Personalizing Cancer Pain Therapy: Insights from the Rational Use of Analgesics (RUA) Group

Introduction: A previous Delphi survey from the Rational Use of Analgesics (RUA) project involving Italian palliative care specialists revealed some discrepancies between current guidelines and clinical practice with a lack of consensus on items regarding the use of strong opioids in treating cancer pain. Those results represented the basis for a new Delphi study addressing a better approach to pain treatment in patients with cancer. Methods: The study consisted of a two-round multidisciplinary Delphi study. Specialists rated their agreement with a set of 17 statements using a 5-point Likert scale (0 = totally disagree and 4 = totally agree). Consensus on a statement was achieved if the median consensus score (MCS) (expressed as value at which at least 50% of participants agreed) was at least 4 and the interquartile range (IQR) was 3–4. Results: This survey included input from 186 palliative care specialists representing all Italian territory. Consensus was reached on seven statements. More than 70% of participants agreed with the use of low dose of strong opioids in moderate pain treatment and valued transdermal route as an effective option when the oral route is not available. There was strong consensus on the importance of knowing opioid pharmacokinetics for therapy personalization and on identifying immediate-release opioids as key for tailoring therapy to patients’ needs. Limited agreement was reached on items regarding breakthrough pain and the management of opioid-induced bowel dysfunction. Conclusion: These findings may assist clinicians in applying clinical evidence to routine care settings and call for a reappraisal of current pain treatment recommendations with the final aim of optimizing the clinical use of strong opioids in patients with cancer

Searches for the Zγ decay mode of the Higgs boson and for new high-mass resonances in pp collisions at √s=13 TeV with the ATLAS detector

This article presents searches for the Zγ decay of the Higgs boson and for narrow high-mass resonances decaying to Zγ, exploiting Z boson decays to pairs of electrons or muons. The data analysis uses 36.1 fb−1 of pp collisions at √s=13 recorded by the ATLAS detector at the CERN Large Hadron Collider. The data are found to be consistent with the expected Standard Model background. The observed (expected — assuming Standard Model pp → H → Zγ production and decay) upper limit on the production cross section times the branching ratio for pp → H → Zγ is 6.6. (5.2) times the Standard Model prediction at the 95% confidence level for a Higgs boson mass of 125.09 GeV. In addition, upper limits are set on the production cross section times the branching ratio as a function of the mass of a narrow resonance between 250 GeV and 2.4 TeV, assuming spin-0 resonances produced via gluon-gluon fusion, and spin-2 resonances produced via gluon-gluon or quark-antiquark initial states. For high-mass spin-0 resonances, the observed (expected) limits vary between 88 fb (61 fb) and 2.8 fb (2.7 fb) for the mass range from 250 GeV to 2.4 TeV at the 95% confidence level

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements

ATPase-Independent Type-III Protein Secretion in Salmonella enterica.

Type-III protein secretion systems are utilized by gram-negative pathogens to secrete building blocks of the bacterial flagellum, virulence effectors from the cytoplasm into host cells, and structural subunits of the needle complex. The flagellar type-III secretion apparatus utilizes both the energy of the proton motive force and ATP hydrolysis to energize substrate unfolding and translocation. We report formation of functional flagella in the absence of type-III ATPase activity by mutations that increased the proton motive force and flagellar substrate levels. We additionally show that increased proton motive force bypassed the requirement of the Salmonella pathogenicity island 1 virulence-associated type-III ATPase for secretion. Our data support a role for type-III ATPases in enhancing secretion efficiency under limited secretion substrate concentrations and reveal the dispensability of ATPase activity in the type-III protein export process

Lengths of flagellar filaments in <i>fliHIJ</i> mutants.

<p>Plot showing the lengths of individual flagellar filaments of the <i>fliHIJ</i> mutants visualized by anti-FliC immunostaining in <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004800#pgen-1004800-g003" target="_blank">Figure 3</a> and <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004800#pgen-1004800-g004" target="_blank">Figure 4</a>. The average lengths of flagellar filaments +/− standard deviation and the number of measured filaments are presented in the upper part of the graph.</p

Flagellin protein secretion is restored in the absence of FliHIJ ATPase components by Δ<i>atpA</i>, <i>ΔflgM</i>, <i>ΔclpX</i>, and <i>fliA^H14D</i> mutations.

<p>Secreted FliC flagellin protein was analyzed by anti-FliC immunostaining in the FliC-phase locked wildtype and <i>fliHIJ</i> mutant strains. (<b>A</b>) Wildtype and <i>fliHIJ</i> mutants in combination with Δ<i>atpA</i>. (<b>B</b>) Wildtype and <i>fliHIJ</i> mutants in combination with Δ<i>flgM</i> and Δ<i>atpA</i>. (<b>C</b>) Wildtype and <i>fliHI</i> deletion mutant in combination with Δ<i>clpX</i> and Δ<i>atpA</i>. (<b>D</b>) Wildtype and <i>fliHI</i> deletion mutant in combination with <i>fliA^H14D</i> and Δ<i>atpA</i>.</p

List of <i>Salmonella enterica</i> servovar Typhimurium LT2 strains used in this study.

<p>List of <i>Salmonella enterica</i> servovar Typhimurium LT2 strains used in this study.</p

Frequency of flagellar filament formation of a <i>fliHI</i> mutant strain is increased in <i>clpX</i> null and <i>fliA^H14D</i> backgrounds.

<p>A deletion in <i>clpX</i> (<b>A</b>) and the more stable <i>fliA^H14D</i> variant (<b>B</b>) increase the frequency of flagellar filament formation in a <i>fliHI</i> mutant strain. Flagellar formation is further enhanced by combination with an <i>atpA</i> mutation. Top: A montage of representative fluorescent microscopy images is shown. Flagellar filaments were stained using anti-FliC immunostaining and detected by FITC-coupled secondary antibodies (green), DNA was stained using Hoechst (blue) and cell membranes using FM-64 (red). Scale bar 2 µm. The percentage of cells with at least one filament is presented in the upper left corner. Bottom: Histogram of counted flagellar filaments per cell body. Number of counted cells and average number of filaments per cell +/− standard deviation based on Gaussian non-linear regression analysis is given in the upper right hand corner.</p

FliH functions as a negative regulator of type-III protein translocation.

<p>Export of FlgE-Bla fusion protein into the periplasm was analyzed in various <i>fliHIJ</i> deletion strains. All strains additionally harbored a deletion of the proximal rod genes (<i>ΔflgBC6557</i>) and the FlgE-Bla fusion protein under its native promoter (<i>flgE6569</i>::<i>bla</i>). (A) Minimal inhibitory concentration (MIC) values with flagellar genes expressed at normal levels. (B) Summary of MIC values with flagellar genes expressed at elevated levels due to a P<i>_flhD</i> promoter-up mutation (P<i>_flhD*</i> = (P1+P4 -10 TATAAT)). The error bars represent the standard error of the mean (SEM) and biological replicates are shown as individual data points.</p