Design of a Bayesian adaptive phase 2 proof-of-concept trial for BAN2401, a putative disease-modifying monoclonal antibody for the treatment of Alzheimer's disease

AbstractIntroductionRecent failures in phase 3 clinical trials in Alzheimer's disease (AD) suggest that novel approaches to drug development are urgently needed. Phase 3 risk can be mitigated by ensuring that clinical efficacy is established before initiating confirmatory trials, but traditional phase 2 trials in AD can be lengthy and costly.MethodsWe designed a Bayesian adaptive phase 2, proof-of-concept trial with a clinical endpoint to evaluate BAN2401, a monoclonal antibody targeting amyloid protofibrils. The study design used dose response and longitudinal modeling. Simulations were used to refine study design features to achieve optimal operating characteristics.ResultsThe study design includes five active treatment arms plus placebo, a clinical outcome, 12-month primary endpoint, and a maximum sample size of 800. The average overall probability of success is ≥80% when at least one dose shows a treatment effect that would be considered clinically meaningful. Using frequent interim analyses, the randomization ratios are adapted based on the clinical endpoint, and the trial can be stopped for success or futility before full enrollment.DiscussionBayesian statistics can enhance the efficiency of analyzing the study data. The adaptive randomization generates more data on doses that appear to be more efficacious, which can improve dose selection for phase 3. The interim analyses permit stopping as soon as a predefined signal is detected, which can accelerate decision making. Both features can reduce the size and duration of the trial. This study design can mitigate some of the risks associated with advancing to phase 3 in the absence of data demonstrating clinical efficacy. Limitations to the approach are discussed

Adaptive homodyne measurement of optical phase

We present an experimental demonstration of the power of real-time feedback in quantum metrology, confirming a theoretical prediction by Wiseman regarding the superior performance of an adaptive homodyne technique for single-shot measurement of optical phase. For phase measurements performed on weak coherent states with no prior knowledge of the signal phase, we show that the variance of adaptive homodyne estimation approaches closer to the fundamental quantum uncertainty limit than any previously demonstrated technique. Our results underscore the importance of real-time feedback for reaching quantum performance limits in coherent telecommunication, precision measurement and information processing.Comment: RevTex4, color PDF figures (separate files), submitted to PR

Chromosome Number Changes Associated with Speciation in Sedges: a Phylogenetic Study in Carex section Ovales (Cyperaceae) Using AFLP Data

Phylogenetic analysis of amplified fragment length polymorphisms (AFLP) was used to infer patterns of morphologic and chromosomal evolution in an eastern North American group of sedges (ENA clade I of Carex sect. Ovales). Distance analyses of AFLP data recover a tree that is topologically congruent with previous phylogenetic estimates based on nuclear ribosomal DNA (nrDNA) sequences and provide support for four species groups within ENA clade I. A maximum likelihood method designed for analysis of restriction site data is used to evaluate the strength of support for alternative topologies. While there is little support for the precise placement of the root, the likelihood of topologies in which any of the four clades identified within the ENA clade I is forced to be paraphyletic is much lower than the likelihood of the optimal tree. Chromosome counts for a sampling of species from throughout sect. Ovales are mapped onto the tree, as well as counts for all species in ENA clade I. Parsimony reconstruction of ancestral character states suggest that: (1) Heilborn’s hypothesis that more highly derived species in Carex have higher chromosome counts does not apply within sect. Ovales, (2) the migration to eastern North America involved a decrease in average chromosome count within sect. Ovales, and (3) intermediate chromosome counts are ancestral within ENA clade I. A more precise understanding of chromosomal evolution in Carex should be possible using likelihood analyses that take into account the intraspecific polymorphism and wide range of chromosome counts that characterize the genus

Initial Survey of Engineering Technology Capstone Courses and TeamworkBuilding Using CATME

This paper represents a first step in what is to become a multi –institutional initiative focused on identifying best practices for developing and improving teamwork skills within the Capstone experiences of engineering, technology and computing programs. Teamwork in this paper is defined and measured as the dimensions measured by the CATME Peer Review [1], which is currently used by thousands of technology and engineering instructors and institutions worldwide. The CATME Peer Review measurement tool is used to collect self and peer evaluations of team members’ contributions on five different teamwork dimensions [2]. These teamwork dimensions are 1) pose the knowledge, skills, and abilities to help the team; 2) expect quality work from the team; 3) keep the team on schedule; 4) positive interactions between teammates to help the team; and 5) all team members contribute to the team\u27s work and success. Pung and Farris[3] used CATME in a one semester junior level design class and reported a “significant improvement” in student behavior when compared to the old system of peer review. A workshop was developed to assemble all the participants, and develop a systematic method of evaluating teamwork building using CATME. All the participating schools and faculty will be testing changes in their Capstone courses and sharing the results of this analysis, in teamwork skills, with their colleagues

Fractional flow reserve versus angiography in guiding management to optimize outcomes in non–ST-elevation myocardial infarction (FAMOUS-NSTEMI): rationale and design of a randomized controlled clinical trial

