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atal death before 28 days, and maternal infection. The findings of this review support a more conservative approach to clinical protocols and clinical decision-making particularly in low-resource settings, along the lines of the World Health Organization's ACS 2015 recommendations, which take into account both the established clinical efficacy of ACS when used in the correct situation and context, and the possibility of important adverse effects when certain conditions are not met. Given the unanticipated results of the ACT trial, further research on strategies to optimise the use of ACS in low-resource settings is justified.Epoxyeicosatrienoic acids (EETs) derived from arachidonic acid exert anti-inflammation effects. We have reported that blocking the degradation of EETs with a soluble epoxide hydrolase (sEH) inhibitor protects mice from lipopolysaccharide (LPS)-induced acute lung injury (ALI). The underlying mechanisms remain essential questions. In this study, we investigated the effects of EETs on the activation of nucleotide-binding domain leucine-rich repeat-containing receptor, pyrin domain-containing-3 (NLRP3) inflammasome in murine macrophages. In an LPS-induced ALI murine model, we found that sEH inhibitor 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl), TPPU, profoundly attenuated the pathological injury and inhibited the activation of the NLRP3 inflammasome, characterized by the reduction of the protein expression of NLRP3, ASC, pro-caspase-1, interleukin precursor (pro-IL-1β), and IL-1β p17 in the lungs of LPS-treated mice. In vitro, primary peritoneal macrophages from C57BL/6 were primed with LPS and activated with exogenous adenosine triphosphate (ATP). TPPU treatment remarkably reduced the expression of NLRP3 inflammasome-related molecules and blocked the activation of NLRP3 inflammasome. Importantly, four EETs (5,6-EET, 8,9-EET, 11,12-EET, and 14,15-EET) inhibited the activation of NLRP3 inflammasome induced by LPS + ATP or LPS + nigericin in macrophages in various degree. While the inhibitory effect of 5,6-EET was the weakest. Mechanismly, EETs profoundly decreased the content of reactive oxygen species (ROS) and restored the calcium overload in macrophages receiving LPS + ATP stimulation. In conclusion, this study suggests that EETs inhibit the activation of the NLRP3 inflammasome by suppressing calcium overload and ROS production in macrophages, contributing to the therapeutic potency to ALI.Background Treatment of patients with Crohn's disease has evolved in recent decades, with increasing use of immunomodulatory medication since 1990 and biologicals since 1998. In parallel, there has been increased use of active disease monitoring. To what extent these changes have influenced the incidence of primary and repeat surgical resection remains debated. Methods In this nationwide cohort study, incident patients of all ages with Crohn's disease, identified in Swedish National Patient Registry between 1990 and 2014, were divided into five calendar periods of diagnosis 1990-1995 and 1996-2000 with use of inpatient registries, 2001, and 2002-2008 and 2009-2014 with use of inpatient and outpatient registries. The cumulative incidence of first and repeat abdominal surgery (except closure of stomas), by category of surgical procedure, was estimated using the Kaplan-Meier method. Results Among 21 273 patients with Crohn's disease, the cumulative incidence of first abdominal surgery within 5 years of Crohn's disease diagnosis decreased continuously from 54·8 per cent in 1990-1995 to 40·4 per cent in 1996-2000 (P less then 0·001), and again from 19·8 per cent in 2002-2008 to 17·3 per cent in 2009-2014 (P less then 0·001). Repeat 5-year surgery rates decreased from 18·9 per cent in 1990-1995 to 16·0 per cent in 1996-2000 (P = 0·009). After 2000, no further significant decreases were observed. Conclusion The 5-year rate of surgical intervention for Crohn's disease has decreased significantly, but the rate of repeat surgery has remained stable despite the introduction of biological therapy.As a multifunctional lactic acid bacterium, Lactobacillus plantarum has been proved to survive in the human gastrointestinal tract, and it can also colonize this tract. In this study, the effects of L. plantarum ATCC 14917 metabolic profile caused by initial acid-base (pH 5.5 and 8.5) stress were investigated using 1 H nuclear magnetic resonance spectroscopy and multivariate data analysis. The results showed that the metabolome mainly consisted of 14 metabolites, including the components like amino acids, sugars, organic acids, and alkaloids. According to the nontargeted principal component analysis, there was a decrease in most of the metabolites in the alkali-treated group (mainly change in PC1) except acetate, whereas the production of lactate and glycine was increased in the acid-treated group (mainly change in PC2). Furthermore, the initial alkali stress inhibits the secretion of lactic acid, as a decrease was observed in the activity of lactate dehydrogenase and acetic dehydrogenase of L. plantarum ATCC 14917 in the alkali group. All these findings revealed that alkali stress could limit the acid environment formation of L. plantarum 14917 in the fermentation process; however, low acid pH is more suitable for the growth of L. plantarum.Domestic violence affects women globally. Domestic violence in India is embedded in structures of patriarchy, cultural norms, and a conservative social structure (Biswas, 2017). Community narratives help to create meaning and impact human behavior and can be tools of empowerment (Rappaport, 1995). They can also provide an important means of detecting changes in norms. Community engagement efforts that focus on empowering communities can play an important role in creating empowering narratives. Organizational settings like grassroots agencies can play a salient role in providing opportunities for community engagement leading to the creation of new community narratives