Miracle-dz/UniFAR-FTUs huggingface dataset:
Generation of combined hepatocellular‐cholangiocarcinoma through transdifferentiation and dedifferentiation in p53‐knockout mice

The two principal histological types of primary liver cancers, hepatocellular carcinoma (HCC) and cholangiocarcinoma, can coexist within a tumor, comprising combined hepatocellular‐cholangiocarcinoma (cHCC‐CCA). Although the possible involvement of liver stem/progenitor cells has been proposed for the pathogenesis of cHCC‐CCA, the cells might originate from transformed hepatocytes that undergo ductular transdifferentiation or dedifferentiation. We previously demonstrated that concomitant introduction of mutant HRASV12 (HRAS) and Myc into mouse hepatocytes induced dedifferentiated tumors that expressed fetal/neonatal liver genes and proteins. Here, we examine whether the phenotype of HRAS‐ or HRAS/Myc‐induced tumors might be affected by the disruption of the Trp53 gene, which has been shown to induce biliary differentiation in mouse liver tumors. Hepatocyte‐derived liver tumors were induced in heterozygous and homozygous p53‐knockout (KO) mice by hydrodynamic tail vein injection of HRAS‐ or Myc‐containing transposon cassette plasmids, which were modified by deleting loxP sites, with a transposase‐expressing plasmid. The HRAS‐induced and HRAS/Myc‐induced tumors in the wild‐type mice demonstrated histological features of HCC, whereas the phenotype of the tumors generated in the p53‐KO mice was consistent with cHCC‐CCA. The expression of fetal/neonatal liver proteins, including delta‐like 1, was detected in the HRAS/Myc‐induced but not in the HRAS‐induced cHCC‐CCA tissues. The dedifferentiation in the HRAS/Myc‐induced tumors was more marked in the homozygous p53‐KO mice than in the heterozygous p53‐KO mice and was associated with activation of Myc and YAP and suppression of ERK phosphorylation. Our results suggest that the loss of p53 promotes ductular differentiation of hepatocyte‐derived tumor cells through either transdifferentiation or Myc‐mediated dedifferentiation.
Dimensions of invasiveness: Links between local abundance, geographic range size, and habitat breadth in Europe’s alien and native floras

Significance Invasive alien species pose major threats to biodiversity and ecosystems. However, identifying drivers of invasion success has been challenging, in part because species can achieve invasiveness in different ways, each corresponding to different aspects of demographics and distribution. Employing a multidimensional perspective of invasiveness to Europe’s alien flora, we find species generally fall along an axis from overall poor invaders to super invaders that become abundant, widespread, and invade diverse habitats. Some species that deviate from this pattern are recently introduced and still spreading, but others represent atypical forms of invasiveness. In addition to identifying species traits and ecological circumstances associated with super invaders (e.g., intercontinental introductions), we explore drivers in atypical invasions, providing increased clarity into invasion processes. Understanding drivers of success for alien species can inform on potential future invasions. Recent conceptual advances highlight that species may achieve invasiveness via performance along at least three distinct dimensions: 1) local abundance, 2) geographic range size, and 3) habitat breadth in naturalized distributions. Associations among these dimensions and the factors that determine success in each have yet to be assessed at large geographic scales. Here, we combine data from over one million vegetation plots covering the extent of Europe and its habitat diversity with databases on species’ distributions, traits, and historical origins to provide a comprehensive assessment of invasiveness dimensions for the European alien seed plant flora. Invasiveness dimensions are linked in alien distributions, leading to a continuum from overall poor invaders to super invaders—abundant, widespread aliens that invade diverse habitats. This pattern echoes relationships among analogous dimensions measured for native European species. Success along invasiveness dimensions was associated with details of alien species’ introduction histories: earlier introduction dates were positively associated with all three dimensions, and consistent with theory-based expectations, species originating from other continents, particularly acquisitive growth strategists, were among the most successful invaders in Europe. Despite general correlations among invasiveness dimensions, we identified habitats and traits associated with atypical patterns of success in only one or two dimensions—for example, the role of disturbed habitats in facilitating widespread specialists. We conclude that considering invasiveness within a multidimensional framework can provide insights into invasion processes while also informing general understanding of the dynamics of species distributions.
Socioeconomic gaps over time in colorectal cancer survival in England: flexible parametric survival analysis

