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Objective Determine the pharmacokinetics (PK) and exposure–response of hydroxychloroquine (HCQ) and desethylhydroxychloroquine (DHCQ) in paediatric SLE (pSLE).Methods We conducted an exploratory phase 2, direct-to-family trial. Children enrolled in the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry with a diagnosis of pSLE were eligible if they were receiving HCQ as standard of care for ≥3 months. Biological samples were collected at up to four visits over a 6-month period. At each visit, plasma was obtained to measure the concentrations of HCQ and DHCQ, as well as cytokines. HCQ and DHCQ plasma PK data were analysed using a population PK modelling approach.Results Twenty-five subjects provided a total of 88 plasma concentrations for PK analysis. There was a poor linear fit between HCQ concentrations and total body weight (R2=0.03). There was a decline in both interferon (IFN)-alpha and IFN-gamma with higher concentrations of HCQ and DHCQ. Volume of distribution for HCQ in plasma was higher in children compared with published values in adults (73 000 L vs 44 000 L), but clearance values in children were similar to adults.Conclusions We report the first population PK model for HCQ and DHCQ in children using data from a novel direct-to-family clinical trial. We observed high interindividual variability in HCQ PK and found that weight-based dosing for HCQ is poorly correlated with drug concentrations, suggesting the need to use therapeutic drug monitoring to individualise dosing. Furthermore, our results suggest that the current weight-based dosing paradigm for HCQ may result in suboptimal drug exposures, particularly for children with obesity. Accordingly, additional studies of HCQ are needed in pSLE to determine the optimal drug concentration and dosing to reduce disease activity and improve outcomes.Trial registration number NCT04358302.

Introduction Direct-to-family clinical trials efficiently provide data while reducing the participation burden for children and their families. Although these trials can offer significant advantages over traditional clinical trials, the process of designing and implementing direct-to-family studies is poorly defined, especially in children with rheumatic disease. This paper provides lessons learnt from the design and implementation of a self-controlled, direct-to-family pilot trial aimed to evaluate the effects of a medication management device on adherence to hydroxychloroquine in paediatric SLE.Methods Several design features accommodate a direct-to-family approach. Participants meeting eligibility criteria from across the USA were identified a priori through a disease registry, and all outcome data are collected remotely. The primary outcome (medication adherence) is evaluated using electronic medication event-monitoring, plasma drug levels, patient questionnaires and pill counts. Secondary and exploratory endpoints include (1) lupus disease activity measured by a remote SLE Disease Activity Index examination and the Systemic Lupus Activity Questionnaire; and (2) hydroxychloroquine pharmacokinetics and pharmacodynamics. Recruitment of the initial target of 20 participants was achieved within 10 days. Due to initial recruitment success, enrolment was increased to 26 participants. Additional participants who were interested were placed on a waiting list in case of dropouts during the study.Discussion and dissemination Direct-to-family trials offer several advantages but present unique challenges. Lessons learnt from the protocol development, design, and implementation of this trial will inform future direct-to-family trials for children and adults with rheumatic diseases. Additionally, the data collected remotely in this trial will provide critical information regarding the accuracy of teleresearch in lupus, the impact of adherence to hydroxychloroquine on disease activity and a pharmacokinetic analysis to inform paediatric-specific dosing of hydroxychloroquine.Trial registration number ClinicalTrials.gov Registry (NCT04358302).

While prominent measures of hope are largely cognitive in nature, many scholars and laypeople view hope primarily as an emotion. Although Snyder’s Elaborated Hope Theory attempts to theoretically balance these two perspectives, no measure yet exists of hope as a purely emotional process, only as a cognitive process. Overlooking the emotional features of hope limits our ability to more fully and precisely understand this construct. As such, across three studies (N = 2,900), we develop and validate the Trait Emotion Hope Scale (TEHS). In Study 1, we report on item development and piloting of the TEHS, examining internal consistency as well as convergent and discriminant validity. Study 2 includes an exploratory factor analysis (EFA) and further examines internal consistency and construct validity. Finally, in Study 3 we report a confirmatory factor analysis (CFA) to cross-validate the factor structure identified in Study 2 in a large, international sample. Importantly, we find that the TEHS accounts for significant unique variance beyond cognitive hope, indicating that the two constructs are distinct and not redundant. Taken together, these three studies demonstrate that the TEHS is psychometrically sound and provides a valid measure for those interested in examining hope as an emotion in their research.

