Inflammation mediators enhance the activity of connexin (Cx) hemichannels especially in the epithelial and endothelial tissues. As potential release route for injury signals like (oligo)nucleotides, Cx hemichannels may contribute to long lasting inflammation. Specific inhibition of Cx hemichannels may therefore be a mode of prevention and treatment of long lasting, chronic sterile inflammation. The activity of Cx hemichannels was analysed in N2A and HeLa cells transfected with human Cx26 and Cx46 as well as in Calu-3 cells using the dye uptake as functional assay. Moreover, possible impact of the bioactive phenolic agents CVB2-61 and CVB4-57 on the barrier function of epithelial cells was analysed using Calu-3 cells. Both agents inhibited the dye uptake in N2A cells expressing Cx26 (> 5 µM) and Cx46 (> 20 µM). In Calu-3 cells, CVB2-61 and CVB4-57 reversible inhibited the dye uptake at concentrations as low as 5 µM, without affecting the gap junction communication and barrier function, even at concentrations of 20 µM. While CVB2-61 or CVB4-57 maintained a reduced dye uptake in Calu-3 cells, an enhancement of the dye uptake in response to stimulation of adenosine signaling was still observed after removal of the agents. The report shows that CVB2-61 and CVB4-57 reversible block Cx hemichannels. Deciphering the interaction mechanisms with Cx hemichannels could allow further development of phenolic compounds to target Cx hemichannels for a better and safer use in treatment of pathologies that involve Cx hemichannels.

Abstract Successful treatment against infectious agents depends on rapid and accurate detection of the causative organisms. Misdiagnosis can hamper such success while leading to improper advising of antibiotics. In Bangladesh, the majority of the diagnostic centers detect and identify pathogens through culture and biochemical test-based methods and suggest antibiotics based solely on the results of disk-diffusion methods. This pilot study tried to validate the identity of the isolates characterized by diagnostic facilities near Dhaka. One hundred and twenty pre-characterized clinical isolates were analyzed biochemically and genotypically. Random Amplification of Polymorphic DNA-PCR, rcsA, and phoA genes-based PCR, and Loop-Mediated Isothermal Amplification (LAMP)-based identification of Klebsiella pneumoniae and Escherichia coli, respectively, followed by 16S rRNA sequencing confirmed misidentification of some clinical pathogens of other genera as Klebsiella spp. and E. coli. According to the antibiotic susceptibility testing guidelines, antibiotic choice, sensitivity pattern, and breakpoint measurement are different for each group of organisms. The lack of adherence to proper standards results in misdiagnosis and may facilitate the development of antibiotic resistance. The pilot study observers misidentification of clinical pathogens identified by the diagnostic centers. Well-characterized rapid molecular techniques like LAMP are suggested in clinical diagnosis to avoid misdiagnosis and subsequently circumvent antibiotic resistance development.

Hepatitis B virus (HBV) is known to cause severe liver diseases such as acute or chronic hepatitis, liver cirrhosis and hepatocellular carcinoma. Chronic hepatitis B (CHB) infection is a major health problem with nearly 300 million individuals infected worldwide. Currently, nucleos(t)ide analogs (NAs) and interferon alpha are clinically approved treatments for HBV infection. NAs are potent antiviral agents that bind to HBV polymerase and block viral reverse transcription and replication. Besifovir dipivoxil maleate (BSV) is a newly developed NA against HBV in the form of acyclic nucleotide phosphonate that is available for oral administration similar to adefovir and tenofovir. Until now, resistance to BSV treatment has not been reported. In this study, we found a CHB patient who showed viral breakthrough after long-term treatment with BSV. The isolated HBV DNA from patient’s serum were cloned into the replication-competent HBV 1.2mer and the sequence of reverse transcriptase (RT) domain of HBV polymerase were analyzed. We also examined the drug susceptibility of generated clones in vitro. Several mutations were identified in HBV RT domain. A particular mutant harboring ten RT mutations showed resistance to BSV treatment in vitro. The ten mutations include rtV23I (I), rtH55R (R), rtY124H (H), rtD134E (E), rtN139K (K), rtL180M (M), rtM204V (V), rtQ267L (L), rtL269I (I) and rtL336M (M). To further identify the responsible mutations for BSV resistance, we performed in vitro drug susceptibility assay on several artificial clones. As a result, our study revealed that rtL180M (M) and rtM204V (V) mutations, already known as lamivudine-resistant mutations, confer resistance to BSV in the CHB patient.

