Tiotropium Respimat efficacy and safety in asthma:Relationship to age

Background: Data are limited on the differential response to long-acting bronchodilators in older versus younger adults with asthma. Objective: To determine whether the response to tiotropium Respimat differed in older versus younger patients with asthma. Methods: Post hoc analyses of 4 randomized, double-blind, placebo-controlled studies in adults with asthma were carried out. Two studies compared tiotropium Respimat 5 μg once daily with placebo, both added to high-dose inhaled corticosteroid (ICS) plus long-acting β2-agonist (ie, severe asthma). The other 2 evaluated tiotropium Respimat 2.5 or 5 μg once daily, salmeterol 50 μg twice daily, or placebo, all added to medium-dose ICS (moderate asthma). Data were analyzed in 2 pools: (1) severe and (2) moderate asthma. Efficacy end points: trough and peak FEV1; trough forced vital capacity; Asthma Control Questionnaire total score and responder percentage, all at week 24. One set of analyses was performed with age as a continuous covariate; the second was conducted in categories less than 40, 40 to 60, and more than 60 years, with treatment-by-age subgroup interaction P values obtained. Safety was analyzed in age categories. Results: Across the age categories, treatment-by-age subgroup interaction P values for trough FEV1 were.13 and.77 for patients with severe and moderate asthma, respectively, not indicating significant impact of age on overall treatment effect, with this observation replicated in the 2 continuum analyses. The other end points (including safety) were also not impacted by age. Conclusions: Once-daily tiotropium Respimat add-on to ICS or ICS/long-acting β2-agonist therapy was effective and well tolerated in patients with asthma independent of age

Microcephalin and pericentrin regulate mitotic entry via centrosome-associated Chk1

Primary microcephaly, Seckel syndrome, and microcephalic osteodysplastic primordial dwarfism type II (MOPD II) are disorders exhibiting marked microcephaly, with small brain sizes reflecting reduced neuron production during fetal life. Although primary microcephaly can be caused by mutations in microcephalin (MCPH1), cells from patients with Seckel syndrome and MOPD II harbor mutations in ataxia telangiectasia and Rad3 related (ATR) or pericentrin (PCNT), leading to disturbed ATR signaling. In this study, we show that a lack of MCPH1 or PCNT results in a loss of Chk1 from centrosomes with subsequently deregulated activation of centrosomal cyclin B–Cdk1

Rethinking drug design in the artificial intelligence era

Artificial intelligence (AI) tools are increasingly being applied in drug discovery. While some protagonists point to vast opportunities potentially offered by such tools, others remain sceptical, waiting for a clear impact to be shown in drug discovery projects. The reality is probably somewhere in-between these extremes, yet it is clear that AI is providing new challenges not only for the scientists involved but also for the biopharma industry and its established processes for discovering and developing new medicines. This article presents the views of a diverse group of international experts on the 'grand challenges' in small-molecule drug discovery with AI and the approaches to address them

Plasmonic Luneburg and Eaton Lenses

Plasmonics is an interdisciplinary field focusing on the unique properties of both localized and propagating surface plasmon polaritons (SPPs) - quasiparticles in which photons are coupled to the quasi-free electrons of metals. In particular, it allows for confining light in dimensions smaller than the wavelength of photons in free space, and makes it possible to match the different length scales associated with photonics and electronics in a single nanoscale device. Broad applications of plasmonics have been realized including biological sensing, sub-diffraction-limit imaging, focusing and lithography, and nano optical circuitry. Plasmonics-based optical elements such as waveguides, lenses, beam splitters and reflectors have been implemented by structuring metal surfaces or placing dielectric structures on metals, aiming to manipulate the two-dimensional surface plasmon waves. However, the abrupt discontinuities in the material properties or geometries of these elements lead to increased scattering of SPPs, which significantly reduces the efficiency of these components. Transformation optics provides an unprecedented approach to route light at will by spatially varying the optical properties of a material. Here, motivated by this approach, we use grey-scale lithography to adiabatically tailor the topology of a dielectric layer adjacent to a metal surface to demonstrate a plasmonic Luneburg lens that can focus SPPs. We also realize a plasmonic Eaton lens that can bend SPPs. Since the optical properties are changed gradually rather than abruptly in these lenses, losses due to scattering can be significantly reduced in comparison with previously reported plasmonic elements.Comment: Accepted for publication in Nature Nanotechnolog