and personal stories. This study sought to examine the work of a grassroots agency in India engaged in community action aimed at social change in the response to domestic violence, with a special focus on understanding shifting community narratives related to the response to domestic violence. Based on data from semi-structured interviews, archival data, and participant-observations, and using a modified-grounded theory approach, our results identified five major themes reflecting counter narratives on domestic violence. These included (a) awareness and discourse on gender related issues, (b) framing domestic violence as a social issue, (c) supporting the empowerment of women, (d) supporting disclosure of violence, and (e) supporting intervening in cases of violence. Implications of our findings for social change work in the response to domestic violence are discussed. HIGHLIGHTS Community narratives can provide an important means of detecting changes in norms. Social movements can target and change community narratives to redefine problems. Community engagement that empowers communities can create empowering narratives. This study highlights various counter narratives in the response to domestic violence. Implications for social change work are discussed.Background & aims Despite surgical and chemotherapeutic advances, the five-year survival rate for Stage IV Hepatoblastoma (HB), the predominant pediatric liver tumor, remains at 27%. YAP1 and β-Catenin co-activation occurs in 80% of children's HB; however, a lack of conditional genetic models precludes tumor maintenance exploration. Thus, the need for a targeted therapy remains unmet. Given the predominance of YAP1 and β-Catenin activation in HB, we sought to evaluate YAP1 as a therapeutic target in HB. Approach & results We engineered the first conditional HB murine model using hydrodynamic injection to deliver transposon plasmids encoding inducible YAP1S127A , constitutive β-CateninDelN90 , and a luciferase reporter to murine liver. Tumor regression was evaluated using bioluminescent imaging, and tumor landscape characterized using RNA and ATAC sequencing, and DNA foot-printing. Here we show that YAP1S127A withdrawal mediates >90% tumor regression with survival for 230+ days in mice. YAP1 S127A withdrawal promotes apoptosis in a subset of tumor cells and in remaining cells induces a cell fate switch driving therapeutic differentiation of HB tumors into Ki-67 negative "hbHep cells" with hepatocyte-like morphology and mature hepatocyte gene expression. YAP1 S127A withdrawal drives formation of hbHeps by modulating liver differentiation transcription factor (TF) occupancy. Indeed, tumor-derived hbHeps, consistent with their reprogrammed transcriptional landscape, regain partial hepatocyte function and rescue liver damage in mice. Conclusions YAP1S127A withdrawal, without silencing oncogenic β-Catenin, significantly regresses hepatoblastoma, providing the first in vivo data to support YAP1 as a therapeutic target for HB. YAP1S127A withdrawal alone sufficiently drives long-term regression in hepatoblastoma because it promotes cell death in a subset of tumor cells and modulates transcription factor occupancy to reverse the fate of residual tumor cells to mimic functional hepatocytes.Background Lanadelumab demonstrated efficacy in preventing HAE attacks in the phase 3 HELP Study. Objective To assess time to onset of effect and long-term efficacy of lanadelumab, based on exploratory findings from the HELP Study. Methods Eligible patients with HAE type I/II received lanadelumab 150 mg every 4 weeks (q4wks), 300 mg q4wks, 300 mg q2wks, or placebo. Ad hoc analyses evaluated day 0-69 findings using a Poisson regression model accounting for overdispersion. Least-squares mean monthly HAE attack rate for lanadelumab was compared with placebo. Intrapatient comparisons for days 0-69 versus steady state (days 70-182) used a paired t-test for continuous endpoints or Kappa statistics for categorical endpoints. Results 125 patients were randomized and treated. During days 0-69, mean monthly attack rate was significantly lower with lanadelumab (0.41-0.76) versus placebo (2.04), including attacks requiring acute treatment (0.33-0.61 vs. 1.66) and moderate/severe attacks (0.31-0.48 vs. 1.33, all P ≤ 0.001). More patients receiving lanadelumab versus placebo were attack free (37.9-48.1% vs 7.3%) and responders (85.7-100% vs. 26.8%). During steady state, the efficacy of lanadelumab versus placebo was similar or improved versus days 0-69. Intrapatient differences were significant with lanadelumab 300 mg q4wks for select outcomes. Lanadelumab efficacy was durable-HAE attack rate was consistently lower versus placebo, from the first 2 weeks of treatment through study end. ALK inhibitor TEAEs were comparable during days 0-69 and 70-182. Conclusion Protection with lanadelumab started from the first dose and continued throughout the entire study period.We previously reported bidirectional gene expression regulation of the Bone Morphogenetic Proteins (BMP2, 4, & 7) in chick retinal pigment epithelium (RPE) in response to imposed optical defocus and form-deprivation (FD). This study investigated whether there are local (regional) differences in these effects. 19-day old White-Leghorn chicks wore monocular +10 or - 10 D lenses, or diffusers (FD) for 2 or 48 h, after which RPE samples were collected from both eyes, from a central circular zone (3 mm radius), and 3 mm wide annular mid-peripheral and peripheral zones in all cases. BMP2, 4, and 7 gene expression levels in RPE from treated and fellow control eyes were compared as well as differences across zones. With the +10 D lens, increased expression of both BMP2 and BMP4 genes was observed in central and mid-peripheral zones but not the peripheral zone after 2 and 48 h. In contrast, with the -10 D lens BMP2 gene expression was significantly decreased in all three zones after 2 and 48 h. Similar patterns of BMP2 gene expression were observed in all three zones after 48 h of FD.