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Abstract Aims Inflammation has emerged as a potential key pathophysiological mechanism in heart failure (HF) in general and acute HF (AHF) specifically, with inflammatory biomarkers shown to be highly predictive of adverse outcomes in these patients. The CORTAHF study builds on both these data and the fact that steroid burst therapy has been shown to be effective in the treatment of respiratory diseases and COVID‐19. Our hypothesis is that in patients with AHF and elevated C‐reactive protein (CRP) levels without symptoms or signs of infection, a 7‐day course of steroid therapy will lead to reduced inflammation and short‐term improvement in quality of life and a reduced risk of worsening HF (WHF) events. Methods and results The study, which is currently ongoing, will include 100 patients with AHF ages 18–85, regardless of ejection fraction, screened within 12 h of presentation. Patients will be included who have NT‐proBNP > 1500 pg/mL and CRP > 20 mg/L at screening. Exclusion criteria include haemodynamic instability and symptoms and signs of infection. After signed consent, eligible patients will be randomized according to a central randomization scheme stratified by centre 1:1 to either treatment once daily for 7 days with 40 mg prednisone orally or to standard care. Patients will be assessed at study day 2, day 4 or at discharge if earlier, and at days 7 and 31 at the hospital; and at day 91 through a telephone follow‐up. The primary endpoint is the change in CRP level from baseline to day 7, estimated from a mixed model for repeated measures (MMRM) including all measured timepoints, in patients without a major protocol violation. Secondary endpoints include the time to the first event of WHF adverse event, readmission for HF, or death through day 91; and changes to day 7 in EQ‐5D visual analogue scale score and utility index. Additional clinical and laboratory measures will be assessed. Conclusions The results of the study will add to the knowledge of the role of inflammation in AHF and potentially inform the design of larger studies with possibly longer duration of anti‐inflammatory therapies in AHF.

Abstract This retrospective cohort study used Taussig Cancer Center’s Myeloma Patient Registry to identify adults with multiple myeloma diagnosed between January 2017-December 2021. Electronic health records data captured time from diagnosis to initial prescription fill for oral antimyeloma medications and initiation of facility administered or oral antimyeloma treatment. We identified 720 patients with a mean age at diagnosis of 67 years ±11; 55% were male, 77% White, 22% Black, 1% other races, covered by private insurance (36%), traditional Medicare (29%), Medicare Advantage (25%), and Medicaid (8.3%). Over a third of patients (37%) resided in an area in the most disadvantaged area deprivation index (ADI) quartile. The median available follow-up was 765 days. Seventy-five percent of the cohort filled an oral antimyeloma medication prescription (excluding corticosteroids), with a median time to fill of 28 days (IQR, 15–61). In the multivariable Cox regression model, Black race (vs. White, adjusted hazard ratio [aHR], 0.61, 95% CI, 0.42–0.87), older age at diagnosis (aHR per 1 year, 0.97, 95% CI, 0.95–0.98), diagnosis during an inpatient admission (aHR, 0.63, 95% CI, 0.43–0.92), and estimated glomerular filtration rate ≤29 ml/min/1.73 m2 (vs. ≥60, aHR, 0.46, 95% CI, 0.29–0.73) were negatively associated with prescription fill for oral antimyeloma medication at 30 days, while insurance type and ADI were not significant predictors.

Abstract The coronavirus disease 19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to a global health crisis with millions of confirmed cases and related deaths. The main protease (Mpro) of SARS-CoV-2 is crucial for viral replication and presents an attractive target for drug development. Despite the approval of some drugs, the search for effective treatments continues. In this study, we systematically evaluated 342 holo-crystal structures of Mpro to identify optimal conformations for structure-based virtual screening (SBVS). Our analysis revealed limited structural flexibility among the structures. Three docking programs, AutoDock Vina, rDock, and Glide were employed to assess the efficiency of virtual screening, revealing diverse performances across selected Mpro structures. We found that the structures 5RHE, 7DDC, and 7DPU (PDB Ids) consistently displayed the lowest EF, AUC, and BEDROCK scores. Furthermore, these structures demonstrated the worst pose prediction results in all docking programs. Two structural differences contribute to variations in docking performance: the absence of the S1 subsite in 7DDC and 7DPU, and the presence of a subpocket in the S2 subsite of 7DDC, 7DPU, and 5RHE. These findings underscore the importance of selecting appropriate Mpro conformations for SBVS, providing valuable insights for advancing drug discovery efforts.

