Effects of ruxolitinib cream on pruritus and quality of life in atopic dermatitis: Results from a phase 2, randomized, dose-ranging, vehicle- and active-controlled study

BACKGROUND: Atopic dermatitis (AD), a chronic, highly pruritic skin disorder, impairs quality of life (QoL). Janus kinase inhibitors suppress inflammatory and pruritus-associated cytokine signaling in AD. OBJECTIVE: To report the effects of ruxolitinib (RUX) cream on itch and QoL in AD. METHODS: A total of 307 adult patients with an Investigator\u27s Global Assessment (score of 2 or 3) and 3% to 20% affected body surface area were randomly assigned for 8 weeks to receive double-blind treatment with RUX (1.5% twice daily, 1.5% once daily, 0.5% once daily, or 0.15% once daily), vehicle twice daily, or triamcinolone cream (0.1% twice daily for 4 weeks then vehicle for 4 weeks). Itch was measured by using the numerical rating scale, and patient QoL was assessed with Skindex-16. RESULTS: Improvements in itch numerical rating scale and Skindex-16 were observed with RUX cream. Overall, 42.5% of patients who applied 1.5% RUX twice daily experienced minimal clinically important difference in itch within 36 hours of treatment (vehicle, 13.6%; P \u3c .01); near-maximal improvement was observed by week 4. Itch reduction was associated with improved QoL burden (Pearson correlation, 0.67; P \u3c .001). Significant improvements in Skindex-16 overall scores were noted at week 2. LIMITATIONS: Facial AD lesions were not treated. CONCLUSION: RUX cream provides a clinically meaningful reduction in itch and QoL burden

Treatment of atopic dermatitis with ruxolitinib cream (JAK1/JAK2 inhibitor) or triamcinolone cream

BACKGROUND: Atopic dermatitis (AD) is a highly pruritic chronic inflammatory skin disorder. Ruxolitinib, a selective inhibitor of Janus kinase 1 and Janus kinase 2, potently suppresses cytokine signaling involved in AD pathogenesis. OBJECTIVE: We sought to evaluate the efficacy and safety of ruxolitinib (RUX) cream in adults with AD. METHODS: In this phase 2 study (NCT03011892), 307 adult patients with AD, an Investigator\u27s Global Assessment score of 2 or 3 (mild or moderate), and 3% to 20% affected body surface area were equally randomized for 8 weeks of double-blind treatment to RUX (1.5% twice daily [BID], 1.5% once daily [QD], 0.5% QD, 0.15% QD), vehicle, or triamcinolone cream (0.1% BID for 4 weeks, then vehicle for 4 weeks). Subsequently, patients could apply 1.5% RUX BID for 4 additional weeks of open-label treatment. The primary end point was the comparison between 1.5% RUX cream BID and vehicle in mean percentage change from baseline in Eczema Area and Severity Index at week 4. RESULTS: All RUX regimens demonstrated therapeutic benefit at week 4; 1.5% BID provided the greatest improvement in Eczema Area and Severity Index (71.6% vs 15.5%; P \u3c .0001) and Investigator\u27s Global Assessment responses (38.0% vs 7.7%; P \u3c .001) versus vehicle. Rapid reductions in the itch numerical rating scale score occurred within 36 hours (1.5% BID vs vehicle, ‒1.8 vs ‒0.2; P \u3c .0001) and were sustained through 12 weeks. Patients who transitioned to 1.5% RUX BID improved in all measures. RUX was not associated with clinically significant application-site reactions. CONCLUSIONS: RUX cream provided rapid and sustained improvements in AD symptoms and was well tolerated

Promoting source separation of Biowaste for a Sustainable Circular Economy in the Baltic Region

