Miracle-dz/UniFAR-FTUs huggingface dataset:
Marketing Travel Services to Senior Consumers

Purpose The purpose of this study is to identify the profiles of current senior travelers using accurate segmentation criteria based on ageing and behavioral tourism variables, shown to be useful in gerontology, marketing and tourism marketing literature. Design/methodology/approach A self-complete questionnaire was administered to a work status-based quota sample of 300 senior consumers (retired people aged 50 - 76). Using behavioral variables, cluster analysis was performed. The clusters were then profiled using a discriminant analysis, involving demographic, ageing, and also some behavioral variables not included in the initial analysis. Finally, the current tourism offers were studied, considering the segments characteristics revealed. Findings Four distinct segments have been identified. Each segment differs considerably from one another on a set of variables, including consumer behaviors' variables. Research implications This paper fills a research gap, outlined by several previous researchers in the senior consumer field, by identifying the current senior travel motivations and the role of the subjective ages towards the tourism consumption.
Assessing the rate of torque development in sprint cycling: a methodological study

ABSTRACT The present study examined (i) the magnitude of the rate of torque development (RTD) and (ii) the between-day reliability of RTD at the start of a cycling sprint when sprint resistance, sprint duration, and the pedal downstroke were altered. Nineteen well-trained cyclists completed one familiarisation and three testing sessions. Each session involved one set of 1-s sprints and one set of 5-s sprints. Each set contained one moderate (0.3 N m kg−1), one heavy (0.6 N m kg−1), and one very heavy (1.0 N m kg−1) resistance sprint. RTD measures (average and peak RTD, RTD 0–100 ms, and RTD 0–200 ms) were calculated for downstroke 1 in the 1-s sprint. For the 5-s sprints, RTD measures were calculated for each of the first three downstrokes, as an average of downstrokes 1 and 2, and as an average of downstrokes 2 and 3. Whilst RTDs were greatest in downstroke 3 at all resistances, the greatest number of reliable RTD measures were obtained using the average of downstrokes 2 and 3 with heavy or very heavy resistances, where average and peak RTD, and RTD 0–200 ms were deemed reliable (ICC ≥ 0.8, CV ≤ 10%). Since only 1–2 downstrokes can be completed within 1 s, the greatest RTD reliability cannot be achieved using a 1-s sprint; therefore, the average of downstrokes 2 and 3 during a >2-s cycling sprint (e.g. 5-s test) with heavy or very heavy resistance is recommended for the assessment of RTD in sprint cyclists. Highlights Whilst RTD measures were greatest in pedal downstroke 3 at all resistances, the greatest number of reliable RTD measures were obtained using the average of pedal downstrokes 2 and 3 with heavy or very heavy resistances, with average and peak RTD, and RTD 0–200 ms having acceptable reliability. RTD 0–100 ms and all RTD measurements for downstroke 1 were not reliable and should not be used. As only 1–2 downstrokes can be performed in 1 s, the greatest RTD reliability cannot be achieved using a 1-s sprint. Instead, RTD may be evaluated using a 5-s sprint.
Effects of photographer physical attractiveness on photograph aesthetic value assessment

Existent studies have demonstrated that being physically attractive leads to preferences and rewards in various scenarios involving performance evaluation. In this study, we explored whether a photographer’s physical attractiveness could affect others’ assessment of a photograph’s aesthetic value. Participants ( N = 54 ) accomplished an online task to pair portraits and non-portrait photographs, followed by completing two questionnaires on cognitive reflection and empathy. Analytical results revealed that an attractive photographer was more likely to be associated with a highly aesthetic photograph, and this bias was moderated by the participant’s level of cognitive reflection and empathy. Meanwhile, it could be reduced by the participant’s professional experience.
Temperature modifies the association between air pollution and respiratory disease mortality in Cape Town, South Africa

