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Asthma is a chronic disease with increasing prevalence and incidence, manifested by allergic inflammatory reactions, and is life-threatening for patients with severe disease. Repetitive challenges with the allergens and limitation of treatment efficacy greatly dampens successful management of asthma. The adverse events related to several drugs currently used, such as corticosteroids and β-agonists, and the low rigorous adherence to preconized protocols likely compromises a more assertive therapy. Flavonoids represent a class of natural compounds with extraordinary antioxidant and anti-inflammatory properties, with their potential benefits already demonstrated for several diseases, including asthma. Advanced technology has been used in the pharmaceutical field to improve the efficacy and safety of drugs. Notably, there is also an increasing interest for the application of these techniques using natural products as active molecules. Flavones, flavonols, flavanones, and chalcones are examples of flavonoid compounds that were tested in controlled delivery systems for asthma treatment, and which achieved better treatment results in comparison to their free forms. This review aims to provide a comprehensive understanding of the development of novel controlled delivery systems to enhance the therapeutic potential of flavonoids as active molecules for asthma treatment.

Pain can be defined as an unpleasant sensory and emotional experience caused by either actual or potential tissue damage or even resemble that unpleasant experience. For years, science has sought to find treatment alternatives, with minimal side effects, to relieve pain. However, the currently available pharmacological options on the market show significant adverse events. Therefore, the search for a safer and highly efficient analgesic treatment has become a priority. Stem cells (SCs) are non-specialized cells with a high capacity for replication, self-renewal, and a wide range of differentiation possibilities. In this review, we provide evidence that the immune and neuromodulatory properties of SCs can be a valuable tool in the search for ideal treatment strategies for different types of pain. With the advantage of multiple administration routes and dosages, therapies based on SCs for pain relief have demonstrated meaningful results with few downsides. Nonetheless, there are still more questions than answers when it comes to the mechanisms and pathways of pain targeted by SCs. Thus, this is an evolving field that merits further investigation towards the development of SC-based analgesic therapies, and this review will approach all of these aspects., Competing Interests: Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article., (©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.)

In 2013, the Global Coalition for Regulatory Science Research (GCRSR) was established with members from over ten countries (www.gcrsr.net). One of the main objectives of GCRSR is to facilitate communication among global regulators on the rise of new technologies with regulatory applications through the annual conference Global Summit on Regulatory Science (GSRS). The 11th annual GSRS conference (GSRS21) focused on "Regulatory Sciences for Food/Drug Safety with Real-World Data (RWD) and Artificial Intelligence (AI)." The conference discussed current advancements in both AI and RWD approaches with a specific emphasis on how they impact regulatory sciences and how regulatory agencies across the globe are pursuing the adaptation and oversight of these technologies. There were presentations from Brazil, Canada, India, Italy, Japan, Germany, Switzerland, Singapore, the United Kingdom, and the United States. These presentations highlighted how various agencies are moving forward with these technologies by either improving the agencies' operation and/or preparing regulatory mechanisms to approve the products containing these innovations. To increase the content and discussion, the GSRS21 hosted two debate sessions on the question of "Is Regulatory Science Ready for AI?" and a workshop to showcase the analytical data tools that global regulatory agencies have been using and/or plan to apply to regulatory science. Several key topics were highlighted and discussed during the conference, such as the capabilities of AI and RWD to assist regulatory science policies for drug and food safety, the readiness of AI and data science to provide solutions for regulatory science. Discussions highlighted the need for a constant effort to evaluate emerging technologies for fit-for-purpose regulatory applications. The annual GSRS conferences offer a unique platform to facilitate discussion and collaboration across regulatory agencies, modernizing regulatory approaches, and harmonizing efforts., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: RR is co-founder and co-director of ApconiX, an integrated toxicology and ion channel company that provides expert advice on non-clinical aspects of drug discovery and drug development to academia, industry, and not-for-profit organizations., (Copyright © 2023. Published by Elsevier Inc.)

We report the synthesis and photophysical properties of a neutral BODIPY photosensitizing copolymer (poly-8-(4-hydroxymethylphenyl)-4,4-difluoro-2,6-diethynyl-4-bora-3a,4a-diaza- s -indacene) containing ethynylbenzene links between the BODIPY units. The copolymer absorbs further towards the red in the UV-vis spectrum compared to the BODIPY precursor. Photolysis of the polymer produces a singlet excited state which crosses to the triplet surface in less than 300 ps. This triplet state was used to form singlet oxygen with a quantum yield of 0.34. The steps leading to population of the triplet state were studied using time-resolved spectroscopic techniques spanning the pico- to nanosecond timescales. The ability of the BODIPY polymer to generate a biocidal species for bactericidal activity in both solution- and coating-based studies was assessed. When the BODIPY copolymer was dropcast onto a surface, 4 log and 6 log reductions in colony forming units/ml representative of Gram-positive and Gram-negative bacteria, respectively, under illumination at 525 nm were observed. The potent broad-spectrum antimicrobial activity of a neutral metal-free copolymer when exposed to visible light conditions may have potential clinical applications in infection management.