BackgroundThe European Union Waste Framework Directive mandates the separate collection and sustainable utilization of biowaste at the source in member states from January 1, 2024, to achieve the EU's target of recycling 65% of municipal solid waste by 2035. However, less than 50% of municipal biowaste is being collected separately in member states. This presents significant challenges for the Baltic countries, where some need to develop new collection systems and waste treatment facilities, while others must improve their existing systems. Moreover, up to 60% of biowaste still ends up in residual waste bins, which poses a concern for the solid waste management system. Study AreaThe cities examined in this study include Bornholm, Lappeenranta, Rostock, and Gdańsk distributed across different countries. The selected cities are located within the geographical vicinity of the Baltic Sea, a brackish inland sea in Northern Europe  (Figure 1).MethodsThis study was a collaborative effort involving experts from Germany, Finland, Denmark, and Poland The methodology employed in this study involved an extensive review of scientific literature and seven discussion meetings from January to March 2023 between involved experts. The research aimed to identify the challenges, gaps, and potential measures to improve the source separation of biowaste in the Baltic region.ResultsManagement of biowaste varies significantly due to consumption patterns, economic wealth, regional policies, technical infrastructure, and public awareness. The studied areas have national-level regulations on biowaste source separation and landfill bans. Aside from Germany, other countries have recently implemented these regulations, leading to a transitional phase in biowaste management.Local authorities often struggle to adapt solutions to their specific context due to limited flexibility and resources. Sharing experiences and knowledge can mitigate repeating mistakes, foster cross-border collaboration, and enhance local authorities' capacity to improve biowaste source separation.</div

Molecular and Cellular Basis of Microvascular Perfusion Deficits Induced by Clostridium perfringens and Clostridium septicum

Reduced tissue perfusion leading to tissue ischemia is a central component of the pathogenesis of myonecrosis caused by Clostridium perfringens. The C. perfringens α-toxin has been shown capable of inducing these changes, but its potential synergy with perfringolysin O (θ-toxin) is less well understood. Similarly, Clostridium septicum is a highly virulent causative agent of spontaneous gas gangrene, but its effect on the microcirculation has not been examined. Therefore, the aim of this study was to use intravital microscopy to examine the effects of C. perfringens and C. septicum on the functional microcirculation, coupled with the use of isogenic toxin mutants to elucidate the role of particular toxins in the resultant microvascular perfusion deficits. This study represents the first time this integrated approach has been used in the analysis of the pathological response to clostridial toxins. Culture supernatants from wild-type C. perfringens induced extensive cell death within 30 min, as assessed by in vivo uptake of propidium iodide. Furthermore, significant reductions in capillary perfusion were observed within 60 min. Depletion of either platelets or neutrophils reduced the alteration in perfusion, consistent with a role for these blood-borne cells in obstructing perfusion. In addition, mutation of either the α-toxin or perfringolysin O structural genes attenuated the reduction in perfusion, a process that was reversed by genetic complementation. C. septicum also induced a marked reduction in perfusion, with the degree of microvascular compromise correlating with the level of the C. septicum α-toxin. Together, these data indicate that as a result of its ability to produce α-toxin and perfringolysin O, C. perfringens rapidly induces irreversible cellular injury and a marked reduction in microvascular perfusion. Since C. septicum induces a similar reduction in microvascular perfusion, it is postulated that this function is central to the pathogenesis of clostridial myonecrosis, irrespective of the causative bacterium

Minimal information for studies of extracellular vesicles (MISEV2023): From basic to advanced approaches

Extracellular vesicles (EVs), through their complex cargo, can reflect the state of their cell of origin and change the functions and phenotypes of other cells. These features indicate strong biomarker and therapeutic potential and have generated broad interest, as evidenced by the steady year-on-year increase in the numbers of scientific publications about EVs. Important advances have been made in EV metrology and in understanding and applying EV biology. However, hurdles remain to realising the potential of EVs in domains ranging from basic biology to clinical applications due to challenges in EV nomenclature, separation from non-vesicular extracellular particles, characterisation and functional studies. To address the challenges and opportunities in this rapidly evolving field, the International Society for Extracellular Vesicles (ISEV) updates its 'Minimal Information for Studies of Extracellular Vesicles', which was first published in 2014 and then in 2018 as MISEV2014 and MISEV2018, respectively. The goal of the current document, MISEV2023, is to provide researchers with an updated snapshot of available approaches and their advantages and limitations for production, separation and characterisation of EVs from multiple sources, including cell culture, body fluids and solid tissues. In addition to presenting the latest state of the art in basic principles of EV research, this document also covers advanced techniques and approaches that are currently expanding the boundaries of the field. MISEV2023 also includes new sections on EV release and uptake and a brief discussion of in vivo approaches to study EVs. Compiling feedback from ISEV expert task forces and more than 1000 researchers, this document conveys the current state of EV research to facilitate robust scientific discoveries and move the field forward even more rapidly