Background Despite persistent reports of socioeconomic inequalities in colorectal cancer survival in England, the magnitude of survival differences has not been fully evaluated. Methods Patients diagnosed with colon cancer (n=68 169) and rectal cancer (n=38 267) in England (diagnosed between January 2010 and March 2013) were analysed as a retrospective cohort study using the National Cancer Registry data linked with other population-based healthcare records. The flexible parametric model incorporating time-varying covariates was used to assess the difference in excess hazard of death and in net survival between the most affluent and the most deprived groups over time. Results Survival analyses showed a clear pattern by deprivation. Hazard ratio of death was consistently higher in the most deprived group than the least deprived for both colon and rectal cancer, ranging from 1.08 to 1.17 depending on the model. On the net survival scale, the socioeconomic gap between the most and the least deprived groups reached approximately −4% at the maximum (−3.7%, 95% CI −1.6 to −5.7% in men, −3.6%, 95% CI −1.6 to −5.7% in women) in stages III for colon and approximately −2% (−2.3%, 95% CI −0.2 to −4.5% in men, −2.3%, 95% CI −0.2 to −4.3% in women) in stage II for rectal cancer at 3 years from diagnosis, after controlling for age, emergency presentation, receipt of resection and comorbidities. The gap was smaller in other stages and sites. For both cancers, patients with emergency presentation persistently had a higher excess hazard of death than those without emergency presentation. Conclusion Survival disparities were profound particularly among patients in the stages, which benefit from appropriate and timely treatment. For the patients with emergency presentation, excess hazard of death remained high throughout three years from the diagnosis. Public health measures should be taken to reduce access inequalities to improve survival disparities.
Chronic selection for early reproductive phenology in an annual plant across a steep, elevational gradient of growing season length

Colonization along ubiquitous gradients of growing season length should require adaptation of phenological traits, driven by natural selection. Although phenology often varies with season length and genetic differentiation in phenological traits sometimes seems adaptive, few studies test whether natural selection is responsible for these patterns. The annual plant Rhinanthus minor is genetically differentiated for phenology across a 1000‐m elevational gradient of growing season length in the Canadian Rocky Mountains. We estimated phenotypic selection on five phenological traits for three generations of naturally occurring individuals at 12 sites (n = 10,112), and two generations of genetically and phenotypically more variable transplanted populations at nine of these sites (n = 24,611). Selection was weak for most traits, but consistently favored early flowering across the gradient rather than only under short seasons. There was no evidence that apparent selection favoring early reproduction arose from failure to consider all components of fitness, or variation in other correlated phenological traits. Instead, selection for earlier flowering may be balanced by selection for strong cogradient phenological plasticity that indirectly favors later flowering. However, this probably does not explain the consistency of selection on flowering time across this steep, elevational gradient of growing season length.
Gemtuzumab Ozogamicin Improves Event-Free Survival and Reduces Relapse in Pediatric KMT2A-Rearranged AML: Results From the Phase III Children's Oncology Group Trial AAML0531

