Assessment of average,population and individual bioequivalence in two- and four-period crossover studies

The aim of bioequivalence studies is to assess the equivalence of two pharmaceutical formulations of the same active drug substance. Currently three types of bioequivalence are distinguished: average, population and individual bioequivalence. Average and population bioequivalence can be assessed in two-period (non-replicated) crossover studies, whereas individual bioequivalence requires three- or four-period replicated studies, with a preference for four-period studies. The PC-program BIOEQV80 is presented for the statistical analysis of average and population bioequivalence from two-period crossover studies. The program BIOEQ2X2 is presented for the statistical analysis of all three types of bioequivalence from four-period replicated crossover studies. The statistical aspects of population and individual bioequivalence are based on a recent Guidance issued by the US Food and Drug Administration.     

Fungal aerosol composition in moldy basements

Experimental aerosolization studies revealed that fungal fragments including small fragments in the submicrometer size are released from fungal cultures and have been suggested to represent an important fraction of overall fungal aerosols in indoor environments. However, their prevalence indoors and outdoors remains poorly characterized. Moldy basements were investigated for airborne fungal particles including spores, submicron fragments, and larger fragments. Particles were collected onto poly‐L‐lysine‐coated polycarbonate filters and qualitatively and quantitatively analyzed using immunogold labeling combined with field emission scanning electron microscopy. We found that the total fungal aerosol levels including spores, submicrometer, and larger fragments in the moldy basements (median: 80 × 10³ m^?3) were not different from that estimated in control basements (63 × 10³ m^?3) and outdoor (90 × 10³ m^?3). However, mixed effect modeling of the fungal aerosol composition revealed that the fraction of fragments increased significantly in moldy basements, versus the spore fraction that increased significantly in outdoor air. These findings provide new insight on the compositional variation of mixed fungal aerosols in indoor as compared to outdoor air. Our results also suggest that further studies, aiming to investigate the role of fungal aerosols in the fungal exposure‐disease relationships, should consider the mixed composition of various types of fungal particles.     

Characterization and pro-inflammatory potential of indoor mold particles

A number of epidemiological studies find an association between indoor air dampness and respiratory health effects. This is often suggested to be linked to enhanced mold growth. However, the role of mold is obviously difficult to disentangle from other dampness-related exposure including microbes as well as non-biological particles and chemical pollutants. The association may partly be due to visible mycelial growth and a characteristic musty smell of mold. Thus, the potential role of mold exposure should be further explored by evaluating information from experimental studies elucidating possible mechanistic links. Such studies show that exposure to spores and hyphal fragments may act as allergens and pro-inflammatory mediators and that they may damage airways by the production of toxins, enzymes, and volatile organic compounds. In the present review, we hypothesize that continuous exposure to mold particles may result in chronic low-grade pro-inflammatory responses contributing to respiratory diseases. We summarize some of the main methods for detection and characterization of fungal aerosols and highlight in vitro research elucidating how molds may induce toxicity and pro-inflammatory reactions in human cell models relevant for airway exposure. Data suggest that the fraction of fungal hyphal fragments in indoor air is much higher than that of airborne spores, and the hyphal fragments often have a higher pro-inflammatory potential. Thus, hyphal fragments of prevalent mold species with strong pro-inflammatory potential may be particularly relevant candidates for respiratory diseases associated with damp/mold-contaminated indoor air. Future studies linking of indoor air dampness with health effects should assess the toxicity and pro-inflammatory potential of indoor air particulate matter and combined this information with a better characterization of biological components including hyphal fragments from both pathogenic and non-pathogenic mold species. Such studies may increase our understanding of the potential role of mold exposure.     

Mediated social touch: a review of current research and future directions

In this paper, we review research and applications in the area of mediated or remote social touch. Whereas current communication media rely predominately on vision and hearing, mediated social touch allows people to touch each other over a distance by means of haptic feedback technology. Overall, the reviewed applications have interesting potential, such as the communication of simple ideas (e.g., through Hapticons), establishing a feeling of connectedness between distant lovers, or the recovery from stress. However, the beneficial effects of mediated social touch are usually only assumed and have not yet been submitted to empirical scrutiny. Based on social psychological literature on touch, communication, and the effects of media, we assess the current research and design efforts and propose future directions for the field of mediated social touch.     

