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Simple Summary: Pancreatic cancer is one of the deadliest cancers due to its subtle onset and advanced stage at diagnosis. With most patients having inoperable cancer at diagnosis, survival rates remain low despite existing treatments. Our review aims to map and summarize current studies on FGFR inhibitors, a promising new treatment targeting specific cancer pathways. We found that while there are many preclinical studies, clinical research is still emerging, focusing mainly on the efficacy and safety of these treatments. Although FGFR alterations are relatively rare in pancreatic cancer, the few available real-life data are promising. Future research should aim to better identify the genetic drivers of this cancer and gather more data on long-term outcomes. This could lead to improved treatments and better survival rates for patients with pancreatic cancer. Pancreatic cancer is a highly lethal disease, often diagnosed at advanced stages, with a 5-year overall survival rate of around 10%. Current treatments have limited effectiveness, underscoring the need for new therapeutic options. This scoping review aims to identify and summarize preclinical and clinical studies on FGFR (Fibroblast Growth Factor Receptor) inhibitors, including tyrosine kinase inhibitors (TKIs) and FGFR-specific inhibitors, in pancreatic cancer with FGFR alterations. We included studies analyzing efficacy, safety, and survival outcomes in various populations. A comprehensive search across major databases identified 73 relevant studies: 32 preclinical, 16 clinical, and 25 from gray literature. The clinical trials focused primarily on efficacy (20 studies) and safety (14 studies), with fewer studies addressing survival outcomes. FGFR1 was the most studied alteration, followed by FGFR2 and FGFR4. Although FGFR alterations are relatively rare in pancreatic cancer, the available data, including promising real-life outcomes, suggest significant potential for FGFR inhibitors. However, more extensive research is needed to identify the correct genetic drivers and gather robust survival data. Ongoing and future trials are expected to provide more comprehensive insights, potentially leading to improved targeted therapies for pancreatic cancer patients with FGFR alterations. [ABSTRACT FROM AUTHOR]

Background: The Satisfaction with Simulation Experience scale is a 5-point Likert scale that measures students' satisfaction in medium and high-fidelity simulation scenarios. This study aims at investigating the psychometric properties of the Satisfaction with Simulation Experience - Italian Version scale. Methods: A multi-centre cross-sectional study was conducted. The scale was administered to a sample of 266 undergraduate nursing students from two Italian universities after attending a medium- and high-fidelity simulation session in November 2022 and March 2023. Cronbach's alpha coefficient and item-total correlation were sorted out to assess internal consistency and reliability. The test-retest method was used as a measure of scale stability over time as well as the confirmatory factor analysis to verify construct validity. Results: The Cronbach's alpha value was 0.94 for the overall scale, indicating excellent reliability, and it was 0.84 or higher for each subscales, indicating good reliability. A large correlation coefficient of 0.60 or higher was found between each item and its subscale and between each item and the overall scale score. A medium test-retest correlation coefficient was found for most items (r > 0.30). The confirmatory factor analysis confirmed the factorial structure found in the original study. Conclusions: Satisfaction is an important teaching and learning quality indicator along with the achievement of learning outcomes in simulation. The Satisfaction with Simulation Experience - Italian Version scale showed good reliability and validity; therefore, it could be a useful tool to assess simulation impact in Italian nursing students. The extensive utilization of the Satisfaction with Simulation Experience scale, along with its various validated versions, could facilitate assessing satisfaction in simulation across diverse contexts and enable comparisons of findings across studies in different countries. [ABSTRACT FROM AUTHOR]

Background: This study, in patients with symptomatic chronic obstructive pulmonary disease (COPD), explored switching therapy from non-extrafine high-dose inhaled corticosteroid/long-acting β2-agonist (ICS/LABA; fluticasone propionate/salmeterol [FP/SLM]) to extrafine medium-dose beclometasone dipropionate/formoterol fumarate dihydrate/glycopyrronium (BDP/FF/G), both via dry-powder inhaler. Functional Respiratory Imaging, a quantitative computed tomography method with 3D reconstructions of pulmonary anatomy, was used to assess airway geometry and lung function. Methods: Patients receiving a stable ICS/LABA regimen for ≥ 8 weeks were switched to FP/SLM 500/50 µg, one inhalation twice-daily (high-dose ICS) for 6 weeks. After baseline assessments (Visit 2 [V2]), therapy was switched to BDP/FF/G 100/6/10 µg, two inhalations twice-daily (medium-dose ICS) for 6 weeks, followed by V3. The primary endpoints were percentage changes in specific image-based airway volume (siVaw) and resistance (siRaw) from baseline to predose at V3 (i.e., chronic effects), assessed at total lung capacity (TLC) in central and distal lung regions. Secondary endpoints included siVaw and siRaw changes from pre-dose to post-dose at V2, and from pre-dose to post-dose at V3 at TLC (i.e., acute effects), and chronic and acute changes in siVaw and siRaw at functional residual capacity (FRC). Pre-dose forced expiratory volume in 1 s (FEV1) and COPD Assessment Test (CAT) were also assessed. Results: There were no significant changes in pre-dose siVaw or siRaw at TLC from baseline to V3, although at FRC there was a significant decrease in mean siRaw in the distal airways (− 63.6%; p = 0.0261). In addition, in the distal airways there were significant acute effects at TLC on mean siVaw and siRaw (siVaw: 39.8% and 62.6%; siRaw: − 51.1% and − 57.2%, V2 and V3, respectively; all p < 0.001) and at FRC at V2 (siVaw: 77.9%; siRaw: − 67.0%; both p < 0.001). At V3, the mean change in pre-dose FEV1 was 62.2 mL (p = 0.0690), and in CAT total score was − 3.30 (p < 0.0001). Conclusions: In patients with symptomatic COPD receiving high-dose ICS/LABA, adding a long-acting muscarinic antagonist while decreasing the ICS dose by switching to medium-dose extrafine BDP/FF/G was associated with improved airway indices, especially in the distal airways, together with improvements in respiratory health status. Trial registration ClinicalTrials.gov (NCT04876677), first posted 6th May 2021 [ABSTRACT FROM AUTHOR]

