Evaluating the ventilatory effect of transnasal humidified rapid insufflation ventilatory exchange in apnoeic small children with two different oxygen flow rates: a randomised controlled trial.

Transnasal humidified rapid insufflation ventilatory exchange prolongs safe apnoeic oxygenation time in children. In adults, transnasal humidified rapid insufflation ventilatory exchange is reported to have a ventilatory effect with PaCO2 levels increasing less rapidly than without it. This ventilatory effect has yet to be reproduced in children. In this non-inferiority study, we tested the hypothesis that children weighing 10-15 kg exhibit no difference in carbon dioxide clearance when comparing two different high-flow nasal therapy flow rates during a 10-min apnoea period. Following standardised induction of anaesthesia including neuromuscular blockade, patients were randomly allocated to high-flow nasal therapy of 100% oxygen at 2 or 4 l.kg-1 .min-1 . Airway patency was ensured by continuous jaw thrust. The study intervention was terminated for safety reasons when SpO2 values dropped < 95%, or transcutaneous carbon dioxide levels rose > 9.3 kPa, or near-infrared spectroscopy values dropped > 20% from their baseline values, or after an apnoeic period of 10 min. Fifteen patients were included in each group. In the 2 l.kg-1 .min-1 group, mean (SD) transcutaneous carbon dioxide increase was 0.46 (0.11) kPa.min-1 , while in the 4 l.kg-1 .min-1 group it was 0.46 (0.12) kPa.min-1 . The upper limit of a one-sided 95%CI for the difference between groups was 0.07 kPa.min-1 , lower than the predefined non-inferiority margin of 0.147 kPa.min-1 (p = 0.001). The lower flow rate of 2 l.kg-1 .min-1 was non-inferior to 4 l.kg-1 .min-1 relative to the transcutaneous carbon dioxide increase. In conclusion, an additional ventilatory effect of either 2 or 4 l.kg-1 .min-1 high-flow nasal therapy in apnoeic children weighing 10-15 kg appears to be absent.

Measurement of airway pressure during high-flow nasal therapy in apnoeic oxygenation: a randomised controlled crossover trial.

It is recognised that high-flow nasal therapy can prevent desaturation during airway management. Studies in spontaneously breathing patients show an almost linear relationship between flow rate and positive airway pressure in the nasopharynx. Positive airway pressure has been suggested as one of the possible mechanisms explaining how high-flow nasal therapy works. However, data on pressures generated by high-flow nasal therapy in apnoeic adults under general anaesthesia are absent. This randomised controlled crossover trial investigated airway pressures generated by different flow rates during high-flow nasal therapy in anaesthetised and paralysed apnoeic patients, comparing pressures with closed and open mouths. Following induction of anaesthesia and neuromuscular blockade, a continuous jaw thrust was used to enable airway patency. Airway pressure was measured in the right main bronchus, the middle of the trachea and the pharynx, using a fibreoptically-placed catheter connected to a pressure transducer. Each measurement was randomised with respect to closed or open mouth and different flow rates. Twenty patients undergoing elective surgery were included (mean (SD) age 38 (18) years, BMI 25.0 (3.3) kg.m-2 , nine women, ASA physical status 1 (35%), 2 (55%), 3 (10%). While closed mouths and increasing flow rates demonstrated non-linear increases in pressure, the pressure increase was negligible with an open mouth. Airway pressures remained below 10 cmH2 O even with closed mouths and flow rates up to 80 l.min-1 ; they were not influenced by catheter position. This study shows an increase in airway pressures with closed mouths that depends on flow rate. The generated pressure is negligible with an open mouth. These data question positive airway pressure as an important mechanism for maintenance of oxygenation during apnoea.

Reference values and clinical predictors of bone strength for HR-pQCT-based distal radius and tibia strength assessments in women and men.

