Composition and micromechanical properties of the femoral neck compact bone in relation to patient age, sex and hip fracture occurrence.

Current clinical methods of bone health assessment depend to a great extent on bone mineral density (BMD) measurements. However, these methods only act as a proxy for bone strength and are often only carried out after the fracture occurs. Besides BMD, composition and tissue-level mechanical properties are expected to affect the whole bone's strength and toughness.

Femtosecond Laser-Induced Periodic Surface Structures in Titanium-Doped Diamond-like Nanocomposite Films: Effects of the Beam Polarization Rotation.

We study the properties of laser-induced periodic surface structures (LIPSS) formed on titanium-doped diamond-like nanocomposite (DLN) a-C:H:Si:O films during ablation processing with linearly-polarized beams of a visible femtosecond laser (wavelength 515 nm, pulse duration 320 fs, pulse repetition rates 100 kHz-2 MHz, scanning beam velocity 0.05-1 m/s). The studies are focused on (i) laser ablation characteristics of Ti-DLN films at different pulse frequencies and constant fluence close to the ablation threshold, (ii) effects of the polarization angle rotation on the properties of low spatial frequency LIPSS (LSFL), and (iii) nanofriction properties of the 'rotating' LIPSS using atomic force microscopy (AFM) in a lateral force mode.

Assessing minipig compact jawbone quality at the microscale.

Preclinical studies often require animal models for in vivo experiments. Particularly in dental research, pig species are extensively used due to their anatomical similarity to humans. However, there is a considerable knowledge gap on the multiscale morphological and mechanical properties of the miniature pigs' jawbones, which is crucial for implant studies and a direct comparison to human tissue.

Sub-Threshold Fabrication of Laser-Induced Periodic Surface Structures on Diamond-like Nanocomposite Films with IR Femtosecond Pulses.

In the paper, we study the formation of laser-induced periodic surface structures (LIPSS) on diamond-like nanocomposite (DLN) a-C:H:Si:O films during nanoscale ablation processing at low fluences-below the single-pulse graphitization and spallation thresholds-using an IR fs-laser (wavelength 1030 nm, pulse duration 320 fs, pulse repetition rate 100 kHz, scanning beam velocity 0.04-0.08 m/s).

The Predictive Individual Effect for Survival Data.

Background: The call for patient-focused drug development is loud and clear, as expressed in the twenty-first Century Cures Act and in recent guidelines and initiatives of regulatory agencies. Among the factors contributing to modernized drug development and improved health-care activities are easily interpretable measures of clinical benefit. In addition, special care is needed for cancer trials with time-to-event endpoints if the treatment effect is not constant over time.

Review on Experimental and Theoretical Investigations of Ultra-Short Pulsed Laser Ablation of Metals with Burst Pulses.

Laser processing with ultra-short double pulses has gained attraction since the beginning of the 2000s. In the last decade, pulse bursts consisting of multiple pulses with a delay of several 10 ns and less found their way into the area of micromachining of metals, opening up completely new process regimes and allowing an increase in the structuring rates and surface quality of machined samples. Several physical effects such as shielding or re-deposition of material have led to a new understanding of the related machining strategies and processing regimes.

Predictively consistent prior effective sample sizes.

Determining the sample size of an experiment can be challenging, even more so when incorporating external information via a prior distribution. Such information is increasingly used to reduce the size of the control group in randomized clinical trials. Knowing the amount of prior information, expressed as an equivalent prior effective sample size (ESS), clearly facilitates trial designs.

Bayesian leveraging of historical control data for a clinical trial with time-to-event endpoint.

The recent 21st Century Cures Act propagates innovations to accelerate the discovery, development, and delivery of 21st century cures. It includes the broader application of Bayesian statistics and the use of evidence from clinical expertise. An example of the latter is the use of trial-external (or historical) data, which promises more efficient or ethical trial designs.

Beyond p-values: A phase II dual-criterion design with statistical significance and clinical relevance.

Background Well-designed phase II trials must have acceptable error rates relative to a pre-specified success criterion, usually a statistically significant p-value. Such standard designs may not always suffice from a clinical perspective because clinical relevance may call for more. For example, proof-of-concept in phase II often requires not only statistical significance but also a sufficiently large effect estimate.

Using phase II data for the analysis of phase III studies: An application in rare diseases.

Background: Clinical research and drug development in orphan diseases are challenging, since large-scale randomized studies are difficult to conduct. Formally synthesizing the evidence is therefore of great value, yet this is rarely done in the drug-approval process. Phase III designs that make better use of phase II data can facilitate drug development in orphan diseases.

Meta-analysis of two studies in the presence of heterogeneity with applications in rare diseases.