Soil microbial diversity and community composition are shaped by various factors linked to land management, topographic position, and vegetation. To study the effects of these drivers, we characterized fungal and bacterial communities from bulk soil at four soil depths ranging from the surface to below the rooting zone of two Swedish grasslands with differing land-use histories, each including both an upper and a lower catenary position. We hypothesized that differences in plant species richness and plant functional group composition between the four study sites would drive the variation in soil microbial community composition and correlate with microbial diversity, and that microbial biomass and diversity would decrease with soil depth following a decline in resource availability. While vegetation was identified as the main driver of microbial community composition, the explained variation was significantly higher for bacteria than for fungi, and the communities differed more between grasslands than between catenary positions. Microbial biomass derived from DNA abundance decreased with depth, but diversity remained relatively stable, indicating diverse microbial communities even below the rooting zone. Finally, plant-microbial diversity correlations were significant only for specific plant and fungal functional groups, emphasizing the importance of functional interactions over general species richness. [ABSTRACT FROM AUTHOR]

Lung dendritic cells (DC) are powerful antigen-presenting cells constituted by various subpopulations that differ in terms of their function and origin and differentially regulate cell-mediated antifungal immunity. The lung is the primary target organ of Cryptococcus neoformans and C. gattii infections, which makes it essential in the establishment of the first line of anti-cryptococcal defense. However, the lung-specific dynamics and function of DC subsets are poorly understood in cryptococcosis. In this study, we provide evidence for the in vivo function of a conventional langerin-expressing DC1 dendritic cell (LangDC1) population during the first week of intratracheal C. neoformans infection in mice. By using conditional depletion of LangDC1 after diphtheria toxin treatment of LangDTREGFP mice, we demonstrate that these animals better control the fungal infection and produce type 1 and 17 cytokines in the context of a type 2 immune response, favoring a predominance of iNOS over arginase-1 expression by pulmonary cells. Our results suggest that LangDC1 cells play a role in impairing immune response for the clearance of C. neoformans in the early stage of pulmonary infection. [ABSTRACT FROM AUTHOR]

Abstract Fasciolosis is a zoonotic disease of increasing importance due to its worldwide distribution and elevated economic losses. Previously, we demonstrated that Fasciola hepatica excretory–secretory products (FhESP) induce immunomodulatory effects on peritoneal macrophages in a Dectin-1 dependent manner. In this study, we observed that peritoneal macrophages from naive BALB/c mice stimulated in vitro with FhESP presented increased expression levels of phosphorylated extracellular-signal-regulated kinase (ERK), and this effect was dependent on Syk, protein kinase C (PKC) and Dectin-1. In this sense, we observed increased levels of arginase activity, IL-10 and TGF-β in macrophages stimulated with FhESP, which were dependent on PKC and ERK. Furthermore, we observed that the increased arginase activity, as well as in TGF-β and IL-10 levels, was partially dependent on IL-10 receptor signaling in macrophages that were pre-incubated with anti-IL10R before being stimulated with FhESP. Taken together, these results suggest the participation of Dectin-1 and Syk in FhESP interaction with peritoneal macrophages and the possible role of ERK and IL-10 in downstream signaling pathways involved in the immunomodulatory effects induced by Fasciola hepatica products. [ABSTRACT FROM AUTHOR]

This study was the first to investigate the direct effects of anomalous concentrations of ozone mediated by summer heat waves on seed germination in alpine plants. During germination, the seeds were exposed to three peaks of O3concentration (125 ppb for 5 and 10 days; 185 ppb for 5 days), derived from measurements taken close to the species growing site. High O3concentration delayed the first germination time, increased the mean germination time, and reduced the germination percentage during and immediately after the treatment, but, in most cases, effects were weak and had almost vanished three weeks after the treatments. In few cases, chronic exposure to O3(125 for 10 days’ treatment) enhanced seed germination compared to the control, suggesting that ozone may induce antioxidant and DNA-repair mechanisms or dormancy-breaking effects in hydrated seeds. Although seed mortality increased during O3treatments in four species, the effect of O3on seed germination is mostly limited to the period of exposure, indicating that it is unlikely to produce permanent negative effects on seeds, during the germination phase. Our results show that the direct effect of O3on seeds of alpine plants may have minor impacts on plant reproductive performance during seed germination. [ABSTRACT FROM PUBLISHER]

Portal hypertension (PH) constitutes a pivotal factor in the progression of cirrhosis, giving rise to severe complications and a diminished survival rate. The transjugular intrahepatic portosystemic shunt (TIPS) procedure has undergone significant evolution, with advancements in stent technology assuming a central role in managing PH-related complications. This review aims to outline the progression of TIPS and emphasizes the significant influence of stent advancement on its effectiveness. Initially, the use of bare metal stents (BMSs) was limited due to frequent dysfunction. However, the advent of expanding polytetrafluoroethylene-covered stent grafts (ePTFE-SGs) heralded a transformative era, greatly enhancing patency rates. Further innovation culminated in the creation of ePTFE-SGs with controlled expansion, enabling precise adjustment of TIPS diameters. Comparative analyses demonstrated the superiority of ePTFE-SGs over BMSs, resulting in improved patency, fewer complications, and higher survival rates. Additional technical findings highlight the importance of central stent placement and adequate stent length, as well as the use of smaller calibers to reduce the risk of shunt-related complications. However, improving TIPS through technical means alone is inadequate for optimizing patient outcomes. An extensive understanding of hemodynamic, cardiac, and systemic factors is required to predict outcomes and tailor a personalized approach. Looking forward, the ongoing progress in SG technology, paired with the control of clinical factors that can impact outcomes, holds the promise of reshaping the management of PH-related complications in cirrhosis. [ABSTRACT FROM AUTHOR]