New interfacial-gel copolymerization technique for steric GRIN polymer optical waveguides and lens arrays

Abstract: A synthetic polymeric lens was designed and fabricated based on a bio-inspired, "Age=5" human eye lens design by utilizing a nanolayered polymer film-based technique. The internal refractive index distribution of an anterior and posterior GRIN lens were characterized and confirmed against design by µATR-FTIR. 3D surface topography of the fabricated aspheric anterior and posterior lenses was measured by placido-cone topography and exhibited confirmation of the desired aspheric surface shape. Furthermore, the wavefronts of aspheric posterior GRIN and PMMA lenses were measured and simulated by interferometry and Zemax software, respectively. Their results show that the gradient index distribution reduces the overall wavefront error as compared a homogenous PMMA lens of an identical geometry. Finally, the anterior and posterior GRIN lenses were assembled into a bio-inspired GRIN human eye lens through which a clear imaging was possible

Tiotropium add-on therapy is safe and reduces seasonal worsening in paediatric asthma patients

There remains an unmet need for effective, well-tolerated therapeutic options in paediatric patients with not fully controlled asthma, for whom safety is of paramount importance. Data were pooled from five randomised, double-blind, placebo-controlled studies evaluating tiotropium 5 or 2.5 mu g versus placebo add-on therapy in patients with symptomatic asthma aged 1-17 years. Analysis included adverse events (AEs) and serious AEs (SAEs) reported throughout and for 30 days following treatment. Of 1691 patients treated, 1119 received tiotropium. Reporting of AEs was low and comparable across all groups: tiotropium 5 mu g (51%), tiotropium 2.5 mu g (51%) and placebo (54%). Reporting of drug-related AEs, those leading to discontinuation and SAEs was also low and balanced between treatment groups, irrespective of age, disease severity or sex. The number of AEs related to asthma symptoms and exacerbations was lower with tiotropium (5 mu g) than with placebo, particularly during the seasonal peaks of these AEs. This comprehensive analysis of a large safety database allowed subgroup analyses that are often impractical with individual trials and provides further support for the safety of once-daily tiotropium Respimat add-on therapy in paediatric patients with symptomatic asthma

Maskless Plasmonic Lithography at 22 nm Resolution

Optical imaging and photolithography promise broad applications in nano-electronics, metrologies, and single-molecule biology. Light diffraction however sets a fundamental limit on optical resolution, and it poses a critical challenge to the down-scaling of nano-scale manufacturing. Surface plasmons have been used to circumvent the diffraction limit as they have shorter wavelengths. However, this approach has a trade-off between resolution and energy efficiency that arises from the substantial momentum mismatch. Here we report a novel multi-stage scheme that is capable of efficiently compressing the optical energy at deep sub-wavelength scales through the progressive coupling of propagating surface plasmons (PSPs) and localized surface plasmons (LSPs). Combining this with airbearing surface technology, we demonstrate a plasmonic lithography with 22 nm half-pitch resolution at scanning speeds up to 10 m/s. This low-cost scheme has the potential of higher throughput than current photolithography, and it opens a new approach towards the next generation semiconductor manufacturing

Differential activation of the lateral premotor cortex during action observation

<p>Abstract</p> <p>Background</p> <p>Action observation leads to neural activation of the human premotor cortex. This study examined how the level of motor expertise (expert vs. novice) in ballroom dancing and the visual viewpoint (internal vs. external viewpoint) influence this activation within different parts of this area of the brain.</p> <p>Results</p> <p>Sixteen dance experts and 16 novices observed ballroom dance videos from internal or external viewpoints while lying in a functional magnetic resonance imaging scanner. A conjunction analysis of all observation conditions showed that action observation activated distinct networks of premotor, parietal, and cerebellar structures. Experts revealed increased activation in the ventral premotor cortex compared to novices. An internal viewpoint led to higher activation of the dorsal premotor cortex.</p> <p>Conclusions</p> <p>The present results suggest that the ventral and dorsal premotor cortex adopt differential roles during action observation depending on the level of motor expertise and the viewpoint.</p