ABSTRACT The aim of this 10-year study was to investigate whether and how temperature modifies the association between daily ambient PM10, NO2, SO2 air pollution and daily respiratory disease mortality in Cape Town. A time-stratified case-crossover epidemiological design was applied. Susceptibility by sex and age groups (15–64 years and ≥65 years) was also investigated. On days with medium Tapp levels, NO2 displayed a stronger association with respiratory mortality than PM10 or SO2. Females appeared to be more susceptible to NO2 at medium Tapp levels to males. The 15-64-year-old age group seemed to be more vulnerable to NO2 and PM10 at medium Tapp levels compared to the elderly (≥65 years). At high Tapp levels, females were more susceptible to PM10. The 15-64-year-old group were more vulnerable to NO2 and SO2. The results can be used in present-day early warning systems and in risk assessments to estimate the impact of increased air pollution and temperature.
Epifriedelanol enhances adriamycin-induced cytotoxicity towards K562/ADM cells by down regulating of P-gp and MRP2

Abstract 1. Multidrug resistance (MDR) is a critical issue during chemotherapy of cancers. Epifriedelanol (Epi) is the effective compounds from the Root Bark of Ulmus davidiana. This study aims to investigate the effect of Epi on MDR and its potential mechanism in the adriamycin (Adr)-resistant K562/ADM cells. 2. The effect of Epi on MDR, P-glycoprotein (P-gp) and multidrug resistance-associated proteins (MRPs) were investigated in the adriamycin (Adr)-resistant K562/ADM cells. In addition, the alterations of nuclear receptor pregnane X receptor (PXR) and constitutive androstane receptor (CAR) mRNA expression levels in K562/ADM cells after Epi treatment were also examined. 3. Epi significantly enhanced Adr-induced cytotoxicity towards K562/ADM cells. Combination of Epi and Adr can significantly reduce the 50% inhibitory concentration (IC50) of K562/ADM cells to Adr. The reversal fold was 1.83 and 3.64 after treated with Epi at 10 and 20 μM, respectively. The intracellular accumulation of Adr was significant increased after exposure to Epi at 5–20 μM compared with the control group. Furthermore, Epi treatment significantly decreased the mRNA and protein expression of P-gp and MRP2 in K562/ADM cells. 4. The present study demonstrated that Epi could enhance Adr-induced cytotoxicity towards K562/ADM cells accompanied by the down-regulation of P-gp and MRP2.
Evolving Concepts in Endothelial Pathobiology of Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is a deadly disease, characterized by increased vascular resistance, pulmonary arteriolar loss, and occlusive arterial remodeling, leading to eventual right heart failure. Evidence increasingly points to the pulmonary endothelium as a central actor in PAH. Endothelial cell apoptosis can result directly in distal lung arteriolar pruning and indirectly in the formation of complex and occlusive arterial lesions, reflecting an imbalance between endothelial injury and repair in the development and progression of PAH. Many of the mutations implicated in PAH are in genes, which are predominantly, or solely, expressed in endothelial cells, and the endothelium is a major target for therapeutic interventions to restore BMP signaling. We explore how arterial pruning can promote the emergence of occlusive arterial remodeling mediated by ongoing endothelial injury secondary to hemodynamic perturbation and pathological increases in luminal shear stress. The emerging role of endothelial cell senescence is discussed in the transition from reversible to irreversible arterial remodeling in advanced PAH, and we review the sometimes conflicting evidence that female sex hormones can both protect or promote vascular changes in PAH. Finally, we explore the contribution of the endothelium to metabolic changes and the altered inflammatory and immune state in the PAH lung, focusing on the role of excessive TGFβ signaling. Given the complexity of the endothelial pathobiology of PAH, we anticipate that emerging technologies that allow the study of molecular events at a single cell level will provide answers to many of the questions raised in this review.
Effect of AXS-05 (Dextromethorphan-Bupropion) in Major Depressive Disorder: A Randomized Double-Blind Controlled Trial.

