Antimonene, a monolayer of β-antimony, is increasingly attracting considerable attention, more than that of other monoelemental two-dimensional materials, due to its intriguing physical and chemical ...properties. Under ambient conditions, antimonene exhibits a high thermodynamic stability and good structural integrity. Some theoretical calculations predicted that antimonene would have a high oxidation tendency. However, it remains poorly investigated from the experimental point of view. In this work, we study the oxidation behavior of antimonene nanosheets (ANS) prepared by ultrasonication-assisted liquid-phase exfoliation. Using a set of forefront analytical techniques, a clear effect of sonication time on the surface chemistry of prepared ANS is found. A dynamic oxidation behavior has been observed, which upon annealing at moderate temperature (210 °C) resulted in a semiconducting behavior with a bandgap of approximately 1 eV measured by ultraviolet photoelectron spectroscopy. This study yields valuable information for future applications of antimonene and paves the way towards novel modification approaches in order to tailor its properties and complement its limitations.
The Moon has long been thought to be highly depleted in volatiles such as water, and indeed published direct measurements of water in lunar volcanic glasses have never exceeded 50 parts per million ...(ppm). Here, we report in situ measurements of water in lunar melt inclusions; these samples of primitive lunar magma, by virtue of being trapped within olivine crystals before volcanic eruption, did not experience posteruptive degassing. The lunar melt inclusions contain 615 to 1410 ppm water and high correlated amounts of fluorine (50 to 78 ppm), sulfur (612 to 877 ppm), and chlorine (1.5 to 3.0 ppm). These volatile contents are very similar to primitive terrestrial mid-ocean ridge basalts and indicate that some parts of the lunar interior contain as much water as Earth's upper mantle.
Air pollution from road traffic is a serious health risk, especially for susceptible individuals. Single-centre studies showed an association with chronic lung allograft dysfunction (CLAD) and ...survival after lung transplantation, but there are no large studies.13 lung transplant centres in 10 European countries created a cohort of 5707 patients. For each patient, we quantified residential particulate matter with aerodynamic diameter ≤10 µm (PM
) by land use regression models, and the traffic exposure by quantifying total road length within buffer zones around the home addresses of patients and distance to a major road or freeway.After correction for macrolide use, we found associations between air pollution variables and CLAD/mortality. Given the important interaction with macrolides, we stratified according to macrolide use. No associations were observed in 2151 patients taking macrolides. However, in 3556 patients not taking macrolides, mortality was associated with PM
(hazard ratio 1.081, 95% CI 1.000-1.167); similarly, CLAD and mortality were associated with road lengths in buffers of 200-1000 and 100-500 m, respectively (hazard ratio 1.085- 1.130). Sensitivity analyses for various possible confounders confirmed the robustness of these associations.Long-term residential air pollution and traffic exposure were associated with CLAD and survival after lung transplantation, but only in patients not taking macrolides.
Highlights • Anecdotal evidence suggests a symptomatic effect of ephedrine in myasthenia gravis. • This series of randomized controlled n-of-1 trials compared ephedrine to placebo. • Ephedrine ...significantly reduced QMG score by 1.0 point. • Adverse events were mild, including palpitations, tremor and restlessness. • Ephedrine add-on treatment resulted in a small but consistent reduction of symptoms
Adherence with controller medication is a major challenge in asthma management. Thus, a reliable method of measurement is mandatory to assess adherence.
To examine the test-retest reliability on ...adherence with inhaled corticosteroids in adults with asthma using, a self-reported adherence score (Foster score).
Patients with asthma and >1 routine follow-up appointment at a university hospital outpatient clinic reported Foster scores. The objective Medication Possession Ratio (MPR) was calculated based on pharmacy redemption data and physician-prescribed doses of inhaled corticosteroids. The difference between Foster score and MPR at the first and second visit was assessed using a Bland-Altman plot, outcomes reported as limits of agreements and bias. Foster scores from both visits were used to calculate an intraclass correlation coefficient (ICC).
