Miracle-dz/UniFAR-FTUs huggingface dataset:
First-line pembrolizumab plus chemotherapy versus chemotherapy in advanced esophageal cancer: Longer-term efficacy, safety, and quality-of-life results from the phase 3 KEYNOTE-590 study.

241 Background: At interim analysis of the phase 3, randomized, double-blind KEYNOTE-590 (NCT03189719) study, 1L pembrolizumab (pembro) + chemotherapy (chemo) vs chemo alone provided superior OS, PFS, and ORR with a manageable safety profile in patients (pts) with untreated, advanced/unresectable or metastatic adenocarcinoma or esophageal squamous cell carcinoma (ESCC) or Siewert type 1 esophagogastric junction adenocarcinoma (EGJ). We report efficacy, safety, and health-related quality of life (HRQoL) results with an additional 12 months (mo) of follow-up. Methods: 749 eligible pts were randomized 1:1 to pembro 200 mg or placebo Q3W for up to 2 yr + chemo. Randomization was stratified by geographic region, histology, and performance status. Treatment continued until progression, unacceptable toxicity, or withdrawal, or 2 yr. No crossover was permitted. Primary endpoints were OS in pts with ESCC PD-L1 combined positive score (CPS) ≥10 tumors, and OS and PFS (RECIST v1.1; by INV) in ESCC, PD-L1 CPS ≥10, and all pts. Secondary endpoints included ORR, DOR, safety, and HRQoL. HRQol was assessed in 711 treated pts with ≥1 HRQoL assessment (356 pembro + chemo; 355 chemo). Data cutoff was July 9, 2021. Results: At data cutoff, median follow-up (randomization to data cutoff) was 34.8 mo. Median OS was longer with pembro + chemo vs chemo in pts with ESCC CPS ≥10 (HR 0.59; 95% CI, 0.45-0.76), ESCC (HR 0.73; 95% CI, 0.61-0.88), CPS ≥10 (HR 0.64; 95% CI, 0.51-0.80), and all pts (HR 0.73, 95% CI, 0.63-0.86). In pts with adenocarcinoma OS HR was 0.73 (95% CI, 0.55-0.99). The 24-mo OS rate in all pts was 26.3% vs 16.1%. Median PFS was longer with pembro + chemo vs chemo in ESCC (HR 0.65; 95% CI, 0.54-0.78), CPS ≥10 (HR 0.51; 95% CI, 0.41-0.65), and all pts (HR 0.64; 95% CI, 0.55-0.75). The 24-mo PFS rate in all pts was 11.6% vs 3.3%. Confirmed ORR was 45.0% (25 CR [6.7%]) vs 29.3% (9 CR [2.4%]), with median DOR of 8.3 vs 6.0 mo. Approximately 20% vs 6% of pts had response duration ≥24 months. Grade 3-5 drug-related AE rates were 72% vs 68%. Discontinuation rates from drug-related AEs were 21% vs 12%. There was no significant difference in least square mean (LSM) change from baseline to wk 18 between arms in EORTC QLQ-C30 global health status/quality-of-life (LSM difference -0.10; 95% CI, -3.40-3.20). LSM change from baseline to wk 18 was better with pembro + chemo vs chemo for QLQ-OES 18 pain (-2.94; 95% CI, -5.86 to -0.02) and dysphagia (-5.54; 95% CI, -10.92 to -0.16). Conclusions: With an additional 12 months of follow-up, pembro + chemo continued to provide significant and clinically meaningful improvement in OS, PFS, and ORR vs chemo with a manageable safety profile, and stable quality-of-life for pts with untreated, advanced esophageal and EGJ cancer. These data continue to support 1L pembro + chemo as a new standard of care in these patients. Clinical trial information: NCT03189719.
The Age-Specific Features and Clinical Significance of NRF2 and MAPK10 Expression in HCC Patients