This research aims to find out whether the synthetic 1, 2, 4-triazine and its derivatives have antifungal effects and can protect humans from infection with Candida albicans. Molecular docking and molecular dynamic simulation are widely used in modern drug design to target a We are interested in using molecular docking and molecular dynamics modelling to investigate the interaction between the derivatives of 1, 2, 4-triazine and the resulting lanosterol 14 - demethylase (CYP51) of Candida albicans The inhibition of Candida albicans CYP51 is the main goal of our research. The 1, 2, 4-triazine and its derivatives have been docked to the CYP51 enzyme, which is involved in Candida albicans Multidrug Drug Resistance (MDR). Autodock tools were used to identifying the binding affinities of molecules against the target proteins. Compared to conventional fluconazole, the molecular docking results indicated that each drug has a high binding affinity for CYP51 proteins and forms unbound interactions and hydrogen bonds with their active residues and surrounding allosteric residues. The docking contacts were made using a 10 ns MD simulation with nine molecules. RMSD, RMSF, hydrogen bonds, and the Rg all confirm these conclusions. In addition, these compounds were expected to have a favorable pharmacological profile and low toxicity. The compounds are being offered as scaffolds for the development of new antifungal drugs and as candidates for future in vitro testing.

Therapeutic resistance in pancreatic ductal adenocarcinoma (PDAC) can be attributed, in part, to a dense extracellular matrix containing excessive collagen deposition. Here, we describe a novel Salmonella typhimurium (ST) vector expressing the bacterial collagenase Streptomyces omiyaensis trypsin (SOT), a serine protease known to hydrolyze collagens I and IV, which are predominantly found in PDAC. Utilizing aggressive models of PDAC, we show that ST-SOT selectively degrades intratumoral collagen leading to enhancement of immune checkpoint blockade (ICB) therapy in tumor-bearing mice. Ultimately, we found that ST-SOT treatment significantly modifies the intratumoral immune landscape to generate a microenvironment more conducive to ICB.

One of the most used markers of cancer stem cells in several cancers, including colorectal cancer and breast cancer, is CD44. CD44 is a glycoprotein that traverses the cell membrane and binds to many ligands including hyaluronan resulting in activation of signaling cascades. Several reports have shown conflicting data on the expression of CD44 and that the expression depends on modes of investigations and subtypes of cancers. In addition, the correlation between CD44 expression and drug resistance, immune infiltration, EMT, metastasis and patients prognosis in several cancer types remains unclear. This study investigated CD44 expression in several cancers and explored its relationship with tumorigenesis using various publicly available databases, including The Cancer Genome Atlas, GEPIA, Oncomine, Genomics of Drug Sensitivity in Cancer and Tumor Immune Estimation Resource. Our analysis reveals that CD44 is differentially expressed in different cancers. CD44 expression is significantly associated with cancer patients’ survival in gastric, pancreatic and colorectal cancers. In addition, CD44 expression is closely linked with immune infiltration and immune suppressive features in pancreatic, colon adenocarcinoma and stomach cancer. High CD44 expression was significantly correlated with the expression of drug resistance-, EMT- and metastasis- linked genes. Tumors expressing high CD44 have higher mutation burden and afflict older patients than tumors expressing low CD44. Cell lines expressing high CD44 are more resistant to anti-cancer drugs compared to those expressing low CD44. Protein-protein interaction investigations and functional enrichment analysis showed that CD44 interacts with gene products related to cell-substrate adhesion, migration, platelet activation, and cellular response to stress. KEGG pathway analysis revealed that these genes play key roles in biological adhesion, cell component organization, locomotion, G-α-signaling and the response to stimulus. Overall, this investigation reveals that CD44 play significant roles in tumorigenesis, can be used as a prognostic biomarker in several cancers and can be therapeutically targeted in cancer therapy.