Self-reported adherence with asthma controller medication measured by Foster score was significantly higher than the objective MPR (p < 0.0001). The Bland-Altman plot for MPR and Foster score at the first and second visit showed upper and lower limits of agreement of 83.5 - (-1.6) and 80.9 - (-6.9) and bias was 41.0 and 37.0, respectively. Of the included patients, 93.1% reported identical Foster scores between visits, resulting in an excellent ICC of 0.92. Absolute median difference between Foster scores and MPR at first and second visit was 8.7 percentage points (p = 0.049).
Foster score shows an excellent ICC; however, its poor agreement with objective measures of adherence suggests that clinicians should not rely on Foster scores alone to assess adherence with inhaled corticosteroids in patients with asthma.
Inexpensive medicines with a long history of use may currently be prescribed off-label for rare indications. Reimbursement is at the discretion of health insurance companies, and may be ...unpredictable. The example addressed was ephedrine as add-on treatment for myasthenia gravis. Stakeholders from academia, a patient organization, the Dutch National Health Care Institute (NHCI) and Dutch Medicines Evaluation Board (MEB) advised on the trial design. The NHCI and MEB agreed to provide scientific advice on the suitability of the evidence generated by the trial, for regulatory decisions. This paper describes the feasibility of the trial and the utility of its aggregated results.
The trialists experienced the trial as feasible. Retrospective interviews showed that the trial as performed was acceptable to patients. The treatment effect in the primary outcome measure, muscle strength, was statistically significant when inferred to the population level, though the effect size was modest. Secondary outcomes were statistically significant in a preplanned, fixed effects analysis within the four patients. The NHCI advised that it could potentially make reimbursement decisions based on the Fitting Evidence framework, should the trialists decide to apply for reimbursement. The MEB advised that for a licensing decision, the N-of-1 design is a last-resort option for demonstrating treatment benefit in a rare disease. N-of-1 trials alone do not provide enough evidence on potential risk. The MEB found the current trial inconclusive. It suggested doing a 2-armed trial of longer duration, possibly with a different outcome measure (postponement of corticosteroid use). It suggested engaging a consultancy or commercial sponsor, should the trialists decide to seek market authorization of the drug.
In theory, evidence from aggregated N-of-1 trials is suitable for use in licensing and reimbursement decisions. The current example illustrates differences in interpretation of N-of-1 results by health authorities. In the era of personalized medicine, consensus is required on the interpretation of data from study designs geared to small groups. Demonstrating effectiveness of inexpensive medicines in small populations may require involvement of non-commercial parties, to preserve affordability.
Background
Disrupted pain regulation has been proposed as a component in functional somatic disorders (FSD). The objective of this study was to examine a general population sample, encompassing three ...delimitations of FSD while assessing pain sensitivity and conditioning pain modulation (CPM).
Methods
Pressure pain thresholds (PPTs) at the tibialis and trapezius muscles were recorded at baseline. During cold pressor stimulation of the hand, the tibialis PPTs were re‐assessed and the difference from baseline measures defined the CPM effect. Participants (n = 2,198, 53% females) were randomly selected from the adult Danish population. FSD was established by self‐reported symptom questionnaires.
Results
With a few exceptions, only weak associations were seen between PPTs and CPM in cases with FSD (p > .1). A high PPT was associated with lower odds of having multi‐organ bodily distress syndrome (ORPPT trapezius: 0.66, 95% CI: 0.49–0.88, p = .005), with the symptom profile characterized by all symptoms (ORPPT trapezius: 0.72, 95% CI: 0.58–0.90, p = .003 and ORPPT tibialis: 0.75, 95% CI: 0.62–0.91, p = .004), and with multiple chemical sensitivity (ORPPT trapezius: 0.81, 95% CI: 0.67–0.97, p = .022). High CPM was associated with high odds of having irritable bowel (ORCPM relative: 1.22, 95% CI: 1.04–1.43, p = .013 and ORCPM absolute = 2.66, 95% CI: 1.07–6.45, p = .033).
Conclusion
However, only PPT measured over the trapezius muscle were still significant after correction for multiple testing for the symptom profile characterized by all symptoms. Findings from this study do not support altered pain regulation in questionnaire‐based FSD which is in contrast with the existing presumption. Further epidemiological studies in this field are needed.