Fasciola hepatica excretory-secretory products (FhESP) induce immunomodulatory effects on macrophages. Previously, we demonstrated that these effects are dependent on Dectin-1. Therefore, the aim of this study was to determine how this affects the CD4 T-cells immune response. We observed that FhESP induce an increased expression of PD-L2 in macrophages via Dectin-1. Furthermore, in co-cultures with CD4 T-cell we observed a suppressive effect on proliferative response, down-modulation of IFN-γ and up-modulation of IL-10 via Dectin-1 on macrophages. These results suggest that FhESP induce T-cell anergy via selective up-regulation of PD-L2 expression on macrophages in a Dectin-1 dependent way. [ABSTRACT FROM AUTHOR]

Abstract: Immunomodulatory properties have been described for Fasciola hepatica excretory–secretory products (FhESP), with their interaction with the innate immune cells being crucial during the early stages of infection. Previously, we demonstrated that FhESP induce eosinophil apoptosis. In this work, the ability of FhESP to induce apoptosis of peritoneal macrophages was evaluated. These parasite products were observed to induce apoptosis in peritoneal macrophages stimulated in vitro with FhESP, as well as in cells recovered from infected mice. The ability of FhESP to modify the viability of macrophages by apoptosis induction may constitute a crucial event for extending its survival in the host. [Copyright &y& Elsevier]

The ability of total homogenate (TH) of Fasciola hepatica conjugated with aluminium hydroxide (alum) or Freund's complete adjuvant (FCA) to protect cattle against experimental fasciolosis was evaluated. Compared with the infected group, the immunized animals with alum-TH and FCA-TH presented a significant reduction in fluke burden (85.9% and 96.8%, respectively), a higher percentage of short-sized worms, a marked reduction in the released eggs in faeces (89% and 57%, respectively), as well as an increased production of specific antibodies before infection. The alum-TH immunized group also showed a significant increase in the antigen-specific proliferation of peripheral blood mononuclear cells (PBMC) as early as 4 weeks before infection. Although both immunized groups (alum-TH and FCA-TH) were able to develop an efficient protective immune response to metacercarial challenge, an earlier PBMC response, lower hepatic damage and less effect on weight gain were found in alum-immunized animals. Therefore, alum is a good candidate for future immunization against bovine fasciolosis. [ABSTRACT FROM PUBLISHER]

Fasciola hepatica releases excretory-secretory products (FhESP), and immunomodulatory properties have been described for the carbohydrates present in these parasite products. The interaction of FhESP with the innate immune cells, such as macrophages, is crucial in the early stage of infection. In this work we observed that peritoneal macrophages from naive BALB/c mice stimulated in vitro with FhESP presented: an increased arginase activity as well as Arginase I expression, and high levels of transforming growth factor-β and interleukin-10. A similar macrophage population was also observed in the peritoneum of infected mice. A partial inhibition of the immunomodulatory effects described above was observed when macrophages were pre-incubated with Mannan, anti-mannose receptor, Laminarin or anti-Dectin-1, and then stimulated with FhESP. In addition, we observed a partial inhibition of these effects in macrophages obtained from mice that were intraperitoneally injected with Mannan or Laminarin before being infected. Taken together, these results suggest the participation of at least two C-type lectin receptors, mannose receptor and Dectin-1, in the interaction of FhESP with macrophages, which allows this parasite to induce immunoregulatory effects on these important innate immune cells and may constitute a crucial event for extending its survival in the host. [ABSTRACT FROM AUTHOR]

Muscle regeneration provides a paradigm by which to study how extrinsic signals coordinate gene expression in somatic stem cells (satellite cells) by directing the genome distribution of chromatin-modifying complexes. Understanding the signal-dependent control of the epigenetic events underlying the transition of muscle stem cells through sequential regeneration stages holds the promise to reveal new targets for selective interventions toward repairing diseased muscles. This review describes the latest findings on how regeneration cues are integrated at the chromatin level to build the transcription network that regulates progression of endogenous muscle progenitors throughout the myogenic program. In particular, we describe how specific epigenetic signatures can confer responsiveness to extrinsic cues on discrete regions of the muscle stem cell genome. [Copyright &y& Elsevier]

Abstract: Eosinophils (Eo) are typically associated with immune response to helminth. Previously, we demonstrated that excretory–secretory products (ESP) from Fasciola hepatica induce eosinophil apoptosis by a caspase-dependent mechanism. In this study, we observed that ESP caused mitochondrial-membrane depolarization of eosinophils leading to the release of cytochrome c. Also, ESP induced an increase in the reactive oxygen species (ROS) production, which preceded the mitochondrial injury. We found a significant rise in hydrogen peroxide, but not in the anion superoxide levels. Furthermore, catalase, but not superoxide dismutase, inhibited the mitochondrial depolarization as well as apoptosis. So, ESP induce in Eo an early increase in the ROS production, mainly hydrogen peroxide, which precedes mitochondrial injury and leads again to apoptosis. Finally, we demonstrated the participation of hydrogen peroxide in the peritoneal Eo apoptosis in vivo, both during the early stages of experimental fasciolosis in rats and after intraperitoneal ESP treatment. [Copyright &y& Elsevier]

Abstract: Eosinophils (Eo) are known to be important effector cells in the host defense against helminth parasites. Excretory-secretory products (ESP) released by helminths have shown wide immunomodulatory properties, such as the induction of cellular apoptosis. We investigated the ability of ESP from Fasciola hepatica to induce Eo apoptosis. In this work, we observed that ESP induced an early apoptosis of rat peritoneal eosinophils and that this phenomenon was time- and concentration-dependent. Furthermore, we demonstrated that activation of protein tyrosine kinases (TyrK) and caspases were necessary to mediate the Eo apoptosis induced by the ESP, and that carbohydrate components present in these antigens were involved in this effect. We have described for the first time the ability of ESP from F. hepatica to modify the viability of Eo by apoptosis induction. Besides that, we have observed Eo apoptosis in the liver of rats 21 days after F. hepatica infection. The diminution in Eo survival in early infection could be a parasite strategy in order to prevent a host immune response. [Copyright &y& Elsevier]