Grapefruit and lemon pectin obtained from the respective waste citrus peels via hydrodynamic cavitation in water only are powerful, broad-scope antimicrobial alternatives to antibiotics against Gram-negative and -positive pathogens. Dubbed IntegroPectin, these pectic polymers functionalized with citrus flavonoids and terpenes show superior antimicrobial activity when compared to commercial citrus pectin. Similarly to commercial pectin, lemon IntegroPectin determined ca. 3 log reduction of Staphylococcus aureus cells, while an enhanced activity of commercial citrus pectin was detected in the case of Pseudomonas aeruginosa cells with a minimal bactericidal concentration (MBC) of 15 mg mL-1. Although grapefruit and lemon IntegroPectin share equal MBC in the case of P. aeruginosa cells, grapefruit IntegroPectin shows boosted activity upon exposure of S. aureus cells with a 40 mg mL-1 biopolymer concentration being sufficient to achieve complete killing of the bacterial cells. Insight on the mechanism of action of these biocompatible antimicrobials and their effect on bacterial cells, at the morphological level, were obtained indirectly through Fourier Transform Infrared spectroscopy and directly through scanning electron microscopy. In the era of antimicrobial resistance, these results are of great societal and sanitary relevance as they open new avenues to develop innovative antimicrobials for the treatment of polymicrobial infections unlikely to develop drug resistance.

The work is devoted to the investigation of virus quasispecies evolution and diversification due to mutations, competition for host cells, and cross-reactive immune responses. The model consists of a nonlocal reaction-diffusion equation for the virus density depending on the genotype considered as a continuous variable and on time. This equation contains two integral terms corresponding to the nonlocal effects of virus interaction with host cells and with immune cells. In the model, a virus strain is represented by a localized solution concentrated around some given genotype. Emergence of new strains corresponds to a periodic wave propagating in the space of genotypes. The conditions of appearance of such waves and their dynamics are described.

In this study, the changes in mass, compressive strength and length were analyzed to investigate sulfate resistance according to ground granulated blast furnace slag (GGBFS) blending ratio and type of sulfate solution. All alkali activated mortars showed excellent sulfate resistance when immersed in sodium sulfate (Na₂SO₄) solution. However, when immersed in magnesium sulfate (MgSO₄) solution, different sulfate resistance results were obtained depending on the presence of GGBFS. Alkali activated GGBFS blended mortars showed a tendency to increase mass, increase length and decrease compressive strength when immersed in magnesium sulfate solution, but the alkali activated FA mortars did not show any significant difference depending on the types of sulfate solution. The deterioration of alkali activated GGBFS blended mortars in the immersion of magnesium sulfate solution was confirmed by the decomposition of C-S-H which is the reaction product by magnesium ion and the formation of gypsum (CaSO₄·2H₂O) and brucite (Mg(OH)₂).

Spin dependent quantum transport properties in twisted carbon nanotube and stretched carbon nanotube are calculated using density functional theory (DFT) and non-equilibrium green’s function (NEGF) formulation. Twisting and stretching have no effect on spin transport in CNTs at low bias voltages. However, at high bias voltages the effects are significant. Stretching restricts any spin-up current in antiparallel configuration (APC) which results in higher magneto resistance (MR). Twisting allows spin-up current almost equivalent to the pristine CNT case resulting in lower MR. High spin filtration is observed in PC and APC for pristine, stretched and twisted structures at all applied voltages. In APC, at low voltages spin filtration in stretched CNT is higher than in pristine and twisted ones with pristine giving higher spin filtration than twisted CNT.

