Density dependence of the Ionization Avalanche in ultracold Rydberg gases

We report on the behaviour of the ionization avalanche in an ensemble of ultracold 87Rb atoms coupled to a high lying Rydberg state and investigate extensions to the current model by including the effects of three-body recombination and plasma expansion. To separate the two effects we study the time dependence of the plasma formation at various densities as well as for different nS and nD states. At medium densities and low n we observe the onset of the avalanche as has been reported in other experiments, as well as a subsequent turn-off of the avalanche for longer excitation times, which we associate with plasma expansion. At higher densities and for higher lying Rydberg states we observe a disappearance of the avalanche signature, which we attribute to three-body recombination.Comment: 5 pages, 4 figure

Image-guided versus blind corticosteroid injections in adults with shoulder pain: A systematic review

<p>Abstract</p> <p>Background</p> <p>Corticosteroid injections can be performed blind (landmark-guided) or with image guidance, and this may account for variable clinical outcomes. The objective of this study was to assess the effectiveness and safety of image-guided versus blind corticosteroid injections in improving pain and function among adults with shoulder pain.</p> <p>Methods</p> <p>MEDLINE, the Cochrane Controlled Trials Register and EMBASE were searched to May 2010. Additional studies were identified by searching bibliographies of shortlisted articles. Search items included blind, landmark, anatomical, clinical exam, image-guided, ultrasound, fluoroscopy, steroid injection, frozen shoulder, random allocation, randomized controlled trial (RCT) and clinical trial.</p> <p>Randomized controlled studies comparing image-guided versus blind (landmark-guided) corticosteroid shoulder injections that examined pain, function and/or adverse events were included. Independent extraction was done by two authors using a form with pre-specified data fields, including risk of bias appraisal. Conflicts were resolved by discussion. The decision to pool data was based on assessment of clinical design homogeneity. When warranted, studies were pooled under a random-effects model.</p> <p>Results</p> <p>Two RCTs for pain, function and adverse events (n = 101) met eligibility criteria. No serious threats to validity were found. Both trials compared ultrasound-guided versus landmark-guided injections and were judged similar in clinical design. Low to moderate heterogeneity was observed: shoulder pain I²= 60%, function I²= 22%. A meta-analysis demonstrated greater improvement with ultrasound-guided injections at 6 weeks after injection in both pain (mean difference = 2.23 [95% CI: 1.27, 3.18]), as assessed with a 0 to 10 visual analogue scale, and shoulder function (standardised mean difference = 1.09 [95% CI: 0.61, 1.57]) as assessed with shoulder function scores. Although more adverse events (all mild) were reported with landmark-guided injections, the difference was not statistically significant (risk ratio = 0.20 [95% CI: 0.04, 1.13]).</p> <p>This review was only based on two moderate-sized trials. Blinding of patients was not performed in both trials, causing some risk of bias in outcome assessment since primary endpoints were wholly or partially patient-reported.</p> <p>Conclusion</p> <p>There is a paucity of RCTs on image-guided versus landmark-guided corticosteroid shoulder injections examining pain, function and adverse events. In this review, patients who underwent image-guided (ultrasound) injections had statistically significant greater improvement in shoulder pain and function at 6 weeks after injection. Image-guided (ultrasound) corticosteroid injections potentially offer a significantly greater clinical improvement over blind (landmark-guided) injections in adults with shoulder pain. However, this apparent benefit requires confirmation from further studies (adequately-powered and well-executed RCTs).</p

Comparison of Resting PD/PA with Fractional Flow Reserve Using a Monorail Pressure Catheter

Background: The RXi™ system (ACIST Medical Systems, MN, USA) is a new Fractional Flow Reserve (FFR) technology utilising an ultrathinmonorail microcatheter (Navvus®; ACIST Medical Systems) with an optical pressure sensor located close to the distal catheter tip. FFR measurement using monorail microcatheter is comparable to the conventional pressure wires. However, the predictive value of resting distal coronary artery pressure/aortic pressure (Pd/Pa) on hyperemic FFR value in the real world practice is unknown. Objective: To explore the diagnostic accuracy of resting Pd/Pa in relation to hyperemic FFR using the monorail pressure catheter. Methods: Resting Pd/Pa and FFR were measured using monorail pressure catheter in 67 consecutive patients with intermediate coronary artery lesions (30% to 80% diameter stenoses) between 01-03-2016 to 17-01-2017. Of 121 studied lesions, 29 (23.97%) were excluded because of no hyperemic FFR due to postive resting Pd/Pa (n=17), severe or non-critical stenosis (n=11) and suboptimal acquisition (n=1), leaving 92 lesions for final analysis. Hyperemic FFR was induced with intracoronary adenosine. The selection of coronary wire and the dose of intracoronary nitroglycerine were at the operators’ discretions. Results: Bland-Altman plots showed a moderate degree of scatter between Pd/Pa and FFR value. On average, Pd/Pa exceeded FFR by 0.066 (-0.09 to +0.22). Receiver-operating characteristic curves of the resting Pd/Pa with FFR≤0.80 as the reference variable showed an area under the curve of 0.78 (95% confidence intervals 0.680 to 0.881, pb0.001), with a diagnostic accuracy of 79.3% when the resting Pd/Pa was ≤0.86. Certain cutoff values of Pd/Pa can reliably predict whether hyperemic FFR was positive or negative (FFR cutoff≤0.80). Resting Pd/Pa value of N0.96 had a negative predictive value (NPV) of 100% and sensitivity of 100%; the resting Pd/Pa value of ≤0.82 had a positive predictive value (PPV) of 100% and specificity of 98.3%. These were consistent regardless of coronary vessel, location of lesion or degree of diameter stenosis. Conclusions: Certain range of resting Pd/Pa measured by monorail pressure catheter had excellent NPV and sensitivity or excellent PPV and specificity to predict hyperemic FFR. Clinical outcome studies are required to determine whether the results might obviate the need for hyperemia in selected patients