The Rb/E2F complex represses S-phase genes both in cycling cells and in cells that have permanently exited from the cell cycle and entered a terminal differentiation pathway. Here we show that S-phase gene repression, which involves histone-modifying enzymes, occurs through distinct mechanisms in these two situations. We used chromatin immunoprecipitation to show that methylation of histone H3 lysine 9 (H3K9) occurs at several Rb/E2F target promoters in differentiating cells but not in cycling cells. Furthermore, phenotypic knock-down experiments using siRNAs showed that the histone methyltransferase Suv39h is required for histone H3K9 methylation and subsequent repression of S-phase gene promoters in differentiating cells, but not in cycling cells. These results indicate that the E2F target gene permanent silencing mechanism that is triggered upon terminal differentiation is distinct from the transient repression mechanism in cycling cells. Finally, Suv39hdepleted myoblasts were unable to express early or late muscle differentiation markers. Thus, appropriately timed H3K9 methylation by Suv39h seems to be part of the control switch for exiting the cell cycle and entering differentiation. [ABSTRACT FROM AUTHOR]

To investigate the role of DNA double strand breaks (DSBs) and of their repair in gene amplification, we analyzed this process in the V3 Chinese hamster cell line and in the parental line AA8, after exposure to γ-rays and to hydrogen peroxide (H2O2). V3 is defective in DSB repair because of a mutation in the DNA-dependent protein kinase catalytic subunit (DNA-PKcs) gene, a gene involved in the non-homologous end-joining pathway. As a measure of gene amplification we used the frequency of colonies resistant to N-(phosphonacetyl)-l-aspartate (PALA), since in rodent cells PALA resistance is mainly achieved through the amplification of the CAD (carbamyl-p-synthetase, aspartate transcarbamylase, dihydro-orotase) gene. After treatment with different doses of γ-rays and of H2O2, we found a dose related increase in the frequency of gene amplification and of chromosome aberrations. When the same doses of damaging agents were used, these increments were higher in V3 than in AA8. These results indicate that DSBs that are not efficiently repaired can be responsible for the induction of gene amplification. H2O2 stimulates gene amplification as well as γ-rays, however, at similar levels of amplification induction, chromosome damage was about 50% lower. This suggests that gene amplification can be induced by H2O2 through pathways alternative to a direct DNA damage. Stimulation of gene amplification by H2O2, which is one of the products of the aerobic metabolism, supports the hypothesis that cellular metabolic products themselves can be a source of genome instability. [ABSTRACT FROM AUTHOR]

It is known that the current flow in high quality Ag-sheathed (Bi,Pb)[sub 2]Sr[sub 2]Ca[sub 2]Cu[sub 3]O[sub 10+x] tapes shows a clear inhomogeneous behavior, as demonstrated by earlier magneto-optical experiments. In order to study this effect in detail we have extracted single filaments from a multifilamentary Ag-sheathed Bi(2223) tape, prepared by the Oxide-Powder-In-Tube technique. The filaments have been isolated by chemical etching of the silver matrix, and individually characterised according to their position inside the conductor. Different series of measurements have been performed on each filament: magnetisation hysteresis loops and zero field cooled DC susceptibility by SQUID magnetometry, electrical resistivity by the fourprobe method, Bi(2223) phase purity and texture by XRD analysis, and local stoichiometry by SEM/EDX analysis. The microstructure analysis, in particular the study of the c-axis parameter and the microprobe analysis have revealed a higher Pb content (matching the starting stoichiometry ) in the innermost filament. In addition to this result, it has been found by magnetisation measurements that the innermost filament carries a critical current density of 53 kA/cm² ( at 77 K ), i.e. a factor of two larger than for all the filaments of the outer shell ( with j[sub c] ranging between 25 and 40 kA/cm² ). This result is in quantitative agreement with the room temperature electrical resistivity measurements performed on the same samples. [ABSTRACT FROM AUTHOR]

Use of propellants with high global warming potential (such as HFA-134a) for pressurised metered-dose inhalers (pMDIs) is being phased down. Switching to dry-powder inhalers may not be clinically feasible for all patients; an alternative is reformulation using propellants with low global warming potential. The combination of beclometasone dipropionate/formoterol fumarate/glycopyrronium bromide (BDP/FF/GB) is available for asthma or chronic obstructive pulmonary disease via pMDI using HFA-134a as propellant. This is being reformulated using the low global warming potential propellant HFA-152a. This manuscript reports three studies comparing BDP/FF/GB pharmacokinetics delivered via pMDI using HFA-152a vs HFA-134a. The studies were four-way crossover, single-dose, randomised, double-blind, in healthy volunteers. In Studies 1 and 2, subjects inhaled four puffs of BDP/FF/GB (Study 1: 100/6/12.5 μg [medium-strength BDP]; Study 2: 200/6/12.5 μg [high-strength]), ingesting activated charcoal in two of the periods (once per propellant). In Study 3, subjects inhaled medium- and high-strength BDP/FF/GB using a spacer. All three studies compared HFA-152a vs HFA-134a in terms of lung availability and total systemic exposure of beclometasone-17-monopropionate (B17MP; active metabolite of BDP), BDP, formoterol and GB. Bioequivalence was concluded if the 90 % confidence intervals (CIs) of the ratios between formulations of the geometric mean maximum plasma concentration (C max) and area under the plasma concentration–time curve between time zero and the last quantifiable timepoint (AUC 0–t) for the analytes were between 80 and 125 %. In Studies 1 and 2, systemic exposure bioequivalence (i.e., comparisons without charcoal block) was demonstrated, except for GB C max in Study 2 (upper 90 % CI 125.11 %). For lung availability (i.e., comparisons with charcoal block), B17MP and formoterol demonstrated bioequivalence in both studies, as did BDP in Study 2; in Study 1, BDP upper CIs were 126.96 % for C max and 127.34 % for AUC 0–t). In Study 1, GB AUC 0–t lower CI was 74.54 %; in Study 2 upper limits were 135.64 % for C max and 129.12 % for AUC 0–t. In Study 3, the bioequivalence criteria were met for BDP, B17MP and formoterol with both BDP/FF/GB strengths, and were met for GB AUC 0–t , although not for C max. Both formulations were similarly well tolerated in all three studies. Overall, while formal bioequivalence cannot be concluded for all analytes, these data suggest therapeutic equivalence of the new formulation with the existing BDP/ FF /GB pMDI formulation, therefore supporting reformulation using a propellant with low global warming potential. • Use of propellants with high global warming potential (such as HFA-134a) inpMDIs is being phased down. • The combination of BDP/FF/GB is now being reformulated using the low global warming potential propellant HFA-152a. • These three studies compared BDP/FF/GB pharmacokinetics when delivered via pMDI using HFA-152a vs HFA-134a as propellant. • Overall, these data suggest therapeutic equivalence of the new formulation and the existing BDP/FF/GB pMDI formulation. [ABSTRACT FROM AUTHOR]