PURPOSE We investigated the impact of the CD33-targeted agent gemtuzumab ozogamicin (GO) on survival in pediatric patients with KMT2A-rearranged (KMT2A-r) acute myeloid leukemia (AML) enrolled in the Children's Oncology Group trial AAML0531 (NCT01407757). METHODS Patients with KMT2A-r AML were identified and clinical characteristics described. Five-year overall survival (OS), event-free survival (EFS), disease-free survival (DFS), and relapse risk (RR) were determined overall and for higher-risk versus not high-risk translocation partners. GO's impact on response was determined and outcomes based on consolidation approach (hematopoietic stem cell transplant [HSCT] v chemotherapy) described. RESULTS Two hundred fifteen (21%) of 1,022 patients enrolled had KMT2A-r AML. Five-year EFS and OS from study entry were 38% and 58%, respectively. EFS was superior with GO treatment (EFS 48% with GO v 29% without, P = .003), although OS was comparable (63% v 53%, P = .054). For patients with KMT2A-r AML who achieved complete remission, GO was associated with lower RR (40% GO v 66% patients who did not receive GO [No-GO], P = .001) and improved 5-year DFS (GO 57% v No-GO 33%, P = .002). GO benefit was observed in both higher-risk and not high-risk KMT2A-r subsets. For patients who underwent HSCT, prior GO exposure was associated with decreased relapse (5-year RR: 28% GO and HSCT v 73% No-GO and HSCT, P = .006). In multivariable analysis, GO was independently associated with improved EFS, improved DFS, and reduced RR. CONCLUSION GO added to conventional chemotherapy improved outcomes for KMT2A-r AML; consolidation with HSCT may further enhance outcomes. Future clinical trials should study CD33-targeted agents in combination with HSCT for pediatric KMT2A-r AML.
Intensified job demands in healthcare and their consequences for employee well-being and patient satisfaction: A multilevel approach.

AIMS Intensified job demands (IJDs) and their effects on employee burnout, work engagement and patient satisfaction were investigated across different work units and occupational groups in a healthcare setting. DESIGN A multilevel study. METHODS One thousand twenty-four healthcare employees responded to a survey in 2019 and rated their experiences of IJDs, burnout and work engagement. Nine hundred fifty-one patients rated their satisfaction with care received from healthcare staff. RESULTS Work units and occupational groups who shared more experiences of increased time pressure and multitasking reported higher exhaustion. Shared perceptions of increased planning and performing one's work autonomously correlated with higher exhaustion and lower patient satisfaction at the work-unit level. Moreover, work intensification was found to be highest in emergency care and among nurses, while job-related planning demands were highest in leadership services. CONCLUSION IJDs are a shared risk to employee well-being among heterogeneous healthcare staff and relate negatively to customer-rated patient satisfaction. We found that high time-pressure demands increase the shared risk of burnout-especially among nurses and healthcare staff working in emergency care. Furthermore, increased independence and self-determination in planning and executing work tasks also increase the shared risk of burnout especially among those in leadership services. This can lead to lower customer/care satisfaction among patients. IMPACT With the accelerating pace of socio-economic change, the pace of work is also getting faster. Our findings help understand how IJDs are experienced among heterogeneous healthcare staff. Because different occupational groups and work units had different demands, this research shows that attempts to mitigate the negative effects of IJDs need to be planned and implemented in a context-specific way. It seems crucial to pay more attention especially to adequate nurse staffing so that the adverse effects of IJDs could be mitigated among them.
Discrimination of simple objects decoded from the output of retinal ganglion cells upon sinusoidal electrical stimulation

Objective. Most neuroprosthetic implants employ pulsatile square-wave electrical stimuli, which are significantly different from physiological inter-neuronal communication. In case of retinal neuroprosthetics, which use a certain type of pulsatile stimuli, reliable object and contrast discrimination by implanted blind patients remained challenging. Here we investigated to what extent simple objects can be discriminated from the output of retinal ganglion cells (RGCs) upon sinusoidal stimulation. Approach. Spatially confined objects were formed by different combinations of 1024 stimulating microelectrodes. The RGC activity in the ex vivo retina of photoreceptor-degenerated mouse, of healthy mouse or of primate was recorded simultaneously using an interleaved recording microelectrode array implemented in a CMOS-based chip. Main results. We report that application of sinusoidal electrical stimuli (40 Hz) in epiretinal configuration instantaneously and reliably modulates the RGC activity in spatially confined areas at low stimulation threshold charge densities (40 nC mm−2). Classification of overlapping but spatially displaced objects (1° separation) was achieved by distinct spiking activity of selected RGCs. A classifier (regularized logistic regression) discriminated spatially displaced objects (size: 5.5° or 3.5°) with high accuracy (90% or 62%). Stimulation with low artificial contrast (10%) encoded by different stimulus amplitudes generated RGC activity, which was classified with an accuracy of 80% for large objects (5.5°). Significance. We conclude that time-continuous smooth-wave stimulation provides robust, localized neuronal activation in photoreceptor-degenerated retina, which may enable future artificial vision at high temporal, spatial and contrast resolution.
Modeling Total Ammonia Nitrogen Concentration: A Case Study in Houston Ship Channel and Upper & Lower Galveston Bay