<p>Background: In patients with acute non–ST-elevation myocardial infarction (NSTEMI), coronary arteriography is usually recommended; but visual interpretation of the angiogram is subjective. We hypothesized that functional assessment of coronary stenosis severity with a pressure-sensitive guide wire (fractional flow reserve [FFR]) would have additive diagnostic, clinical, and health economic utility as compared with angiography-guided standard care.</p> <p>Methods and design: A prospective multicenter parallel-group 1:1 randomized controlled superiority trial in 350 NSTEMI patients with ≥1 coronary stenosis ≥30% severity (threshold for FFR measurement) will be conducted. Patients will be randomized immediately after coronary angiography to the FFR-guided group or angiography-guided group. All patients will then undergo FFR measurement in all vessels with a coronary stenosis ≥30% severity including culprit and nonculprit lesions. Fractional flow reserve will be disclosed to guide treatment in the FFR-guided group but not disclosed in the “angiography-guided” group. In the FFR-guided group, an FFR ≤0.80 will be an indication for revascularization by percutaneous coronary intervention or coronary artery bypass surgery, as appropriate. The primary outcome is the between-group difference in the proportion of patients allocated to medical management only compared with revascularization. Secondary outcomes include the occurrence of cardiac death or hospitalization for myocardial infarction or heart failure, quality of life, and health care costs. The minimum and average follow-up periods for the primary analysis are 6 and 18 months, respectively.</p> <p>Conclusions: Our developmental clinical trial will address the feasibility of FFR measurement in NSTEMI and the influence of FFR disclosure on treatment decisions and health and economic outcomes.</p&gt

Effects of coal contamination on early life history processes of a reef-building coral, Acropora tenuis

Successful reproduction and larval dispersal are important for the persistence ofmarine invertebrate populations, and these early life history processes can be sensitive to marine pollution. Coal is emerging as a contaminant of interest due to the proximity of ports and shipping lanes to coral reefs. To assess the potential hazard of this contaminant, gametes, newly developedembryos, larvae and juveniles of the coral Acropora tenuis were exposed to a range of coal leachate, suspended coal, and coal smothering treatments. Fertilisation was the most sensitive reproductive process tested. Embryo survivorship decreased with increasing suspended coal concentrations and exposure duration, effects on larval settlement varied between treatments, while effects on juvenile survivorship were minimal. Leachate exposures had negligible effects on fertilisation and larval settlement. These results indicate that coral recruitment could be affected by spills that produce plumes of suspended coal particles which interact with gametes and embryos soon after spawning

Soil crusts in the Molopo Basin, southern Africa

Biological soil crusts are a common feature of many dryland soils. The cyanobacteria and algae that make up the crusts can fix atmospheric nitrogen and sequester carbon dioxide directly from the atmosphere. Crusts, therefore, have an important role in nutrient cycling as well as erosion control. This paper provides the first evidence of widespread biological soil crusts in the Molopo Basin on the southern margins of the Kalahari. The crusts appear to be more resistant to disturbance than those reported elsewhere and are able to thrive despite a relatively high vascular plant cover

Isotopic Signature of Massive, Buried Ice in Eastern Taylor Valley, Antarctica: Implications for Its Origin

The coastal regions of the McMurdo Dry Valleys, Antarctica, contain deposits of the Ross Sea Drift, sedimentary material left from the Ross Sea ice sheet from the advance of the West Antarctic ice sheet during the Last Glacial Maximum. Much of this deposit is ice-cored, but data on the stable isotopic composition of water from this ice, which may contain a valuable climate archive, are sparse or incomplete. Widespread thermokarstic ground subsidence in this “coastal thaw zone” of the McMurdo Dry Valleys suggests that these potential records are rapidly being lost due to the melting of ground ice and permafrost. We collected samples of massive buried ice from the Ross Sea Drift in eastern Taylor Valley for δ18O-H2O and δ2H-H2O and measured a broad range of values (δ18O = −27.7 to −37.3 ‰; δ2H = −210 to −295 ‰). These buried ice deposits do not show evidence of alteration through sublimation or evaporation, plot along the local meteoric water line, and have values that indicate ice deposition under a colder climate than present conditions. We propose that this ice was sourced from the Ross Sea ice sheet during the Last Glacial Maximum and contains a valuable and accessible climate record

Electrophysiological Signatures of Spatial Boundaries in the Human Subiculum.

Environmental boundaries play a crucial role in spatial navigation and memory across a wide range of distantly related species. In rodents, boundary representations have been identified at the single-cell level in the subiculum and entorhinal cortex of the hippocampal formation. Although studies of hippocampal function and spatial behavior suggest that similar representations might exist in humans, boundary-related neural activity has not been identified electrophysiologically in humans until now. To address this gap in the literature, we analyzed intracranial recordings from the hippocampal formation of surgical epilepsy patients (of both sexes) while they performed a virtual spatial navigation task and compared the power in three frequency bands (1-4, 4-10, and 30-90 Hz) for target locations near and far from the environmental boundaries. Our results suggest that encoding locations near boundaries elicited stronger theta oscillations than for target locations near the center of the environment and that this difference cannot be explained by variables such as trial length, speed, movement, or performance. These findings provide direct evidence of boundary-dependent neural activity localized in humans to the subiculum, the homolog of the hippocampal subregion in which most boundary cells are found in rodents, and indicate that this system can represent attended locations that rather than the position of one\u27s own body