12,407 research outputs found

    The quality of non-prescription medicine counselling in Finnish pharmacies – a simulated patient study

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    Background: Medication counselling provided by pharmacists is important for ensuring the safe use of medicines. Objective: To assess the quality of non-prescription medicines counselling in Finnish pharmacies. Methods: Three scenarios using simulated patient methodology were conducted: the patient requesting a specific brand name Burana® (ibuprofen, OTC medicine), Pronaxen® (naproxen, behind-the-counter (BTC) medicine) and a nasal spray. The visits were conducted in 146 pharmacies by trained simulated patients. Each pharmacy was visited twice. The quality of counselling was defined as poor (1–2 points), moderate (3–4 points), or high (5–6 points) based on developed scenario-based scoring criteria. Results: The total number of conducted visits was 292, of which only 29 received high quality counselling. The quality was high in 20% of the cases for Pronaxen® and in 7% of the cases for Nasal spray scenarios. In the Burana® scenario, counselling quality was high only in 2% of the cases. Patients who requested a nasal spray were often asked questions about their symptoms (93%). In the Pronaxen®-scenario, the most frequently asked questions were related to contraindications and drug interactions (56%). The most often given instructions varied between the scenarios, being follow-up in the Burana® and Nasal spray scenarios (17% and 70%, respectively) and how to use the medicine in the Pronaxen®-scenario (63%). Conclusions: Non-prescription medicine counselling is rarely performed with high quality. However, the quality of counselling depends on the medication in question. There is room to improve medication counselling and the assessment of the necessity and suitability of treatment, especially when a patient requests an OTC pain medicine by its brand name

    Topical Potassium Channel Blockage Improves Pharyngeal Collapsibility: A Translational, Placebo-Controlled Trial

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    Background: Potassium (KĂľ) channel inhibition has been identified in animal models as a potential target to increase pharyngeal dilator muscle activity and to treat OSA. However, these findings have not yet been translated to humans. Research Question: Does a novel, potent, tandem of P domains in a weak inward rectifying KĂľ channel (TWIK)-related acid-sensitive KĂľ (TASK) 1/3 channel antagonist, BAY2586116, improve pharyngeal collapsibility in pigs and humans, and secondarily, what is the optimal dose and method of topical application? Study Design and Methods: In the preclinical study, pharyngeal muscle activity and upperairway collapsibility via transient negative pressure application was quantified in 13 anesthetized pigs during administration of placebo, 0.3mg, 3mg, and 30mg nasal drops of BAY2586116. In the clinical study, 12 people with OSA instrumented with polysomnography equipment, an epiglottic pressure catheter, pneumotachograph, and nasal mask to monitor sleep and breathing performed up to four detailed upper airway sleep physiology studies. Participants received BAY2586116 (160 mg) or placebo nasal spray before sleep via a double-masked, randomized, crossover design. Most participants also returned for three additional overnight visits: (1) nasal drops (160 mg), (2) half-dose nasal spray (80 mg), and (3) direct endoscopic application (160 mg). The upper-airway critical closing pressure (Pcrit) during sleep was quantified at each visit. Results: Consistent and sustained improvements in pharyngeal collapsibility to negative pressure were found with 3 and 30 mg of BAY2586116 vs placebo in pigs. Similarly, BAY2586116 improved pharyngeal collapsibility by an average of approximately 2 cm H2O vs placebo, regardless of topical application method and dose (P < .008, mixed model) in participants with OSA. Interpretation: Acute topical application of BAY2586116 improves upper-airway collapsibility in anesthetized pigs and sleeping humans with OSA. These novel physiologic findings highlight the therapeutic potential to target potassium channel mechanisms to treat OSAAmal M. Osman, Sutapa Mukherjee, Thomas J. Altree, Martina Delbeck, Doris Gehring, Michael Hahn, Tina Lang, Charles Xing, Thomas Muller, Gerrit Weimann, and Danny J. Ecker

    Designing carbon fibre-reinforced composites with improved structural retention on exposure to heat/fire