Premise: Climate warming has altered the start and end of growing seasons in temperate regions. Ultimately, these changes occur at the individual level, but little is known about how previous seasonal life‐history events, temperature, and plant‐resource state simultaneously influence the spring and autumn phenology of plant individuals. Methods: We studied the relationships between the timing of leaf‐out and shoot senescence over 3 years in a natural population of the long‐lived understory herb Lathyrus vernus and investigated the effects of spring temperature, plant size, reproductive status, and grazing on spring and autumn phenology. Results: The timing of leaf‐out and senescence were consistent within individuals among years. Leaf‐out and senescence were not correlated with each other within years. Larger plants leafed out and senesced later, and size had no effect on growing season length. Reproductive plants leafed out earlier and had longer growing seasons than nonreproductive plants. Grazing had no detectable effects on phenology. Colder spring temperatures delayed senescence in two of three study years. Conclusions: The timing of seasonal events, such as leaf‐out and senescence in plants can be expressed largely independently within and among seasons and are influenced by different factors. Growing season start and length can often be dependent on plant condition and reproductive status. Knowledge about the drivers of growing season length of individuals is essential to more accurately predict species and community responses to environmental variation. [ABSTRACT FROM AUTHOR]

Citizen science has grown in importance in recent years: many projects have been launched and records are being collected on an unprecedented scale. However, certain less charismatic invertebrate groups are still underreported and the accuracy and quality of their records in crowd-sourced citizen-science projects have rarely been investigated. Here, we used expert review to conduct quality control of nonmarine mollusc observations from central Italy on the online citizen-science platform iNaturalist (https://www.inaturalist.org/). As of December 2019, c. 400 observations of nonmarine molluscs had been reported from Tuscany on iNaturalist. Most records (59.4%) were identified to species level by the iNaturalist community and included a total of 90 taxa, providing interesting new chorological data of certain entities. Although identification of more than half the observations uploaded by the community was confirmed by expert malacologists, some major issues emerged: low quality of photographic vouchers; bias in favour of a few large common species; poor taxonomic knowledge producing incorrect identifications; and difficulty of identifying many taxa without anatomical study. Expert review remains an essential tool for verification and improvement of data quality in citizen-science projects. In this regard, information on the main diagnostic characters of the more common species (e.g. certain medium–large-sized snails and slugs) as well as tips on how to take good quality photographic images could be provided to volunteers in the form of simple guides and tutorials. High-quality training resources to support recorders and regular feedback and teamwork between scientists and citizens could prevent unverified or inaccurate records from impairing the accuracy of citizen-science datasets and offer a real opportunity to discover and conserve less charismatic taxa. [ABSTRACT FROM AUTHOR]

Overt hepatic encephalopathy (OHE) is a major complication of transjugular intrahepatic portosystemic shunt (TIPS) placement, given its high incidence and possibility of refractoriness to medical treatment. Nevertheless, the impact of post-TIPS OHE on mortality has not been investigated in a large population. We designed a multicenter, non-inferiority, observational study to evaluate the mortality rate at 30 months in patients with and without OHE after TIPS. We analyzed a database of 614 patients who underwent TIPS in three Italian centers and estimated the cumulative incidence of OHE and mortality with competitive risk analyses, setting the non-inferiority limit at 0.12. During a median follow-up of 30 months (IQR 12-30), 293 patients developed at least one episode of OHE. Twenty-seven (9.2%) of them experienced recurrent/persistent OHE. Patients with OHE were older (64 [57-71] vs. 59 [50-67] years, p < 0.001), had lower albumin (3.1 [2.8-3.5] vs. 3.25 [2.9-3.6] g/dl, p = 0.023), and had a higher prevalence of pre-TIPS OHE (15.4% vs. 9.0%, p = 0.023). Child-Pugh and MELD scores were similar. The 30-month difference in mortality between patients with and without post-TIPS OHE was 0.03 (95% CI -0.042 to 0.102). Multivariable analysis showed that age (subdistribution hazard ratio 1.04, 95% CI 1.02–1.05, p < 0.001) and MELD score (subdistribution hazard ratio 1.09, 95% CI 1.05–1.13, p < 0.001), but not post-TIPS OHE, were associated with a higher mortality rate. Similar results were obtained when patients undergoing TIPS for variceal re-bleeding prophylaxis (n = 356) or refractory ascites (n = 258) were analyzed separately. The proportion of patients with persistent OHE after TIPS was significantly higher in the group of patients who died. The robustness of these results was increased following propensity score matching. Episodic OHE after TIPS is not associated with mortality in patients undergoing TIPS, regardless of the indication. Overt hepatic encephalopathy (OHE) is a common complication in patients with advanced liver disease and it is particularly frequent following transjugular intrahepatic portosystemic shunt (TIPS) placement. In patients with cirrhosis outside the setting of TIPS, the development of OHE negatively impacts survival, regardless of the severity of cirrhosis or the presence of acute-on-chronic liver failure. In this multicenter, non-inferiority, observational study we demonstrated that post-TIPS OHE does not increase the risk of mortality in patients undergoing TIPS, irrespective of the indication. This finding alleviates concerns regarding the weight of this complication after TIPS. Intensive research to improve patient selection and risk stratification remains crucial to enhance the quality of life of patients and caregivers and to avoid undermining the positive effects of TIPS on survival. [Display omitted] • In patients with cirrhosis outside the setting of TIPS, the development of OHE negatively impacts survival. • OHE is considered a major complication in patients treated with TIPS. • We show that post-TIPS episodic OHE does not increase the risk of death in patients undergoing TIPS, irrespective of the indication. • This finding alleviates concerns regarding the impact of this complication on survival after TIPS. [ABSTRACT FROM AUTHOR]