Assessment of Type I Interferon Signaling in Pediatric Inflammatory Disease

International audiencePURPOSE: Increased type I interferon is considered relevant to the pathology of a number of monogenic and complex disorders spanning pediatric rheumatology, neurology, and dermatology. However, no test exists in routine clinical practice to identify enhanced interferon signaling, thus limiting the ability to diagnose and monitor treatment of these diseases. Here, we set out to investigate the use of an assay measuring the expression of a panel of interferon-stimulated genes (ISGs) in children affected by a range of inflammatory diseases. DESIGN, SETTING, AND PARTICIPANTS: A cohort study was conducted between 2011 and 2016 at the University of Manchester, UK, and the Institut Imagine, Paris, France. RNA PAXgene blood samples and clinical data were collected from controls and symptomatic patients with a genetically confirmed or clinically well-defined inflammatory phenotype. The expression of six ISGs was measured by quantitative polymerase chain reaction, and the median fold change was used to calculate an interferon score (IS) for each subject compared to a previously derived panel of 29 controls (where +2 SD of the control data, an IS of \textgreater2.466, is considered as abnormal). Results were correlated with genetic and clinical data. RESULTS: Nine hundred ninety-two samples were analyzed from 630 individuals comprising symptomatic patients across 24 inflammatory genotypes/phenotypes, unaffected heterozygous carriers, and controls. A consistent upregulation of ISG expression was seen in 13 monogenic conditions (455 samples, 265 patients; median IS 10.73, interquartile range (IQR) 5.90-18.41), juvenile systemic lupus erythematosus (78 samples, 55 patients; median IS 10.60, IQR 3.99-17.27), and juvenile dermatomyositis (101 samples, 59 patients; median IS 9.02, IQR 2.51-21.73) compared to controls (78 samples, 65 subjects; median IS 0.688, IQR 0.427-1.196), heterozygous mutation carriers (89 samples, 76 subjects; median IS 0.862, IQR 0.493-1.942), and individuals with non-molecularly defined autoinflammation (89 samples, 69 patients; median IS 1.07, IQR 0.491-3.74). CONCLUSIONS AND RELEVANCE: An assessment of six ISGs can be used to define a spectrum of inflammatory diseases related to enhanced type I interferon signaling. If future studies demonstrate that the IS is a reactive biomarker, this measure may prove useful both in the diagnosis and the assessment of treatment efficacy

Mediterranean-style diet in pregnant women with metabolic risk factors (ESTEEM): A pragmatic multicentre randomised trial

Barts CharityCalifornia Walnut CommissionBlue Diamond Grower

A dual role for the N-terminal domain of the IL-3 receptor in cell signalling

The interleukin-3 (IL-3) receptor is a cell-surface heterodimer that links the haemopoietic, vascular and immune systems and is overexpressed in acute and chronic myeloid leukaemia progenitor cells. It belongs to the type I cytokine receptor family in which the α-subunits consist of two fibronectin III-like domains that bind cytokine, and a third, evolutionarily unrelated and topologically conserved, N-terminal domain (NTD) with unknown function. Here we show by crystallography that, while the NTD of IL3Rα is highly mobile in the presence of IL-3, it becomes surprisingly rigid in the presence of IL-3 K116W. Mutagenesis, biochemical and functional studies show that the NTD of IL3Rα regulates IL-3 binding and signalling and reveal an unexpected role in preventing spontaneous receptor dimerisation. Our work identifies a dual role for the NTD in this cytokine receptor family, protecting against inappropriate signalling and dynamically regulating cytokine receptor binding and function.Sophie E. Broughton, Timothy R. Hercus, Tracy L. Nero, Winnie L. Kan ... Timothy P. Hughes, Angel F. Lopez ... et al

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