Propensity score stratified MAP prior and posterior inference for incorporating information across multiple potentially heterogeneous data sources.

Incorporation of external information is becoming increasingly common when designing clinical trials. Availability of multiple sources of information has inspired the development of methodologies that account for potential heterogeneity not only between the prospective trial and the pooled external data sources but also between the different external data sources themselves. Our approach proposes an intuitive way of handling such a scenario for the continuous outcomes setting by using propensity score-based stratification and then utilizing robust meta-analytic predictive priors for each stratum to incorporate the prior data to distinguish among different external data sources in each stratum. Through extensive simulations, our approach proves to be more efficient and less biased than the currently available methods. A real case study using clinical trials that study schizophrenia from multiple different sources is also included.

Duration of and time to response in oncology clinical trials from the perspective of the estimand framework.

Duration of response (DOR) and time to response (TTR) are typically evaluated as secondary endpoints in early-stage clinical studies in oncology when efficacy is assessed by the best overall response and presented as the overall response rate. Despite common use of DOR and TTR in particular in single-arm studies, the definition of these endpoints and the questions they are intended to answer remain unclear. Motivated by the estimand framework, we present relevant scientific questions of interest for DOR and TTR and propose corresponding estimand definitions. We elaborate on how to deal with relevant intercurrent events which should follow the same considerations as implemented for the primary response estimand. A case study in mantle cell lymphoma illustrates the implementation of relevant estimands of DOR and TTR. We close the paper with practical recommendations to implement DOR and TTR in clinical study protocols.

Biodiesel exhaust particle airway toxicity and the role of polycyclic aromatic hydrocarbons.

Renewable alternatives to fossil diesel (FD) including fatty acid methyl ester (FAME) biodiesel have become more prevalent. However, toxicity of exhaust material from their combustion, relative to the fuels they are displacing has not been fully characterised. This study was carried out to examine particle toxicity within the lung epithelium and the role for polycyclic aromatic hydrocarbons (PAHs). Exhaust particles from a 20% (v/v) blend of FAME biodiesel had little impact on primary airway epithelial toxicity compared to FD derived particles but did result in an altered profile of PAHs, including an increase in particle bound carcinogenic B[a]P. Higher blends of biodiesel had significantly increased levels of more carcinogenic PAHs, which was associated with a higher level of stress response gene expression including CYP1A1, NQO1 and IL1B. Removal of semi-volatile material from particulates abolished effects on airway cells. Particle size difference and toxic metals were discounted as causative for biological effects. Finally, combustion of a single component fuel (Methyl decanoate) containing the methyl ester molecular structure found in FAME mixtures, also produced more carcinogenic PAHs at the higher fuel blend levels. These results indicate the use of FAME biodiesel at higher blends may be associated with an increased particle associated carcinogenic and toxicity risk.

Small Airway Susceptibility to Chemical and Particle Injury.

Small airways (SA) in humans are commonly defined as those conducting airways <2 mm in diameter. They are susceptible to particle- and chemical-induced injury and play a major role in the development of airway disease such as COPD and asthma. Susceptibility to injury can be attributed in part to structural features including airflow dynamics and tissue architecture, but recent evidence may indicate a more prominent role for cellular composition in directing toxicological responses. Animal studies support the hypothesis that inherent cellular differences across the tracheobronchial tree, including metabolic CYP450 expression in the distal conducting airways, can influence SA susceptibility to injury. Currently, there is insufficient information in humans to make similar conclusions, prompting further necessary work in this area. An understanding of why the SA are more susceptible to certain chemical and particle exposures than other airway regions is fundamental to our ability to identify hazardous materials, their properties, and accompanying exposure scenarios that compromise lung function. It is also important for the ability to develop appropriate models for toxicity testing. Moreover, it is central to our understanding of SA disease aetiology and how interventional strategies for treatment may be developed. In this review, we will document the structural and cellular airway regional differences that are likely to influence airway susceptibility to injury, including the role of secretory club cells. We will also describe recent advances in single-cell sequencing of human airways, which have provided unprecedented details of cell phenotype, likely to impact airway chemical and particle injury.

Serological responses to COVID-19 Comirnaty booster vaccine, London, United Kingdom, September to December 2021.