Background Nuclear factor (erythroid-derived 2)-like 2 (NRF2) functions decline with age; however, cancer cells can hijack its pathways to ensure survival and aggressiveness. Yet, the role of NRF2 in hepatocellular carcinoma (HCC) is rarely investigated in an age-specific manner. This study investigates the expression of NRF2 and its activator (MAPK10) in different age groups of HCC patients, in addition to the age-specific features of NRF2 and MAPK10 interaction and their clinical significance. Methods Tumor and near-tumor tissue samples of 181 HCC patients were used to complete a protein expression analysis of NRF2 and MAPK10. Patients’ survival and clinical data were collected for clinical analysis. Global databases (TCGA, ICGC) were used to collect MAPK10 genetic mutation and mRNA expression data in patients with HCC, colorectal, stomach, and pancreatic cancers. Results Our findings revealed an increase in NRF2 protein expression but only in younger HCC patients, along with a decline in MAPK10 ability to activate NRF2 in older patients. We also found an increased MAPK10 genetic mutation rate and decreased mRNA expression in older patients. Low MAPK10 and NRF2 expression levels were associated with shorter survival and poorer prognosis due to positive correlation with microvascular invasion, tumor thrombus, elevated AFP levels, and larger tumor size. Conclusion NRF2 expression and oxidative stress mechanism in HCC patients are influenced by age. This magnifies the need to consider patients’ age in treatment strategies and guidelines and re-evaluates the application of studies’ age-standardized findings in older patients who are usually excluded from relevant research.
Risk-Increasing and Risk-Reducing Factors for Violence: A Qualitative Study of Forensic Patients’ Perceptions

Abstract This study investigated forensic patients’ perceptions of relevant factors for violence risk, to facilitate an understanding of potential reasons for violence and the effect of risk management interventions. Semi-structured interviews with 13 forensic patients were analyzed with qualitative content analysis using an inductive approach. The sample of participants could identify an array of potentially relevant factors for their use of violence related to themselves, the external context, social and relational aspects, as well as situational factors. Most also actively strived to manage such risk. Considering patients’ perceptions could potentially add relevant perspectives and improve clinical and structured risk assessments.
Differences in Hygiene Habits among Children Aged 8 to 11 Years by Type of Schooling

Personal hygiene is one of the basic activities in the care of our body. Parents are responsible for their children’s hygiene to prevent infections and keep them healthy. However, children must acquire hygiene habits correctly and independently. This study examines the sociodemographic profile, hygiene habits and knowledge, and level of autonomy of children who are starting to perform their personal care autonomously to identify the areas in which their habits could be improved. A descriptive cross-sectional study was conducted concerning 125 children aged 8–11 years attending schools in northern Extremadura, Spain. The children were surveyed with the HICORIN® questionnaire and the resulting data were statistically processed with SPSS 22.0 (IBM, Armonk, NY, USA). The majority of participating children required help to perform personal hygiene activities. Children in preferential schooling (PS) require less help than children in mainstream schooling (MS) but have less knowledge about personal hygiene. Different habits were observed in the frequency and time of day for performing personal hygiene between groups (p-values < 0.005). In general, more than 80% of children aged 8 to 11 years are not autonomous in some aspect of their personal hygiene, and they are not all familiar with personal hygiene. Because of this, it is necessary to conduct theory and practical workshops with children who must acquire correct personal hygiene habits autonomously to prevent infection and promote health.
Sex change and reproductive output of the protandric shrimp Merguia rhizophorae (Rathbun, 1900) (Decapoda, Merguiidae)

ABSTRACT The aim of this study was to confirm the type of protandry adopted by M. rhizophorae and to describe the size at which sex change occurs in order to test predictions of sex allocation theory. The reproductive output also was investigated, based on fecundity and embryo volume. Specimens were collected cohabiting burrows built by mud shrimps Upogebia omissa in an estuary region in the northeast of Brazil. The body size (carapace length, CL) and sex of the shrimps were recorded. Observations were made developmental stages of the embryos, fecundity, and embryo volume. A total of 204 M. rhizophorae individuals was sampled, of which 170 (83.3%) male phase (MP) and 34 (16.7%) female phase (FP) individuals. The body size (mean ± SD) of the individuals in the MP was smaller than in the FP: 3.91 ± 0.78 and 6.18 ± 0.52 mm CL, respectively. The size at which 50% of the shrimps changed to FP (CL50) was 5.62 ± 0.01 mm CL. Reproductive output (fecundity and embryo volume) increased linearly with shrimp body size. An increase in embryo size during development and the loss of embryos during final stage of development were recorded. In this study, the behaviour exhibited by M. rhizophorae (share a burrow with another shrimp species) was recorded for the first time, expanding knowledge about the ecology of this semi-terrestrial shrimp. Our results indicate the adoption of strict protandric hermaphroditism by M. rhizophorae. Our study supports the prediction of sex allocation theory that sex ratio is significantly biased towards the first-sex in sequential hermaphrodites. We also found evidence of possible trade-offs between the size in which the sex change occurs and the reproductive strategy exhibited by M. rhizophorae.
Physicochemical Characterization of In Vitro LDL Glycation and Its Inhibition by Ellagic Acid (EA): An In Vivo Approach to Inhibit Diabetes in Experimental Animals