Salt induced corrosion of sandstone

Different types of sandstone react differently to salt induced corrosion. Three sandstones were chosen for corrosion tests in this study. The three different types of sandstone were subject to two different types of corrosion tests, one in which salt crystallization was enhanced by evaporation and the other where crystallization was minimized by submerging samples into the leachant solution --Abstract, page iii

More thoughts on defaults

The developers of models used to simulate the evacuation from fire events, referred to here as egress models, are in a difficult position. It is in their interest to develop models that are quick and easy to employ, especially given the profusion of models and the expansion of application opportunities. At the same time, it is also in the model developers’ interest to reduce model misuse by inexpert users. Model misuse is characterized here as instances where results are produced through the use of inappropriate data and/or behavioural settings, which can lead to the generation of inappropriate or incredible results. While the authors advocate for the proper use of egress models in quantifying egress performance of a building design, the authors of this article are sceptical advocates of egress models, particularly in their design, their use in regulatory guidance, and the expertise of users. This paper represents an attempt to promote the proper use of egress models by suggesting a means to combat accidental model misuse. Previous work by the authors of this paper considered the availability of default values in simulation tools, and in particular egress models, and their potential for contributing to model misuse. Here, the term ‘default’ relates to a pre-set, fixed value (or distribution) for a parameter (e.g. the value for unimpeded walking speed) or the application of a specific behavioural algorithm in the model (e.g. agents travel along the path to their nearest exit). While the inclusion of default values enables out-of-the-box use of models without in-depth familiarization with input formats and data structures, defaults often represent optimistic and even unrealistic evacuation conditions or occupant behaviour, which can lead to model misuse. Most egress models provide default values for five core behavioural elements: pre-evacuation time, travel speeds, route usage and availability, and flow conditions. These five core behavioural elements typically need to be represented in order for the model to function at all. The authors suggest that bounding default settings, rather than optimistic values, should be provided for each of the core behavioural elements. In the context of this article, a bounding default setting is a value derived from relevant empirical data that prolongs the overall evacuation time produced for a particular design. If the model user wishes to decrease the conservative nature of a particular estimate or set of estimates, which will almost certainly be the case, he/she would then be required to explicitly justify the modification of the bounding default value. This approach then allows the immediate use of the model, but in effect forces the user to modify the settings in order to obtain a credible scenario for the purposes of design. These bounding values are not presented as values typically used in engineering scenarios. They are instead presented as values that would produce conservative results if used and would therefore typically require the user to modify the values in order to represent the scenario of interest. The bounding values suggested are therefore deliberately conservative in order to ensure both user intervention and user justification of this intervention to third parties reviewing the engineering process. The approach presented is designed to support model developers in their desire to have potential engineers use the model out-of-the-box, encouraging training and familiarization efforts, while aiding third party reviewers of the results, allowing them to compare any parameters employed with an accepted set of bounding parameter values. The use of bounding model default parameters is presented as an initial step in addressing accidental model misuse, with the acknowledgement that it would need to be refined and developed. However, this approach might also be integrated into other more substantive regulatory and licensing efforts should they be instigated

Modelling and influencing human behaviour in fire

The purpose of this article is to present a conceptual model of human behaviour in fire and its impact on egress modelling, life safety analyses and evacuation procedures. This model is based on a theoretical framework of individual decision-making and response to emergencies. From this foundation, the conceptual model is populated with behavioural statements or mini-theories distilled from articles and authoritative reports describing emergency incidents, observations from within the field of evacuation analysis and studies of human behaviour in fire and other emergencies. The conceptual model is intended to guide the egress tool developer, user and practitioner to better account for human behaviour in their respective roles. It is contended that a more credible representation of the evacuee response, that incorporates the behavioural statements described, provides both theoretical and practical advantages