grain (BSG), sugar beet pulp (SBP) and apple pomace (AP), on the nutritional properties of directly expanded snack products based on corn grits was investigated. Snack products were produced in a laboratory single screw extruder with the addition of 5, 10 and 15% d. m. of these by-products in corn grits. Chemical composition, total phenolic content, antioxidant activity, dietary fiber, resistant starch, starch damage and pasting properties of the mixtures and extruded samples were determined. Extrusion process and by-product additions had a significant effect on the proximate chemical composition. All three by-products increased contents of both soluble and insoluble dietary fiber, while the extrusion caused a reduction of insoluble fiber and increase of soluble fiber. After the extrusion process starch damage and antioxidant activity increased, while resistant starch content and total polyphenol content decreased. According to obtained results, it can be concluded that the investigated by-products can be used in the production of nutritionally more valuable corn snacks.
Dietary Modulation of Bacteriophages as an Additional Player in Inflammation and Cancer

Simple Summary The role and function of bacteriophages (phages) in the intestine, its health and microbial homeostasis has been underestimated so far. This interdisciplinary review highlights the effect of dietary compounds on phages and puts this into perspective with putative contributions of phages to gastrointestinal diseases, specifically inflammation, infection, and cancer. The review discusses novel fields of opportunities in this context. These include, but are not limited to, perspectives how a better understanding of modulating the activity of specific phages by particular nutritional components may contribute to reorganizing the microbial network, thus supporting in the combat, or even prevention, of inflammation or even cancer in the gut. Abstract Natural compounds such as essential oils and tea have been used successfully in naturopathy and folk medicine for hundreds of years. Current research is unveiling the molecular role of their antibacterial, anti-inflammatory, and anticancer properties. Nevertheless, the effect of these compounds on bacteriophages is still poorly understood. The application of bacteriophages against bacteria has gained a particular interest in recent years due to, e.g., the constant rise of antimicrobial resistance to antibiotics, or an increasing awareness of different types of microbiota and their potential contribution to gastrointestinal diseases, including inflammatory and malignant conditions. Thus, a better knowledge of how dietary products can affect bacteriophages and, in turn, the whole gut microbiome can help maintain healthy homeostasis, reducing the risk of developing diseases such as diverse types of gastroenteritis, inflammatory bowel disease, or even cancer. The present review summarizes the effect of dietary compounds on the physiology of bacteriophages. In a majority of works, the substance class of polyphenols showed a particular activity against bacteriophages, and the primary mechanism of action involved structural damage of the capsid, inhibiting bacteriophage activity and infectivity. Some further dietary compounds such as caffeine, salt or oregano have been shown to induce or suppress prophages, whereas others, such as the natural sweeter stevia, promoted species-specific phage responses. A better understanding of how dietary compounds could selectively, and specifically, modulate the activity of individual phages opens the possibility to reorganize the microbial network as an additional strategy to support in the combat, or in prevention, of gastrointestinal diseases, including inflammation and cancer.
Zero Echo Time 17O-MRI Reveals Decreased Cerebral Metabolic Rate of Oxygen Consumption in a Murine Model of Amyloidosis

The cerebral metabolic rate of oxygen consumption (CMRO2) is a key metric to investigate the mechanisms involved in neurodegeneration in animal models and evaluate potential new therapies. CMRO2 can be measured by direct 17O magnetic resonance imaging (17O-MRI) of H217O signal changes during inhalation of 17O-labeled oxygen gas. In this study, we built a simple gas distribution system and used 3D zero echo time (ZTE-)MRI at 11.7 T to measure CMRO2 in the APPswe/PS1dE9 mouse model of amyloidosis. We found that CMRO2 was significantly lower in the APPswe/PS1dE9 brain than in wild-type at 12–14 months. We also estimated cerebral blood flow (CBF) from the post-inhalation washout curve and found no difference between groups. These results suggest that the lower CMRO2 observed in APPswe/PS1dE9 is likely due to metabolism impairment rather than to reduced blood flow. Analysis of the 17O-MRI data using different quantification models (linear and 3-phase model) showed that the choice of the model does not affect group comparison results. However, the simplified linear model significantly underestimated the absolute CMRO2 values compared to a 3-phase model. This may become of importance when combining several metabolic fluxes measurements to study neuro-metabolic coupling.
Survey-Based Analysis of Current Trends for Prescribing Gastrointestinal Protectants among Small-Animal General Practitioners in Portugal