Nitrogen is an essential nutrient to form amino acids for fauna and flora. Its compound ammonia, however, is also one of the most important contaminants in an aquatic environment for its highly toxic nature and ubiquity in the surface water. Monitoring and controlling the total ammonia nitrogen are vital for human health and sustainable economic development. This paper attempts to develop an optimal model to monitor and predict the development of total ammonia nitrogen in a water body. A case study was carried out in the Houston Ship Channel and Galveston Bay in Texas, whichaquatic environment is a nursery and spawning ground for diverse types of marine life. Meanwhile, the Bay also assimilates ammonia pollutants from Texas’s municipal and industrial wastewater. The toxic threat of total ammonia nitrogen in the bay was assessed, based on observed samples and forecasted values. Forty years of samples were collected from the Texas Commission on Environmental Quality. Correlations analysis was conducted between all physical, biological and chemical parameters and the total ammonia nitrogen. The trends of total ammonia nitrogen were modeled through a multivariate regression and an auto-regression, followed by an estimation of hazard quotient. The outcome shows that the total ammonia nitrogen in this study area is spatially correlated. For upstream flow, most measured parameters were highly correlated with the total ammonia nitrogen, whereas for downstream flow, weak correlations were noticed. Modeling results indicate that the auto-regression models can better fit the observed data than the multivariate regression models. Meanwhile, the predicted total ammonia nitrogen and the hazard quotient will remain at a lower level, meeting the ambient water criteria continuous concentration.
Budding yeast Rap1, but not telomeric DNA, is inhibitory for multiple stages of DNA replication in vitro

Abstract Telomeres are copied and reassembled each cell division cycle through a multistep process called telomere replication. Most telomeric DNA is duplicated semiconservatively during this process, but replication forks frequently pause or stall at telomeres in yeast, mouse and human cells, potentially causing chronic telomere shortening or loss in a single cell cycle. We have investigated the cause of this effect by examining the replication of telomeric templates in vitro. Using a reconstituted assay for eukaryotic DNA replication in which a complete eukaryotic replisome is assembled and activated with purified proteins, we show that budding yeast telomeric DNA is efficiently duplicated in vitro unless the telomere binding protein Rap1 is present. Rap1 acts as a roadblock that prevents replisome progression and leading strand synthesis, but also potently inhibits lagging strand telomere replication behind the fork. Both defects can be mitigated by the Pif1 helicase. Our results suggest that GC-rich sequences do not inhibit DNA replication per se, and that in the absence of accessory factors, telomere binding proteins can inhibit multiple, distinct steps in the replication process.
Association Between Injury Mechanisms and Magnetic Resonance Imaging Findings in Rectus Femoris Injuries in 105 Professional Football Players

