Heuristics for designing user-centric drug products: Lessons learned from Human Factors and Ergonomics.

Even the most effective drug product may be used improperly and thus ultimately prove ineffective if it does not meet the perceptual, motor and cognitive capacities of its target users. Currently, no comprehensive guideline for systematically designing user-centric drug products that would help prevent such limitations exists. We have compiled a list of approximate but nonetheless useful strategies-heuristics-for implementing a user-centric design of drug products and drug product portfolios. First, we present a general heuristic for user-centric design based on the framework of Human Factors and Ergonomics (HF/E). Then we demonstrate how to implement this general heuristic for older drug users (i.e., patients and caregivers aged 65 years and older) and with respect to three specific challenges (use-cases) of medication management: (A) knowing what drug product to take/administer, (B) knowing how and when to take/administer it, and (C) actually taking/administering it. The presented heuristics can be applied prospectively to include existing knowledge about user-centric design at every step during drug discovery, pharmaceutical drug development, and pre-clinical and clinical trials. After a product has been released to the market, the heuristics may guide a retrospective analysis of medication errors and barriers to product usage as a basis for iteratively optimizing both the drug product and its portfolio over their life cycle.

Showing their mettle: extraradical mycelia of arbuscular mycorrhizae form a metal filter to improve host Al tolerance and P nutrition.

BACKGROUND: New evidence has shown that arbuscular mycorrhizal (AM) fungi can contribute to the aluminum (Al3+ ) tolerance of host plants growing in acidic soils with phytotoxic levels of Al3+ . The aim of this study was to investigate the role of AM fungi isolated from naturally occurring Al3+ acidic soils in conferring host tolerance to Al3+ toxicity in three wheat cultivars differing in Al3+ sensitivity. The experiment was conducted in a soilless substrate (vermiculite/perlite, 2:1 v/v) using two Al3+ -tolerant wheat genotypes and one Al3+ -sensitive wheat genotype. The wheat was colonized with a consortium of AM fungi isolated from an Andisol, with or without Al3+ at a concentration of 200 µmol L-1 . RESULTS: The response of wheat to Al3+ in the medium was dependent on both the plant genotype and AM colonization. The benefits of the AM fungi to the wheat cultivars included an increased P concentration and relatively low Al3+ accumulation in the plants. This was achieved through two mechanisms. First, the metal-chelating capacity of the AM fungi was clear in two of the cultivars ('Tukan' and 'Porfiado'), in which the enhanced extraradical mycelium development was able to retain Al3+ in the glomalin and hyphae. Second, the increased AM-induced acid phosphatase activity in the rhizosphere of the other cultivar ('Atlas 66') increased host nutrition possibly by hyphae-mediated nutrient uptake and glomalin-related soil protein. CONCLUSION: The results suggest that the role of AM fungi in cultivar-specific Al3+ detoxification can be achieved by increased extraradical mycelial filters and enhanced bioavailability of P in the host rhizosphere. © 2019 Society of Chemical Industry.

Does size matter? Spacious car cockpits may increase the probability of parking violations.

Cockpit design is a core area of human factors and ergonomics (HF/E). Ideally, good design compensates for human capacity limitations by distributing task requirements over human and interface to improve safety and performance. Recent empirical findings suggest that the mere spatial layout of car cockpits may influence driver behaviour, expanding current views on HF/E in cockpit design. To assess the reliability of findings showing that an expansive driver seat space predicts parking violations, we replicated an original field study in a geographically and socio-culturally different location and included an additional covariate. After controlling for car length, brand status, and car price, driver seat space remained a positive predictor of illegal parking. This suggests that the spatial design of vehicle cockpits may indeed have an influence on driver behaviour and may therefore be a relevant dimension to be included in research and applications of HF/E in cockpit design. Practitioner summary: In car cockpit design, ergonomists typically focus on optimising human-machine interfaces to improve traffic safety. We replicate evidence showing that increasing physical space surrounding the driver relates to an increased probability of parking violations. This suggests that spatial design should be added to the ergonomist's toolbox for reducing traffic violations.

Navigating the Frontier of Synthetic Biology: An AI-Driven Analytics Platform for Exploring Research Trends and Relationships.