OBJECTIVE Altered glutamatergic neurotransmission is implicated in the pathogenesis of major depressive disorder. AXS-05 (dextromethorphan-bupropion) is an oral NMDA receptor antagonist and sigma-1 receptor agonist, which utilizes inhibition of CYP2D6 to increase its bioavailability. This phase 2 trial assessed the efficacy and safety of dextromethorphan-bupropion in the treatment of major depressive disorder. METHODS This randomized, double-blind, multicenter, parallel-group trial evaluated dextromethorphan-bupropion versus the active comparator sustained-release bupropion in patients 18-65 years old with a diagnosis of major depressive disorder of moderate or greater severity. Patients were randomly assigned to receive either dextromethorphan-bupropion (45 mg/105 mg tablet) or bupropion (105 mg tablet), once daily for the first 3 days and twice daily thereafter, for a total of 6 weeks. The primary endpoint was overall treatment effect on Montgomery-Åsberg Depression Rating Scale (MADRS) score (average of the change from baseline for weeks 1-6), assessed in all randomized patients whose diagnosis and severity were confirmed by an independent assessor and who received at least one dose of study medication and had at least one postbaseline assessment. RESULTS Of 97 patients randomized, 17 did not have a confirmed diagnosis and severity based on the independent assessment, resulting in 80 patients in the efficacy population (dextromethorphan-bupropion, N=43; bupropion, N=37). The mean change from baseline in MADRS score over weeks 1-6 (overall treatment effect) was significantly greater with dextromethorphan-bupropion than with bupropion (-13.7 points vs. -8.8 points; least-squares mean difference=-4.9; 95% CI=-3.1, -6.8). MADRS score change with dextromethorphan-bupropion was significantly greater than with bupropion at week 2 and every time point thereafter (week 6: -17.3 vs. -12.1 points; least-squares mean difference=-5.2, 95% CI=-1.1, -9.3). Remission rates were significantly greater with dextromethorphan-bupropion at week 2 and every time point thereafter (week 6: 46.5% vs. 16.2%; least-squares mean difference=30.3%, 95% CI=11.2, 49.4). Response rates (≥50% decrease in MADRS score from baseline) at week 6 were 60.5% with dextromethorphan-bupropion and 40.5% with bupropion (least-squares mean difference=19.9%, 95% CI=-1.6, 41). Most secondary outcomes favored dextromethorphan-bupropion. The most common adverse events with dextromethorphan-bupropion were dizziness, nausea, dry mouth, decreased appetite, and anxiety. Dextromethorphan-bupropion was not associated with psychotomimetic effects, weight gain, or sexual dysfunction. CONCLUSIONS In patients with major depression, dextromethorphan-bupropion (AXS-05) significantly improved depressive symptoms compared with bupropion and was generally well tolerated.
Characterization of uridine-cytidine kinase like-1 nucleoside kinase activity and its role in tumor growth

Uridine-cytidine kinase like-1 (UCKL-1) is a largely uncharacterized protein with high sequence similarity to other uridine-cytidine kinases (UCKs). UCKs play an important role in the pyrimidine salvage pathway, catalyzing the phosphorylation of uridine and cytidine to UMP and CMP, respectively. Only two human UCKs have been identified, UCK1 and UCK2. Previous studies have shown both enzymes phosphorylate uridine and cytidine using ATP as the phosphate donor. No studies have evaluated the kinase potential of UCKL-1. We cloned and purified UCKL-1 and found that it successfully phosphorylated uridine and cytidine using ATP as the phosphate donor. The catalytic efficiency (calculated as kcat/KM) was 1.2 × 104 s−1, M−1 for uridine and 0.7 × 104 s−1, M−1 for cytidine. Our lab has previously shown that UCKL-1 is up-regulated in tumor cells, providing protection against natural killer (NK) cell killing activity. We utilized small interfering RNA (siRNA) to down-regulate UCKL-1 in vitro and in vivo to determine the effect of UCKL-1 on tumor growth and metastasis. The down-regulation of UCKL-1 in YAC-1 lymphoma cells in vitro resulted in decreased cell counts and increased apoptotic activity. Down-regulation of UCKL-1 in K562 leukemia cells in vivo led to decreased primary tumor growth and less tumor cell dissemination and metastasis. These results identify UCKL-1 as a bona fide pyrimidine kinase with the therapeutic potential to be a target for tumor growth inhibition and for diminishing or preventing metastasis.
Semi-Supervised Neuron Segmentation via Reinforced Consistency Learning