Random-effects meta-analyses are used to combine evidence of treatment effects from multiple studies. Since treatment effects may vary across trials due to differences in study characteristics, heterogeneity in treatment effects between studies must be accounted for to achieve valid inference. The standard model for random-effects meta-analysis assumes approximately normal effect estimates and a normal random-effects model.

Meta-analysis of few small studies in orphan diseases.

Meta-analyses in orphan diseases and small populations generally face particular problems, including small numbers of studies, small study sizes and heterogeneity of results. However, the heterogeneity is difficult to estimate if only very few studies are included. Motivated by a systematic review in immunosuppression following liver transplantation in children, we investigate the properties of a range of commonly used frequentist and Bayesian procedures in simulation studies.

Robust meta-analytic-predictive priors in clinical trials with historical control information.

Historical information is always relevant for clinical trial design. Additionally, if incorporated in the analysis of a new trial, historical data allow to reduce the number of subjects. This decreases costs and trial duration, facilitates recruitment, and may be more ethical.

The current state of Bayesian methods in medical product development: survey results and recommendations from the DIA Bayesian Scientific Working Group.

Bayesian applications in medical product development have recently gained popularity. Despite many advances in Bayesian methodology and computations, increase in application across the various areas of medical product development has been modest. The DIA Bayesian Scientific Working Group (BSWG), which includes representatives from industry, regulatory agencies, and academia, has adopted the vision to ensure Bayesian methods are well understood, accepted more broadly, and appropriately utilized to improve decision making and enhance patient outcomes.

Use of historical control data for assessing treatment effects in clinical trials.

Clinical trials rarely, if ever, occur in a vacuum. Generally, large amounts of clinical data are available prior to the start of a study, particularly on the current study's control arm. There is obvious appeal in using (i.

Using historical control information for the design and analysis of clinical trials with overdispersed count data.

Results from clinical trials are never interpreted in isolation. Previous studies in a similar setting provide valuable information for designing a new trial. For the analysis, however, the use of trial-external information is challenging and therefore controversial, although it seems attractive from an ethical or efficiency perspective.

Collection, synthesis, and interpretation of evidence: a proof-of-concept study in COPD.

We present a clinical proof-of-concept (PoC) study in chronic obstructive pulmonary disease with the objective of assessing the bronchodilatory effect of an experimental drug as compared with an active control treatment. In such an exploratory Phase II setting, we discuss the formal inclusion of relevant historical information and tailored PoC criteria for the purpose of a more efficient use of the available evidence to support clinical decision making. We provide guidance with regard to practical and methodological aspects for assessing the relevance of the historical data, synthesizing the evidence via a meta-analytic-predictive approach, and defining transparent statistical PoC decision criteria that are aligned with the clinical context.

The network meta-analytic-predictive approach to non-inferiority trials.

In non-inferiority clinical trials, a test treatment is compared to an active-control rather than to placebo. Such designs are considered when placebo is unethical or not feasible. The critical question is whether the test treatment would have been superior to placebo, had placebo been used in the non-inferiority trial.

Discussion of the article by Trippa, Rosner, and Müller on Bayesian enrichment strategies for randomized discontinuation trials.

We congratulate Trippa, Rosner, and Müller (2011, Biometrics, in press) on an intriguing and timely article. The randomized discontinuation design (RDD) has only recently been used in cancer clinical trials, and methodological understanding on how to best design such studies is limited. The authors’ approach to optimize RDD designs based on prior information and utility considerations is an important step forward.

A proof of concept phase II non-inferiority criterion.

Traditional phase III non-inferiority trials require compelling evidence that the treatment vs control effect bfθ is better than a pre-specified non-inferiority margin θ(NI) . The standard approach compares this margin to the 95 per cent confidence interval of the effect parameter. In the phase II setting, in order to declare Proof of Concept (PoC) for non-inferiority and proceed in the development of the drug, different criteria that are specifically tailored toward company internal decision making may be more appropriate.

Bayesian models for subgroup analysis in clinical trials.

Background: In a pharmaceutical drug development setting, possible interactions between the treatment and particular baseline clinical or demographic factors are often of interest. However, the subgroup analysis required to investigate such associations remains controversial. Concerns with classical hypothesis testing approaches to the problem include low power, multiple testing, and the possibility of data dredging.

Summarizing historical information on controls in clinical trials.

Background: Historical information is always relevant when designing clinical trials, but it might also be incorporated in the analysis. It seems appropriate to exploit past information on comparable control groups.

Purpose: Phase IV and proof-of-concept trials are used to discuss aspects of summarizing historical control data as prior information in a new trial.

A note on the power prior.

The power prior by Ibrahim and Chen (Statist. Sci. 2000; 15:46-60) is one of several methods to incorporate historical data in the analysis of a clinical trial.