During HVDC earth return operation systems, a high magnitude current will be injected into soil through earth electrode, the potential on the surface would change widely and produce unfavorable effects on the AC systems around. This paper presents an effective finite element method (FEM) coupling electric field with thermal field to evaluate the electrical field induced by the injected DC current. Firstly, owe to the characteristic of FEM, this method can consider arbitrary soil and earth electrode structure. Secondly, by setting the electrical and thermal parameters of soil as a function of temperature at the same time, the dynamic coupling process of electric field and thermal field is simulated accurately. Thirdly, to deal with the singular point in FEM subdivision and the huge computation in traditional three-dimensional FEM, the FEM coupling 2-D earth electrode with 3-D soil based on "shell" theory is introduced. Finally, based on the suggested method, the effect of abnormal resistance region (ARR) near DC earth electrode on electric field distribution is analyzed.

We conducted a retrospective analysis of the immunohistochemical (IHC) staining GRP94, an ER stress protein on large B-cell lymphoma (LBCL) cells, intracellular p53, and 15 factors involved in the metabolism of CHOP regimen :AKR1C3 (HO-metabolism), CYP3A4 (CHOP-metabolism) and HO efflux pumps (MDR1, MRP1). The study subjects were 42 patients with LBCL at our hospital. IHC staining using antibodies against the 17 factors. The odds ratios by logistic regression analysis using a dichotomous variable of CR, non-CR/relapse were statistically significant: for MDR1, MRP1, and AKR1C3. The overall survival (OS) after R-CHOP was compared by the log-rank test. The four groups showed that Very good (5-year OS, 100%) consisted of 4 patients showed negative IHC staining for both GRP94 and CYP3A4. Very poor (1-year OS, 0%), consisted of 3 patients who showed positive results of IHC for both GRP94 and CYP3A4. The remaining 35 patients comprised two subgroups: Good (5-year OS 60-80%.): 15 patients who showed negative staining for both MDR1 and AKR1C3, Poor: 5-year OS, 10-20%) :20 patients who showed positive staining for either MDR, AKR1C3,,MRP1 or p53. The Histological Prognostic Index (HPI) (The four groups: Very poor, Poor, Good, and Very pood) is a breakthrough method for stratifying patients based on factors involved in the development of treatment resistance.

The sweetpotato whitefly, Bemisia tabaci MEAM1, is a pest known to significantly impact tomato development and yields through direct damage and virus transmission. To manage this pest, the current study compared the effectiveness of various insecticide rotations. Field trials included rotations involving synthetic insecticides, biochemicals, and microbial agents, applied according to their labeled highest concentrations. Results indicated that while standard synthetic insecticides consistently reduced whitefly egg and nymph counts significantly, microbial biopesticide rotations also achieved reductions, although less consistently. This study demonstrated that while traditional chemical treatments remain highly effective, integrating microbial biopesticides containing Beauveria bassiana and Cordyceps javanica present a viable alternative that could mitigate resistance development and reduce environmental impact. The findings suggest the potential for optimizing integrated pest management (IPM) and Insecticide Resistance Management (IRM) strategies by incorporating a variety of modes of action to sustainably manage B. tabaci MEAM1 populations in agricultural settings.

