Atomically Resolved Tissue Integration

In the field of biomedical technology, a critical aspect is the ability to control and understand the integration of an implantable device in living tissue. Despite the technical advances in the development of biomaterials, the elaborate interplay encompassing materials science and biology on the atomic level is not very well understood. Within implantology, anchoring a biomaterial device into bone tissue is termed osseointegration. In the most accepted theory, osseointegration is defined as an interfacial bonding between implant and bone; however, there is lack of experimental evidence to confirm this. Here we show that atom probe tomography can be used to study the implant–tissue interaction, allowing for three-dimensional atomic mapping of the interface region. Interestingly, our analyses demonstrated that direct contact between Ca atoms and the implanted titanium oxide surface is formed without the presence of a protein interlayer, which means that a pure inorganic interface is created, hence giving experimental support to the current theory of osseointegration. We foresee that this result will be of importance in the development of future biomaterials as well as in the design of in vitro evaluation techniques

Comparison of outlier heartbeat identification and spectral transformation strategies for deriving heart rate variability indices for drivers at different stages of sleepiness

<p><b>Objective</b>: Appropriate preprocessing for detecting and removing outlier heartbeats and spectral transformation is essential for deriving heart rate variability (HRV) indices from cardiac monitoring data with high accuracy. The objective of this study is to evaluate agreement between standard preprocessing methods for cardiac monitoring data used to detect outlier heartbeats and perform spectral transformation, in relation to estimating HRV indices for drivers at different stages of sleepiness.</p> <p><b>Methods</b>: The study analyzed more than 3,500 5-min driving epochs from 76 drivers on a public motorway in Sweden. Electrocardiography (ECG) data were recorded in 3 studies designed to evaluate the physiological differences between awake and sleepy drivers. The Pan-Tompkins algorithm was used for peak detection of heartbeats from ECG data. Two standard methods were used for identifying outlier heartbeats: (1) percentage change (PC), where outliers were defined as interbeat interval deviating >30% from the mean of the 4 previous intervals, and (2) standard deviation (SD), where outliers were defined as interbeat interval deviating >4 SD from the mean interval duration in the current epoch. Three standard methods were used for spectral transformation, which is needed for deriving HRV indices in the frequency domain; these methods were (1) the Fourier transform; (2) an autoregressive model; and (3) the Lomb-Scargle periodogram. The preprocessing methods were compared quantitatively and by assessing agreement between estimations of 13 common HRV indices using Bland-Altman plots and paired Student's <i>t</i>-tests.</p> <p><b>Results</b>: The PC method detected more than 4 times as many outliers (0.28%) than SD (0.065%). Most HRV indices derived using different preprocessing methods exhibited significant systematic (<i>P</i> <.05) and substantial random variations.</p> <p><b>Conclusions</b>: The standard preprocessing methods for HRV data for outlier heartbeat detection and spectral transformation show low levels of agreement. This finding implies that, prior to designing algorithms for detection of sleepy drivers based on HRV analysis, the impact of different preprocessing methods and combinations thereof on driver sleepiness assessment needs to be studied.</p

Discovery of Highly Isoform Selective Orally Bioavailable Phosphoinositide 3‑Kinase (PI3K)‑γ Inhibitors

In this paper, we describe the discovery and optimization of a new chemotype of isoform selective PI3Kγ inhibitors. Starting from an HTS hit, potency and physicochemical properties could be improved to give compounds such as <b>15</b>, which is a potent and remarkably selective PI3Kγ inhibitor with ADME properties suitable for oral administration. Compound <b>15</b> was advanced into in vivo studies showing dose-dependent inhibition of LPS-induced airway neutrophilia in rats when administered orally

Discovery of Highly Isoform Selective Orally Bioavailable Phosphoinositide 3‑Kinase (PI3K)‑γ Inhibitors

In this paper, we describe the discovery and optimization of a new chemotype of isoform selective PI3Kγ inhibitors. Starting from an HTS hit, potency and physicochemical properties could be improved to give compounds such as <b>15</b>, which is a potent and remarkably selective PI3Kγ inhibitor with ADME properties suitable for oral administration. Compound <b>15</b> was advanced into in vivo studies showing dose-dependent inhibition of LPS-induced airway neutrophilia in rats when administered orally