The mining industry is pivotal in ensuring Armenia's foreign exchange earnings. Therefore, we investigate the role of real exports of companies representing the mining of metal ores industry using quarterly data (2012q1 2023q2) in explaining statistically significant changes in the real GDP in the short run based on the least squares estimation technique. We conclude that significant positive changes in the real GDP are not associated with the increase in the industry's real exports since the growth of the mining of metal ores industry in Armenia mainly reflects the developments in the global commodity market. Hence, we find no evidence of the “multiplier effect.” Based on the findings, we substantiate the main challenges the industry could face and highlight the prospects ahead while meeting the objectives that the Mining Sector Development Strategy (until 2035) defined to ensure the industry's growth and attract new investors.

Globally, COVID-19 has been shown to have had a wide ranging and significant impact on individuals' daily living, and physical and mental health. However, there are some groups of individuals who may encounter unique challenges with regards to COVID-19 and whose experiences have not been investigated thus far. Therefore, this study aimed to understand the experiences of adults with a facial visible difference in relation to COVID-19 and lockdown. Semi-structured interviews were conducted with 21 adults with a variety of facial visible differences (e.g., cleft lip/palate, facial scars, skin conditions) and analyzed using inductive reflexive thematic analysis. This analysis generated three themes (Escaping the external gaze; Existing feelings manifesting in new challenges; COVID-19 taking priority). The results of this study suggest that the first U.K. lockdown from the COVID-19 pandemic created significant challenges for some individuals with a facial visible difference, and ongoing restrictions and social distancing measures might be particularly challenging for those who experience anxiety around social encounters. These findings highlight the importance of providing appropriate and accessible support for people with facial differences during lockdown and as restrictions ease., Author(s): Philippa Tollow [sup.1] , Claire Hamlet [sup.1] , Fabio Zucchelli [sup.1] , Heidi Williamson [sup.1] , Diana Harcourt [sup.1] Author Affiliations: (1) grid.6518.a, 0000 0001 2034 5266, Centre for [...]

Extracellular vesicles released by the protozoan parasite Leishmania display immunomodulatory properties towards mammalian immune cells. In this study, we have evaluated the potential of extracellular vesicles derived from the non-pathogenic protozoan Leishmania tarentolae towards the development of a vaccine adjuvant. As a proof of concept, we expressed in L. tarentolae a codon-optimized SARS-CoV-2 Spike protein fused to the L. mexicana secreted acid phosphatase signal peptide in the N-terminal and to a 6×-His stretch in the C-terminal. Extracellular vesicles released by the engineered L. tarentolae were isolated by ultracentrifugation and fast protein liquid chromatography and were characterized via nanoparticle tracking analysis and transmission electron microscopy. The recombinant S protein was present in extracellular vesicles released by L. tarentolae, as determined by Western blot analyses and immunoelectron microscopy. Next, we evaluated the immunomodulatory potential of extracellular vesicles containing the S protein towards bone-marrow-derived macrophages and bone-marrow-derived dendritic cells. Our data show that in bone-marrow-derived dendritic cells, extracellular vesicles containing the S protein induced an increased expression of proinflammatory genes compared to plain extracellular vesicles whereas the opposite was observed in bone-marrow-derived macrophages. These findings reveal the immunomodulatory potential of L. tarentolae extracellular vesicles and provide a proof of concept that they can be used as adjuvant in the context of dendritic cell stimulation.

ABSTRACT: Necrotic enteritis is a devastating disease to poultry caused by the bacterium Clostridium perfringens. As a novel approach to combating poultry necrotic enteritis, we identified and characterized several hundred single domain antibody fragments (or nanobodies) capable of binding either the NetB toxin or the collagen-binding adhesin (CnaA) of C. perfringens. Many of the nanobodies could neutralize the in vitro functions of NetB or CnaA with inhibitory concentrations in the nanomolar range. The nanobodies were also screened for proteolytic stability in an extract derived from gastrointestinal tract fluids of chickens. A collection of 6 nanobodies (4 targeting NetB and 2 targeting CnaA) with high neutralizing activity and high gastrointestinal tract extract stability were expressed and secreted by Pichia pastoris or Bacillus subtilis. Chickens were given a feed with 1 of the 2 nanobody-containing groups: 1) nanobody-containing P. pastoris supernatants that were semi-purified, lyophilized, and enterically coated, or 2) B. subtilis spores from strains containing the nanobody genes. Compared to untreated chickens (23.75% mortality), mortality of chickens receiving feed modified with the P. pastoris and B. subtilis products decreased to 11.25 and 7.5%, respectively. These results offer a new opportunity to improve the control of poultry necrotic enteritis by incorporating highly specific nanobodies or bacteria expressing these nanobodies directly into chicken feed.