Emerging deep learning-based methods have enabled great progress in automatic neuron segmentation from Electron Microscopy (EM) volumes. However, the success of existing methods is heavily reliant upon a large number of annotations that are often expensive and time-consuming to collect due to dense distributions and complex structures of neurons. If the required quantity of manual annotations for learning cannot be reached, these methods turn out to be fragile. To address this issue, in this article, we propose a two-stage, semi-supervised learning method for neuron segmentation to fully extract useful information from unlabeled data. First, we devise a proxy task to enable network pre-training by reconstructing original volumes from their perturbed counterparts. This pre-training strategy implicitly extracts meaningful information on neuron structures from unlabeled data to facilitate the next stage of learning. Second, we regularize the supervised learning process with the pixel-level prediction consistencies between unlabeled samples and their perturbed counterparts. This improves the generalizability of the learned model to adapt diverse data distributions in EM volumes, especially when the number of labels is limited. Extensive experiments on representative EM datasets demonstrate the superior performance of our reinforced consistency learning compared to supervised learning, i.e., up to 400% gain on the VOI metric with only a few available labels. This is on par with a model trained on ten times the amount of labeled data in a supervised manner. Code is available at https://github.com/weih527/SSNS-Net.
Processes and patterns: Insights on cranial covariation from an Apert syndrome mouse model

Major cell‐to‐cell signaling pathways, such as the fibroblast growth factors and their four receptors (FGF/FGFR), are conserved across a variety of animal forms. FGF/FGFRs are necessary to produce several “vertebrate‐specific” structures, including the vertebrate head. Here, we examine the effects of the FGFR2 S252W mutation associated with Apert syndrome on patterns of cranial integration. Our data comprise micro‐computed tomography images of newborn mouse skulls, bred to express the Fgfr2 S252W mutation exclusively in either neural crest or mesoderm‐derived tissues, and mice that express the Fgfr2 S252W mutation ubiquitously.
Relationship between the Bolsa Família national cash transfer programme and suicide incidence in Brazil: A quasi-experimental study

Background Socioeconomic factors have been consistently associated with suicide, and economic recessions are linked to rising suicide rates. However, evidence on the impact of socioeconomic interventions to reduce suicide rates is limited. This study investigates the association of the world’s largest conditional cash transfer programme with suicide rates in a cohort of half of the Brazilian population. Methods and findings We used data from the 100 Million Brazilian Cohort, covering a 12-year period (2004 to 2015). It comprises socioeconomic and demographic information on 114,008,317 individuals, linked to the “Bolsa Família” programme (BFP) payroll database, and nationwide death registration data. BFP was implemented by the Brazilian government in 2004. We estimated the association of BFP using inverse probability of treatment weighting, estimating the weights for BFP beneficiaries (weight = 1) and nonbeneficiaries by the inverse probability of receiving treatment (weight = E(ps)/(1-E(ps))). We used an average treatment effect on the treated (ATT) estimator and fitted Poisson models to estimate the incidence rate ratios (IRRs) for suicide associated with BFP experience. At the cohort baseline, BFP beneficiaries were younger (median age 27.4 versus 35.4), had higher unemployment rates (56% versus 32%), a lower level of education, resided in rural areas, and experienced worse household conditions. There were 36,742 suicide cases among the 76,532,158 individuals aged 10 years, or older, followed for 489,500,000 person-years at risk. Suicide rates among beneficiaries and nonbeneficiaries were 5.4 (95% CI = 5.32, 5.47, p < 0.001) and 10.7 (95% CI = 10.51, 10.87, p < 0.001) per 100,000 individuals, respectively. BFP beneficiaries had a lower suicide rate than nonbeneficiaries (IRR = 0.44, 95% CI = 0.42, 0.45, p < 0.001). This association was stronger among women (IRR = 0.36, 95% CI = 0.33, 0.38, p < 0.001), and individuals aged between 25 and 59 (IRR = 0.41, 95% CI = 0.40, 0.43, p < 0.001). Study limitations include a lack of control for previous mental disorders and access to means of suicide, and the possible under-registration of suicide cases due to stigma. Conclusions We observed that BFP was associated with lower suicide rates, with similar results in all sensitivity analyses. These findings should help to inform policymakers and health authorities to better design suicide prevention strategies. Targeting social determinants using cash transfer programmes could be important in limiting suicide, which is predicted to rise with the economic recession, consequent to the Coronavirus Disease 2019 (COVID-19) pandemic.
Cryoglobulinemia and double‐filtration plasmapheresis: Personal experience and literature review

