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Professional vs . individual reference use in survivors involving close spouse assault.
RESULTS Of 1377 patients, 47% were boys with a median age of 4.0 (interquartile range 1.4-11.6) years, 1.5% (20) died, 90% were compliant with TTAA goals, 40% required PICU admission, 38% had ≥2 unique complex chronic conditions, 71% received antibiotics in ≤2 hours, and 30% had a culture-positive bacterial etiology. There were no significant associations between TTAA and outcomes. CONCLUSIONS We found no association with TTAA and any clinical outcomes, adding to the growing body of literature questioning the timing benchmark of antibiotic administration. Although the importance of antibiotics is not in question, elucidating the target TTAA may improve resource use and decrease inappropriate or unnecessary antibiotic exposure. Copyright © 2020 by the American Academy of Pediatrics.BACKGROUND Cancer projections to the current year help in policy development, planning of programs and allocation of resources. We sought to provide an overview of the expected incidence and mortality of cancer in Canada in 2020 in follow-up to the Canadian Cancer Statistics 2019 report. METHODS We obtained incidence data from the National Cancer Incidence Reporting System (1984-1991) and Canadian Cancer Registry (1992-2015). Mortality data (1984-2015) were obtained from the Canadian Vital Statistics - Death Database. All databases are maintained by Statistics Canada. Cancer incidence and mortality counts and age-standardized rates were projected to 2020 for 23 cancer types by sex and geographic region (provinces and territories) for all ages combined. RESULTS An estimated 225 800 new cancer cases and 83 300 cancer deaths are expected in Canada in 2020. The most commonly diagnosed cancers are expected to be lung overall (29 800), breast in females (27 400) and prostate in males (23 300). Lung cancer is also expected to be the leading cause of cancer death, accounting for 25.5% of all cancer deaths, followed by colorectal (11.6%), pancreatic (6.4%) and breast (6.1%) cancers. Incidence and mortality rates will be generally higher in the eastern provinces than in the western provinces. INTERPRETATION The number of cancer cases and deaths remains high in Canada and, owing to the growing and aging population, is expected to continue to increase. Although progress has been made in reducing deaths for most major cancers (breast, prostate and lung), there has been limited progress for pancreatic cancer, which is expected to be the third leading cause of cancer death in Canada in 2020. Additional efforts to improve uptake of existing programs, as well as to advance research, prevention, screening and treatment, are needed to address the cancer burden in Canada. © 2020 Joule Inc. or its licensors.The voltage-gated potassium channel Kv1.5 plays important roles in atrial repolarization and regulation of vascular tone. In the present study, we investigated the effects of mechanical stretch on Kv1.5 channels. We induced mechanical stretch by centrifuging or culturing Kv1.5-expressing HEK 293 cells and neonatal rat ventricular myocytes in low osmolarity (LO) medium, and then recorded Kv1.5 current (IKv1.5) in a normal, isotonic solution. We observed that mechanical stretch increased IKv1.5, and this increase required the intact long, proline-rich extracellular S1-S2 linker of the Kv1.5 channel. The LO-induced IKv1.5 increase also required an intact intracellular N-terminus, which contains the binding motif for endogenous Src tyrosine kinase that constitutively inhibits IKv1.5 Disrupting the Src-binding motif of Kv1.5 through N-terminal truncation or mutagenesis abolished the mechanical stretch-mediated increase in IKv1.5 Our results further showed that the extracellular S1-S2 linker of Kv1.5 communicates with the intracellular N-terminus. While the S1-S2 linker of WT Kv1.5 could be cleaved by extracellularly applied proteinase K (PK), an N-terminal truncation up to amino acid residue 209 altered the conformation of the S1-S2 linker and made it no longer susceptible to PK-mediated cleavage. In summary, the findings of our study indicate that the S1-S2 linker of Kv1.5 represents a mechanosensor that regulates the activity of this channel. By targeting the S1-S2 linker, mechanical stretch may induce a change in the N-terminal conformation of Kv1.5 that relieves Src-mediated tonic channel inhibition and results in an increase in IKv1.5. Published under license by The American Society for Biochemistry and Molecular Biology, Inc.The interplay between the transforming growth factor β (TGF-β) signaling proteins, SMAD family member 2 (SMAD2) and SMAD3, and the TGF-β inhibiting SMAD, SMAD7, seems to play a vital role in proper pancreatic endocrine development, and also in normal β cell function in adult pancreatic islets. Here, we generated conditional SMAD7 knockout mice by crossing insulin1Cre mice with SMAD7fx/fx mice. We also created a β cell-specific SMAD7 overexpressing mouse line by crossing insulin1Dre mice with HPRT-SMAD7/RosaGFP mice. We analyzed β cell function in adult islets either when SMAD7 was absent or overexpressed in β cells. Loss of SMAD7 in β cells inhibited proliferation, and SMAD7 overexpression enhanced cell proliferation. However, alterations in basic glucose homeostasis were not detectable following either SMAD7 deletion or overexpression in β cells. Our results show that either the absence or overexpression of SMAD7 affect TGF-β signaling and modulate β cell proliferation, but does not appear to alter β cell function. Reversible, SMAD7 overexpression may represent an attractive therapeutic option to enhance β cell proliferation without negative effects on β cell function. Published under license by The American Society for Biochemistry and Molecular Biology, Inc.The linear ubiquitin assembly complex (LUBAC) is an essential component of the innate and adaptive immune system. Modification of cellular substrates with linear polyubiquitin chains is a key regulatory step in signal transduction that impacts cell death and inflammatory signaling downstream of various innate immunity receptors. learn more Loss of function mutations in the LUBAC components HOIP and HOIL-1 yields a systemic autoinflammatory disease in humans, while their genetic ablation is embryonically lethal in mice. Deficiency of the LUBAC adaptor protein Sharpin results in a multi-organ inflammatory disease in mice characterized by chronic proliferative dermatitis (cpdm), which is propagated by TNFR1-induced and RIPK1-mediated keratinocyte cell death. We have previously shown that caspases-1 and -11 promoted the dermatitis pathology of cpdm mice and mediated cell death in the skin. Here, we describe a reciprocal regulation of caspase-1 and LUBAC activities in keratinocytes. We show that LUBAC interacted with caspase-1 via HOIP and modified its CARD domain with linear polyubiquitin, and that depletion of HOIP or Sharpin resulted in heightened caspase-1 activation and cell death in response to inflammasome activation, unlike what is observed in macrophages.
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