BackgroundInsulin is the primary treatment for type 1 and some type 2 diabetes but remains costly in the United States, even though it was discovered more than a century ago. High prices can lead to nonadherence and are often sustained by patents and regulatory exclusivities that limit competition on brand-name products. We sought to examine how manufacturers have used patents and regulatory exclusivities on insulin products approved from 1986 to 2019 to extend periods of market exclusivity.Methods and findingsWe used the publicly available Food and Drug Administration (FDA) Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) to identify all approved biosynthetic insulin products. Individual products approved under the same New Drug Application (NDA)-e.g., a vial and pen-were considered as separate products for the purposes of analysis. We recorded all patents and regulatory exclusivities listed in the Orange Book on each product and used Google Patents to extract the timing of patent application and whether patents were obtained on delivery devices or others aspects of the product. The primary outcome was the duration of expected protection, which was determined by subtracting the FDA approval date for each product from its last-to-expire patent or regulatory exclusivity (whichever occurred later). We performed a secondary analysis that considered overall protection on insulin lines-defined as groups of products approved under the same NDA with the same active ingredients manufactured by the same company. We also examined competition from follow-on insulin products-defined as products approved with the same active ingredients as originators but manufactured by different companies (approved via a specific drug approval pathway under section 505(b)(2) of the Food, Drug, and Cosmetic Act). During the study period, the FDA approved 56 individual products across 25 different insulin lines and 5 follow-ons across 3 different insulin lines. Thirty-three (59%) of the 56 products were drug-device combinations. Manufacturers of 9 products approved during the study period obtained patents filed after FDA approval that extended their duration of expected protection (by a median of 6 years). Approximately 63% of all patents on drug-device combinations approved during the study period were related to delivery devices. The median duration of expected protection on insulin products was 16.0 years, and the median protection on insulin lines was 17.6 years. An important limitation of our analysis is that manufacturers may continue to add patents on existing insulin products while competitors may challenge patents; therefore, periods of protection may change over time.ConclusionsAmong several strategies that insulin manufacturers have employed to extend periods of market exclusivity on brand-name insulin products are filing patents after FDA approval and obtaining a large number of patents on delivery devices. Policy reforms are needed to promote timely competition in the pharmaceutical market and ensure that patients have access to low-cost drugs.

We present a case where Hyphopichia burtonii, a yeast, speciated from peritoneal fluid in a cirrhotic patient with secondary peritonitis. The patient, a man in his 60s with decompensated cirrhosis, was admitted for an upper gastrointestinal (GI) bleed. On admission, he was treated empirically for spontaneous bacterial peritonitis (SBP) but failed to improve with antibiotics. Serial paracenteses revealed polymicrobial peritonitis and rising peritoneal polymorphonuclear leukocytes (PMNs). These findings raised concerns for secondary peritonitis, prompting an abdominal computed tomography (CT) scan which revealed ischemic bowel. Among the peritoneal microbiota isolated, Hyphopichia burtonii predominated. Hyphopichia burtonii has only recently been reported as a human pathogen, previously it had only reported as a pathogen in bats[1,2].

The article identifies three principles of classification of initial and mixed abbreviations relating to the vocabulary of the nuclear industry: according to their lexical and grammatical category (appellatives, nomens, onyms), their pronunciation (alphabetism and acronyms) and their origin (proper and borrowed abbreviations). The types and characteristics of abbreviations are studied by means of the descriptive, contextual, pragmatic and structural methods in order to identify their specific features which are likely to denote the abbreviations of the professional discourse. The sample language material includes the vocabulary of the nuclear industry. The outcomes of the research make it possible to draw the following conclusions about the general and specific characteristics of abbreviations in professional discourse: 1) according to the communicative-discursive approach, the abbreviation process ensures the success of a communicative act providing the idea to be short and clear; 2) the use of abbreviations outside the professional discourse can lead to communicative failure due to the existing discursive antinomy friend or foe that defines professional language users and people irrelevant to the professional discourse; 3) the abbreviations-appellatives are likely to predominate due to long-word terms as a characteristic of a developing industry and a young terminological system; 4) the numerical or alphabetic part of abbreviations is seen as their specific features that can make sense for professionals and absolutely vague for the rest of native speakers; 5) abbreviations-onyms, including ergonyms and chrematonyms, follow the general linguistic trends; 6) alphabetisms come over acronyms that is non-typical for Modern Russian and is caused by a great number of long-word terms, often including abbreviations with hard-to-pronounce sound combinations, as well as preserving the informational significance of components or provoking homonymous repulsion processes.