Insulin resistance/hyperinsulinemia as an independent risk factor for the development and worsening of HFpEF. Serafino Fazio MD¹, Valentina Mercurio MD, PhD2, Valeria Fazio MD3, Antonio Ruvolo MD⁴, Flora Affuso MD, PhD⁵. Authors’ Affiliation: ¹ Department of Internal Medicine (retired Professor). Federico II University, Via Sergio Pansini 5. 80135 Naples, Italy. 2 Department of Translational Medical Sciences. Federico II University. Via Sergio Pasini 5. 80135 Naples, Italy. ³ UOC Medicina Interna, Azienda Ospedaliera di Caserta, 81100 Caserta, Italy, ⁴ UOC Cardiologia AORN dei colli PO CTO, Viale Colli Aminei 21, 80100 Naples, Italy. ⁵ Independent researcher, Viale Raffaello 74, 80129 Naples, Italy. Abstract Heart failure (HF) has become a subject of continuous interest since it has been declared new pandemic in 1997 because of the exponential increase in hospitalizations for HF in the latest years. HF is the final state to which all heart diseases of different etiologies lead if not adequately treated, therefore it is highly prevalent worldwide, with a progressive increase with age, reaching a prevalence of 10% in subjects over the age of 65 years. It should also be underlined that lately, while the prevalence of HF with left ventricular reduced ejection fraction (HFrEF) is slowly decreasing, the incidence of HF with left ventricular preserved ejection fraction (HFpEF) is progressively increasing. In deed, among patients consecutively hospitalized for HF between 1987 and 2001 in a study from the Mayo Clinic Hospitals in Olmsted County, Minnesota, prevalence of HFpEF increased from 38% to 54%. HFpEF is typically characterized by concentric remodeling of the left ventricle (LV) with impaired diastolic function and increased filling pressures. Over the years, also the prevalence of insulin resistance/hyperinsulinemia in the general adult population has progressively increased, primarily due to lifestyle changes, particularly in developed and developing countries, with a range that globally ranges between 15.5% and 46.5%. Notably, insulin resistance (IR)/hyperinsulinemia (Hyperins) is present in up to 60% of patients with HF and is significantly higher in subjects with HfpEF. In the scientific literature it has been well highlighted that the increased circulating levels of insulin are associated with conditions of insulin resistance are responsible for progressive cardiovascular alterations over the years. In the setting of HFpEF, insulin stimulates the concentric remodeling of the left ventricle with associated diastolic dysfunction, which, coincidentally. Unfortunately, IR/Hyperins, despite being a well-known cardiovascular risk factor, is still not screened in the general population and is not treated as promptly as it should be, and this could at least in part concur in the progressive increase in prevalence of HFpEF in the general adult population. The aim of this manuscript was to review scientific literature that support a pathophysiologic connection between IR/Hyperins and HFpEF to stimulate the scientific community towards the identification of hyperinsulinemia associated with insulin resistance as an independent cardiovascular risk factor in development and worsening of HF, believing that its adequate screening in the general population and appropriate treatment could reduce the prevalence of HFpEF and improve its progression.

The normal ageing process significantly affects resistance arteries, leading to various biological and physiological consequences. Systolic hypertension is a common occurrence in ageing individuals, accompanied by increased large artery stiffening, heightened pulsatility, small artery remodeling, and damage to critical microvascular structures. Starting from young adulthood, there is a progressive elevation in mean arterial pressure, supported by clinical and epidemiological evidence as well as findings from animal models. The myogenic response, a protective mechanism for the microcirculation, may face disruptions during ageing. Dysregulation of calcium entry channels (T-type, L-type, TRP channels), dysfunction in intracellular calcium storage and extrusion mechanisms, altered expression of potassium channels, and a change in smooth muscle calcium sensitization may contribute to age-related dysregulation of myogenic tone. Flow-mediated vasodilatation, a hallmark of endothelial function, is compromised in ageing. This result of endothelial dysfunction is related to oxidative stress, lower nitric oxide bioavailability and a low-grade inflammatory response, further exacerbating vascular dysfunction. Resistance artery remodeling in ageing emerges as a hypertrophic response of the vessel wall, often seen in conjunction with outward remodeling (in normotension), but can also present as inward hypertrophic remodeling (in hypertension). The remodeling process involves oxidative stress, inflammation, reorganization of extracellular matrix fiber proteins and actin cytoskeletal components. Reactive oxygen species (ROS) signaling and chronic low-grade inflammation, often referred to as "inflammaging”, play substantial roles in age-related vascular dysfunction. Due to its role in regulation of vascular tone as well as structural proteins, the RhoA/Rho-kinase pathway becomes a new target in age-related vascular dysfunction and associated diseases. Understanding the intricate interplay of these factors is crucial for developing targeted interventions to mitigate the consequences of ageing on resistance arteries and enhance overall vascular health.