Baylisascaris spp. are ascarid worms that parasitize the small intestines of multiple species. The primary definitive host for B. procyonis roundworms is the raccoon (Procyon lotor), although other carnivores, including [...]

Multiple sclerosis (MS) is a chronic inflammatory autoimmune neurological disease characterized by the recurrent appearance of demyelinating lesions and progressive disability. Currently, there are multiple disease-modifying treatments, however, there is a significant need to develop new therapeutic targets, especially for the progressive forms of the disease. This review article provides an overview of the most recent studies aimed at understanding the inflammatory processes that are activated in response to the accumulation of kynurenine pathway (KP) metabolites, which exacerbate an imbalance between immune system cells (e.g., Th1, Th2, and T reg) and promote the release of pro-inflammatory interleukins that modulate different mechanisms: membrane-receptors function; nuclear factors expression; and cellular signals. Together, these alterations trigger cell death mechanisms in brain cells and promote neuron loss and axon demyelination. This hypothesis could represent a remarkable approach for disease-modifying therapies for MS. Here, we also provide a perspective on the repositioning of some already approved drugs involved in other signaling pathways, which could represent new therapeutic strategies for MS treatment.

Muscular dystrophies (MDs) are a heterogeneous group of diseases of genetic origin characterized by progressive skeletal muscle degeneration and weakness. There are several types of MDs, varying in terms of age of onset, severity, and pattern of the affected muscles. However, all of them worsen over time, and many patients will eventually lose their ability to walk. In addition to skeletal muscle effects, patients with MDs may present cardiac and respiratory disorders, generating complications that could lead to death. Interdisciplinary management is required to improve the surveillance and quality of life of patients with an MD. At present, pharmacological therapy is only available for Duchene muscular dystrophy (DMD)—the most common type of MD—and is mainly based on the use of corticosteroids. Other MDs caused by alterations in dystrophin-associated proteins (DAPs) are less frequent but represent an important group within these diseases. Pharmacological alternatives with clinical potential in patients with MDs and other proteins associated with dystrophin have been scarcely explored. This review focuses on drugs and molecules that have shown beneficial effects, mainly in experimental models involving alterations in DAPs. The mechanisms associated with the effects leading to promising results regarding the recovery or maintenance of muscle strength and reduction in fibrosis in the less-common MDs (i.e., with respect to DMD) are explored, and other therapeutic targets that could contribute to maintaining the homeostasis of muscle fibers, involving different pathways, such as calcium regulation, hypertrophy, and maintenance of satellite cell function, are also examined. It is possible that some of the drugs explored here could be used to affordably improve the muscular function of patients until a definitive treatment for MDs is developed.

We describe a case of Baylisascaris procyonis roundworm infection in a child in Washington, USA, with autism spectrum disorder. Environmental assessment confirmed nearby raccoon habitation and B. procyonis eggs. B. procyonis infections should be considered a potential cause of human eosinophilic meningitis, particularly among young children and persons with developmental delays.

This report aims to show the results of the second excavation campaign at Dvin/Dabīl (Armenia), conducted by the Italian-Armenian research group in Autumn 2022. The excavations involved three areas in distinct sectors of the city: the southern portion of the Lower Fortress, where the 2021 square was deepened and enlarged; the so-called ‘Market’ area, where the 2021 excavations were expanded and a micro-stratigraphic trench was opened; the area southeast of the central district, where an exploratory trench was dug to investigate the archaeological evidence at the site of the future building of the Dvin Museum. Additionally, the last paragraph shows the chemical analysis of pottery samples carried out between 2021 and 2022.

IntroductionThe Eidolon helvum fruit bat is one of the most widely distributed fruit bats in Africa and known to be a reservoir for several pathogenic viruses that can cause disease in animals and humans. To assess the risk of zoonotic spillover, we conducted a serological survey of 304 serum samples from E. helvum bats that were captured for human consumption in Makurdi, Nigeria.MethodsUsing pseudotyped viruses, we screened 304 serum samples for neutralizing antibodies against viruses from the Coronaviridae, Filoviridae, Orthomyxoviridae and Paramyxoviridae families.ResultsWe report the presence of neutralizing antibodies against henipavirus lineage GH-M74a virus (odds ratio 6.23; p

