A 2-compartment PPK model with first-order absorption and nonlinear clearance from the central compartment described the data well. PPK identified weight as the main intrinsic factor and food as the main extrinsic factor affecting SXB PK, and predicts similar PK profiles on a mg/kg basis across ages. These results, along with previously reported efficacy and safety outcomes, support weight-based SXB dose initiation in pediatric patients. This article is protected by copyright. All rights reserved.Since 2006, the US Congress has appropriated ~ 7 billion dollars in total toward the (CTSA) program of the National Institutes of Health (NIH), representing ~ 1.5% of the NIH total budget. There is no doubt this investment has led to substantial improvements in clinical and translational research, but the impact of these large NIH-sponsored awards to academic medical centers have largely been documented by anecdotal accomplishments. This paper provides a purely quantitative assessment of the impact of these awards on clinical trials registered on ClinicalTrials.gov. In particular, we find a dramatic increase in the number of registered clinical trials and clinical trial enrollment associated with the CTSA grant award. Additionally, the impact is shown to be magnified with the number of years of receiving CTSA funding. © 2020 The Author. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of the American Society of Clinical Pharmacology and Therapeutics.Megavoltage computed tomography (MVCT) image quality metrics were evaluated on an Accuray Radixact unit to recommend scan settings for the implementation of a consistent adaptive radiotherapy program. Megavoltage computed tomography image quality was evaluated and compared to a kilovoltage CT (kVCT) simulator using a commercial cone beam computed tomography image quality phantom. Megavoltage computed tomographies were acquired on the Accuray Radixact using fine, normal, and coarse pitches, with all available reconstruction slice thicknesses, each of which were reconstructed using standard and iterative reconstruction (IR). Image quality metrics (IQM) were evaluated using DoseLab automatically and manually calculated spatial resolution, subject contrast, and contrast-to-noise ratio (CNR). Scanning time was 15.6 s/cm for fine, 8.1 s/cm for normal, and 5.6 s/cm for coarse pitch. Automatically evaluated spatial resolutions ranged from 0.39, 0.41, to 0.42 lp/mm for standard reconstruction and from 0.24, 0.21, to 0tion of Physicists in Medicine.Monitoring the release and activation of prodrug formulations provides essential information about the outcome of a therapy. While the prodrug delivery can be confirmed using different imaging techniques, confirming the release of active payload using imaging is  a challenge. Here, we have discovered that the switchable fluorescence of doxorubicin can validate drug release upon its uncaging reaction with a highly specific chemical partner. We have observed that the conjugation of doxorubicin with a trans -cyclooctene diminishes its fluorescence at 595 nm. This quenched fluorescence of doxorubicin prodrug is recovered upon its bond-cleaving reaction with tetrazine. Clinically assessed iron oxide nanoparticles were used to formulate a doxorubicin nanodrug. The release of doxorubicin from nanodrug was studied under various experimental conditions. Five-fold increase in doxorubicin fluorescence is observed after complete release. The studies were carried out in vitro  using MDA-MB-231 breast cancer cells. Increase in Dox signal was observed upon tetrazine administration. This switchable fluorescence mechanism of Dox could be employed for fundamental studies, i.e., the reactivity of various tetrazine and TCO linker types under different experimental conditions. In addition, the system could be instrumental for translational research where the release and activation of doxorubicin prodrug payloads can be monitored using optical imaging systems. © 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.Mucopolysaccharidosis Type IVA (MPS IVA), also known as Morquio A syndrome, is an autosomal recessive lysosomal storage disorder that results from variants in the GALNS gene that encodes the enzyme galactosamine-6-sulfate sulfatase. This syndrome has systemic manifestations including, but not limited to, musculoskeletal, respiratory, cardiovascular, rheumatologic, neurologic, dental, ophthalmologic, and otologic. This condition is usually detected within the first few years of life with an average life expectancy of 25.3 ± 17.43 years. We report the natural history of two of the oldest known females with MPS IVA who were each clinically diagnosed at 4 years of age and who are now 74 and 70 years of age, respectively. They are both affected by pathogenic variants c.319G>A (p.Ala107Thr) and c.824 T>C (p.Leu275Pro) in the GALNS gene. © 2020 Wiley Periodicals, Inc.BACKGROUND A new generation of succinate dehydrogenase inhibitors (SDHIs) with high efficiency and broad-spectrum antifungal activity has been frequently used in crop production. Sclerotinia stem rot is a major disease of various plants and crops caused by Sclerotinia sclerotiorum. Although benzovindiflupyr and isopyrazam reportedly have high activity against S. sclerotiorum, little is known about the bioactivity of different SDHIs classes against S. sclerotiorum or the mechanism of their differential antifungal activity. RESULTS The in vitro tests revealed that the pyrazole-4-carboxamides of SDHIs (benzovindiflupyr, isopyrazam, fluxapyroxad, pydiflumetofen) had the highest activity against S. sclerotiorum followed by pyridine carboxamides (boscalid), pyridinyl-ethyl benzamides (fluopyram) and thiazole carboxamides (thifluzamide), among them thifluzamide showed poor antifungal activity with EC50 values over than 6.01 mg L-1 . The pyrazole-4-carboxamides of SDHIs showed both satisfactory protective and curative activity against Sclerotinia stem rot. After treated with the pyrazole-4-carboxamides of SDHIs, mitochondrial function in S. sclerotiorum decreased obviously. The enzyme activity assays revealed a lower affinity between thifluzamide and the Sc-Sdh complex than was observed for the other six fungicides, with IC50 values ranging from 0.0036 to 1.2088 μmol L-1 . Additionally, the docking positions of fungicides were similar, yet binding energies were differed in the docking study with the Sdh complex. The correspondingly weaker hydrogen bonds may be responsible for the poor activity of thifluzamide against S. sclerotiorum. CONCLUSION Understanding different binding features of various SDHIs classes with the Sc-Sdh complex might be beneficial for the design and development of highly effective broad-spectrum fungicides to ensure high yield and quality in crops by reducing fungicide use. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.Recent progress in the Internet of Things and artificial intelligence has made it possible to utilize the vast quantity of personal health records, clinical data, and scientific findings for prognosis, diagnosis, and therapy. These innovative technologies provide new possibilities with the development of medical devices (MDs), whose behaviors can be continuously modified. A novel regulatory framework covering these MDs is now under discussion in Japan. In this review, we introduce the regulatory initiative for MDs and the importance of a paradigm shift from regulation to innovation regarding MDs. © 2020 The Authors. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of the American Society of Clinical Pharmacology and Therapeutics.In this study, a series of chiral stationary phases based on N-[(4-methylphenyl)sulfonyl]-L-leucine amide, whose enantiorecognition property has never been studied, were synthesized. Their enantioseparation abilities were chromatographically evaluated by 67 enantiomers. The chiral stationary phase derived from N-[(4-methylphenyl)sulfonyl]-L-leucine showed much better enantioselectivities than that based on N-(4-Methylbenzoyl)-L-leucine amide. The construction of C2 symmetric chiral structure greatly improved the enantiorecognition performance of the stationary phase. The C2 symmetric chiral stationary phase exhibited superior enantioresolutions to other chiral stationary phases for most of the chiral analytes, especially for the chiral analytes with C2 symmetric structures. By comparing the enantioseparations of the enantiomers with similar structures, the importance of hydrogen bond interaction, π-π interaction and steric hindrance on enantiorecognition was elucidated. The enantiorecognition mechanism of trans-N,N’-(1,2-diphenyl-1,2-ethanediyl)bis-acetamide, which had an excellent separation factor on the C2 symmetric chiral stationary phase, was investigated by 1 H-NMR and two-dimensional 1 H-1 H Nuclear Overhauser Enhancement Spectroscopy (NOESY) NMR. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.Long emission wavelengths, high fluorescence quantum yields (FQYs), and large Stokes shifts are highly desirable features for fluorescent probes in biological imaging. However, the current development of many fluorescent probes remains largely trial-and-error and lacks efficiency. Moreover, to achieve far-red/near-infrared emission, a significant extension in the π -conjugation is usually adopted but accompanied by other drawbacks such as fluorescence loss. In this review, we discuss an effective red-shifting strategy built upon the green fluorescent protein chromophore, which enables a synergistic tuning of both the electronic ground and excited states. This approach could shorten the path toward redder emission in comparison to the conventional intramolecular charge transfer (ICT) strategy. We envision that this spectroscopy and computation-aided strategy may advance the noncanonical fluorescent protein design and be generalized to various fluorophore scaffolds for redder emission while preserving other superior properties such as high FQYs. © 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.Enzyme promiscuity has important implications in the field of biocatalysis. In some cases, structural analogues of simple metabolic building blocks can be processed through entire pathways and, thereby, lead to natural product derivatives, which are not readily accessible by chemical means. In this study, we explored the plasticity of the aurachin biosynthesis pathway regarding the utilization of fluoro- and chloroanthranilic acids, which are not abundant in the bacterial producers of these quinolone antibiotics. The incorporation rates of the tested precursor molecules disclosed a regiopreference for halogen substitution as well as steric limitations of enzymatic substrate tolerance. Three previously not described fluorinated aurachin derivatives were produced in preparative amounts by fermentation and structurally characterized. Furthermore, their antibacterial activities were evaluated in comparison to their natural congener aurachin D. © 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.