Sanguinarin is a plant alkaloid with a wide spectrum of biological activity. The effectiveness of sanguinarin can be increased by its integration into liposomal nanoparticles. The aim of this study was to obtain and purify the pegylated liposome sanguinarine, to study its properties, as well as antitumor and antimicrobial activity in vitro. Pegylated liposome nanoparticles containing sanguinarinewere obtained. The size of the liposomes was 61.8+5.7 nm; the effectiveness of the inclusion of sanguinarine in liposomes was 82.3+4.9%. The article studies the release of sanguinarin from liposome particles and demonstrates its prolonged nature. An in vitro study showed that liposomal sanguinarine exhibited dose-dependent cytotoxic activity against tumor cells of MCF-7 (12.8 μM), L1210 (17.4 μM), A431 (18.67 μM) and HepG2 (20.7 μM). The antimicrobial effect of the liposome form of the drug was established for Gram-positive (B.subtilis ATC 6633 and B.coagulans 429) and Gram-negative (E.coli ATCC 8739) bacteria, as well as opportunistic fungi Aspergillus ustus 6K. The results indicate the prospects of further study of pegylated liposomal sanguinarine as an antitumor and antimicrobial agent.

The aim of the study was to obtain and characterize liposomal silibinin, as well as to study its antitumor and antimicrobial activity. Liposomes were obtained by hydration of a thin-layer film with a buffer solution followed by multiple freezing-thawing of the dispersion of phosphatidylcholine-cholesterol-silibinin. It has been established that liposomal silibinin has an inhibitory effect against liver (HepG2 line) and prostate gland (DU145 line) tumor cells. In addition, liposomalosilinin has a pronounced antibacterial effect against bacteria and a fungistatic effect on toxigenic micromycetes, which may indicate its effectiveness as an antimicrobial and fungistatic agent for reducing the negative effect of mycotoxins of mold fungi.

The article discusses the development of a new method of producing Laetiporus sulphureus (Bull.) Murrill basidiomycete mycelium immobilized on a bacterial cellulose matrix. Mycelium contains biologically active compounds with antimicrobial activity against Gram-positive bacteria, including resistant staphylococcus. The aim of the work was to obtain immobilized mycelium by co-cultivation of L.sulphureus with the producer of bacterial cellulose Gluconacetobacter hansenii. The authors found that when co-culturing the basidial L.sulphureus strain with the bacterial cellulose producing G.hansenii strain, productivity increases by 3.2 times on H5/1 synthetic medium and by 1.9 times on natural Maltax-10 medium (concentration 5%). The resulting immobilized L.sulphureus mycelium has antibacterial properties; its aqueous extracts contain glucans.

The article describes the development of a new method for obtaining mycelium of the basidiomycete Fomitopsis officinalis (Vill.:Fr.) Bond. Et Sing., immobilized on a matrix of bacterial cellulose. Mycelium of F.officinalis contains biologically active compounds, the most important of which is agaricic acid. The known methods for producing mycelium using surface solid-phase and submerged cultivation make it possible to obtain biomass of mycelium in an amount of 3.5 to 5 g/L of absolutely dry mass. Considering that F.officinalis is a xylotrophic macromycete, the use of cellulose as a food source can show higher productivity in the cultivation of mycelium in artificial biotechnological systems. The aim of the work was to obtain immobilized mycelium by co-cultivation of F.officinalis with the producer of bacterial cellulose Gluconacetobacter hansenii. The research established that with the co-cultivation of the basidial strain of F.officinalis with G.hansenii, the producer strain of bacterial cellulose, the productivity increases by 3.2 times on synthetic medium H5/1 and on the natural medium Maltax-10 (5% concentration) — by 1.9 times. The obtained immobilized mycelium of F.officinalis contains agaricic acid, the amount of which is 5.4—6.8%. The study of the structure of agaricic acid, isolated from the mycelium of the strain, was carried out by comparing the 13C NMR spectra with the spectra of a standard sample (Sigma cat). The results of the research confirmed the identity of the compounds.