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    Carbon fibre-reinforced composites (CFRCs) are increasing in popularity due to their high strength-to-weight ratio and resistance to corrosion. However, when exposed to temperatures above 300°C, the polymer matrix within CFRCs decomposes and then starts burning, exposing carbon fibres to the surroundings. The residual carbon fibres being electrically conductive, may pose a hazard to the surrounding electronics. Moreover, at over 550°C the carbon fibres begin to oxidise. This can lead to fibre defibrillation which also poses significant harm to human health as broken fibres can be sharp enough to cut through human skin, and under 7µm these particles are considered respirable where on inhalation they can causes damage to the trachea and lungs. While considerable work has been carried out on assessing the effect of heat/fire on degradation of the composite resin (matrix) and CFRCs themselves, there are limited studies on identifying the damage to carbon fibres within CFRCs and the hazards posed by the exposed damaged carbon fibres. This study examined the damage caused by high temperatures, radiant heat and flames on carbon fibres and CFRCs, and the effects on their physical properties. A methodology was developed to study and quantify the structural damage to carbon fibres and CFRCs after exposure to a range of heat/fire conditions. These included thermogravimetric analysis (up to 900oC in nitrogen and air atmospheres), the tube furnace (450oC–900oC), cone calorimeter (35kWm-2 to 75kWm-2 ) and a propane burner (116kWm-2 ) to simulate jet fuel fire conditions. Residual fibres were removed from different parts of the CFRCs and the physical properties were studied, such as fibre diameter reduction, change in electrical conductivity and decrease in tensile strength. It was found that at heat fluxes ≥60kWm-2 oxidation of the carbon fibres occurred. After 10min exposure to the propane flame, fibres in direct contact with the flame showed signs of internal oxidation.The aim of this PhD project was to also improve the structural retention of CFRCs on exposure to heat/fire so that the structural integrity is maintained and the carbon fibres are not exposed to the environment. To address this, the following approaches were undertaken: • Modification of the resin by adding flame retardants and nanoparticles in order to reduce the flammability of CFRCs, improve the mechanical integrity of the char and its adherence to the fibre. Flame retardants included ammonium polyphosphate, resorcinol bis-(diphenyl phosphate), 9,10-dihydro-9-oxa-10-phosphaphenanthrene 10-oxide, and the nano-additives, nano-clay, layered double hydroxide and carbon nano-tubes. Cone calorimeter testing at 75kWm-2 showed that the addition of 15wt% ammonium polyphosphate resulted in large char formation and adherence to fibres in the underlying plies, which resulted in less oxidation to these carbon fibres. The addition of layered double hydroxides and carbon nano-tubes on the other hand caused pitting on fibres. • Provide heat protection to carbon fibres within CFRCs by the inclusion of high performance fibrous veils/woven fabrics of aramid, basalt, E-glass, polyphenylene sulphide and Kevlar. The inclusion of the woven E-glass resulted in a notable reduction in the percentage of carbon fibre oxidised. However, the volatiles produced during the decomposition of Kevlar and PPS sensitised the carbon fibre to oxidation, causing it to occur more rapidly and at a lower temperature. • Using high temperature chemical coatings to individually coat carbon fibres prior to making the CFRCs. Ceramic compounds (silica, alumina and zirconia), chosen as coating materials because of their high thermal stability, were applied by different processes. The most promising coatings included alumina and silica formed via sol-gel process and polysiloxane deposited during plasma exposure. Tows coated in these chemicals underwent heat testing in a tube furnace where those coated with alumina maintained the largest fibre diameters. While polysiloxane coating provided oxidation protection up to 600°C, after which cracks in the coating were observed. This was attributed to the mechanical mismatch of the polysiloxane coating and the carbon fibre

    Pathogenesis and treatment of chronic rhinosinusitis from the perspective of sinonasal epithelial dysfunction

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    BackgroundChronic rhinosinusitis (CRS) is a clinical syndrome primarily characterized by long-term mucosal inflammation of the nasal cavity and sinuses. The pathogenesis of CRS is still unclear due to its high heterogeneity. A number of studies have recently focused on the sinonasal epithelium. Thus, there has been a quantum leap in awareness of the role of the sinonasal epithelium, which is now understood as an active functional organ rather than simply an inert mechanical barrier. Undoubtedly, epithelial dysfunction plays a vital role in the onset and development of CRS.ObjectiveIn this article, we discuss the potential contribution of sinonasal epithelium dysfunction to CRS pathogenesis and explore a few current and developing therapeutic options targeting the sinonasal epithelium.ResultsImpaired mucociliary clearance (MCC) and an abnormal sinonasal epithelial barrier are usually considered to be the main causative factors in CRS. Epithelial-derived bioactive substances, such as cytokines, exosomes, and complements, play a vital role in the regulation of innate and adaptive immunity and contribute to the pathophysiological alterations of CRS. The phenomena of epithelial–mesenchymal transition (EMT), mucosal remodeling, and autophagy observed in CRS offer some novel insights into the pathogenesis of this disease. In addition, existing treatment options targeting disorder of sinonasal epithelium can help to relieve the main symptoms associated with CRS to some extent.ConclusionThe presence of a normal epithelium is fundamental for maintaining homeostasis in the nasal and paranasal sinuses. Here, we describe various aspects of the sinonasal epithelium and highlight the contributions of epithelial dysfunction to CRS pathogenesis. Our review provides sound evidence of the need for in-depth study of the pathophysiological alterations of this disease and for the development of novel epithelium-targeting alternative treatments