Environmental pollution caused by petroleum-derived plastics continues to increase annually. Consequently, current research is interested in the search for eco-friendly bacterial polymers. The importance of Bacillus bacteria as producers of polyhydroxyalkanoates (PHAs) has been recognized because of their physiological and genetic qualities. In this study, twenty strains of Bacillus genus PHA producers were isolated. Production was initially evaluated qualitatively to screen the strains, and subsequently, the strain B12 or Bacillus sp. 12GS, with the highest production, was selected through liquid fermentation. Biochemical and molecular identification revealed it as a novel isolate of Bacillus cereus. Production optimization was carried out using the Taguchi methodology, determining the optimal parameters as 30 °C, pH 8, 150 rpm, and 4% inoculum, resulting in 87% and 1.91 g/L of polyhydroxybutyrate (PHB). Kinetic studies demonstrated a higher production within 48 h. The produced biopolymer was analyzed using Fourier-transform infrared spectroscopy (FTIR), confirming the production of short-chain-length (scl) polyhydroxyalkanoate, named PHB, and differential scanning calorimetry (DSC) analysis revealed thermal properties, making it a promising material for various applications. The novel B. cereus isolate exhibited a high %PHB, emphasizing the importance of bioprospecting, study, and characterization for strains with biotechnological potential.

Oral bone defects occur as a result of trauma, cancer, infections, periodontal diseases, and caries. Autogenic and allogenic grafts are the gold standard used to treat and regenerate damaged or defective bone segments. However, these materials do not possess the antimicrobial properties necessary to inhibit the invasion of the numerous deleterious pathogens present in the oral microbiota. In the present study, poly(ε-caprolactone) (PCL), nano-hydroxyapatite (nHAp), and a commercial extract of Humulus lupulus L. (hops) were electrospun into polymeric matrices to assess their potential for drug delivery and bone regeneration. The fabricated matrices were analyzed using scanning electron microscopy (SEM), tensile analysis, thermogravimetric analysis (TGA), FTIR assay, and in vitro hydrolytic degradation. The antimicrobial properties were evaluated against the oral pathogens Streptococcus mutans, Porphyromonas gingivalis, and Aggregatibacter actinomycetemcomitans. The cytocompatibility was proved using the MTT assay. SEM analysis established the nanostructured matrices present in the three-dimensional interconnected network. The present research provides new information about the interaction of natural compounds with ceramic and polymeric biomaterials. The hop extract and other natural or synthetic medicinal agents can be effectively loaded into PCL fibers and have the potential to be used in oral applications.

The quest for microbial cellulases has intensified as a response to global challenges in biofuel production. The efficient deconstruction of lignocellulosic biomass holds promise for generating valuable products in various industries such as food, textile, and detergents. This article presents a systematic bioprospection aimed at isolating actinomycetes with exceptional cellulose deconstruction capabilities. Our methodology explored the biodiverse oligotrophic region of Cuatro Cienegas, Coahuila, within the Chihuahuan Desert. Among the evaluated actinomycetes collection, 78% exhibited cellulolytic activity. Through a meticulous screening process based on enzymatic index evaluation, we identified a highly cellulolytic Streptomyces strain for further investigation. Submerged fermentation of this strain revealed an endoglucanase enzymatic activity of 149 U/mg. Genomic analysis of strain Streptomyces sp. STCH565-A revealed unique configurations of carbohydrate-active enzyme (CAZyme) genes, underscoring its potential for lignocellulosic bioconversion applications. These findings not only highlight the significance of the Chihuahuan Desert as a rich source of cellulolytic microorganisms but also offer insights into the systematic exploration and selection of high-performing cellulolytic microorganisms for application in diverse environmental contexts. In conclusion, our bioprospecting study lays a foundation for harnessing the cellulolytic potential of actinomycetes from the Chihuahuan Desert, with implications for advancing cellulose deconstruction processes in various industries. The findings can serve as a blueprint for future bioprospecting efforts in different regions, facilitating the targeted discovery of microorganisms with exceptional cellulosic deconstruction capabilities.

The goal of this study was to examine in-hospital complications in patients with acute ST-elevation myocardial infarction with a different renal function.