Artifact metrics is a technology for authenticating artifacts based on their unique characteristics. The artifact-metric system offers "clone resistance," i.e., it makes it highly improbable to create another object exhibiting the same measured values as a genuine artifact. However, determined adversaries may still attempt to create imitations or clones with close physical characteristics to those of registered products, even if they cannot perfectly replicate the genuine product. Such clones serve to deceive users into believing they are genuine rather than counterfeits. Thus, in this study, we consider a scenario in which we measure raster-scanning-generated clones via a non-raster scanning method. Further, we employ image processing techniques to generate image data representing the clones and theoretically assess the filtering effects on these images. Our findings reveal that applying filters to specific frequency components in the spatial frequency domain can effectively highlight differences between raster-scanning-created clones and the corresponding genuine artifacts. Thus, we demonstrate directional emphasis filtering in artifact metrics as an effective approach for rejecting raster-scanning-created clones.

The chemical reaction of ion-adsorption type rare earth during in-situ leaching process is accompanied by ion migration and charge movement, making the leaching process electrochemical in nature. The chemical reaction rate plays an important role in the leaching rate of rare earth elements. In this work, electrochemical impedance spectroscopy (EIS) was used to reveal characteristics of electrical resistance alteration and leaching rate of rare earth elements during in-situ leaching. The equivalent circuit model of the leaching process was established, and two critical parameters of solution resistance Rs and charge transfer resistance Rt were analyzed to reflect the electrochemical characteristics. According to the characteristics of electrical resistance alteration, the leaching process was divided into four stages: wetting, reaction, equilibrium, and top water stage. The resistance parameters Rs and Rt decreased first and then increased during the leaching process. The maximum value of Rs was 1330Ω∙cm2 at the end of the top water stage, and the minimum value was 135Ω∙cm2 at the beginning of the equilibrium stage. The maximum value of Rt was 8310Ω∙cm2 at the beginning of the leaching stage, and the minimum value was 21Ω∙cm2 at the end of the reaction stage. Rs and Rt were negatively correlated with the pore size and chemical reaction rate during leaching. With increasing of pore size and reaction rate , the resistance parameter decrease. This study provide a new idea for intelligent monitoring of rare earth ore.

This research examines the fire resistance of geopolymer composites (GCs), formulated using alka-li-activated metakaolin and aluminum powder. The production method involves spray-coating carbon steel plates with fresh GCs, followed by a 28-day curing period at room temperature. Sub-sequently, fire performance and aging tests are conducted to evaluate fire resistance. The study investigates GC properties, including apparent density, bending strength, compression strength, thermal conductivity, porosity, and production cost. Morphological changes before and after fire and aging tests are analyzed using scanning electron microscopy (SEM). Results demonstrate GC foams' outstanding thermal insulation, providing up to 75 minutes of fire resistance with a 6 mm coating, reducing temperatures by 300 °C compared to uncoated steel. GCs exhibit a density of 670 kg/m³, thermal conductivity of 0.166 W/m·K, 68% porosity, and cost efficiency at 250 dollars per cubic meter. This study underscores the potential of foamed geopolymer coatings for effective and economical surface protection.