    Pollution-induced community tolerance in freshwater biofilms – from molecular mechanisms to loss of community functions

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    Exposure to herbicides poses a threat to aquatic biofilms by affecting their community structure, physiology and function. These changes render biofilms to become more tolerant, but on the downside community tolerance has ecologic costs. A concept that addresses induced community tolerance to a pollutant (PICT) was introduced by Blanck and Wängberg (1988). The basic principle of the concept is that microbial communities undergo pollution-induced succession when exposed to a pollutant over a long period of time, which changes communities structurally and functionally and enhancing tolerance to the pollutant exposure. However, the mechanisms of tolerance and the ecologic consequences were hardly studied up to date. This thesis addresses the structural and functional changes in biofilm communities and applies modern molecular methods to unravel molecular tolerance mechanisms. Two different freshwater biofilm communities were cultivated for a period of five weeks, with one of the communities being contaminated with 4 μg L-1 diuron. Subsequently, the communities were characterized for structural and functional differences, especially focusing on their crucial role of photosynthesis. The community structure of the autotrophs was assessed using HPLC-based pigment analysis and their functional alterations were investigated using Imaging-PAM fluorometry to study photosynthesis and community oxygen profiling to determine net primary production. Then, the molecular fingerprints of the communities were measured with meta-transcriptomics (RNA-Seq) and GC-based community metabolomics approaches and analyzed with respect to changes in their molecular functions. The communities were acute exposed to diuron for one hour in a dose-response design, to reveal a potential PICT and uncover related adaptation to diuron exposure. The combination of apical and molecular methods in a dose-response design enabled the linkage of functional effects of diuron exposure and underlying molecular mechanisms based on a sensitivity analysis. Chronic exposure to diuron impaired freshwater biofilms in their biomass accrual. The contaminated communities particularly lost autotrophic biomass, reflected by the decrease in specific chlorophyll a content. This loss was associated with a change in the molecular fingerprint of the communities, which substantiates structural and physiological changes. The decline in autotrophic biomass could be due to a primary loss of sensitive autotrophic organisms caused by the selection of better adapted species in the course of chronic exposure. Related to this hypothesis, an increase in diuron tolerance has been detected in the contaminated communities and molecular mechanisms facilitating tolerance have been found. It was shown that genes of the photosystem, reductive-pentose phosphate cycle and arginine metabolism were differentially expressed among the communities and that an increased amount of potential antioxidant degradation products was found in the contaminated communities. This led to the hypothesis that contaminated communities may have adapted to oxidative stress, making them less sensitive to diuron exposure. Moreover, the photosynthetic light harvesting complex was altered and the photoprotective xanthophyll cycle was increased in the contaminated communities. Despite these adaptation strategies, the loss of autotrophic biomass has been shown to impair primary production. This impairment persisted even under repeated short-term exposure, so that the tolerance mechanisms cannot safeguard primary production as a key function in aquatic systems.:1. The effect of chemicals on organisms and their functions .............................. 1 1.1 Welcome to the anthropocene .......................................................................... 1 1.2 From cellular stress responses to ecosystem resilience ................................... 3 1.2.1 The individual pursuit for homeostasis ....................................................... 3 1.2.2 Stability from diversity ................................................................................. 5 1.3 Community ecotoxicology - a step forward in monitoring the effects of chemical pollution? ................................................................................................................. 6 1.4 Functional ecotoxicological assessment of microbial communities ................... 9 1.5 Molecular tools – the key to a mechanistic understanding of stressor effects from a functional perspective in microbial communities? ...................................... 12 2. Aims and Hypothesis ......................................................................................... 14 2.1 Research question .......................................................................................... 14 2.2 Hypothesis and outline .................................................................................... 15 2.3 Experimental approach & concept .................................................................. 16 2.3.1 Aquatic freshwater biofilms as model community ..................................... 16 2.3.2 Diuron as model herbicide ........................................................................ 17 2.3.3 Experimental design ................................................................................. 18 3. Structural and physiological changes in microbial communities after chronic exposure - PICT and altered functional capacity ................................................. 21 3.1 Introduction ..................................................................................................... 21 3.2 Methods .......................................................................................................... 