Objectives: The role of community pharmacists continues to evolve to meet the changing medication-related needs of patients in the United States, requiring a fundamental shift in the pharmacist's workflow and tasks including medication dispensing and medication therapy management (MTM). To compare community pharmacists' current and idealized time allocation. Barriers to, and potential facilitators of, typical and specific pharmacist functions are also reported, with an emphasis on MTM practices. A secondary objective included interpreting how pharmacists perceived the value of social determinants of health to the MTM process., Methods: Community pharmacists practicing in Tennessee were surveyed online with 3 distinct foci: time allocation and delegation, MTM barriers, and the perceived value of health-related and social data to the MTM process. For the first 2 sections, the respondents provided responses in 2 different scenarios: (1) current workflow and (2) an idealized workflow. Paired Wilcoxon signed-rank and chi-square tests compared the responses to workday items, and Spearman correlations assessed the relationships between preferences and perceived barriers., Results: The pharmacists reported spending the largest share of time verifying product (32.8% [SD 19.28]), and most indicated that they spent no time in either point-of-care testing (POCT) or physical patient assessment. In an ideal work environment, more patient-focused roles would be preferred (e.g., health screening, POCT, MTM, and vaccinations), with more than 80% indicating that they would delegate register activities, data entry, and product verification to technicians. In performing MTM, the pharmacists indicated that they would prefer delegating more data collection and patient management activities to technicians to reserve time for patient assessment and care plan creation. Key barriers to MTM included a lack of time, staff support, and patients' willingness to participate., Conclusion: Ideally, pharmacists would prefer to do no prescription filling or selling or register activities. Facilitating community pharmacy practice evolution will require focusing on building teams around support personnel., (Copyright © 2020 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

A novel 4,4-difuoro-4-bora-3a,4a-diaza-s-indacene (BODIPY) copolymer with diethynylbenzene has been synthesised, and its ability to act as a photosensitiser for the photocatalytic generation of hydrogen was investigated by time-resolved spectroscopic techniques spanning the ps- to ns-timescales. Both transient absorption and time-resolved infrared spectroscopy were used to probe the excited state dynamics of this photosensitising unit in a variety of solvents. These studies indicated how environmental factors can influence the photophysics of the BODIPY polymer. A homogeneous photocatalytic hydrogen evolution system has been developed using the BODIPY copolymer and cobaloxime which provides hydrogen evolution rates of 319 μmol h -1 g -1 after 24 h of visible irradiation., (Copyright © 2020 Cullen, Heintz, O'Reilly, Long, Heise, Murphy, Karlsson, Gibson, Greetham, Towrie and Pryce.)

The title compound 2,2'-bipyridin-1'-ium 1-oxide bromide crystallizes as a monohydrate, C 10 H 9 N 2 + ·Br - ·H 2 O. Structural disorder is observed due to the fact that protonation, as well as oxidation, of the N atoms of 2,2'-bi-pyridine occurs at either of the N atoms. The disorder extends to the remainder of the cation, with a refined occupancy rate of 0.717 (4) for the major moiety. An intra-molecular N-H⋯O hydrogen bond forces the bi-pyridine unit into an s - cis conformation. Each pair of neighbouring 2,2'-bipyridin-1'-ium ions forms a dimeric aggregate by hydrogen bonds between their respective N-O and the N-H functions. These dimers and hydrogen-bonding inter-actions with bromide ions and the water mol-ecule give rise to a complex supra-molecular arrangement.

Obstruction of fluid flow by stationary bubbles in a microchannel hemodialyzer decreases filtration performance and increases damage to blood cells through flow maldistribution. A polyethylene oxide (PEO)-polybutadiene (PB)-polyethylene oxide surface modification, previously shown to reduce protein fouling and water/air contact angle in polycarbonate microchannel hemodialyzers, can improve microchannel wettability and may reduce bubble stagnation by lessening the resistive forces that compete with fluid flow. In this study, the effect of the PEO-PB-PEO coating on bubble retention in a microchannel array was investigated. Polycarbonate microchannel surfaces were coated with PEO-PB-PEO triblock polymer via radiolytic grafting. Channel obstruction was measured for coated and uncoated microchannels after injecting a short stream of air bubbles into the device under average nominal water velocities of 0.9 to 7.2 cm/s in the channels. The presence of the PEO coating reduced obstruction of microchannels by stationary bubbles within the range of 1.8 to 3.6 cm/s, average nominal velocity. Numerical simulations based on the lattice Boltzmann method indicate that beneficial effects may be due to the maintenance of a lubricating, thin liquid film around the bubble. The determined effective range of the PEO coating for bubble management serves as an important design constraint. These findings serve to validate the multiutility of the PEO-PB-PEO coating (bubble lubrication, biocompatibility, and therapeutic loading). © 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 104B: 941-948, 2016., (© 2015 Wiley Periodicals, Inc.)