Lipofuscin of retinal pigment epithelium (RPE) cells is a complex heterogeneous system of chromophores which accumulates as granules during the cell’s lifespan. Lipofuscin serves as a source of various cytotoxic effects linked with oxidative stress. Several age-related eye diseases such as macular degeneration of the retina, as well as some severe inherited eye pathologies, are accompanied by a significant increase in lipofuscin granule concentration. The accumulation of carotenoids in the RPE could provide an effective antioxidant protection against lipofuscin cytotoxic manifestations. Given the highly lipophilic nature of carotenoids, their targeted delivery to the vulnerable tissues can potentially be assisted by special proteins. In this study, we demonstrate how protein-mediated delivery of zeaxanthin using water-soluble Bombyx mori carotenoid-binding protein (BmCBP-ZEA) suppresses the photoinducible oxidative stress in RPE cells caused by irradiation of lipofuscin with intense white light. We implemented fluorescence lifetime imaging of the RPE cell culture ARPE-19 fed with lipofuscin granules and then irradiated by white light with and without the addition of BmCBP-ZEA. We demonstrate that after irradiation the mean fluorescence lifetime of lipofuscin significantly increases, while the presence of BmCBP-ZEA at 200 nM concentration suppresses the increase in the average lifetime of lipofuscin fluorescence, indicating an approx. 35% inhibition of the oxidative stress. This phenomenon serves as indirect yet important evidence of the efficiency of the protein-mediated carotenoid delivery into pigment epithelium cells.

The article focuses on studying chrematonyms in nuclear and space industry professional discourse. The analysis of 734 Russian, English, Italian, French, German, Polish and Japanese lexemes nominating spacecraft, spaceships, nuclear reactors and nuclear research facilities resulted in discovering three common ways in the process of generating and functioning of chrematonyms in the professional discourse, including a lexico-semantic nomination (formed by means of onimization of appellatives, transonymization of personal and precedent names, toponyms, chrematonyms and cosmonims, deonimization); the word-formation considers the sound, syllabic and mixed abbreviation, as well as the formation of compound words; the syntactic method involves the formation of simple and complex substantive combinations of words. The authors conclude that chrematonyms as a class of onims have a specific linguistic meaning, affecting the semantic generation of the proper name in an inanimate object of material culture and emphasizing the unique and differential feature of the object and point to their specifically professional linguistic feature: motivation, derivative character, terminological unity, and frequency of usage. The research demonstrates the following special aspects of functioning of chrematonyms in the professional discourse: play on words, allusions and metaphors, ameliorative and deteriorative connotative meanings, which reflect non-typical processes for professional lexis and perform a peace-maintaining function of the language.

Abstract Background Primary spontaneous pneumothorax is a common disorder occurring in young adults without underlying lung disease. Although tobacco smoking is a well-documented risk factor for spontaneous pneumothorax, an association between electronic cigarette use (that is, vaping) and spontaneous pneumothorax has not been noted. We report a case of spontaneous pneumothoraces correlated with vaping. Case presentation An 18-year-old Caucasian man presented twice with recurrent right-sided spontaneous pneumothoraces within 2 weeks. He reported a history of vaping just prior to both episodes. Diagnostic testing was notable for a right-sided spontaneous pneumothorax on chest X-ray and computed tomography scan. His symptoms improved following insertion of a chest tube and drainage of air on each occasion. In the 2-week follow-up visit for the recurrent episode, he was asymptomatic and reported that he was no longer using electronic cigarettes. Conclusions Providers and patients should be aware of the potential risk of spontaneous pneumothorax associated with electronic cigarettes.