23 3.2.1 Biofilm cultivation ...................................................................................... 23 3.2.2 Dry weight and autotrophic index ............................................................. 23 3.2.4 Pigment analysis of periphyton ................................................................. 23 3.2.4.1 In-vivo pigment analysis for community characterization ....................... 24 3.2.4.2 In-vivo pigment analysis based on Imaging-PAM fluorometry ............... 24 3.2.4.3 In-vivo pigment fluorescence for tolerance detection ............................. 26 3.2.4.4 Ex-vivo pigment analysis by high-pressure liquid-chromatography ....... 27 3.2.5 Community oxygen metabolism measurements ....................................... 28 3.3 Results and discussion ................................................................................... 29 3.3.1 Comparison of the structural community parameters ............................... 29 3.3.2 Photosynthetic activity and primary production of the communities after selection phase ................................................................................................. 33 3.3.3 Acquisition of photosynthetic tolerance .................................................... 34 3.3.4 Primary production at exposure conditions ............................................... 36 3.3.5 Tolerance detection in primary production ................................................ 37 3.4 Summary and Conclusion ........................................................................... 40 4. Community gene expression analysis by meta-transcriptomics ................... 41 4.1 Introduction to meta-transcriptomics ............................................................... 41 4.2. Methods ......................................................................................................... 43 4.2.1 Sampling and RNA extraction................................................................... 43 4.2.2 RNA sequencing analysis ......................................................................... 44 4.2.3 Data assembly and processing................................................................. 45 4.2.4 Prioritization of contigs and annotation ..................................................... 47 4.2.5 Sensitivity analysis of biological processes .............................................. 48 4.3 Results and discussion ................................................................................... 48 4.3.1 Characterization of the meta-transcriptomic fingerprints .......................... 49 4.3.2 Insights into community stress response mechanisms using trend analysis (DRomic’s) ......................................................................................................... 51 4.3.3 Response pattern in the isoform PS genes .............................................. 63 4.5 Summary and conclusion ................................................................................ 65 5. Community metabolome analysis ..................................................................... 66 5.1 Introduction to community metabolomics ........................................................ 66 5.2 Methods .......................................................................................................... 68 5.2.1 Sampling, metabolite extraction and derivatisation................................... 68 5.2.2 GC-TOF-MS analysis ............................................................................... 69 5.2.3 Data processing and statistical analysis ................................................... 69 5.3 Results and discussion ................................................................................... 70 5.3.1 Characterization of the metabolic fingerprints .......................................... 70 5.3.2 Difference in the metabolic fingerprints .................................................... 71 5.3.3 Differential metabolic responses of the communities to short-term exposure of diuron ............................................................................................................ 73 5.4 Summary and conclusion ................................................................................ 78 6. Synthesis ............................................................................................................. 79 6.1 Approaches and challenges for linking molecular data to functional measurements ...................................................................................................... 79 6.2 Methods .......................................................................................................... 83 6.2.1 Summary on the data ............................................................................... 83 6.2.2 Aggregation of molecular data to index values (TELI and MELI) .............. 83 6.2.3 Functional annotation of contigs and metabolites using KEGG ................ 83 6.3 Results and discussion ................................................................................... 85 6.3.1 Results of aggregation techniques ........................................................... 85 6.3.2 Sensitivity analysis of the different molecular approaches and endpoints 86 6.3.3 Mechanistic view of the molecular stress responses based on KEGG functions ............................................................................................................ 89 6.4 Consolidation of the results – holistic interpretation and discussion ............... 93 6.4.1 Adaptation to chronic diuron exposure - from molecular changes to community effects.............................................................................................. 93 6.4.2 Assessment of the ecological costs of Pollution-induced community tolerance based on primary production ............................................................. 94 6.5 Outlook ............................................................................................................ 9

