Aliment Pharmacol Ther 28, 312–325
Summary
Background Post‐operative ileus (POI) affects most patients undergoing abdominal surgery.
Aim To evaluate the effect of alvimopan, a peripherally acting ...mu‐opioid receptor antagonist, on POI by negating the impact of opioids on gastrointestinal (GI) motility without affecting analgesia in patients outside North America.
Methods Adult subjects undergoing open abdominal surgery (n = 911) randomly received oral alvimopan 6 or 12 mg, or placebo, 2 h before, and twice daily following surgery. Opioids were administered as intravenous patient‐controlled analgesia (PCA) or bolus injection. Time to recovery of GI function was assessed principally using composite endpoints in subjects undergoing bowel resection (n = 738).
Results A nonsignificant reduction in mean time to tolerate solid food and either first flatus or bowel movement (primary endpoint) was observed for both alvimopan 6 and 12 mg; 8.5 h (95% CI: 0.9, 16.0) and 4.8 h (95% CI: −3.2, 12.8), respectively. However, an exploratory post hoc analysis showed that alvimopan was more effective in the PCA (n = 317) group than in the non‐PCA (n = 318) group. Alvimopan was well tolerated and did not reverse analgesia.
Conclusion Although the significant clinical effect of alvimopan on reducing POI observed in previous trials was not reproduced, this trial suggests potential benefit in bowel resection patients who received PCA.
It is important to explore the diversity of characteristics of low-mass, low-density planets to understand the nature and evolution of this class of planets. We present a homogeneous analysis of 12 ...new and 9 previously published broad-band photometric observations of the Uranus-sized extrasolar planet GJ 3470b, which belongs to the growing sample of sub-Jovian bodies orbiting M dwarfs. The consistency of our analysis explains some of the discrepancies between previously published results and provides updated constraints on the planetary parameters. Our data are also consistent with previous transit observations of this system. The physical properties of the transiting system can only be constrained as well as the host star is characterized, so we provide new spectroscopic measurements of GJ 3470 from 0.33 to 2.42 μm to aid our analysis. We find R
* = 0.48 ± 0.04 R⊙, M
* = 0.51 ± 0.06 M⊙, and T
eff = 3652 ± 50K for GJ 3470, along with a rotation period of 20.70 ± 0.15 d and an R-band amplitude of 0.01 mag, which is small enough that current transit measurements should not be strongly affected by stellar variability. However, to report definitively whether stellar activity has a significant effect on the light curves, this requires future multiwavelength, multi-epoch studies of GJ 3470. We also present the most precise orbital ephemeris for this system: T
o
= 2455983.70472 ± 0.00021BJDTDB, P = 3.336 6487
$^{+0.000\,0043}_{-0.000\,0033}$
d, and we see no evidence for transit timing variations greater than 1 min. Our reported planet to star radius ratio is 0.076 42 ± 0.000 37. The physical parameters of this planet are R
p = 3.88 ± 0.32 R⊕ and M
p = 13.73 ± 1.61 M⊕. Because of our revised stellar parameters, the planetary radius we present is smaller than previously reported values. We also perform a second analysis of the transmission spectrum of the entire ensemble of transit observations to date, supporting the existence of an H2-dominated atmosphere exhibiting a strong Rayleigh scattering slope.
We present Hubble Space Telescope optical and near-IR transmission spectra of the transiting hot-Jupiter WASP-31b. The spectrum covers 0.3-1.7 mu m at a resolution R similar to 70, which we combine ...with Spitzer photometry to cover the full-optical to IR. The spectrum is dominated by a cloud deck with a flat transmission spectrum which is apparent at wavelengths > 0.52 mu m. The cloud deck is present at high altitudes and low pressures, as it covers the majority of the expected optical Na line and near-IR H2O features. While Na I absorption is not clearly identified, the resulting spectrum does show a very strong potassium feature detected at the 4.2- sigma confidence level. Broadened alkali wings are not detected, indicating pressures below similar to 10 mbar. The lack of Na and strong K is the first indication of a sub-solar Na/K abundance ratio in a planetary atmosphere (lnNa/K = -3.3 plus or minus 2.8), which could potentially be explained by Na condensation on the planet's night side, or primordial abundance variations. A strong Rayleigh scattering signature is detected at short wavelengths, with a 4- sigma significant slope. Two distinct aerosol size populations can explain the spectra, with a smaller sub-micron size grain population reaching high altitudes producing a blue Rayleigh scattering signature on top of a larger, lower lying population responsible for the flat cloud deck at longer wavelengths. We estimate that the atmospheric circulation is sufficiently strong to mix micron size particles upwards to the required 1-10 mbar pressures, necessary to explain the cloud deck. These results further confirm the importance of clouds in hot Jupiters, which can potentially dominate the overall spectra and may alter the abundances of key gaseous species.
