Liquorice for pain?

Liquorice has a long history of use in traditional Chinese, Ayurvedic and herbal medicine. The liquorice plant contains numerous bioactive compounds, including triterpenes, flavonoids and secondary metabolites, with glycyrrhizin being the main active compound. Liquorice constituents have been found to have anti-inflammatory, antioxidant, antiviral, anticancer, hepatoprotective and neuroprotective properties. In addition, they appear to have antidepressant actions and effects on morphine tolerance. Glycyrrhizin, its metabolite glycyrrhetic (glycyrrhetinic) acid and other liquorice-derived compounds such as isoflavonoids and trans-chalcones, exert potent anti-inflammatory effects via a wide range of mechanisms including high mobility group box 1 protein (HMGB1) inhibition, gap junction blockade and alpha(2A)-adrenoceptor antagonism. These properties, together with an increasing body of preclinical studies and a long history of use in herbal medicine, suggest that liquorice constituents may be useful for pain management. Glycyrrhizin is used widely in the confectionary, food and tobacco industries, but has documented adverse effects that may limit clinical use. Whether liquorice plant-derived compounds represent a novel class of analgesics is yet to be established. Having a host of bioactive compounds with a broad range of mechanisms of effect, liquorice is a plant that, in the future, may give rise to new therapies for pain.Peer reviewe

Effect of early interdisciplinary rehabilitation for trauma patients: a systematic review

Objective To perform a systematic review to assess the current scientific evidence concerning the effect of EIR for trauma patients with or without an associated traumatic brain injury. Data Source We performed a systematic search of several electronic (Ovid MEDLINE, Embase, Cochrane Library Central Register of Controlled Trials, Cumulative Index to Nursing and Allied Health, and SveMed+) and 2 clinical trial registers (clinicaltrials.gov and International Clinical Trials Registry Platform). In addition, we handsearched reference lists from relevant studies. Data Extraction Two review authors independently identified studies that were eligible for inclusion. The primary outcome measures were functional-related outcomes and return to work. The secondary outcome measures were length of stay in hospital, number of days on respirator, complication rate, physical and mental health measures, quality of life, and socioeconomic costs. Data Synthesis Four studies with a total number of 409 subjects, all with traumatic brain–associated injuries, were included in this review. The included trials varied considerably in study design, inclusion and exclusion criteria, and had small numbers of participants. All studies were judged to have at least 1 high risk of bias. We found the quality of evidence, for both our primary and secondary outcomes, low. Conclusions No studies that matched our inclusion criteria for EIR for trauma patients without traumatic brain injuries could be found. For traumatic brain injuries, there are a limited number of studies demonstrating that EIR has a positive effect on functional outcomes and socioeconomic costs. This review highlights the need for further research in trauma care regarding early phase interdisciplinary rehabilitation.publishedVersio

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Evidence and methodology in clinical pain trials with special focus on ketamine

Aims: To establish the evidence base for the use of the NMDA receptor antagonist ketamine in the treatment of acute postoperative pain and cancer pain, and in doing so, to assess the methodology used in acute pain and cancer pain trials. Methods: In paper I a clinical model was developed and tested. Paper II is a quantitative and qualitative Cochrane systematic review on perioperative ketamine for acute postoperative pain. Paper III is a qualitative Cochrane systematic review on ketamine as adjuvant to opioid for cancer pain. Paper IV is a qualitative systematic review of the methodology used in clinical trials of oral opioids for cancer pain. Results: The model developed in Paper I was tested and found to be sensitive. Thirty-seven randomised, controlled trials (RCTs) were included in paper II. The meta-analysis found that perioperative ketamine reduced 24 hr PCA morphine consumption and reduced PONV. In paper III, four RCT’s concerning ketamine as adjuvant to opioid for cancer pain were identified. Two were excluded due to flawed methodology. Both trials found that ketamine improved morphine analgesia. Meta-analysis was not appropriate. Thirty- four RCT’s were included in paper IV. Significant limitations in the trial methodology were identified. Conclusions: There is level 1 (strong) evidence that perioperative ketamine reduces 24 hr PCA morphine consumption, and post-operative nausea and vomiting. Adverse effects were mild or absent.There is currently insufficient evidence to permit conclusions regarding the benefits and harms of ketamine as adjuvant to opioid for cancer pain. Randomised, controlled trials are needed. Clinical pain trials require rigorous methodology if they are to produce reliable results. Recommendations for future analgesic trials in acute and cancer pain are made