Serum samples were collected pre- and post-booster vaccination with Comirnaty in 626 participants (aged ≥ 50 years) who had received two Comirnaty doses < 30 days apart, two Comirnaty doses ≥ 30 days apart or two Vaxzevria doses ≥ 30 days apart. Irrespective of primary vaccine type or schedule, spike antibody GMTs peaked 2-4 weeks after second dose, fell significantly ≤ 38 weeks later and rose above primary immunisation GMTs 2-4 weeks post-booster. Higher post-booster responses were observed with a longer interval between primary immunisation and boosting.

Sexual selection protects against extinction.

Reproduction through sex carries substantial costs, mainly because only half of sexual adults produce offspring. It has been theorized that these costs could be countered if sex allows sexual selection to clear the universal fitness constraint of mutation load. Under sexual selection, competition between (usually) males and mate choice by (usually) females create important intraspecific filters for reproductive success, so that only a subset of males gains paternity. If reproductive success under sexual selection is dependent on individual condition, which is contingent to mutation load, then sexually selected filtering through 'genic capture' could offset the costs of sex because it provides genetic benefits to populations. Here we test this theory experimentally by comparing whether populations with histories of strong versus weak sexual selection purge mutation load and resist extinction differently. After evolving replicate populations of the flour beetle Tribolium castaneum for 6 to 7 years under conditions that differed solely in the strengths of sexual selection, we revealed mutation load using inbreeding. Lineages from populations that had previously experienced strong sexual selection were resilient to extinction and maintained fitness under inbreeding, with some families continuing to survive after 20 generations of sib × sib mating. By contrast, lineages derived from populations that experienced weak or non-existent sexual selection showed rapid fitness declines under inbreeding, and all were extinct after generation 10. Multiple mutations across the genome with individually small effects can be difficult to clear, yet sum to a significant fitness load; our findings reveal that sexual selection reduces this load, improving population viability in the face of genetic stress.

Modified cardiopulmonary bypass circuit for the use of the AngioVac® system in a case with high paradoxical embolization risk.

The AngioVac® is a vacuum-assisted percutaneous thrombectomy suction system. In critically ill patients, the sudden volume shift can result in abrupt hemodynamic changes thus leading to a cardiac right-left shunt with a high risk of paradoxical embolization. We describe a modified cardiopulmonary bypass circuit for the use of the AngioVac® system that enables full cardiopulmonary support and reduces paradoxical thromboembolic risk.

Mating patterns influence vulnerability to the extinction vortex.

Earth's biodiversity is undergoing mass extinction due to anthropogenic compounding of environmental, demographic and genetic stresses. These different stresses can trap populations within a reinforcing feedback loop known as the extinction vortex, in which synergistic pressures build upon one another through time, driving down population viability. Sexual selection, the widespread evolutionary force arising from competition, choice and reproductive variance within animal mating patterns could have vital consequences for population viability and the extinction vortex: (a) if sexual selection reinforces natural selection to fix 'good genes' and purge 'bad genes', then mating patterns encouraging competition and choice may help protect populations from extinction; (b) by contrast, if mating patterns create load through evolutionary or ecological conflict, then population viability could be further reduced by sexual selection. We test between these opposing theories using replicate populations of the model insect Tribolium castaneum exposed to over 10 years of experimental evolution under monogamous versus polyandrous mating patterns. After a 95-generation history of divergence in sexual selection, we compared fitness and extinction of monogamous versus polyandrous populations through an experimental extinction vortex comprising 15 generations of cycling environmental and genetic stresses. Results showed that lineages from monogamous evolutionary backgrounds, with limited opportunities for sexual selection, showed rapid declines in fitness and complete extinction through the vortex. By contrast, fitness of populations from the history of polyandry, with stronger opportunities for sexual selection, declined slowly, with 60% of populations surviving by the study end. The three vortex stresses of (a) nutritional deprivation, (b) thermal stress and (c) genetic bottlenecking had similar impacts on fitness declines and extinction risk, with an overall sigmoid decline in survival through time. We therefore reveal sexual selection as an important force behind lineages facing extinction threats, identifying the relevance of natural mating patterns for conservation management.

Resistance to natural and synthetic gene drive systems.