    Targeted proteomics links virulence factor expression with clinical severity in staphylococcal pneumonia

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    IntroductionThe bacterial pathogen Staphylococcus aureus harbors numerous virulence factors that impact infection severity. Beyond virulence gene presence or absence, the expression level of virulence proteins is known to vary across S. aureus lineages and isolates. However, the impact of expression level on severity is poorly understood due to the lack of high-throughput quantification methods of virulence proteins.MethodsWe present a targeted proteomic approach able to monitor 42 staphylococcal proteins in a single experiment. Using this approach, we compared the quantitative virulomes of 136 S. aureus isolates from a nationwide cohort of French patients with severe community-acquired staphylococcal pneumonia, all requiring intensive care. We used multivariable regression models adjusted for patient baseline health (Charlson comorbidity score) to identify the virulence factors whose in vitro expression level predicted pneumonia severity markers, namely leukopenia and hemoptysis, as well as patient survival.ResultsWe found that leukopenia was predicted by higher expression of HlgB, Nuc, and Tsst-1 and lower expression of BlaI and HlgC, while hemoptysis was predicted by higher expression of BlaZ and HlgB and lower expression of HlgC. Strikingly, mortality was independently predicted in a dose-dependent fashion by a single phage-encoded virulence factor, the Panton-Valentine leucocidin (PVL), both in logistic (OR 1.28; 95%CI[1.02;1.60]) and survival (HR 1.15; 95%CI[1.02;1.30]) regression models.DiscussionThese findings demonstrate that the in vitro expression level of virulence factors can be correlated with infection severity using targeted proteomics, a method that may be adapted to other bacterial pathogens

    Diagnosis and Treatment in Asthma and Allergic Rhinitis: Past, Present, and Future

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    Respiratory diseases are pathological conditions that affect airways, hampering breathing and causing high mortality. In particular, asthma and allergic rhinitis (AR) are two of the most common airway diseases that affect millions of people and have a high prevalence in childhood and adulthood. Asthma is a heterogeneous chronic inflammatory disease characterized by wheezing, chest tightness, shortness of breath, and cough. AR occurs with rhinorrhea, nasal congestion, and sneezing. Indeed, these pathologies share common physiopathological mechanisms such as airway hyperresponsiveness and similar immunopathology such as tissue eosinophilia and T-helper type 2 inflammation. Moreover, AR can be an important risk factor for suffering asthma. Thus, early diagnosis and effective treatment are crucial to improving the health and quality of life of these patients. Classical drugs such as corticosteroids have been used; however, in the last decades, efforts to improve treatments have increased, focusing on biological agents and specific allergen immunotherapy development. Moreover, more precise diagnostic tools have been elaborated, besides classical methods (medical history, physical examination, and pulmonary function tests), such as basophil activation test, and specific cellular and molecular biomarkers (microRNAs, sputum/blood eosinophils, IgE serum, and periostin levels). Therefore, in this review, we compile all these important issues for managing asthma and AR.Espada-Sánchez M, Sáenz de Santa María R, Martín-Astorga MdC, Lebrón-Martín C, Delgado MJ, Eguiluz-Gracia I, Rondón C, Mayorga C, Torres MJ, Aranda CJ, Cañas JA. Diagnosis and Treatment in Asthma and Allergic Rhinitis: Past, Present, and Future. Applied Sciences. 2023; 13(3):1273. https://doi.org/10.3390/app1303127

    In Silico and In Vitro Inhibition of SARS-CoV-2 PLpro with Gramicidin D

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    Finding an effective drug to prevent or treat COVID-19 is of utmost importance in tcurrent pandemic. Since developing a new treatment takes a significant amount of time, drug repurposing can be an effective option for achieving a rapid response. This study used a combined in silico virtual screening protocol for candidate SARS-CoV-2 PLpro inhibitors. The Drugbank database was searched first, using the Informational Spectrum Method for Small Molecules, followed by molecular docking. Gramicidin D was selected as a peptide drug, showing the best in silico interaction profile with PLpro. After the expression and purification of PLpro, gramicidin D was screened for protease inhibition in vitro and was found to be active against PLpro. The current study’s findings are significant because it is critical to identify COVID-19 therapies that are efficient, affordable, and have a favorable safety profil
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