Reference values for radius and tibia strength using multiple-stack high-resolution peripheral quantitative computed tomography (HR-pQCT) with homogenized finite element analysis are presented in order to derive critical values improving risk prediction models of osteoporosis. Gender and femoral neck areal bone mineral density (aBMD) were independent predictors of bone strength. INTRODUCTION: The purpose was to obtain reference values for radius and tibia bone strength computed by using the homogenized finite element analysis (hFE) using multiple stacks with a HR-pQCT. METHODS: Male and female healthy participants aged 20-39 years were recruited at the University Hospital of Bern. They underwent interview and clinical examination including hand grip, gait speed and DXA of the hip. The nondominant forearm and tibia were scanned with a double and a triple-stack protocol, respectively, using HR-pQCT (XCT II, SCANCO Medical AG). Bone strength was estimated by using the hFE analysis, and reference values were calculated using quantile regression. Multivariable analyses were performed to identify clinical predictors of bone strength. RESULTS: Overall, 46 women and 41 men were recruited with mean ages of 25.1 (sd 5.0) and 26.2 (sd 5.2) years. Sex-specific reference values for bone strength were established. Men had significantly higher strength for radius (mean (sd) 6640 (1800) N vs. 4110 (1200) N; p < 0.001) and tibia (18,200 (4220) N vs. 11,970 (3150) N; p < 0.001) than women. In the two multivariable regression models with and without total hip aBMD, the addition of neck hip aBMD significantly improved the model (p < 0.001). No clinical predictors of bone strength other than gender and aBMD were identified. CONCLUSION: Reference values for radius and tibia strength using multiple HR-pQCT stacks with hFE analysis are presented and provide the basis to help refining accurate risk prediction models. Femoral neck aBMD and gender were significant predictors of bone strength.

Predicting drug efficacy in chronic low back pain by quantitative sensory tests.

BACKGROUND: Drugs are prescribed for chronic low back pain without knowing in advance whether a patient will respond to them or not. Quantitative sensory tests (QST) can discriminate patients according to sensory phenotype, possibly reflecting underlying mechanisms of pain processing. QST may therefore be a screening tool to identify potential responders to a certain drug. The aim of this study was to investigate whether QST can predict analgesic effects of oxycodone, imipramine and clobazam in chronic low back pain. METHODS: Oxycodone 15 mg (n = 50), imipramine 75 mg (n = 50) and clobazam 20 mg (n = 49) were compared to active placebo tolterodine 1 mg in a randomized, double-blinded, crossover fashion. Electrical, pressure and thermal QST were performed at baseline and after 1 and 2 h. Pain intensity was assessed on a 0-10 numeric rating scale every 30 min for up to 2 h. The ability of baseline QST to predict pain reduction after 2 h was analysed using linear mixed models. Genetic variants of drug-metabolizing enzymes and genes affecting pain sensitivity were examined as covariables. RESULTS: No predictor of analgesic effect was found for oxycodone and clobazam. Thermal QST was associated with analgesic effect of imipramine: patients more sensitive to heat or cold were more likely to experience an effect of imipramine. Pharmacogenetic variants and pain-related candidate genes were not associated with drug efficacy. CONCLUSIONS: Thermal QST have the potential to predict imipramine effect in chronic low back pain. Oxycodone and clobazam effects could not be predicted by any of the selected QST or genetic variants. SIGNIFICANCE: Predicting drug efficacy in chronic low back pain remains difficult. There is some evidence that patients more sensitive to heat and cold pain respond better to imipramine.

First Dark Matter Search Results from the XENON1T Experiment.