Objective: To describe the injury mechanism and its association with magnetic resonance imaging (MRI) injury findings in acute rectus femoris injuries. Design: Combined retrospective and prospective descriptive injury study. Retrospective cohort from January 2010 to October 2013 and prospective cohort from October 2013 to January 2019. Setting: Specialized sports medicine hospital. Participants: Male professional football players older than 18 years playing in a national football league, referred for injury assessment within 7 days after an acute rectus femoris injury, with a positive finding on MRI. Independent variables: Rectus femoris muscle injury MRI findings in relation to injury mechanism in male football players. Main outcome measures: Rectus femoris injury mechanism (kicking, sprinting, and others), MRI injury location, and grade. Results: There were 105 injuries in total, with 60 (57.1%) and 45 (42.8%) injuries from the retrospective and prospective cohorts, respectively. Kicking was the injury mechanism in 57 (54.3%) of all acute rectus femoris injuries, sprinting represented 32 (30.4%), and 16 (15.2%) were classified as others. There were 20 (19.05%) free tendon, 67 (63.8%) myotendinous junction and/or intramuscular tendon, and 18 (17.1%) peripheral myofascial located injuries. All free tendon injuries were related to kicking and graded as a complete tear of at least one of the tendons in 15/20 (75.0%) cases. Conclusions: Kicking seems to be an important mechanism related to complete ruptures and injuries occurring at the proximal free tendon. Sprinting was the other most common mechanism but was never associated with injury to the proximal free tendon.
The use of telemedicine in the PICU: A systematic review and meta-analysis

The use of telemedicine in ICUs has grown and is becoming increasingly recognized. However, its impact on PICUs remains unclear. This systematic review and meta-analysis aimed to evaluate whether telemedicine in the PICU has the potential to improve clinical and non-clinical outcomes. PubMed, Scopus, LILACS, and CINAHL electronic databases were searched to identify studies that assessed the impact of telemedicine on clinical outcomes, with no publication date restrictions. The reference lists of the selected articles were hand-searched for additional studies that had not been identified by the initial electronic search. Studies were included if they had a cohort design, used telemedicine, were conducted in PICUs or specialized PICUs, and were published in Portuguese, English, or Spanish. Two groups of reviewers independently screened titles and abstracts for inclusion. The same group of reviewers independently assessed the full-text articles for eligibility and extracted the following information: telecommunication method, intervention characteristics, patient characteristics, sample size, and main results. Studies were meta-analyzed using a random-effects model to estimate the pooled prevalence of PICU mortality and length of PICU stay. Risk of bias was assessed using the Newcastle-Ottawa Scale. Of 2703 studies initially identified, 2226 had their titles and abstracts screened. Of these, 53 were selected for full-text reading, of which 10 were included and analyzed. The main results of interest were length of PICU stay, number of deaths or mortality rate, and satisfaction of health professionals and family members. The results of meta-analysis show that the mortality rate reduced by 34% with an increase of the length of PICU stay in the PICUs with the use of telemedicine. Family members and health professionals were satisfied with the use of telemedicine. Telemedicine has the potential to improve PICU outcomes, such as mortality rate and family and staff satisfaction. However, it extended length of PICU stay in the studies included in this systematic review.
Gastrointestinal manifestations of pediatric coronavirus disease and their relationship with a severe clinical course: A systematic review and meta-analysis

Abstract Background Data on the gastrointestinal (GI) manifestations of Pediatric Corona Virus Disease (COVID-19) is conflicting and the relationship between GI involvement and the severity of COVID-19 disease has not been evaluated. The objectives of this systematic review was to determine the GI manifestations of pediatric COVID-19 and to evaluate their role as risk factors for a severe clinical course. Methods A systematic literature search was carried out in PubMed and Scopus for studies published before December 31, 2020 with information about the GI manifestations of pediatric COVID-19. Patients with a severe and non-severe clinical course were compared using the inverse variance heterogeneity model and odds ratio (OR) as the effect size. A sensitivity analysis was performed if the heterogeneity was high among studies. Results A total of 811 studies were identified through systematic search of which 55 studies (4369 patients) were included in this systematic review. The commonest GI symptoms were diarrhea—19.08%(95%CI : 10.6–28.2), nausea/vomiting 19.7%(95%CI : 7.8–33.2) and abdominal pain 20.3%(95%CI : 3.7–40.4). The presence of diarrhea was significantly associated with a severe clinical course with a pooled OR of 3.97 (95%CI: 1.80–8.73; p < 0.01). Abdominal pain and nausea/vomiting were not associated with disease severity. Conclusions Diarrhea, nausea/vomiting or abdominal pain are present in nearly one-fifth of all children with COVID-19. The presence of diarrhea portends a severe clinical course.