Scientists are rapidly developing synthetic gene drive elements intended for release into natural populations. These are intended to control or eradicate disease vectors and pests, or to spread useful traits through wild populations for disease control or conservation purposes. However, a crucial problem for gene drives is the evolution of resistance against them, preventing their spread. Understanding the mechanisms by which populations might evolve resistance is essential for engineering effective gene drive systems. This review summarizes our current knowledge of drive resistance in both natural and synthetic gene drives. We explore how insights from naturally occurring and synthetic drive systems can be integrated to improve the design of gene drives, better predict the outcome of releases and understand genomic conflict in general.

Dynamic Covalent Formation of Concave Disulfide Macrocycles Mechanically Interlocked with Single-Walled Carbon Nanotubes.

The formation of discrete macrocycles wrapped around single-walled carbon nanotubes (SWCNTs) has recently emerged as an appealing strategy to functionalize these carbon nanomaterials and modify their properties. Here, we demonstrate that the reversible disulfide exchange reaction, which proceeds under mild conditions, can install relatively large amounts of mechanically interlocked disulfide macrocycles on the one-dimensional nanotubes. Size-selective functionalization of a mixture of SWCNTs of different diameters were observed, presumably arising from error correction and the presence of relatively rigid, curved π-systems in the key building blocks. A combination of UV/Vis/NIR, Raman, photoluminescence excitation, and transient absorption spectroscopy indicated that the small (6,4)-SWCNTs were predominantly functionalized by the small macrocycles 12 , whereas the larger (6,5)-SWCNTs were an ideal match for the larger macrocycles 22 . This size selectivity, which was rationalized computationally, could prove useful for the purification of nanotube mixtures, since the disulfide macrocycles can be removed quantitatively under mild reductive conditions.

Modular Covalent Graphene Functionalization with C60 and the Endohedral Fullerene Sc3 N@C80 : A Facile Entry to Synthetic-Carbon-Allotrope Hybrids.

Two novel graphene-fullerene hybrid structures, containing C60 and endohedral Sc3 N@C80 bound to graphene, instead of the formerly used graphene oxide, were efficiently synthesized via a reductive activation/exfoliation approach starting from pristine graphite. The structures of these multifunctional hybrid systems were unambiguously characterized by statistical Raman spectroscopy, TG-MS, TG-GC-MS, and LD-TOF mass spectroscopy, confirming the covalent bonding of the respective C60 /Sc3 N@C80 moieties to the pristine graphene. Furthermore, assisted by temperature-dependent Raman spectroscopy studies the corresponding defunctionalization processes were also investigated. Finally, the formation of a carbon allotrope hybrid material on the basis of C60 /Sc3 N@C80 moieties coupled to graphene could be visualized by HRTEM.

Covalent Inter-Carbon-Allotrope Architectures Consisting of the Endohedral Fullerene Sc3 N@C80 and Single-Walled Carbon Nanotubes.

Using a reductive sidewall functionalization concept, we prepared for the first time a covalent inter-carbon-allotrope hybrid consisting of single-walled carbon nanotubes (SWCNTs) and the endohedral fullerene Sc3 N@C80 . The new compound type was characterized through a variety of techniques including absorption spectroscopy, Raman spectroscopy, TG-MS, TG-GC-MS, and MALDI-TOF MS. HRTEM investigations were carried out to visualize this highly integrated architecture.

Oxo-Functionalized Graphene: A Versatile Precursor for Alkylated Graphene Sheets by Reductive Functionalization.

Controlled covalent functionalization of graphene remains a challenging task owing to the heterogeneous nature of materials. Functionalization approaches for graphene either lack in quantifying the degree of functionalization or they do not discriminate between covalent and non-covalent functionalization. Here, graphite is oxidized and exfoliated in a three-step procedure and subsequently reduced and functionalized by hexylation. Although Raman spectroscopy is powerful to determine the degree of in-plane lattice defects (θLD ) and functionalization (θFD ), the method fails at detecting introduced hexyl groups at a concentration of about 0.03 %, next to the pre-existing in-plane lattice defects of 0.7 %. However, sensitive thermogravimetric analysis coupled with gas chromatography and mass spectrometry (TGA-GC/MS) can prove the hexylation reaction. The efficiency of functionalization is comparable to reductive functionalization of pristine chemical vapor deposition (CVD)-graphene and bulk graphite.

Optical second harmonic generation from nanostructured graphene: a full wave approach.