The expression of the Fasciola hepatica Carboxylesterase type B (CestB) gene is induced in response to the anthelmintic triclabendazole (TCBZ), resulting in a significant increase in enzymatic specific activity. Furthermore, the amino acid sequence of CestB exhibits variations that could lead to substantial amino acid substitutions at the ligand-binding site. These substitutions have the potential to affect the interaction between the ligand and the protein, as well as the catalytic properties of the enzyme. The objective of this study was to identify new CestB polymorphisms in TCBZ-resistant parasites using 3D modeling against the metabolically oxidized form of the anthelmintic TCBZSOX. Our aim was to observe the formation of TCBZSOX-specific binding pockets that could potentially explain the resistance to anthelmintic agents. We identified a CestB polymorphism in a TCBZ-resistant strain of parasites exhibiting three radical amino acid substitutions at positions 147, 215, and 243, resulting in the formation of a TCBZSOX-affinity pocket capable of binding the anthelmintic drug. Additionally, our 3D modeling analysis revealed that these amino acid substitutions also had an impact on the configuration of the CestB catalytic site, affecting the enzyme's interaction with chromogenic carboxylic ester substrates and altering its catalytic properties; however, the identified TCBZSOX-binding pocket was located far from the enzyme's catalytic site, making the enzymatic hydrolysis of TCBZSOX theoretically impossible. Nonetheless, the increased affinity for the anthelmintic may explain a drug-sequestration type of anthelmintic resistance and lays the foundation for the development of a molecular diagnostic tool for identifying anthelmintic resistance in F. hepatica.

Polycystic ovary syndrome (PCOS) is a common endocrinopathy of reproductive-aged women characterized by hyperandrogenism, oligo-anovulation and insulin resistance closely linked with preferential abdominal fat accumulation. As an ancestral primate trait, PCOS was likely further selected in humans when scarcity of food in hunter-gatherers of the late Pleistocene additionally programmed for enhanced fat storage to meet the metabolic demands of reproduction in later life. As an evolutional model for PCOS, healthy normal-weight women with hyperandrogenic PCOS have subcutaneous (SC) abdominal adipose stem cells that favor fat storage through exaggerated lipid accumulation during development to adipocytes in vitro. In turn, fat storage is counterbalanced by reduced insulin sensitivity and preferential accumulation of highly-lipolytic intra-abdominal fat in vivo. This metabolic adaptation in PCOS balances energy storage with glucose availability and fatty acid oxidation for optimal energy use during reproduction; its accompanying oligo-anovulation allowed PCOS women from antiquity sufficient time and strength for childrearing of fewer offspring with a greater likelihood of childhood survival. Heritable PCOS characteristics are now affected by today’s contemporary environment through epigenetic events that predispose to lipotoxicity with excess weight gain and pregnancy complications, calling for an emphasis on preventive healthcare to optimize the long-term, endocrine-metabolic health of PCOS women in today’s obesogenic environment.

This study explores the intriguing relationship between personality traits, self-rated fitness (SRF), and physical activity (PA) variables among German university students (N = 4,244), and sheds light on the impact of personality on adherence to PA guidelines. Employing an online cross-sectional study, the short-form of the Big Five Inventory-2 assessed five domains of personality traits (Extraversion, Negative Emotionality, Agreeableness, Conscientiousness, and Open-Mindedness). PA, including sitting time, was assessed using the International Physical Activity Questionnaire (short-form). SRF and muscle-strengthening activities (MSA) were assessed with one item each. Multiple linear and logistic regression analyses examined associations of individual personality trait domains and all domains combined with SFR, PA variables, and adherence to PA guidelines, controlling for sociodemographic, behavioral, and (mental) health covariates. Most reliably, Extraversion and Conscientiousness revealed positive associations with PA variables, while Negative Emotionality yielded inverse relationships with PA variables. For instance, each unit increase in Extraversion corresponded to additional 17 minutes weekly MSA. Contrary, daily sitting time was unrelated to personality. Of note, high Open-Mindedness was associated with lower odds for adhering to current PA guidelines. The findings have implications for developing targeted interventions that promote a physically active lifestyle and support students' well-being and academic success.