In both human and veterinary healthcare, gastrointestinal protectants (GIPs) are considered a staple of clinical practice in that they are prescribed by general practitioners (GPs) and specialists alike. Concerning GIP use, overprescription of proton pump inhibitors (PPIs) has become a growing concern among human healthcare providers. This trend has also been documented within veterinary practice, prompting the American College of Veterinary Internal Medicine (ACVIM) to publish a consensus statement in 2018 concerning evidence-based indications for GIP use. This observational cross-sectional study evaluated self-reported prescribing protocols among Portuguese GPs to determine whether there is adherence to the consensus guidelines. Respondents were Portuguese GPs recruited by social media posts in veterinarian online forums. Data were collected from 124 respondents concerning their GIPs of choice and their rationales for prescribing them. Data were mined for prescription patterns and protocols. Among GIPs, PPIs were prescribed more often. Rationales for use included gastrointestinal ulceration and erosion (GUE), prophylactic management of nonerosive gastritis, pancreatitis, reflux esophagitis, and steroid-induced ulceration. Once-daily administration of PPIs was the most frequent dosing regime among respondents. Ninety-six percent of PPI prescribers advocated that the drug be administered either shortly before or at mealtime. Forty-nine percent of respondents supported long-term use of PPIs. Fifty-nine percent of respondents acknowledged discontinuing PPIs abruptly. This study supports that Portuguese GPs commonly prescribe GIPs in accordance with ACVIM recommendations to medically manage GUE. However, misuse of GIPs does occur, and they have been prescribed where their therapeutic value is debatable. Educational strategies should target GPs in an effort to reduce GIP misuse.
Active Transportation to School. Utopia or a Strategy for a Healthy Life in Adolescence

The way adolescents travel to school can be an important contribution to achieving their daily physical activity recommendations. The main objective of this research is to know which variables are associated with the mode of transportation used to and from school by Portuguese adolescents. The 2018 Health Behaviour in School-aged Children questionnaire was applied to 5695 adolescents with an average age of 15.5 (SD ± 1.8), 53.9% of whom were female. The associations were studied by applying χ2 tests and multivariate logistic regression models. In this study, 36.5% of the participants reported walking or cycling to school. Active transportation to school is associated with age (OR = 1.3; p < 0.05), sufficient physical activity (OR = 1.2; p < 0.05), adequate number of hours of sleep (OR = 1.2; p < 0.05), perception of happiness (OR = 1.2; p < 0.05) and living near the school (OR = 2.4; p < 0.05). The results revealed that adolescents’ choice to travel to/from school using an active mode of transportation increased with age, physical activity, hours of sleep, perception of happiness, and living near the school.
Role of Tuber Developmental Processes in Response of Potato to High Temperature and Elevated CO2

Potato is adapted to cool environments, and there is concern that its performance may be diminished considerably due to global warming and more frequent episodes of heat stress. Our objectives were to determine the response of potato plants to elevated CO2 (700 μmol/mol) and high temperature (35/25 °C) at tuber initiation and tuber bulking, and to elucidate effects on sink developmental processes. Potato plants were grown in controlled environments with treatments at: Tuber initiation (TI), during the first two weeks after initiating short-day photoperiods, and Tuber bulking (TB). At TI, and 25 °C, elevated CO2 increased tuber growth rate, while leaves and stems were not affected. Whole-plant dry matter accumulation rate, was inhibited by high temperature about twice as much at TI than at TB. Elevated CO2 partially ameliorated high temperature inhibition of sink organs. At TI, with 25 °C, elevated CO2 primarily affected tuber cell proliferation. In contrast, tuber cell volume and endoreduplication were unaffected. These findings indicate that the TI stage and cell division is particularly responsive to elevated CO2 and high temperature stress, supporting the view that attention should be paid to the timing of high-temperature stress episodes with respect to this stage.
Perspectives of compounding pharmacists on alcohol-based hand sanitizer production and utilization for COVID-19 prevention in Addis Ababa, Ethiopia: A descriptive phenomenology study