Effect of early interdisciplinary rehabilitation for trauma patients: a systematic review

Objective To perform a systematic review to assess the current scientific evidence concerning the effect of EIR for trauma patients with or without an associated traumatic brain injury. Data Source We performed a systematic search of several electronic (Ovid MEDLINE, Embase, Cochrane Library Central Register of Controlled Trials, Cumulative Index to Nursing and Allied Health, and SveMed+) and 2 clinical trial registers (clinicaltrials.gov and International Clinical Trials Registry Platform). In addition, we handsearched reference lists from relevant studies. Data Extraction Two review authors independently identified studies that were eligible for inclusion. The primary outcome measures were functional-related outcomes and return to work. The secondary outcome measures were length of stay in hospital, number of days on respirator, complication rate, physical and mental health measures, quality of life, and socioeconomic costs. Data Synthesis Four studies with a total number of 409 subjects, all with traumatic brain–associated injuries, were included in this review. The included trials varied considerably in study design, inclusion and exclusion criteria, and had small numbers of participants. All studies were judged to have at least 1 high risk of bias. We found the quality of evidence, for both our primary and secondary outcomes, low. Conclusions No studies that matched our inclusion criteria for EIR for trauma patients without traumatic brain injuries could be found. For traumatic brain injuries, there are a limited number of studies demonstrating that EIR has a positive effect on functional outcomes and socioeconomic costs. This review highlights the need for further research in trauma care regarding early phase interdisciplinary rehabilitation

Jet fragmentation transverse momentum distributions in pp and p-Pb collisions at s \sqrt{s} , sNN \sqrt{s_{\mathrm{NN}}} = 5.02 TeV

Jet fragmentation transverse momentum (j$_{T}$) distributions are measured in proton-proton (pp) and proton-lead (p-Pb) collisions at $\sqrt{s_{\mathrm{NN}}}$ = 5.02 TeV with the ALICE experiment at the LHC. Jets are reconstructed with the ALICE tracking detectors and electromagnetic calorimeter using the anti-k$_{T}$ algorithm with resolution parameter R = 0.4 in the pseudorapidity range |η| < 0.25. The j$_{T}$ values are calculated for charged particles inside a fixed cone with a radius R = 0.4 around the reconstructed jet axis. The measured j$_{T}$ distributions are compared with a variety of parton-shower models. Herwig and Pythia 8 based models describe the data well for the higher j$_{T}$ region, while they underestimate the lower j$_{T}$ region. The j$_{T}$ distributions are further characterised by fitting them with a function composed of an inverse gamma function for higher j$_{T}$ values (called the “wide component”), related to the perturbative component of the fragmentation process, and with a Gaussian for lower j$_{T}$ values (called the “narrow component”), predominantly connected to the hadronisation process. The width of the Gaussian has only a weak dependence on jet transverse momentum, while that of the inverse gamma function increases with increasing jet transverse momentum. For the narrow component, the measured trends are successfully described by all models except for Herwig. For the wide component, Herwig and PYTHIA 8 based models slightly underestimate the data for the higher jet transverse momentum region. These measurements set constraints on models of jet fragmentation and hadronisation

Measurements of the groomed and ungroomed jet angularities in pp collisions at s \sqrt{s} = 5.02 TeV