We report a case of Enterocytozoon bieneusi infection in a pediatric hematopoietic stem cell transplant recipient in Argentina. Spores were visualized in feces using Calcofluor White and modified trichrome stainings. PCR and sequencing identified E. bieneusi genotype D in fecal samples and liver samples, confirming extraintestinal dissemination of the parasite. [ABSTRACT FROM AUTHOR]

In individuals with compensated advanced chronic liver disease (cACLD), the severity of portal hypertension (PH) determines the risk of decompensation. Invasive measurement of the hepatic venous pressure gradient (HVPG) is the diagnostic gold standard for PH. We evaluated the utility of machine learning models (MLMs) based on standard laboratory parameters to predict the severity of PH in individuals with cACLD. A detailed laboratory workup of individuals with cACLD recruited from the Vienna cohort (NCT03267615) was utilised to predict clinically significant portal hypertension (CSPH, i.e., HVPG ≥10 mmHg) and severe PH (i.e. , HVPG ≥16 mmHg). The MLMs were then evaluated in individual external datasets and optimised in the merged cohort. Among 1,232 participants with cACLD, the prevalence of CSPH/severe PH was similar in the Vienna (n = 163, 67.4%/35.0%) and validation (n = 1,069, 70.3%/34.7%) cohorts. The MLMs were based on 3 (3P: platelet count, bilirubin, international normalised ratio) or 5 (5P: +cholinesterase, +gamma-glutamyl transferase, +activated partial thromboplastin time replacing international normalised ratio) laboratory parameters. The MLMs performed robustly in the Vienna cohort. 5P-MLM had the best AUCs for CSPH (0.813) and severe PH (0.887) and compared favourably to liver stiffness measurement (AUC: 0.808). Their performance in external validation datasets was heterogeneous (AUCs: 0.589-0.887). Training on the merged cohort optimised model performance for CSPH (AUCs for 3P and 5P: 0.775 and 0.789, respectively) and severe PH (0.737 and 0.828, respectively). Internally trained MLMs reliably predicted PH severity in the Vienna cACLD cohort but exhibited heterogeneous results on external validation. The proposed 3P/5P online tool can reliably identify individuals with CSPH or severe PH, who are thus at risk of hepatic decompensation. We used machine learning models based on widely available laboratory parameters to develop a non-invasive model to predict the severity of portal hypertension in individuals with compensated cirrhosis, who currently require invasive measurement of hepatic venous pressure gradient. We validated our findings in a large multicentre cohort of individuals with advanced chronic liver disease (cACLD) of any cause. Finally, we provide a readily available online calculator, based on 3 (platelet count, bilirubin, international normalised ratio) or 5 (platelet count, bilirubin, activated partial thromboplastin time, gamma-glutamyltransferase, choline-esterase) widely available laboratory parameters, that clinicians can use to predict the likelihood of their patients with cACLD having clinically significant or severe portal hypertension. [Display omitted] • Models that can non-invasively assess portal hypertension severity are an unmet clinical need. • Machine learning models trained on 3/5 laboratory parameters enabled non-invasive assessment of portal hypertension severity. • These models could predict portal pressures of ≥10 mmHg or ≥16 mmHg in individuals with compensated cirrhosis. • An online tool based on these models has been made available and can be used for portal hypertension risk stratification. [ABSTRACT FROM AUTHOR]

Buccal administration of sumatriptan succinate might be an interesting alternative to the present administration routes, due to its non-invasiveness and rapid onset of action, but because of its low permeability, a permeation enhancement strategy is required. The aim of this work was then to study, in-vitro , buccal iontophoresis of sumatriptan succinate. Permeation experiments were performed in-vitro across pig esophageal epithelium, a recently proposed model of human buccal mucosa, using vertical diffusion cells. The iontophoretic behavior of the tissue was characterized by measuring its isoelectric point (Na + transport number and the electroosmotic flow of acetaminophen determination) and by evaluating tissue integrity after current application. The results obtained confirm the usefulness of pig esophageal epithelium as an in-vitro model membrane for buccal drug delivery. The application of iontophoresis increased sumatriptan transport, proportionally to the current density applied, without tissue damage: electrotransport was the predominant mechanism. Integrating the results of the present work with literature data on the transport of other molecules across the buccal mucosa and across the skin, we can draw a general conclusion: the difference in passive transport across buccal mucosa and across the skin is influenced by permeant lipophilicity and by the penetration pathway. Finally, buccal iontophoretic administration of sumatriptan allows to administer 6 mg of the drug in 1 h, representing a promising alternative to the current administration routes. [ABSTRACT FROM AUTHOR]

Vitamin D is a crucial nutrient with many pleiotropic effects on health and various chronic diseases. The purpose of this review is to provide a detailed report on the pathophysiological mechanisms underlying vitamin D deficiency in patients with chronic liver disease, addressing the different liver etiologies and the condition of advanced chronic liver disease (cirrhosis) with related complications. To date, patients with liver disease, regardless of underlying etiology, have been shown to have reduced levels of vitamin D. There is also evidence of the predictive role of vitamin D values in complications and progression of advanced disease. However, specific indications of vitamin D supplementation are not conclusive concerning what is already recommended in the general population. Future studies should make an effort to unify and validate the role of vitamin D supplementation in chronic liver disease. [ABSTRACT FROM AUTHOR]