The transition from a raw model of development to a creative one, the transformation into a technologically dynamic country capable of developing, producing, and applying high technologies, innovations for large-scale production of competitive goods and services, are considered the most significant components of the strategy for modernizing the economy at the present stage. The study mainly discusses the concept of “creative economy”, its main characteristics, principles, and the international experience of the design economy. Attention is also paid to the consideration of design as a tool and factor in the country’s economic development. The main purpose of writing the article is to study the expanded innovative reproduction system of the economy, to identify its main structural elements. In the last decade, the intensification of globalization, regionalization, modernization and transformation of the economic system has led to a kind of creative development, whose direction and pace are determined by man as an innovator, which increases the relevance of the research topic. The methodological basis of the research was the works of German and other foreign scientists on the problems of economic design. The following research methods were used to perform the tasks: monographic (to study the principles of management of the economic system); system-structural (to study the essence of sustainable economic design); institutional (to study the application of the design problem in institutions); abstract-logical (to make theoretical and methodological generalizations and formulate the results). The main result of the research over time is that the study of the relationship between economics and culture in existing economic models allows for a more in-depth study of the phenomenon of creativity as a factor in innovative processes. The development of research on the role of culture in the formation of human capital can be useful in the study of the main categories of economic development, such as productivity, innovation, creativity. Changes in the focus of cultural economics from the study of cultural heritage and art (welfare model and neoclassical model), as well as a reconsideration of the concept and content of culture, which we observe in these models, can lead to changes in cultural development. Originality/scientific novelty. The scientific novelty of the research consists of its plan and the points that were clarified for the first time. The rationality of the funds allocated by the state for creativity, the inactivity of business in this area, the lack of scientific research, the reduction in the number of researchers and engineers were cited as factors hindering the development of the creative economy. Practical value/implications. The practical significance of the research is related to the fact that the research topic, i.e, the creative economy, affects not only the creation of new products, but also their production methods. For example, practical research has shown that Japan is active in this matter. It was known that Japan was the first country to adopt non-traditional and creative approaches, given the peculiarities of the formation and development of the creative economy. Taking into account the Japanese experience, the use of creative abilities of employees based on physical labor can be applied. Given that Japan is constantly improving technologies, methods, directions, forms, industrial ideas, models and organizations to manage production processes and people, we can consider the possibility of applying this practice in our countries.

Enabling women to be meaningful participants and leaders in rural community-based water and sanitation governance remains a challenge. While the benefits of and barriers to women's participation and leadership have been reported on, there is limited understanding of the role of empowerment in addressing these challenges. To help bridge this knowledge gap, we used a household survey to measure men and women's empowerment in water and sanitation in the rural Tupiza watershed, Bolivia, and key informant interviews with women leaders to identify barriers to leadership. Overall, among survey respondents, fewer men than women were disempowered. Community-level factors, especially those related to comfort in speaking in community meetings and reporting service problems, contributed more to women's disempowerment, as did household-level factors related to work balance and input into decisions about who participates in community water and sanitation activities. Among interviewed community water leaders, many women felt their positions were costly to their households and reported challenges in obtaining technical training and local government assistance, which not only disempowered them as leaders but also was likely tied to poor service delivery and related health outcomes in their communities. We discuss the implications of our findings for rural Bolivia and future research opportunities. HIGHLIGHTS This study is one of the first to assess the relationship between women's empowerment and participation in community-managed water and sanitation.; We measured men's and women's empowerment in water and sanitation and examined the associated barriers to women's successful participation and leadership in rural Bolivia with mixed methods.; Women's discomfort in speaking in community meetings and reporting service problems contributed more to their disempowerment than to men's.; Women leaders' disempowerment was related to their domestic workloads and challenges in obtaining technical training and local government assistance.; By focusing on barriers linked to women's disempowerment, we highlighted the central role of empowerment in improving participation and identified barriers that matter most for gender, water, and sanitation goals.;

We report the identification of 89 new systems containing ultracool dwarf companions to main-sequence stars and white dwarfs, using the citizen science project Backyard Worlds: Planet 9 and cross-reference between Gaia and CatWISE2020. 32 of these companions and 33 host stars were followed up with spectroscopic observations, with companion spectral types ranging from M7–T9 and host spectral types ranging from G2–M9. These systems exhibit diverse characteristics, from young to old ages, blue to very red spectral morphologies, potential membership to known young moving groups, and evidence of spectral binarity in nine companions. 20 of the host stars in our sample show evidence for higher-order multiplicity, with an additional 11 host stars being resolved binaries themselves. We compare this sample’s characteristics with those of the known stellar binary and exoplanet populations, and find our sample begins to fill in the gap between directly imaged exoplanets and stellar binaries on mass ratio–binding energy plots. With this study, we increase the population of ultracool dwarf companions to FGK stars by ∼42%, and more than triple the known population of ultracool dwarf companions with separations larger than 1000 au, providing excellent targets for future atmospheric retrievals.

A complete accounting of nearby objects—from the highest-mass white dwarf progenitors down to low-mass brown dwarfs—is now possible, thanks to an almost complete set of trigonometric parallax determinations from Gaia, ground-based surveys, and Spitzer follow-up. We create a census of objects within a Sun-centered sphere of 20 pc radius and check published literature to decompose each binary or higher-order system into its separate components. The result is a volume-limited census of ∼3600 individual star formation products useful in measuring the initial mass function across the stellar (