Hundreds of millions of people around the globe are afflicted by diabetes mellitus. The alteration in glucose fixation process might result into hyperglycaemia and could affect the circulating plasma proteins to undergo nonenzymatic glycation reaction. If it is unchecked, it may lead to diabetes with increase in advanced glycation end products (AGEs). Therefore, the present study was designed to inhibit the diabetes and glycation by using natural antioxidant “ellagic acid” (EA). In this study, we explored the antidiabetes and antiglycation potential of EA in both in vitro (EA at micromolar concentration) and in vivo systems. The EA concentrations of 10 and 20 mg kg−1B.W. /day were administered orally for 25 days to alloxan-induced diabetic rats, a week after confirmation of stable diabetes in animals. Intriguingly, EA supplementation in diabetic rats reversed the increase in fasting blood sugar (FBS) and hemoglobin A1c (HbA1c) level. EA also showed an inhibitory role against glycation intermediates including dicarbonyls, as well as AGEs, investigated in a glycation mixture with in vitro and in vivo animal plasma samples. Additionally, EA treatment resulted in inhibition of lipid peroxidation-mediated malondialdehyde (MDA) and conjugated dienes (CD). Furthermore, EA exhibited an antioxidant property, increased the level of plasma glutathione (GSH), and also helped to decrease histological changes evaluated by histoimmunostaining of animal kidney tissues. The results from our investigation clearly indicates the antiglycative property of EA, suggesting EA as an adequate inhibitor of glycation and diabetes, which can be investigated further in preclinical settings for the treatment and management of diabetes-associated complications.
Learning Curve for Metastatic Liver Tumor Open Resection in Patients with Primary Colorectal Cancer: Use of the Cumulative Sum Method

Background: Liver resections have become the first-line treatment for primary and metastatic tumors and, therefore, are considered a core aspect of surgical training. This study aims to evaluate the learning curve of the extent and safety of liver resection procedures for patients with metastatic colorectal cancer. Methods: This single tertiary center retrospective analysis includes 158 consecutive cases of small liver resection (SLR) (n = 107) and major liver resection (MLR) (n = 58) procedures. A cumulative sum control chart (CUSUM) method was used to investigate the learning curve. Results: The operative time, total blood loss level, and incidence of adverse effects showed a learning curve. For SLRs, the CUSUM curve for operative time and blood loss level peaked at the 19th and 17th case, respectively, while for MLRs, these curves peaked at the 28th and 24th case, respectively. The CUSUM curve for minor adverse effects (MAEs) and severe adverse effects (SAEs) showed a downward slope after the 16th and 68th procedures in the SLRs group and after the 29th and 39th procedures in the MLRs cohort; however, it remained within the acceptable range throughout the entire study. Conclusion: SLR procedures were performed faster with less intraoperative blood loss and shorter postoperative stays than MLRs, and a higher number of completed procedures was required to gain stabilization and repeatability in the operating time and intraoperative blood loss level. In MLR procedures, the reduction of SAEs was accomplished significantly later than the stabilization of the operative time and intraoperative blood loss level.
Intracellular Trafficking of Cationic Carbon Dots in Cancer Cell Lines MCF-7 and HeLa—Time Lapse Microscopy, Concentration-Dependent Uptake, Viability, DNA Damage, and Cell Cycle Profile