International audienceThe jet angularities are a class of jet substructure observables which characterize the angular and momentum distribution of particles within jets. These observables are sensitive to momentum scales ranging from perturbative hard scatterings to nonperturbative fragmentation into final-state hadrons. We report measurements of several groomed and ungroomed jet angularities in pp collisions at $\sqrt{s}$ = 5.02 TeV with the ALICE detector. Jets are reconstructed using charged particle tracks at midrapidity (|η| < 0.9). The anti-k$_{T}$ algorithm is used with jet resolution parameters R = 0.2 and R = 0.4 for several transverse momentum {p}_{\mathrm{T}}^{\mathrm{ch}} ^{jet} intervals in the 20–100 GeV/c range. Using the jet grooming algorithm Soft Drop, the sensitivity to softer, wide-angle processes, as well as the underlying event, can be reduced in a way which is well-controlled in theoretical calculations. We report the ungroomed jet angularities, λ$_{α}$, and groomed jet angularities, λ$_{α,g}$, to investigate the interplay between perturbative and nonperturbative effects at low jet momenta. Various angular exponent parameters α = 1, 1.5, 2, and 3 are used to systematically vary the sensitivity of the observable to collinear and soft radiation. Results are compared to analytical predictions at next-to-leading-logarithmic accuracy, which provide a generally good description of the data in the perturbative regime but exhibit discrepancies in the nonperturbative regime. Moreover, these measurements serve as a baseline for future ones in heavy-ion collisions by providing new insight into the interplay between perturbative and nonperturbative effects in the angular and momentum substructure of jets. They supply crucial guidance on the selection of jet resolution parameter, jet transverse momentum, and angular scaling variable for jet quenching studies.[graphic not available: see fulltext

Inclusive quarkonium production in pp collisions at s=5.02\sqrt{s} = 5.02 TeV

This article reports on the inclusive production cross section of several quarkonium states, $\mathrm{J}/\psi$, $\psi {\rm (2S)}$, $\Upsilon\rm(1S)$, $\Upsilon\rm(2S)$, and $\Upsilon\rm(3S)$, measured with the ALICE detector at the LHC, in \pp collisions at $\sqrt{s} = 5.02$ TeV. The analysis is performed in the dimuon decay channel at forward rapidity ($2.5 < y < 4$). The measured cross sections, assuming unpolarized quarkonia, are: $\sigma_{\mathrm{J}/\psi} = 5.88 \pm 0.03 \pm 0.34\ \mu$b, $\sigma_{\psi {\rm (2S)}} = 0.87 \pm 0.06 \pm 0.10\ \mu$b, $\sigma_{\Upsilon\rm(1S)} = 45.5 \pm 3.9 \pm 3.5$ nb, $\sigma_{\Upsilon\rm(2S)} = 22.4 \pm 3.2 \pm 2.7$ nb, and $\sigma_{\Upsilon\rm(3S)} = 4.9 \pm 2.2 \pm 1.0$ nb, where the first (second) uncertainty is the statistical (systematic) one. The transverse-momentum ($p_{\rm T}$) and rapidity ($y$) differential cross sections for $\mathrm{J}/\psi$, $\psi {\rm (2S)}$, $\Upsilon\rm(1S)$, and the $\psi {\rm (2S)}$-to-$\mathrm{J}/\psi$ cross section ratios are presented. For the first time, the cross sections of the three $\Upsilon$ states, as well as the $\psi {\rm (2S)}$ one as a function of $p_{\rm T}$ and $y$, are measured at $\sqrt{s} = 5.02$ TeV at forward rapidity. These measurements also significantly extend the $\mathrm{J}/\psi$$p_{\rm T}$ reach with respect to previously published results. A comparison with ALICE measurements in pp collisions at $\sqrt{s} = 2.76$, 7, 8, and 13 TeV is presented and the energy dependence of quarkonium production cross sections is discussed. Finally, the results are compared with the predictions from several production models