Significance
Disrupted pain regulation as measured by abnormal pain thresholds has been hypothesized as a central mechanism in Functional Somatic Disorders (FSD). The hypothesis has been raised in clinical setting where patients presented subjective and objective features of hypersensitivity. The present population‐based study does not support this notion. This points to the importance of further studies into the underlying pathophysiology mechanisms of FSD.
Purpose
To characterize exposure–response relationships of AMG 386 in a phase 2 study in advanced ovarian cancer for the facilitation of dose selection in future studies.
Methods
A population ...pharmacokinetic model of AMG 386 (
N
= 141) was developed and applied in an exposure–response analysis using data from patients (
N
= 160) with recurrent ovarian cancer who received paclitaxel plus AMG 386 (3 or 10 mg/kg once weekly) or placebo. Reduction in the risk of progression or death with increasing exposure (steady-state area under the concentration-versus-time curve AUC
ss
) was assessed using Cox regression analyses. Confounding factors were tested in multivariate analysis. Alternative AMG 386 doses were explored with Monte Carlo simulations using population pharmacokinetic and parametric survival models.
Results
There was a trend toward increased PFS with increased AUC
ss
(hazard ratio HR for each one-unit increment in AUC
ss
, 0.97;
P
= 0.097), suggesting that the maximum effect on prolonging PFS was not achieved at the highest dose tested (10 mg/kg). Among patients with AUC
ss
≥ 9.6 mg h/mL, PFS was 8.1 months versus 5.7 months for AUC
ss
< 9.6 mg h/mL and 4.6 months for placebo. No relationship between AUC
ss
and grade ≥3 adverse events was observed. Simulations predicted that AMG 386 15 mg/kg once weekly would result in an AUC
ss
≥ 9.6 mg h/mL in >90% of patients with median PFS of 8.2 months versus 5.0 months for placebo (HR 15 mg/kg vs. placebo, 0.56).
Conclusions
Increased exposure to AMG 386 was associated with improved clinical outcomes in recurrent ovarian cancer, supporting the evaluation of a higher dose in future studies.
IntroductionMyasthenia gravis (MG), a rare neuromuscular disease, is often initially treated using acetylcholinesterase inhibitors. Patients who do not respond adequately depend on the use of ...corticosteroids or other immunosuppressive medication, but these may have serious side effects. Clinical observations suggest that ephedrine can diminish, postpone or even prevent the need for immunosuppressive therapy when added to acetylcholinesterase inhibitors or low-dose prednisone. In the Netherlands, ephedrine is not licensed for MG nor is reimbursement guaranteed. MG is a rare condition, and ephedrine might be indicated only in a subset of patients. Thus, randomised controlled trials comparing large groups are difficult to conduct. We, therefore, aim to aggregate data from a small series of n-of-1 trials (also known as single patient trials) to assess the effect of ephedrine as add-on treatment for MG.Methods and analysisSingle-centre, placebo-controlled, double-blind, randomised, multiple crossover n-of-1 studies in 4 adult patients with generalised MG who show inadequate improvement on pyridostigmine and/or immunosuppressive drugs. Each n-of-1 trial has 3 cycles of two 5-day intervention periods. Treatment: 25 mg ephedrine or placebo, twice daily. Main outcome measure: Quantitative Myasthenia Gravis (QMG) test. Statistical analysis: fixed effects linear model for QMG for all patients combined. Secondary outcome measures: Clinical: effects on MG-Composite and MG-Activities of Daily Living (MG-ADL) scales; QMG at individual level; adverse events. Acceptability of trial design: number of patients eligible and enrolled; number of treatment cycles completed; patients’ and caregivers’ experiences.Ethics and disseminationThis study was approved by the Medical Ethics Committee of Leiden University Medical Center, No. P14.108. Results of the trial will be reported in a peer-reviewed publication. Regulatory stakeholders will comment on the suitability of the trial for market authorisation and reimbursement purposes.Trial registration numberThis study is registered under EudraCT number 2014-001355-23, protocol no. 40960, V.1.0, registration date 27 March 2014.
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