Summary: In this study low-input RNA-sequencing was used to annotate the molecular identity of endothelial cells isolated and immunopurified with CD144 microbeads. Using this technique, comparative gene expression profiling from healthy subjects and patients with type 2 diabetes mellitus identified both known and novel pathways linked with EC dysfunction. Modeling of diabetes by treating cultured ECs with high glucose identified shared changes in gene expression in diabetic cells. Overall, the data demonstrate how purified ECs from patients can be used to generate new hypotheses about mechanisms of human vascular disease. Key Words: endothelial cells, gene expression, diabetes mellitus, endothelial cell dysfunction

The present research has been conducted within the scope of such relevant direction of linguistics as functional lexicology, and is associated with the identification of semantic modifications of the word, which are conditioned by contextual features of its use. The adjectives atomic and nuclear became the object of the analysis: we give their characteristics in the lexical system of the Russian language, present the frequency of their use in different types of discourse, study more than 300 contexts of their use with nouns in the modern political discourse. The adjectives are studied in their direct and figurative meanings in neutral texts, as well as in pejorative (negative) and ameliotory (positive) contexts. It has been established that the Russian political discourse is characterized by prevailing use of adjectives atomic and nuclear in direct meaning. It has been revealed that the basis of metaphorization as the main way of creating figurative meanings of the adjectives in the political discourse is represented with such features as powerful release of energy, concentration, innovativeness, progress. We show the mechanism of leveling the pejorative axiological component of the phrase atomic bomb arising from its use in direct meaning and the appearance of ameliotory connotative meanings in the neutral phrase nuclear reactor. It has been found that the units under study are not recorded by lexicographic sources in figurative meanings, since they express an occasional sense in the political discourse.

Candida spp. are the fourth leading cause of nosocomial blood stream infections in North America. Candida glabrata is the second most frequently isolated species, and rapid development of antifungal resistance has made treatment a challenge. In this study, we investigate the therapeutic potential of metformin, a biguanide with well-established action for diabetes, as an antifungal agent against C. glabrata. Both wild type and antifungal-resistant isolates of C. glabrata were subjected to biguanide and biguanide-antifungal combination treatment. Metformin, as well as other members of the biguanide family, were found to have antifungal activity against C. glabrata, with MIC50 of 9.34 ± 0.16 mg/mL, 2.09 ± 0.04 mg/mL and 1.87 ± 0.05 mg/mL for metformin, phenformin and buformin, respectively. We demonstrate that biguanides enhance the activity of several antifungal drugs, including voriconazole, fluconazole, and amphotericin, but not micafungin. The biguanide-antifungal combinations allowed for additional antifungal effects, with fraction inhibition concentration indexes ranging from 0.5 to 1. Furthermore, metformin was able to lower antifungal MIC50 in voriconazole and fluconazole-resistant clinical isolates of C. glabrata. We also observed growth reduction of C. glabrata with rapamycin and an FIC of 0.84 ± 0.09 when combined with metformin, suggesting biguanide action in C. glabrata may be related to inhibition of the mTOR complex. We conclude that the biguanide class has direct antifungal therapeutic potential and enhances the activity of select antifungals in the treatment of resistant C. glabrata isolates. These data support the further investigation of biguanides in the combination treatment of serious fungal infections.

Background. Vaginal cancer is a rare disease with poor clinical outcomes and limited therapeutic options. In the United States (US), minority women and older women are disproportionately diagnosed with late-stage vaginal cancer. Sociodemographic characteristics, risk behaviors, and cooccurring conditions are linked to vaginal intraepithelial neoplasia (VaIN). The diagnosis of VaIN is more prevalent among older women and women living with HIV (WLWH). The Caribbean basin has one of the highest rates of anogenital cancers in the Western Hemisphere. In the US, vaginal infections are more prevalent among Caribbean women, and these infections contribute to higher rates of Human Papilloma Virus (HPV). Given the high rate of anogenital cancers in the Caribbean and the high rates of HPV among Caribbean women in the US, we sought to describe the occurrence of VaIN in a cohort of Black non-Hispanic WLWH. The cohort was followed by an interdisciplinary team of providers with the University of Miami, Miller School of Medicine. Results. Caribbean Americans were living with HIV longer and more were uninsured; more African Americans endorsed cigarette and illicit substance use. Caribbean Americans trended towards the highest grades of VaIN (VaIN 2+) at baseline, but more African Americans progressed to VaIN 2+ in subsequent biopsies. Conclusion. In this cohort of Caribbean American and African American women living with HIV diagnosed with VaIN, Caribbean Americans had the highest grade of VaIN at baseline, but more African Americans progressed to more advanced stages of the disease.