• Mannitol is a hyperosmotic agent administered BID via dry-powder inhaler for CF. • This study provides confirmatory evidence on the use of mannitol in adults with CF. • Mannitol 400 mg BID provided significant improvements in FEV 1 versus control. • These improvements were supported by secondary pulmonary function endpoints. • Mannitol 400 mg BID was well tolerated, with few treatment-related adverse events. : Mannitol is a mucoactive hyperosmotic agent used as add-on therapy in patients with cystic fibrosis (CF), administered twice-daily (BID) via a small, portable, breath-actuated dry-powder inhaler. This study was conducted to provide confirmatory evidence of mannitol's efficacy and safety in adults. : This multicenter, double-blind, randomized, parallel-group, controlled clinical trial recruited adults (aged ≥18 years) with CF, and forced expiratory volume in 1 second (FEV 1) 40–90% predicted. Subjects received either mannitol 400 mg or mannitol 50 mg (control), BID via dry-powder inhaler for 26 weeks. Primary endpoint: FEV 1 averaged over the 26-week treatment period. : Of 423 subjects randomized (209 or 214 receiving mannitol 400 mg BID or control, respectively), 373 (88.2%) completed the study, with a similar proportion completing in the two groups. For FEV 1 averaged over 26 weeks, mannitol 400 mg BID was statistically superior to control (adjusted mean difference 54 mL [95% CI 8, 100 mL]; p = 0.020). This was supported by sensitivity analyses of the primary endpoint, and by observed improvements in secondary pulmonary function endpoints (eg, absolute adjusted mean difference in percent predicted FEV 1 averaged over 26 weeks 1.21% [0.07%, 2.36%]; p = 0.037). Adverse events were mainly mild or moderate in severity, with treatment-related adverse events in 15.5 and 12.2% of subjects receiving mannitol 400 mg BID and control, respectively. : In adults with CF, mannitol 400 mg BID inhaled as a dry-powder statistically significantly improved lung function (FEV 1) compared with control, with this improvement supported by sensitivity analyses and secondary pulmonary function endpoints. Mannitol had a good overall safety and tolerability profile. ClinicalTrials.gov: NCT02134353. [ABSTRACT FROM AUTHOR]

Background: A single-inhaler extrafine triple combination of beclometasone dipropionate (BDP), formoterol fumarate (FF) and glycopyrronium (G) has been developed for maintenance therapy of chronic obstructive pulmonary disease (COPD). This study evaluated the efficacy and safety of BDP/FF/G in patients in three eastern Asian areas: China, Republic of Korea and Taiwan.Methods: TRIVERSYTI was a double-blind, randomised, active-controlled, parallel-group study in patients with COPD, post-bronchodilator forced expiratory volume in 1 s (FEV1) < 50% predicted, ≥ 1 exacerbation in the previous 12 months, and receiving inhaled maintenance medication. Patients received either extrafine BDP/FF/G 100/6/10 µg via pressurised metered-dose inhaler, or non-extrafine budesonide/formoterol (BUD/FF) 160/4.5 µg via dry-powder inhaler, both administered as two puffs twice-daily for 24 weeks. The co-primary objectives (analysed in the overall population) were to demonstrate superiority of BDP/FF/G over BUD/FF for change from baseline in pre-dose morning and 2-h post-dose FEV1 at Week 24 (these were analysed as key secondary objectives in the China subgroup). The rate of moderate/severe COPD exacerbations was a secondary endpoint.Results: Of 708 patients randomised, 88.8% completed. BDP/FF/G was superior to BUD/FF for pre-dose and 2-h post-dose FEV1 at Week 24 [adjusted mean differences 62 (95% CI 38, 85) mL and 113 (87, 140) mL; both p < 0.001]. The annualised moderate/severe exacerbation rate was 43% lower with BDP/FF/G [rate ratio 0.57 (95% CI 0.42, 0.77); p < 0.001]. Adverse events were reported by 61.1% and 67.0% patients with BDP/FF/G and BUD/FF. Results were similar in the China subgroup.Conclusions: In patients with COPD, FEV1 < 50% and an exacerbation history despite maintenance therapy, treatment with extrafine BDP/FF/G improved bronchodilation, and was more effective at preventing moderate/severe COPD exacerbations than BUD/FF. Trial registration CFDA CTR20160507 (registered 7 Nov 2016, http://www.chinadrugtrials.org.cn/index.html ). [ABSTRACT FROM AUTHOR]

Background: Evidence is scarce on the relative risk-benefit of inhaled triple therapy, consisting of inhaled corticosteroid, long-acting muscarinic antagonist, and long-acting β2-agonist, versus dual bronchodilation for chronic obstructive pulmonary disease (COPD). We aimed to compare a single-inhaler triple combination of beclometasone dipropionate, formoterol fumarate, and glycopyrronium (BDP/FF/G) versus a single-inhaler dual bronchodilator combination of indacaterol plus glycopyrronium (IND/GLY) in terms of the rate of moderate-to-severe COPD exacerbations over 52 weeks of treatment.Methods: This randomised, parallel-group, double-blind, double-dummy study was done at 187 sites across 17 countries. Eligible patients had symptomatic COPD, severe or very severe airflow limitation, at least one moderate or severe exacerbation in the previous year, and were receiving inhaled maintenance medication. After a 2 week run-in period with one inhalation per day of IND/GLY (85 μg/43 μg), patients were randomly assigned (1:1), via an interactive response technology system, to receive 52 weeks of treatment with two inhalations of extrafine BDP/FF/G (87 μg/5 μg/9 μg) twice per day or one inhalation of IND/GLY (85 μg/43 μg) per day. Randomisation was stratified by country and severity of airflow limitation. The primary endpoint was the rate of moderate-to-severe COPD exacerbations across 52 weeks of treatment in all randomised patients who received at least one dose of study drug and had at least one post-baseline efficacy assessment. Safety was assessed in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT02579850.Findings: Between May, 29 2015, and July 10, 2017, 1532 patients received BDP/FF/G (n=764) or IND/GLY (n=768). Moderate-to-severe exacerbation rates were 0·50 per patient per year (95% CI 0·45-0·57) for BDP/FF/G and 0·59 per patient per year (0·53-0·67) for IND/GLY, giving a rate ratio of 0·848 (0·723-0·995, p=0·043) in favour of BDP/FF/G. Adverse events were reported by 490 (64%) of 764 patients receiving BDP/FF/G and 516 (67%) of 768 patients receiving IND/GLY. Pneumonia occurred in 28 (4%) patients receiving BDP/FF/G versus 27 (4%) patients receiving IND/GLY. One treatment-related serious adverse event occurred in each group: dysuria in a patient receiving BDP/FF/G and atrial fibrillation in a patient receiving IND/GLY.Interpretation: In patients with symptomatic COPD, severe or very severe airflow limitation, and an exacerbation history despite maintenance therapy, extrafine BDP/FF/G significantly reduced the rate of moderate-to-severe exacerbations compared with IND/GLY, without increasing the risk of pneumonia.Funding: Chiesi Farmaceutici. [ABSTRACT FROM AUTHOR]