Fluorescent carbon dots (CDs) are potential tools for the labeling of cells with many advantages such as photostability, multicolor emission, small size, rapid uptake, biocompatibility, and easy preparation. Affinity towards organelles can be influenced by the surface properties of CDs which affect the interaction with the cell and cytoplasmic distribution. Organelle targeting by carbon dots is promising for anticancer treatment; thus, intracellular trafficking and cytotoxicity of cationic CDs was investigated. Based on our previous study, we used quaternized carbon dots (QCDs) for treatment and monitoring the behavior of two human cancer cell MCF-7 and HeLa lines. We found similarities between human cancer cells and mouse fibroblasts in the case of QCDs uptake. Time lapse microscopy of QCDs-labeled MCF-7 cells showed that cells are dying during the first two hours, faster at lower doses than at higher ones. QCDs at a concentration of 100 µg/mL entered into the nucleus before cellular death; however, at a dose of 200 µg/mL, blebbing of the cellular membrane occurred, with a subsequent penetration of QCDs into the nuclear area. In the case of HeLa cells, the dose-depended effect did not happen; however, the labeled cells were also dying in mitosis and genotoxicity occurred nearly at all doses. Moreover, contrasted intracellular compartments, probably mitochondria, were obvious after 24 h incubation with 100 µg/mL of QCDs. The levels of reactive oxygen species (ROS) slightly increased after 24 h, depending on the concentration, thus the genotoxicity was likely evoked by the nanomaterial. A decrease in viability did not reach IC 50 as the DNA damage was probably partly repaired in the prolonged G0/G1 phase of the cell cycle. Thus, the defects in the G2/M phase may have allowed a damaged cell to enter mitosis and undergo apoptosis. The anticancer effect in both cell lines was manifested mainly through genotoxicity.
Hydroclimate and ENSO Variability Recorded by Oxygen Isotopes From Tree Rings in the South American Altiplano

Hydroclimate variability in tropical South America is strongly regulated by the South American Summer Monsoon (SASM). However, past precipitation changes are poorly constrained due to limited observations and high‐resolution paleoproxies. We found that summer precipitation and the El Niño‐Southern Oscillation (ENSO) variability are well registered in tree‐ring stable oxygen isotopes (δ18OTR) of Polylepis tarapacana in the Chilean and Bolivian Altiplano in the Central Andes (18–22°S, ∼4,500 m a.s.l.) with the northern forests having the strongest climate signal. More enriched δ18OTR values were found at the southern sites likely due to the increasing aridity toward the southwest of the Altiplano. The climate signal of P. tarapacana δ18OTR is the combined result of moisture transported from the Amazon Basin, modulated by the SASM, ENSO, and local evaporation, and emerges as a novel tree‐ring climate proxy for the southern tropical Andes.
The Cognitive Image and Behavioral Loyalty of A Coastal and Marine Destination: A Study in Acapulco, Mexico

ABSTRACT The objectives of this study were: (i) to identify the factors of the attributes related to the cognitive image of a coastal and marine destination; (ii) to segment the demand based on the satisfaction generated by the attributes; and (iii) to establish what image attributes can predict loyalty. This study took place in Acapulco, a coastal and marine destination in Mexico. This quantitative study used 441 valid questionnaires from domestic tourists. The data were analyzed using factor analysis, and a K-means segmentation was performed. A step-by-step multiple regression was also used. The results show six factors: “Personal attention,” “Tourist infrastructure,” “Cultural activities,” “Quality of service,” “Natural and aquatic activities,” and “Entertainment. ” Also, three segments were identified, based on the attributes of the image: “Want it all,” tourists who are satisfied with all the attributes of the image; “Coastal activity seekers,” visitors experiencing a greater satisfaction level with natural, aquatic, and cultural activities; and “Passive tourists,” who had lower levels of satisfaction compared to the other groups. Concerning the attributes that can predict loyalty, “Acapulco as a vacation spot for the family” was the most important predictor of intentions to return and intentions to recommend the destination.
Systems-Level Analysis of the Global Regulatory Mechanism of CodY in Lactococcus lactis Metabolism and Nisin Immunity Modulation