The field of synthetic biology has experienced rapid growth in recent years, leading to an overwhelming amount of literature that can make it difficult to comprehend the scope and trends of the discipline. In this study, we employ topic modeling to comprehensively map research topics within synthetic biology, revealing subtopics and their relationships, as well as trends over time. We utilize metadata to identify the most significant journals and countries in the field and discuss potential policy impact on the research output. In addition, we investigate co-authorship networks to analyze collaborations among authors, institutions, and countries. We believe that our findings could serve as a valuable resource for gaining a deeper understanding of synthetic biology and provide a foundation for analyzing other disciplines.

Signatures of the interplay between chaos and local criticality on the dynamics of scrambling in many-body systems.

Fast scrambling, quantified by the exponential initial growth of out-of-time-ordered correlators (OTOCs), is the ability to efficiently spread quantum correlations among the degrees of freedom of interacting systems and constitutes a characteristic signature of local unstable dynamics. As such, it may equally manifest both in systems displaying chaos or in integrable systems around criticality. Here we go beyond these extreme regimes with an exhaustive study of the interplay between local criticality and chaos right at the intricate phase-space region where the integrability-chaos transition first appears. We address systems with a well-defined classical (mean-field) limit, as coupled large spins and Bose-Hubbard chains, thus allowing for semiclassical analysis. Our aim is to investigate the dependence of the exponential growth of the OTOCs, defining the quantum Lyapunov exponent λ_{q} on quantities derived from the classical system with mixed phase space, specifically the local stability exponent of a fixed point λ_{loc} as well as the maximal Lyapunov exponent λ_{L} of the chaotic region around it. By extensive numerical simulations covering a wide range of parameters we give support to a conjectured linear dependence 2λ_{q}=aλ_{L}+bλ_{loc}, providing a simple route to characterize scrambling at the border between chaos and integrability.

Trimming the genomic fat: minimising and re-functionalising genomes using synthetic biology.

Naturally evolved organisms typically have large genomes that enable their survival and growth under various conditions. However, the complexity of genomes often precludes our complete understanding of them, and limits the success of biotechnological designs. In contrast, minimal genomes have reduced complexity and therefore improved engineerability, increased biosynthetic capacity through the removal of unnecessary genetic elements, and less recalcitrance to complete characterisation. Here, we review the past and current genome minimisation and re-functionalisation efforts, with an emphasis on the latest advances facilitated by synthetic genomics, and provide a critical appraisal of their potential for industrial applications.

Parallel laboratory evolution and rational debugging reveal genomic plasticity to S. cerevisiae synthetic chromosome XIV defects.

Synthetic chromosome engineering is a complex process due to the need to identify and repair growth defects and deal with combinatorial gene essentiality when rearranging chromosomes. To alleviate these issues, we have demonstrated novel approaches for repairing and rearranging synthetic Saccharomyces cerevisiae genomes. We have designed, constructed, and restored wild-type fitness to a synthetic 753,096-bp version of S. cerevisiae chromosome XIV as part of the Synthetic Yeast Genome project. In parallel to the use of rational engineering approaches to restore wild-type fitness, we used adaptive laboratory evolution to generate a general growth-defect-suppressor rearrangement in the form of increased TAR1 copy number. We also extended the utility of the synthetic chromosome recombination and modification by loxPsym-mediated evolution (SCRaMbLE) system by engineering synthetic-wild-type tetraploid hybrid strains that buffer against essential gene loss, highlighting the plasticity of the S. cerevisiae genome in the presence of rational and non-rational modifications.

The influence of arthroscopic subscapularis tendon and capsule release on internal rotation strength in treatment of frozen shoulder.