Cryoglobulinemia is defined as the presence of an abnormal immunoglobulin that may be responsible for vasculitis of small‐caliber vessels. Apheresis can be used in order to temporarily eliminate circulating cryoglobulins. The aim of this study was to assess the effectiveness of apheresis (double‐filtration plasmapheresis‐DFPP‐) in symptomatic and/or severe cryoglobulinemias.
Evaluation of Machine Learning Models for Clinical Prediction Problems*

In this issue of Pediatric Critical Care Medicine, Trujillo Rivera et al (1) report the results of a retrospective cohort study using a multicenter dataset from a major electronic health record (EHR) vendor. The overall goal of the work was to evaluate a deep learning approach for dynamic mortality prediction in critically ill children. The authors have previously developed a system that predicts the probability of a child being in the ICU during each 6-hour time window, which they termed the “Criticality Index” (2). The incremental value of this article is the extrapolation of the Criticality Index to mortality risk prediction. They found that their model had good discrimination of mortality with an area under the receiver operator characteristics (AUROC) curve of greater than 0.8 and good calibration in most time periods. Overall, strengths of this article include the large and highly granular EHR-based dataset and the broad patient cohort. Weaknesses include the complexity of the approach with a large number of variables and different neural network for each 6-hour time window and the fact that it was not benchmarked against a more parsimonious and interpretable model. The main focus of investigators developing clinical prediction models is often on performance, and novel machine learning (ML) approaches, including deep learning, offer the promise of remarkable accuracy. However, several other model characteristics are critical to the success of these models in a clinical environment, even though they are often overlooked in the literature. Below we describe these ideal characteristics of clinical prediction models and provide a rationale (see also Table 1).
Lamina propria interleukin 17 A aggravates natural killer T‐cell activation in autoimmune hepatitis

Autoimmune hepatitis is an interface hepatitis characterized by the progressive destruction of the liver parenchyma, the cause of which is still obscure. Interleukin (IL)‐17A is a major driver of autoimmunity, which can be produced by innate immune cells against several intracellular pathogens. Here, we investigated the involvement of IL‐17A in a mice model of immune‐mediated hepatitis with the intestine exposed to Salmonella typhimurium. Our results showed more severe Concanavalin (Con) A‐induced liver injury and gut microbiome dysbiosis when the mice were treated with a gavage of S. typhimurium. Then, the natural killer (NK) T cells were overactivated by the accumulated IL‐17A in the liver in the Con A and S. typhimurium administration group. IL‐17A could activate NKT cells by inducing CD178 expression via IL‐4/STAT6 signaling. Furthermore, via the portal tract, the laminae propria mucosal‐associated invariant T (MAIT)‐cell‐derived IL‐17A could be the original driver of NKT cell overactivation in intragastric administration of S. typhimurium and Con A injection. In IL‐17A‐deficient mice, Con A‐induced liver injury and NKT cell activation were alleviated. However, when AAV‐sh‐mIL‐17a was used to specifically knock down IL‐17A in liver, it seemed that hepatic IL‐17a knock down did not significantly influence the liver injury. Our results suggested that, under Con A‐induction, laminae propria MAIT‐derived IL‐17A activated hepatic NKT, and this axis could be a therapeutic target in autoimmune liver disease.
Current status and future prospects of antibody–drug conjugates in urological malignancies

Antibody‐drug conjugates represent a promising new treatment option that uses the targeting ability of an antibody to deliver cytotoxic drugs directly to tumors. Antibody‐drug conjugates provide the opportunity to deliver drugs to antigen‐expressing cancer cells while minimizing toxicity to normal tissue, achieving wider therapeutic windows. To date, three antibody‐drug conjugates have been approved by the US Food and Drug Administration, and many antibody‐drug conjugates are under clinical development for urological malignancies. In this paper, we review the mechanism, history, and development of antibody‐drug conjugates, and review the current landscape of antibody‐drug conjugates in urological malignancies including 12 targets and 18 antibody‐drug conjugates in prostate cancer, renal cancer, and urothelial cancer. Furthermore, we review the rational combination of antibody‐drug conjugates with immune checkpoint inhibitors and consider future prospects to enhance the therapeutic activity of antibody‐drug conjugates in urological malignancies.