Durum wheat ( Triticum durum L.) plays a key role for Italian agriculture and for world pasta production. Wheat production largely depends on weather. The aim of this study is to develop an operational tool to supply early forecasts of the final yield. Early forecasts will provide information for a more effective crop management that will help minimizing the uncertainty related to crop production. The climate impact on the yield, and the ability of the Leaf Area Index (LAI) to describe the environmental influences on the crop, were assessed through the model CERES-wheat in a long-term analysis. The results showed a highly significant correlation between yield and the rainfall during the leaf growth and plant tillering stages. A highly significant correlation was also found between yield and the LAI reached at the end of the vegetative season. Then, the number of March non-rainy days and the April LAI were used as independent variables in a multi-regressive model for the final yield estimation. The model was validated with ground measurements to test its ability as a simplified forecasting index. The resulting yield estimates showed highly significant correlation with those observed. The results showed that the forecasting index is suitable for operational farming applications, being able to provide, with a few input data, the first forecasts in early April well in advance to maturity. [ABSTRACT FROM AUTHOR]

Mechanisms of transcriptional repression are important during cell differentiation. Mammalian heterochromatin protein 1 isoforms HP1α, HP1β, and HP1γ play important roles in the regulation of chromatin structure and function. We explored the possibility of different roles for the three HP1 isoforms in an integrated system, skeletal muscle terminal differentiation. In this system, terminal differentiation is initiated by the transcription factor MyoD, whose target genes remain mainly silent until myoblasts are induced to differentiate. Here we show that HP1α and HP1β isoforms, but not HP1γ, interact with MyoD in myoblasts. This interaction is direct, as shown using recombinant proteins in vitro. A gene reporter assay revealed that HP1α and HP1β, but not HP1γ, inhibit MyoD transcriptional activity, suggesting a model in which MyoD could serve as a bridge between nucleosomes and chromatin-binding proteins such as HDACs and HP1. Chromatin immunoprecipitation assays show a preferential recruitment of HP1 proteins on MyoD target genes in proliferating myoblasts. Finally, modulation of HP1 protein level impairs MyoD target gene expression and muscle terminal differentiation. Together, our data show a nonconventional interaction between HP1 and a tissue-specific transcription factor, MyoD. In addition, they strongly suggest that HP1 isoforms play important roles during muscle terminal differentiation in an isoform-dependent manner. [ABSTRACT FROM AUTHOR]

Studies anisotropic texture development during the Bi(2223)/Ag multifilamentary superconducting tape processing. Magnetic study of texturing; Transverse and longitudinal angles at various steps of the thermo-mechanical process for different multifilamentary tapes; X-ray diffraction patterns of multifilamentary superconductors.

We have studied the response of long superconducting (Bi,Pb)[sub 2]Sr[sub 2]Ca[sub 2]Cu[sub 3]O[sub 10] based conductors fabricated by the Oxide Powder In Tube method when exposed to a radiofrequency magnetic field excitation. In particular, we have characterized their properties when employed as a part of L-C resonators typical of pick-up coil devices in Magnetic Resonance Imaging. In these conditions, Bi(2223) conductors cooled down to 77 K have shown superior properties compared to already optimized copper based devices: tri-dimensional superconducting pick-up coils conceived for a resonance frequency between 6 and 9 MHz present an improvement of the quality factor Q by more than an order of magnitude, and an increase of the signal-to-noise ratio by a factor larger than three. This promising result opens new perspectives for Bi-based conductors in the field of the detection of weak high frequency signals. [ABSTRACT FROM AUTHOR]

We have developed a method that allows, by a simple set of magnetic measurements, to study the texturing of the grains inside a BSCCO-Ag tape. Because the texture is anisotropie we define the angle ...[sub L] that identifies the mean grain misalignment angle with respect to the tape surface in longitudinal direction (i.e. rolling direction) and the angle ...[sub T] in transverse direction. The technique is based on the assumption that, because of the very high anisotropy of the critical current density in BSCCO superconducting compounds, the magnetic moment is essentially generated by the current circulating in the a-b planes of the BSCCO grains. The different magnetisation cycles, measured when the orientation of the magnetic field with respect to the tape surface is changed, depend only on the grain orientation inside the tape, which determines the effective magnetic field component normal to the a-b planes of the grains. Here we present the texture evolution of the BSCCO grains inside silver sheated multifilamentary tape starting from the initial steps of the mechanical deformation up to the final heating stage. The results obtained from the magnetic method are compared with those obtained with other methods, i.e. X-ray diffraction and critical current density anisotropy. Also results obtained on samples prepared in different way will be presented. [ABSTRACT FROM AUTHOR]