Optical second harmonic generation (SHG) from nanostructured graphene has been studied in the framework of classical electromagnetism using a surface integral equation method. Single disks and dimers are considered, demonstrating that the nonlinear conversion is enhanced when a localized surface plasmon resonance is excited at either the fundamental or second harmonic frequency. The proposed approach, beyond the electric dipole approximation used in the quantum description, reveals that SHG from graphene nanostructures with centrosymmetric shapes is possible when retardation effects and the excitation of high plasmonic modes at the second harmonic frequency are taken into account. Several SHG effects similar to those arising in metallic nanostructures, such as the silencing of the nonlinear emission and the design of double resonant nanostructures, are also reported. Finally, it is shown that the SHG from graphene disk dimers is very sensitive to a relative vertical displacement of the disks, opening new possibilities for the design of nonlinear plasmonic nanorulers.

Simulation-based adjustment after exploratory biomarker subgroup selection in phase II.

As part of the evaluation of phase II trials, it is common practice to perform exploratory subgroup analyses with the aim of identifying patient populations with a beneficial treatment effect. When investigating targeted therapies, these subgroups are typically defined by biomarkers. Promising results may lead to the decision to select the respective subgroup as the target population for a subsequent phase III trial. However, a selection based on a large observed treatment effect may potentially induce an upwards-bias leading to over-optimistic expectations on the success probability of the phase III trial. We describe how Approximate Bayesian Computation techniques can be used to derive a simulation-based bias adjustment method in this situation. Recommendations for the implementation of the approach are given. Simulation studies show that the proposed method reduces bias substantially compared with the maximum likelihood estimator. The procedure is illustrated with data from an oncology trial. Copyright © 2017 John Wiley & Sons, Ltd.

Probability of success for phase III after exploratory biomarker analysis in phase II.

The probability of success or average power describes the potential of a future trial by weighting the power with a probability distribution of the treatment effect. The treatment effect estimate from a previous trial can be used to define such a distribution. During the development of targeted therapies, it is common practice to look for predictive biomarkers. The consequence is that the trial population for phase III is often selected on the basis of the most extreme result from phase II biomarker subgroup analyses. In such a case, there is a tendency to overestimate the treatment effect. We investigate whether the overestimation of the treatment effect estimate from phase II is transformed into a positive bias for the probability of success for phase III. We simulate a phase II/III development program for targeted therapies. This simulation allows to investigate selection probabilities and allows to compare the estimated with the true probability of success. We consider the estimated probability of success with and without subgroup selection. Depending on the true treatment effects, there is a negative bias without selection because of the weighting by the phase II distribution. In comparison, selection increases the estimated probability of success. Thus, selection does not lead to a bias in probability of success if underestimation due to the phase II distribution and overestimation due to selection cancel each other out. We recommend to perform similar simulations in practice to get the necessary information about the risk and chances associated with such subgroup selection designs.

Continuous Processes and Flow Chemistry at the Universities of Applied Sciences in Switzerland.

This article provides an overview of activities in the fields of continuous processes, flow chemistry and microreactors at the Universities of Applied Sciences in Switzerland.

Semihydrogenation of Acetylene on Indium Oxide: Proposed Single-Ensemble Catalysis.

Indium oxide catalyzes acetylene hydrogenation with high selectivity to ethylene (>85 %); even with a large excess of the alkene. In situ characterization reveals the formation of oxygen vacancies under reaction conditions, while an in depth theoretical analysis links the surface reduction with the creation of well-defined vacancies and surrounding In3 O5 ensembles, which are considered responsible for this outstanding catalytic function. This behavior, which differs from that of other common reducible oxides, originates from the presence of four crystallographically inequivalent oxygen sites in the indium oxide surface. These resulting ensembles are 1) stable against deactivation, 2) homogeneously and densely distributed, and 3) spatially isolated and confined against transport; thereby broadening the scope of oxides in hydrogenation catalysis.

Standard first-line chemotherapy with or without nintedanib for advanced ovarian cancer (AGO-OVAR 12): a randomised, double-blind, placebo-controlled phase 3 trial.