We report the first dark matter search results from XENON1T, a ∼2000-kg-target-mass dual-phase (liquid-gas) xenon time projection chamber in operation at the Laboratori Nazionali del Gran Sasso in Italy and the first ton-scale detector of this kind. The blinded search used 34.2 live days of data acquired between November 2016 and January 2017. Inside the (1042±12)-kg fiducial mass and in the [5,40] keV_{nr} energy range of interest for weakly interacting massive particle (WIMP) dark matter searches, the electronic recoil background was (1.93±0.25)×10^{-4} events/(kg×day×keV_{ee}), the lowest ever achieved in such a dark matter detector. A profile likelihood analysis shows that the data are consistent with the background-only hypothesis. We derive the most stringent exclusion limits on the spin-independent WIMP-nucleon interaction cross section for WIMP masses above 10 GeV/c^{2}, with a minimum of 7.7×10^{-47} cm^{2} for 35-GeV/c^{2} WIMPs at 90% C.L.

Analgesic effect of clobazam in chronic low-back pain but not in experimentally induced pain.

BACKGROUND: Chronic pain is frequently associated with hypersensitivity of the nervous system, and drugs that increase central inhibition are therefore a potentially effective treatment. Benzodiazepines are potent modulators of GABAergic neurotransmission and are known to exert antihyperalgesic effects in rodents, but translation into patients are lacking. This study investigates the effect of the benzodiazepine clobazam in chronic low-back pain in humans. The aim of this study is to explore the effect of GABA modulation on chronic low-back pain and on quantitative sensory tests. METHODS: In this double-blind cross-over study, 49 patients with chronic low-back pain received a single oral dose of clobazam 20 mg or active placebo tolterodine 1 mg. Pain intensity on the 0-10 numeric rating scale and quantitative sensory tests were assessed during 2 h after drug intake. RESULTS: Pain intensity in the supine position was significantly reduced by clobazam compared to active placebo (60 min: 2.9 vs. 3.5, p = 0.008; 90 min: 2.7 vs. 3.3, p = 0.024; 120 min: 2.4 vs. 3.1, p = 0.005). Pain intensity in the sitting position was not significantly different between groups. No effects on quantitative sensory tests were observed. CONCLUSIONS: This study suggests that clobazam has an analgesic effect in patients with chronic low-back pain. Muscle relaxation or sedation may have contributed to the effect. Development of substances devoid of these side effects would offer the potential to further investigate the antihyperalgesic action of GABAergic compounds. SIGNIFICANCE: Modulation of GABAergic pain-inhibitory pathways may be a potential future therapeutic target.

Search for Electronic Recoil Event Rate Modulation with 4 Years of XENON100 Data.

We report on a search for electronic recoil event rate modulation signatures in the XENON100 data accumulated over a period of 4 yr, from January 2010 to January 2014. A profile likelihood method, which incorporates the stability of the XENON100 detector and the known electronic recoil background model, is used to quantify the significance of periodicity in the time distribution of events. There is a weak modulation signature at a period of 431_{-14}^{+16} day in the low energy region of (2.0-5.8) keV in the single scatter event sample, with a global significance of 1.9σ; however, no other more significant modulation is observed. The significance of an annual modulation signature drops from 2.8σ, from a previous analysis of a subset of this data, to 1.8σ with all data combined. Single scatter events in the low energy region are thus used to exclude the DAMA/LIBRA annual modulation as being due to dark matter electron interactions via axial vector coupling at 5.7σ.

Search for Event Rate Modulation in XENON100 Electronic Recoil Data.

We have searched for periodic variations of the electronic recoil event rate in the (2-6) keV energy range recorded between February 2011 and March 2012 with the XENON100 detector, adding up to 224.6 live days in total. Following a detailed study to establish the stability of the detector and its background contributions during this run, we performed an unbinned profile likelihood analysis to identify any periodicity up to 500 days. We find a global significance of less than 1σ for all periods, suggesting no statistically significant modulation in the data. While the local significance for an annual modulation is 2.8σ, the analysis of a multiple-scatter control sample and the phase of the modulation disfavor a dark matter interpretation. The DAMA/LIBRA annual modulation interpreted as a dark matter signature with axial-vector coupling of weakly interacting massive particles to electrons is excluded at 4.8σ.