BACKGROUND: Arthroscopic release of the capsule is a popular treatment option for chronic refractory frozen shoulder. Additional release of the intra-articular part of the subscapularis is controversial regarding possible impairment of subscapularis function. HYPOTHESIS: Arthroscopic release of the intra-articular part of the subscapularis produces good clinical results and does not lead to reduced internal rotation strength. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Twenty-two patients were retrospectively evaluated 53 months (range, 12-106) after undergoing arthroscopic anterior capsular release, including release of the intra-articular portion of the subscapularis. Clinical outcome was evaluated using the American Shoulder and Elbow Surgeons score and the Constant score. Isometric and isokinetic strength for internal and external rotation were determined at the time of follow-up in both shoulders using a Cybex dynamometer. RESULTS: The Constant score was improved significantly from 17.7 points to 82.8 points (P < .0001) and the American Shoulder and Elbow Surgeons score increased significantly from 23.5 points to 76.8 points (P < .0001). The mean range of motion was significantly improved for external rotation from 16 degrees to 58 degrees , from 66 degrees to 142 degrees for abduction, and from 76 degrees to 155 degrees for forward flexion. Isometric and isokinetic strength in the standard abduction position of the Cybex dynamometer showed no significant side-to-side difference. CONCLUSION: Arthroscopic capsular release combined with a release of the intra-articular portion of the subscapularis tendon revealed good clinical results in the arthroscopic treatment of adhesive capsulitis without significant loss of internal rotation strength.

Distribution of substance-P nerves inside the infrapatellar fat pad and the adjacent synovial tissue: a neurohistological approach to anterior knee pain syndrome.

INTRODUCTION: The purpose of the study was to determine the distribution and number of nerves inside the infrapatellar fat pad and the adjacent synovium, in particular with regards to nociceptive substance-P nerves. MATERIALS AND METHODS: The infrapatellar fat pad of the knee was resected from 21 patients (4 male, 17 female, mean age 69 years) during the course of standard total knee arthroplasty operations performed in our clinic. The fat pad was dissected into five standardized segments, fixed in formalin and embedded in paraffin. Immunohistochemical techniques using antibodies against S-100 protein and substance-P (SP) were employed to determine and specify the nerves. RESULTS: Studying all the detectable nerves present in 50 observation fields (200-fold magnification), we found an average of 106 S-100 versus 25 SP nerves (24%) in the synovium and 27 S-100- versus 7 SP nerves (26%) in the interior of the fat pad. The total nerve count was significantly (P < 0.001) higher in the synovium than in the fat pad for both marker types. The number of S-100 nerves was significantly (P < 0.05) higher in the central and lateral segments of the fat pad, while SP nerves were equally distributed throughout all segments of the fat-pad. SP nerves were significantly more frequently associated with blood vessels inside the fat pad (43%, P < 0.05) than in the synovial tissue (28%). CONCLUSION: The occurrence and distribution of SP nerves inside the infrapatellar fat pad suggest a nociceptive function and a neurohistological role in anterior knee pain syndrome. The data support the hypothesis that a neurogenous infection of the infrapatellar fat pad could contribute to anterior knee pain syndrome.

Increasing sensitivity and decreasing spot size using an inexpensive, removable hydrophobic coating for matrix-assisted laser desorption/ionisation plates.

Spot size reduction and increased detection sensitivity in matrix-assisted laser desorption/ionisation (MALDI) of small molecules are accomplished by using an inexpensive and removable hydrophobic coating for MALDI targets, based on 3M Scotch Gard surface treatment. Several variations in sample preparation were explored, such as surface coating technique, identity of the matrix, solvent composition, and the type of metal support plate used. These were investigated on both uncoated and coated surfaces and their impact on spot size, crystal coverage, and sensitivity is presented here. Additionally, crystallisation behaviour obtained on coated plates is compared with that on uncoated plates using scanning electron microscope analysis. To demonstrate the potential of the new coating technique, erythromycin A and valinomycin are studied to determine the increase in detection sensitivity of coated plates in comparison to uncoated plates, and to reveal the suitability of the plates for application in combined high-performance liquid chromatography/MALDI (HPLC/MALDI), where widely varying solvent compositions and droplet volumes are observed. It is shown that enhancements in detection sensitivities correlate very well with the achieved spot size reduction. The versatility of the coated plates is also exhibited by the ease of removing the surface layer, after which the plates can be rigorously cleaned without worry about damaging the hydrophobic surface, followed by a quick reapplication of new hydrophobic coating material. This makes the non-polar coating superior to more expensive commercial hydrophobic-coated targets, which are much more delicate to clean. Furthermore, cleaning and reapplication eliminate potential carry-over effects and the easy application procedure also makes the fabrication of inexpensive, disposable MALDI targets readily possible.