BACKGROUND: Angiogenesis is a target in the treatment of ovarian cancer. Nintedanib, an oral triple angiokinase inhibitor of VEGF receptor, platelet-derived growth factor receptor, and fibroblast growth factor receptor, has shown activity in phase 2 trials in this setting. We investigated the combination of nintedanib with standard carboplatin and paclitaxel chemotherapy in patients with newly diagnosed advanced ovarian cancer. METHODS: In this double-blind phase 3 trial, chemotherapy-naive patients (aged 18 years or older) with International Federation of Gynecology and Obstetrics (FIGO) IIB-IV ovarian cancer and upfront debulking surgery were stratified by postoperative resection status, FIGO stage, and planned carboplatin dose. Patients were randomly assigned (2:1) via an interactive voice or web-based response system to receive six cycles of carboplatin (AUC 5 mg/mL per min or 6 mg/mL per min) and paclitaxel (175 mg/m(2)) in addition to either 200 mg of nintedanib (nintedanib group) or placebo (placebo group) twice daily on days 2-21 of every 3-week cycle for up to 120 weeks. Patients, investigators, and independent radiological reviewers were masked to treatment allocation. The primary endpoint was investigator-assessed progression-free survival analysed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01015118. FINDINGS: Between Dec 9, 2009, and July 27, 2011, 1503 patients were screened and 1366 randomly assigned by nine study groups in 22 countries: 911 to the nintedanib group and 455 to the placebo group. 486 (53%) of 911 patients in the nintedanib group experienced disease progression or death compared with 266 (58%) of 455 in the placebo group. Median progression-free survival was significantly longer in the nintedanib group than in the placebo group (17·2 months [95% CI 16·6-19·9] vs 16·6 months [13·9-19·1]; hazard ratio 0·84 [95% CI 0·72-0·98]; p=0·024). The most common adverse events were gastrointestinal (diarrhoea: nintedanib group 191 [21%] of 902 grade 3 and three [<1%] grade 4 vs placebo group nine [2%] of 450 grade 3 only) and haematological (neutropenia: nintedanib group 180 [20%] grade 3 and 200 (22%) grade 4 vs placebo group 90 [20%] grade 3 and 72 [16%] grade 4; thrombocytopenia: 105 [12%] and 55 [6%] vs 21 [5%] and eight [2%]; anaemia: 108 [12%] and 13 [1%] vs 26 [6%] and five [1%]). Serious adverse events were reported in 376 (42%) of 902 patients in the nintedanib group and 155 (34%) of 450 in the placebo group. 29 (3%) of 902 patients in the nintedanib group experienced serious adverse events associated with death compared with 16 (4%) of 450 in the placebo group, including 12 (1%) in the nintedanib group and six (1%) in the placebo group with a malignant neoplasm progression classified as an adverse event by the investigator. Drug-related adverse events leading to death occurred in three patients in the nintedanib group (one without diagnosis of cause; one due to non-drug-related sepsis associated with drug-related diarrhoea and renal failure; and one due to peritonitis) and in one patient in the placebo group (cause unknown). INTERPRETATION: Nintedanib in combination with carboplatin and paclitaxel is an active first-line treatment that significantly increases progression-free survival for women with advanced ovarian cancer, but is associated with more gastrointestinal adverse events. Future studies should focus on improving patient selection and optimisation of tolerability. FUNDING: Boehringer Ingelheim.

On confidence intervals for the hazard ratio in randomized clinical trials.

The log-rank test is widely used to compare two survival distributions in a randomized clinical trial, while partial likelihood (Cox, 1975) is the method of choice for making inference about the hazard ratio under the Cox (1972) proportional hazards model. The Wald 95% confidence interval of the hazard ratio may include the null value of 1 when the p-value of the log-rank test is less than 0.05. Peto et al. (1977) provided an estimator for the hazard ratio based on the log-rank statistic; the corresponding 95% confidence interval excludes the null value of 1 if and only if the p-value of the log-rank test is less than 0.05. However, Peto's estimator is not consistent, and the corresponding confidence interval does not have correct coverage probability. In this article, we construct the confidence interval by inverting the score test under the (possibly stratified) Cox model, and we modify the variance estimator such that the resulting score test for the null hypothesis of no treatment difference is identical to the log-rank test in the possible presence of ties. Like Peto's method, the proposed confidence interval excludes the null value if and only if the log-rank test is significant. Unlike Peto's method, however, this interval has correct coverage probability. An added benefit of the proposed confidence interval is that it tends to be more accurate and narrower than the Wald confidence interval. We demonstrate the advantages of the proposed method through extensive simulation studies and a colon cancer study.