The outcome of infection is dependent on the ability of viruses to manipulate the infected cell to evade immunity, and the ability of the immune response to overcome this evasion. Understanding this ...process is key to understanding pathogenesis, genetic risk factors, and both natural and vaccine-induced immunity. SARS-CoV-2 antagonises the innate interferon response, but whether it manipulates innate cellular immunity is unclear. An unbiased proteomic analysis determined how cell surface protein expression is altered on SARS-CoV-2-infected lung epithelial cells, showing downregulation of activating NK ligands B7-H6, MICA, ULBP2, and Nectin1, with minimal effects on MHC-I. This occurred at the level of protein synthesis, could be mediated by Nsp1 and Nsp14, and correlated with a reduction in NK cell activation. This identifies a novel mechanism by which SARS-CoV-2 host-shutoff antagonises innate immunity. Later in the disease process, strong antibody-dependent NK cell activation (ADNKA) developed. These responses were sustained for at least 6 months in most patients, and led to high levels of pro-inflammatory cytokine production. Depletion of spike-specific antibodies confirmed their dominant role in neutralisation, but these antibodies played only a minor role in ADNKA compared to antibodies to other proteins, including ORF3a, Membrane, and Nucleocapsid. In contrast, ADNKA induced following vaccination was focussed solely on spike, was weaker than ADNKA following natural infection, and was not boosted by the second dose. These insights have important implications for understanding disease progression, vaccine efficacy, and vaccine design.
Although the mechanism of Aβ action in the pathogenesis of Alzheimer's disease (AD) has remained elusive, it is known to increase the expression of the antagonist of canonical wnt signalling, ...Dickkopf-1 (Dkk1), whereas the silencing of Dkk1 blocks Aβ neurotoxicity. We asked if clusterin, known to be regulated by wnt, is part of an Aβ/Dkk1 neurotoxic pathway. Knockdown of clusterin in primary neurons reduced Aβ toxicity and DKK1 upregulation and, conversely, Aβ increased intracellular clusterin and decreased clusterin protein secretion, resulting in the p53-dependent induction of DKK1. To further elucidate how the clusterin-dependent induction of Dkk1 by Aβ mediates neurotoxicity, we measured the effects of Aβ and Dkk1 protein on whole-genome expression in primary neurons, finding a common pathway suggestive of activation of wnt-planar cell polarity (PCP)-c-Jun N-terminal kinase (JNK) signalling leading to the induction of genes including EGR1 (early growth response-1), NAB2 (Ngfi-A-binding protein-2) and KLF10 (Krüppel-like factor-10) that, when individually silenced, protected against Aβ neurotoxicity and/or tau phosphorylation. Neuronal overexpression of Dkk1 in transgenic mice mimicked this Aβ-induced pathway and resulted in age-dependent increases in tau phosphorylation in hippocampus and cognitive impairment. Furthermore, we show that this Dkk1/wnt-PCP-JNK pathway is active in an Aβ-based mouse model of AD and in AD brain, but not in a tau-based mouse model or in frontotemporal dementia brain. Thus, we have identified a pathway whereby Aβ induces a clusterin/p53/Dkk1/wnt-PCP-JNK pathway, which drives the upregulation of several genes that mediate the development of AD-like neuropathologies, thereby providing new mechanistic insights into the action of Aβ in neurodegenerative diseases.
Biallelic inactivation of SMARCB1, encoding a member of the SWI/SNF chromatin remodeling complex, is the hallmark genetic aberration of atypical teratoid rhabdoid tumors (ATRT). Here, we report how ...loss of SMARCB1 affects the epigenome in these tumors. Using chromatin immunoprecipitation sequencing (ChIP-seq) on primary tumors for a series of active and repressive histone marks, we identified the chromatin states differentially represented in ATRTs compared with other brain tumors and non-neoplastic brain. Re-expression of SMARCB1 in ATRT cell lines enabled confirmation of our genome-wide findings for the chromatin states. Additional generation of ChIP-seq data for SWI/SNF and Polycomb group proteins and the transcriptional repressor protein REST determined differential dependencies of SWI/SNF and Polycomb complexes in regulation of diverse gene sets in ATRTs.
•ATRT epigenomes display a global depletion of H3K27ac and H3K27me3•Neuronal genes bound by SMARCB1 in normal brain are repressed by EZH2 in ATRT•ATRT harbor many active genes occupied by EZH2 but without occupancy of H3K27me3•Residual SWI/SNF occupancy maintains genes active in the presence of Polycomb complex
Erkek et al. show that in atypical teratoid rhabdoid tumors (ATRT), which often lack the SWI/SNF complex component SMARCB1, a large fraction of SMARCB1 binding loci in normal brain is bound by EZH2 but without H3K27me3 and remains in an active state, and some of these genes are essential for ATRT survival.
•A meta-analysis was executed with 11 articles to assess depression and anxiety.•Adolescents with a visible difference experience more anxiety than unaffected peers.•No significant effects were found ...for symptoms of depression.