The marked increase in surface-to-volume ratio associated with microscale devices for hemodialysis leads to problems with hemocompatibility and blood flow distribution that are more challenging to manage than those encountered at the conventional scale. In this work stable surface modifications with pendant polyethylene oxide (PEO) chains were produced on polydimethylsiloxane (PDMS), polycarbonate microchannel, and polyacrylonitrile membrane materials used in construction of microchannel hemodialyzer test articles. PEO layers were prepared by radiolytic grafting of PEO-polybutadiene-PEO (PEO-PB-PEO) triblock polymers to the material surfaces. Protein repulsion was evaluated by measurement of surface-bound enzyme activity following contact of uncoated and PEO-coated surfaces with β-galactosidase. Protein adsorption was decreased on PEO-coated polycarbonate and PDMS materials to about 20% of the level recorded on the uncoated materials. Neither the triblocks nor the irradiation process was observed to have any effect on protein interaction with the polyacrylonitrile membrane, or its permeability to urea. This approach holds promise as a means for in situ application of safe, efficacious coatings to microfluidic devices for blood processing that will ensure good hemocompatibility and blood flow distribution, with no adverse effects on mass transfer., (© 2013 Wiley Periodicals, Inc.)

Objective: To describe the development, feasibility and validity of a wireless intra-vaginal pressure transducer (IVT) which can be used to measure intra-abdominal pressure in real-world settings., Study Design: A feasibility study was conducted in sixteen physically active women to determine retention and comfort of various IVT prototype designs during activity. A criterion validity study was conducted among women undergoing urodynamic testing to determine the accuracy of the IVT prototypes when compared to accepted clinical standards., Results: A final prototype wireless IVT was developed after four design revisions of the second generation model. The feasibility study found that women reported the final prototype comfortable to wear and easily retained during physical activity. Intra-abdominal pressure measurements from the final prototype IVT compared favorably to standard urodynamic transducers, thus confirming evidence of its utility., Conclusion: We have successfully advanced the design of a wireless, intra-vaginal pressure transducer which provides accurate measures of intra-abdominal pressure. The final wireless IVT is better tolerated by patients and overcomes limitations of traditional urodynamic testing while laying the foundations for intra-abdominal pressure monitoring outside of the clinic environment.

OBJECTIVES: The aims of this study were to describe women's stated knowledge of the primary urogynecologic diagnostic terms (urinary incontinence, pelvic floor disorder, and pelvic organ prolapse) and to assess factors associated with knowledge. METHODS: Before any education about pelvic floor disorders, 376 women presenting to primary care-level gynecologic clinics were asked whether they knew what the terms urinary incontinence, pelvic organ prolapse, and pelvic floor disorder meant. χ(2) and t tests were used to compare characteristics of women with complete knowledge versus partial or no knowledge of terms. P < 0.05 was considered significant. RESULTS: Of all women, 25% knew all 3 terms and 18% knew none. Moreover, 80%, 52%, and 27% of women reported that they knew the meaning of the terms urinary incontinence, pelvic organ prolapse, and pelvic floor disorder, respectively. Of women with stress urinary incontinence symptoms, 88% knew the term urinary incontinence compared with 78% without stress urinary incontinence (P = 0.07). Of 41 women, 31 (76%) with the symptom of vaginal bulge knew the term pelvic organ prolapse compared with 49% without (P = 0.001). Only higher education and symptom of vaginal bulge were associated with complete knowledge of the 3 terms; 30% of women who completed college or higher reported complete knowledge compared with 18% who did not (P = 0.013). CONCLUSIONS: Public health campaigns using terms pelvic organ prolapse or pelvic floor disorders are unlikely to reach most women. Further education and research are needed to improve women's health literacy in urogynecology.