Automated protein-ligand crystallography for structure-based drug design

An approach to automate protein-ligand crystallography is presented, with the aim of increasing the number of structures available to structure-based drug design. The methods we propose deal with the automatic interpretation of diffraction data for targets with known protein structures, and provide easy access to the results. Central to the system is a novel procedure that fully automates the placement of ligands into electron density maps. Automation provides an objective way to structure solution, whereas manual placement can be rather subjective, especially for data of low to medium resolution. Ligands are placed by docking into electron density, whilst taking care of protein-ligand interactions. The ligand fitting procedure has been validated on both public domain and in-house examples. Some of the latter deal with cocktails of low-molecular weight compounds, as used in fragment-based drug discovery by crystallography. For such library-screening experiments we show that the method can automatically identify which of the compounds from a cocktail is bound.     

Organic electronic ratchets doing work

The possibility to extract work from periodic, undirected forces has intrigued scientists for over a century—in particular, the rectification of undirected motion of particles by ratchet potentials, which are periodic but asymmetric functions. Introduced by Smoluchowski and Feynman to study the (dis)ability to generate motion from an equilibrium situation, ratchets operate out of equilibrium, where the second law of thermodynamics no longer applies. Although ratchet systems have been both identified in nature and used in the laboratory for the directed motion of microscopic objects, electronic ratchets have been of limited use, as they typically operate at cryogenic temperatures and generate subnanoampere currents and submillivolt voltages. Here, we present organic electronic ratchets that operate up to radio frequencies at room temperature and generate currents and voltages that are orders of magnitude larger. This enables their use as a d.c. power source. We integrated the ratchets into logic circuits, in which they act as the d.c. equivalent of the a.c. transformer, and generate enough power to drive the circuitry. Our findings show that electronic ratchets may be of actual use.     

Perceptual attributes of crosstalk in 3D images

Nowadays, crosstalk is probably one of the most annoying distortions in 3D displays. So far, display designers still have a relative lack of knowledge about the relevant subjective attributes of crosstalk and how they are combined in an overall 3D viewing experience model. The aim of the current experiment is to investigate three perceptually important attributes influencing the overall viewing experience: perceived image distortion, perceived depth, and visual strain. The stimulus material used in this experiment consisted of two natural scenes varying in depth (0, 4, and 12 cm camera base distance) and crosstalk level (0, 5, 10, and 15%). Subjects rated the attributes according to the ITU BT.500–10 in a controlled experiment. Results show that image distortion ratings show a clear increase with increasing crosstalk and increasing camera base distance. Especially higher crosstalk levels are more visible at larger camera base distances. Ratings of visual strain and perceived depth only increase with increasing camera base distance and remain constant with increasing crosstalk (at least until 15% crosstalk).     

Human scFv SIgA expressed on Lactococcus lactis as a vector for the treatment of mucosal disease

The gastrointestinal tract is a complex niche and the main port of entry of many pathogens that trigger a wide range of diseases like inflammatory bowel disease (IBD) and colon cancer. Antibodies are effective for treating such diseases, but a system capable of local delivery at the site of the pathology, thus avoiding systemic side effects, is not yet available. Here we report a novel recombinant scFvSIgA1 protein produced by Lactococcus lactis, anchored to the bacterial membrane, which retains its full immuno-recognizing potential. This scFv fragment employed was specific for a colon cancer epitope, epithelial glycoprotein protein-2 (EGP-2). Accordingly L. lactis expressing this chimeric protein was capable of binding cells expressing this epitope. Expression of specific antibodies on bacteria may allow local delivery of anticancer agents produced by such bacteria in conjunction with the antibody and provides a new avenue in the quest for targeted drug delivery.     

Reductant flow control for NOX removal from lean exhaust gases

This review article describes and discusses the literature on reducing agent control systems for NO_x emission reduction in the exhaust gas of full lean‐burn engines. The literature can be classified as feedback, feedforward, feedforward‐feedback, feedforward/feedforward‐feedback and periodical dosing control systems, which can be further classified as classical, override, co‐ordinated, constrained and split systems or a combination of those. As long as reproducible, fast and cheap NO_x sensors are not commercially available, the control system should be an inferential feedforward or feedforward‐feedback system supplied with constraints for environmental and economical reasons. For future applications an oxidation catalyst downstream of the deNO_x catalyst should be applied to convert any inevitable reductant slip, due to modelling errors, to harmless compounds.