Background Globally, the safety of patients and healthcare providers is at risk due to health care-associated infections (HCAIs). World Health Organization and the Centers for Disease Control and Prevention recommend using alcohol-based hand rub (ABHR) for hand hygiene in healthcare settings to prevent HCAIs. Irrational use of ABHR will have undesirable consequences including wastage of products, exposure of healthcare providers to infections and emergence of microbial resistance to the alcohol in hand sanitizers. This study aimed to explore the perspective and experiences of compounding pharmacists on production and utilization of ABHR solution for coronavirus disease in 2019 (COVID-19) prevention in public hospitals of Addis Ababa, Ethiopia. Methods A descriptive qualitative study using in-depth interview of 13 key-informants serving as compounding pharmacists in public hospitals of Addis Ababa, Ethiopia, was conducted. The study participants were identified and selected by purposive sampling. All transcribed interviews were subjected to thematic analysis and transcripts were analyzed manually. Findings The compounding pharmacists in this study had a mean age of 30.6 (±3.1) years and nine of the thirteen participants were men. Ten participants believed that the compounding practice in their respective sites followed the principles of good compounding practice. More than half of the participants did not believe that ABHR products were used rationally in health facilities. They argued that users did not have enough awareness when and how to use sanitizers. Most of the interviewees reported that compounding personnel had no formal training on ABHR solution production. Study participants suggested incentive mechanisms and reimbursements for experts involved in the compounding of ABHR solutions. Conclusion Three of the compounding pharmacists indicated that ABHR production in their setting lack compliance to good compounding practice due to inadequate compounding room, quality control tests, manpower and equipment. Despite this, most study participants preferred the in-house ABHR products than the commercially available ones. Thus, training, regular monitoring and follow-up of the hospital compounding services can further build staff confidence.
Mental Health and Wellbeing at Schools: Health Promotion in Primary Schools with the Use of Digital Methods

Mental health disorders among primary school children remain a crucial issue. Early health promotion interventions can positively affect and prevent the onset of mental disorders. Promising digital mental health methods have been implemented for adolescents and youths with scarce evidence among younger ages. Therefore, the aim of the current systematic review was to identify health promotion interventions on mental health and wellbeing, with the use of digital methods, delivered in primary school settings. Six digital interventions have been identified, three of which were targeting teachers and the others students. Regardless of the limited number of studies, the effectiveness of the web-based interventions upon teachers’ knowledge and attitudes and the positive impact on children’s behavioral improvements has been documented. The lack of adequate evidence highlights the need for further research in the field. The current review provides information for professionals working in primary schools useful for the design and implementation of effective mental health and wellbeing interventions.
Effect of Soluble Adenylyl Cyclase (ADCY10) Inhibitors on the LH-Stimulated cAMP Synthesis in Mltc-1 Leydig Cell Line

In contrast to all transmembrane adenylyl cyclases except ADCY9, the cytosolic soluble adenylyl cyclase (ADCY10) is insensitive to forskolin stimulation and is uniquely modulated by calcium and bicarbonate ions. In the present paper, we focus on ADCY10 localization and a kinetic analysis of intracellular cAMP accumulation in response to human LH in the absence or presence of four different ADCY10 inhibitors (KH7, LRE1, 2-CE and 4-CE) in MTLC-1 cells. ADCY10 was immuno-detected in the cytoplasm of MLTC-1 cells and all four inhibitors were found to inhibit LH-stimulated cAMP accumulation and progesterone level in MLTC-1 and testosterone level primary Leydig cells. Interestingly, similar inhibitions were also evidenced in mouse testicular Leydig cells. In contrast, the tmAC-specific inhibitors ddAdo3′ and ddAdo5′, even at high concentration, exerted weak or no inhibition on cAMP accumulation, suggesting an important role of ADCY10 relative to tmACs in the MLTC-1 response to LH. The strong synergistic effect of HCO3− under LH stimulation further supports the involvement of ADCY10 in the response to LH.