Lactococcus lactis, a species of lactic acid bacteria (LAB) widely used in food fermentation, has been the model strain in genetic engineering, and its application has extended from food to microbial cell factories. CodY is a global regulator in low-G+C Gram-positive bacteria. ABSTRACT Bacteria adapt to the constantly changing environment by regulating their metabolism. The global transcriptional regulator CodY is known to regulate metabolism in low-G+C Gram-positive bacteria. Systems-level identification of its direct targets by proteome and chromatin immunoprecipitation followed by sequencing (ChIP-seq) assays have rarely been reported. Here, we identified that CodY serves as an activator or a repressor of hundreds of genes involved in nitrogen metabolism, carbohydrate metabolism, and transcription through iTRAQ proteome and ChIP-seq. Combined with the electrophoretic mobility shift assay (EMSA), apart from the genes associated with amino acid biosynthesis (ilvD, leuA, optS, ybbD, dtpT, and pepN), genes involved in cell wall synthesis (murD and ftsW) and nisin immunity (nisI) were identified as being regulated by CodY. Moreover, it was demonstrated by nisin resistance assay that CodY activated the transcription of nisI and contributed to nisin immunity. Intriguingly, CodY showed a self-regulation through binding to the motif AAAGGTGTGACAACT in the coding sequence (CDS) region of codY, as verified by DNase I footprinting assay and MEME analysis. In addition, a novel conserved AT-rich motif, AATWTTCTGACAATT, was obtained in L. lactis F44. This study provides new insights into the comprehensive CodY regulation in L. lactis by controlling metabolism, nisin immunity, and self-expression. IMPORTANCE Lactococcus lactis, a species of lactic acid bacteria (LAB) widely used in food fermentation, has been the model strain in genetic engineering, and its application has extended from food to microbial cell factories. CodY is a global regulator in low-G+C Gram-positive bacteria. Its function and direct target genes at the genome-level are little known in L. lactis. In this study, we describe the comprehensive regulation mechanism of CodY. It widely modulated the metabolism of nitrogen and carbohydrate, cell wall synthesis, and nisin immunity in L. lactis F44, and its expression level was regulated by feedback control.
Child Sexual Abuse Studies in Arab Societies: A Systematic Review and Directions for Future Research

Although child sexual abuse (CSA) is acknowledged as a worldwide social phenomenon, less is known about CSA within Arab societies. The current systematic literature review was designed to highlight the empirical knowledge on CSA in Arab societies. Guided by PRISMA principles, key databases were searched, with no time limit, for studies meeting the inclusion criteria. Fifty-seven studies were identified. The majority focused on the prevalence of CSA in various Arab societies around the world, with a wide range of rates reported. It is important to stress two main barriers addressed by the included studies. The first relates to the issue of taboo and the forbidden discussion of sexual content. The second is ethical, in which the researchers expressed their fear of creating emotional distress for their participants. A small group of studies examined parents’ perceptions of CSA and the need for parents’ involvement in the protection of their children. Another small group of studies focused on professionals’ perceptions and experiences in contending with CSA, as well as their distress, conflict, and urgent need for support and guidance. The conclusions from the systematic literature review emphasized the enormous challenge of conducting studies on CSA in Arab societies and the urgent need to advance this research while also including children and adult survivors, whose perceptions and experiences are currently understudied. Moreover, the discussion stresses the need to adopt an intersectionality paradigm in future studies to advance the improvement of CSA policy and practice.
The Mental Health and Social Media Use of Young Australians during the COVID-19 Pandemic

Young people may be particularly vulnerable to the mental health impacts of the COVID-19 pandemic and may also be more likely to use social media at this time. This study aimed to explore young people’s mental health and social media use during the COVID-19 pandemic and examined their use of social media to seek and provide support for suicidal thoughts and self-harm during this period. Young people aged 16–25 (n = 371, M = 21.1) from the general population in Australia completed an anonymous, cross-sectional online survey advertised on social media from June to October 2020. Participants reported high levels of psychological distress, with over 40% reporting severe levels of anxiety and depression, and those with a mental health diagnosis were more likely to perceive the pandemic to have had a negative impact on their mental health. Gender-diverse participants appeared the most negatively impacted. Social media use was high, with 96% reporting use at least once a day, and two-thirds reporting an increase in social media use since the start of the pandemic. One-third had used social media to seek support for suicidal thoughts or self-harm, and half had used it to support another person. This study adds to a growing literature suggesting social media can provide an opportunity to support young people experiencing psychological distress and suicide risk. Uniquely, this study points to the utility of using social media for this purpose during high-risk periods such as pandemics, where access to face-to-face support may be limited. To promote the quality and safety of support provided on social media, resources for help-seekers and help-givers should be developed and disseminated. Social media companies must consider the vulnerability of some users during pandemics and do what they can to promote wellbeing and safety.