Macrophages play a critical role in the elimination of fungal pathogens. They are sensed via cell surface pattern-recognition receptors and are phagocytosed into newly formed organelles called phagosomes. Phagosomes mature through the recruitment of proteins and lysosomes, resulting in addition of proteolytic enzymes and acidification of the microenvironment. Our earlier studies demonstrated an essential role of Dectin-1-dependent activation of spleen tyrosine kinase (Syk) in the maturation of fungal containing phagosomes. The absence of Syk activity interrupted phago-lysosomal fusion resulting in arrest at an early phagosome stage. In this study, we sought to define the contribution of Syk to the control of phagocytosed live Candida glabrata in primary macrophages. To accurately measure intracellular yeast division, we designed a carboxyfluorescein succinimidyl ester (CFSE) yeast division assay in which bright fluorescent parent cells give rise to dim daughter cells. The CFSE-labeling of C. glabrata did not affect the growth rate of the yeast. Following incubation with macrophages, internalized CFSE-labeled C. glabrata were retrieved by cellular lysis, tagged using ConA-647, and the amount of residual CFSE fluorescence was assessed by flow cytometry. C. glabrata remained undivided (CFSE bright) for up to 18 h in co-culture with primary macrophages. Treatment of macrophages with R406, a specific Syk inhibitor, resulted in loss of intracellular control of C. glabrata with initiation of division within 4 h. Delayed Syk inhibition after 8 h was less effective indicating that Syk is critically required at early stages of macrophage–fungal interaction. In conclusion, we demonstrate a new method of tracking division of C. glabrata using CFSE labeling. Our results suggest that early Syk activation is essential for macrophage control of phagocytosed C. glabrata.

Improvements to leaf photosynthetic rates of crops can be achieved by targeted manipulation of individual component processes, such as the activity and properties of RuBisCO or photoprotection. This study shows that simple forward genetic screens of mutant populations can also be used to rapidly generate photosynthesis variants that are useful for breeding. Increasing leaf vein density (concentration of vascular tissue per unit leaf area) has important implications for plant hydraulic properties and assimilate transport. It was an important step to improving photosynthetic rates in the evolution of both C3 and C4 species and is a foundation or prerequisite trait for C4 engineering in crops like rice (Oryza sativa). A previous high throughput screen identified five mutant rice lines (cv. IR64) with increased vein densities and associated narrower leaf widths (Feldman et al., 2014). Here, these high vein density rice variants were analyzed for properties related to photosynthesis. Two lines were identified as having significantly reduced mesophyll to bundle sheath cell number ratios. All five lines had 20% higher light saturated photosynthetic capacity per unit leaf area, higher maximum carboxylation rates, dark respiration rates and electron transport capacities. This was associated with no significant differences in leaf thickness, stomatal conductance or CO2 compensation point between mutants and the wild-type. The enhanced photosynthetic rate in these lines may be a result of increased RuBisCO and electron transport component amount and/or activity and/or enhanced transport of photoassimilates. We conclude that high vein density (associated with altered mesophyll cell length and number) is a trait that may confer increased photosynthetic efficiency without increased transpiration.

The goal of the present study was the development of composition analysis method for vision pigments chromophore groups of different animals with the use of high performance liquid chromatography as well as the development of synthetic method for all-E-3,4-didehydroretinal – one of standard compounds. The all-E-3,4- didehydroretinal synthetic route developed earlier has been polished, and the product structure has been confirmed by physical-chemical analysis methods. The chromatographic separation process of Z-isomers of natural retinal and 3,4-didehydroretinal has been studied under isocratic flow conditions with the use of one and two sequentially connected normal phase columns. Optimal chromatographic conditions have been proposed for the separation and analysis of both retinoid model mixtures and animal eye extracts.