Background: Standard chemotherapy protocols in NSCLC are of limited clinical benefit. Histone deacetylase (HDAC) inhibitors represent a new strategy in human cancer therapy. In this study the combination of the HDAC inhibitor phenylbutyrate (PB) and the nucleoside analogue gemcitabine (GEM) was evaluated and the mechanisms underlying increased cell death were analyzed., Methods: Dose escalation studies evaluating the cytotoxicity of PB (0.01-100 mM), GEM (0.01-100 microg/ml) and a combination of the two were performed on two NSCLC cell lines (BEN and KNS62). Apoptotic cell death was quantified. The involvement of caspase-dependent cell death and MAP-kinase activation was analyzed. Additionally, mitochondrial damage was determined. In an orthotopic animal model the combined effect of PB and GEM on therapy was analyzed., Results: Applied as a single drug both GEM and PB revealed limited potential to induce apoptosis in KNS62 and Ben cells. Combination therapy was 50-80% (p = 0.012) more effective than either agent alone. On the caspase level, combination therapy significantly increased cleavage of the pro-forms compared to single chemotherapy. The broad spectrum caspase-inhibitor zVAD was able to inhibit caspase cleavage completely, but reduced the frequency of apoptotic cells only by 30%. Combination therapy significantly increased changes in MTP and the release of cyto-c, AIF and Smac/Diabolo into the cytoplasm. Furthermore, the inhibitors of apoptosis c-IAP1 and c-IAP2 were downregulated and it was shown that in combination therapy JNK activation contributed significantly to induction of apoptosis. The size of the primary tumors growing orthotopically in SCID mice treated for 4 weeks with GEM and PB was significantly reduced (2.2-2.7 fold) compared to GEM therapy alone. The Ki-67 (KNS62: p = 0.015; Ben: p = 0.093) and topoisomerase IIalpha (KNS62: p = 0.008; Ben: p = 0.064) proliferation indices were clearly reduced in tumors treated by combination therapy, whereas the apoptotic index was comparably low in all groups., Conclusion: Therapy combining GEM and the HDAC inhibitor PB initiates a spectrum of apoptosis-inducing mitochondrial and further JNK-dependent events, thereby overcoming the therapeutic resistance of NSCLC tumor cells. In vivo, the combination therapy substantially reduced tumor cell proliferation, suggesting that the well tolerated PB is a useful supplemental therapeutic agent in NSCLC.

Patients with myasthenia gravis might develop various cardiac disorders, yet a causal relationship remains unestablished. Because causes of sudden death in this population have not been ascertained, further attention to possible cardiac disease in this population is warranted. We summarize the current literature and describe the possible etiologies and implications of cardiac disease in myasthenics.

Previous studies have shown that absorption of growth factors occurs through the gastrointestinal tract and the oral cavity. The non-obese diabetic (NOD) mouse, a model for spontaneous development of type 1 insulin-dependent diabetes (IDDM), was evaluated for the absorption and systemic distribution of growth factors. Radiolabeled epidermal growth factor (EGF) and insulin-like growth factor, type I (IGF-I), were administered by gavage into the stomach or by lozenge into the sublingual vasculature of either diabetic or nondiabetic mice. After a time-dependent uptake, the levels of absorption and distribution through the tissues were measured. A similar time course of EGF absorption following gavage administration was determined for NOD and C57BL/6 mice, with a maximum tissue distribution by 30-min post infusion. Diabetic NOD mice showed similar levels of IGF uptake and tissue distribution compared with nondiabetic NOD and normal healthy C57BL/6 mice, whether administered by gavage or sublingual lozenge. On the other hand, gavage uptake and tissue distribution of EGF was significantly higher in diabetic mice when compared to sublingual administration in nondiabetic NOD or C57BL/6 healthy control mice. These findings suggest that the overall potential uptake and distribution of saliva-derived growth factors in systemic wound-healing processes is retained with diabetes onset, and may offer a new avenue to treating this complication of diabetes.

Small GTP-binding proteins are encoded by ras-like genes and play a central role in cell differentiation and membrane vesicle transport. By screening genomic and cDNA libraries of the Ascomycete fungus Neurospora crassa with Zmypt genes from Zea mays we have isolated a member of the ypt gene family, Ncypt1. The gene resides on a 4 kb fragment of genomic DNA and contains four introns, which interrupt the coding sequence of a protein of 203 amino acid residues. The Ncytp1 gene was assigned to a single-copy gene encoding a transcript of 1.5 kb and a protein of 26,000 daltons. The gene maps on linkage group IIR between DB0001 and ccg-2 close to the Fsr-3 locus. Analysis of the nucleotide sequence and the deduced protein sequence revealed a striking homology to yeast, mouse and human genes encoding small GTP-binding proteins that are related to the ras supergene family. Homology was most significant to ypt1 from Schizosaccharomyces pombe, Mus musculus and Homo sapiens sharing 84.8%, 82.3%, and 82.3% identity, respectively. Common domains present in other small GTP-binding proteins were identified in the predicted sequence of the NCYPT1 protein, and the arrangement of peptide motifs sharing similarity with well characterized, small GTP-binding proteins suggests that the NCYPT1 protein is a GTPase. The C-terminal region extending from amino acid residues 175 to 199 shares only weak amino acid sequence similarity with other eukaryotic GTPases. Like other RAS proteins the NCYPT1 protein contains two conserved C-terminal cysteine residues, suggesting post-translational modification(s) by fatty acylation required for membrane anchoring. The high degree of homology between the NCYPT1 protein and eukaryotic YPT proteins suggests that NCYPT1 could be involved in the control of secretory processes.