Living with a visible difference can entail challenging social situations, associated with psychosocial symptoms. However, it is not clear whether adolescents with a visible difference experience more anxiety and depression than unaffected peers. We aim to determine whether adolescents with a visible difference experience more symptoms of anxiety and depression than unaffected peers. A literature search was conducted in Embase, Medline Ovid, Web of Science, Cochrane CENTRAL, PsycINFO Ovid, and Google Scholar. Meta-analyses were done using random-effects models to calculate a standardised mean difference. Analyses for subgroups were used to study causes of visible difference. Eleven studies were identified (n = 1075, weighted mean age = 15.80). Compared to unaffected peers, adolescents with a visible difference experience more symptoms of anxiety (SMD = 0.253, 95 % CI 0.024, 0.482, p = .030), but not depression (SMD = 0.236, 95 % CI −0.126, 0.599, p = .202). Adolescents with a skin condition did not experience more symptoms of anxiety (SMD = 0.149, 95 % CI −0.070, 0.369, p = .182) or depression (SMD = 0.090, 95 % CI −0.082, 0.262, p = .305) when compared to unaffected peers. Overall, more symptoms of anxiety are found in adolescents with a visible difference compared to peers. No differences in anxiety or depression were found for skin differences. Screening for anxiety is recommended.
IntroductionThis paper outlines the study protocol for the Dutch Young People (YP) Face IT Study. Adolescents with a visible difference (ie, disfigurement) often experience challenging social ...situations such as being stared at, receiving unwanted questions or being teased. As a consequence, some of these adolescents experience adverse psychosocial outcomes and appearance-related distress. To address this appearance-related distress, an online psychotherapeutic intervention, YP Face IT, has been developed. YP Face IT uses social interaction skills training and cognitive–behavioural therapy. The Dutch YP Face IT Study tests whether this intervention is effective in reducing social anxiety and improving body esteem.Methods and analysisParticipants are adolescents aged 12–18 with a visible difference and experiencing appearance-related distress. In this two-armed randomised controlled trial, 224 adolescents will be randomised to care as usual or YP Face IT. Adolescents will complete questionnaires at baseline, at 13 weeks and at 25 weeks. Primary outcomes are differences in social anxiety and body esteem between YP Face IT and care as usual. Secondary outcomes are differences in aspects of self-worth, perceived stigmatisation, health-related quality of life, life engagement, appearance-related distress and depressive symptoms between the two groups.Ethics and disseminationResearch ethics approval was obtained from the medical ethics review committee in Rotterdam (reference number MEC-2018-052/NL63955.078.18). Findings will be disseminated through academic peer-reviewed publications, conferences and newsletters to patient associations and participants of the study.Trial registration numberThe Netherlands Trial Register (NL7626).
Kaposi’s sarcoma herpesvirus (KSHV) is an oncogenic human virus and the leading cause of mortality in HIV infection. KSHV reactivation from latent- to lytic-stage infection initiates a cascade of ...viral gene expression. Here we show how these changes remodel the host cell proteome to enable viral replication. By undertaking a systematic and unbiased analysis of changes to the endothelial cell proteome following KSHV reactivation, we quantify >7,000 cellular proteins and 71 viral proteins and provide a temporal profile of protein changes during the course of lytic KSHV infection. Lytic KSHV induces >2-fold downregulation of 291 cellular proteins, including PKR, the key cellular sensor of double-stranded RNA. Despite the multiple episomes per cell, CRISPR-Cas9 efficiently targets KSHV genomes. A complementary KSHV genome-wide CRISPR genetic screen identifies K5 as the viral gene responsible for the downregulation of two KSHV targets, Nectin-2 and CD155, ligands of the NK cell DNAM-1 receptor.
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•Quantitative proteomics identifies changes in host proteins induced by lytic KSHV•Targeting KSHV with CRISPR identifies CD155 and Nectin-2 as KSHV K5 substrates•Lytic KSHV downregulates protein kinase R in human endothelial cells•Kinetic profiling of lytic KSHV unravels PAA-sensitive and ORF57-dependent proteins
Gabaev et al. describe how a human oncogenic herpesvirus, KSHV, changes the proteome of endothelial cells and modulates the host immune system. By targeting KSHV with CRISPR, they show that viral K5 protein downregulates ligands for the NK cell DNAM-1 receptor and antiviral protein PKR is depleted in an K5-independent manner.
Mach-Zehnder interferometer thermooptic switches were made using a thin-silicon-on-insulator material system. The switches use single-mode strip-Si waveguides, 0.26×0.4 μm, operating at 1.5 μm. The ...waveguides were heated directly by passing current through them, resulting in switching power of 6 mW, and a rise time of 0.6 μs. By heating both arms of the interferometer differentially, so one arm is cooling while the other heating, the switching-signal input power is reduced to <100 μW. In this differential mode, the switching time can be decreased to 50 ns by pulsing the electrical input to 10 mW. Modeling indicates 10-ns-switching time would require /spl sim/23 mW of pulsed power.
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