Durability of concrete requires a dense microstructure which can be achieved by using self-compacting concrete (SCC). Both calcined clay (CC) and rice husk ash (RHA) are promising supplementary cementitious materials (SCMs) that can partially replace cement, but their use in SCC is critical due to their higher water demand and specific surface area (SSA) compared to cement. Empirical method of SCC design was adopted considering the physical properties of both CC and RHA. The influence of partially substituting cement at 20 vol-% with binary and ternary blends of CC and RHA were investigated. The fresh properties of SCC were investigated using a variety of tests. The time dependent workability was monitored by plunger method and flow resistance determined based on the rheological measurements of SCC. The evolution of the hydrate phases of the binder in SCC was determined by thermogravimetric analysis, while the durability was evaluated by rapid chloride migration test. Cement partial replacement with 20 vol-% CC has no significant effect on SCC fresh, time dependent, compressive strength and durability properties. 20 vol-% RHA on the other hand requires higher dosage of SP to achieve self-compactability and increased the viscosity of SCC. Its workability retention is only up to 30 min after mixing and exhibited higher flow resistance. It consumes more CH and improves compressive strength and chloride resistance of SCC. The ternary blending with CC and RHA yielded better fresh SCC properties compared to the binary blend with RHA, while an improved chloride penetration resistance could be achieved compared to binary CC blend.

Shear thickening fluids (STF) are a class of fluids whose viscosity significantly rises under external loads. The research on these fluids has been advancing in recent years regarding prospective practical applications, including developing impact-absorbing composites. Following the green agendas governments and legislators advocate, this study investigates the combination of STF and other sustainable materials. Cork is a naturally occurring cellular material with a negative carbon footprint and superior energy absorption properties. With varying concentrations of STF material, cork agglomerates were formed. Notably, the analysed blends are homogeneous, contrasting with previous literary works. A series of experiments were conducted in quasi-static and dynamic conditions to determine the various mechanical responses. STF appears to influence the mechanical behaviour of cork agglomerates by providing softer deceleration rates and dispersing more energy through disaggregation mechanisms.

Polycystic ovary syndrome (PCOS) is increasingly being characterized as an evolutionary mismatch disorder that presents with a complex mixture of metabolic and endocrine symptoms. The Evolutionary Model proposes that PCOS arises from a collection of inherited polymorphisms that have been consistently demonstrated in a variety of ethnic groups and races. In-utero developmental programming of susceptible genomic variants are thought to predispose the offspring to develop PCOS. Postnatal exposure to lifestyle and environmental risk factors results in epigenetic activation of developmentally programmed genes and disturbance of the hallmarks of health. The resulting pathophysiological changes represent the consequences of poor-quality diet, sedentary behaviour, endocrine disrupting chemicals, stress, circadian disruption, and other lifestyle factors. Emerging evidence suggests that lifestyle-induced gastrointestinal dysbiosis plays a central role in the pathogenesis of PCOS. Lifestyle and environmental exposures initiate changes that result in disturbance of the gastrointestinal microbiome (dysbiosis), immune dysregulation (chronic inflammation), altered metabolism (insulin resistance), endocrine and reproductive imbalance (hyperandrogenism), and central nervous system dysfunction (neuroendocrine, autonomic nervous system). PCOS can be a progressive metabolic condition that leads to obesity, gestational diabetes, type 2 diabetes, metabolic-associated fatty liver disease, metabolic syndrome, cardiovascular disease, and cancer. This review explores the mechanisms that underpin the evolutionary mismatch between ancient survival pathways and contemporary lifestyle factors involved in the pathogenesis and pathophysiology of PCOS.

Ventricina del Vastese is a traditional dry fermented sausage from Central Italy not yet charac-terized for occurrence, identity and safety of coagulase negative staphylococci (CNS), a bacterial group technologically important for this kind of products. Therefore, in this study, 98 CNS isolates from four manufacturers were differentiated by Repetitive element palindromic PCR (Rep-PCR) and identified by 16S rRNA gene sequencing. These were examined for genes encoding biogenic amine (BA) production, resistance to aminoglycosides, β-lactams and tetracyclines and staphylococcal enterotoxins (SEs). Staphylococcus succinus (55%) predominated, followed by S. xylosus (30%), S. epidermidis (7.4%), S. equorum (3.1%), S. saprophyticus (3.1%) and S. warneri (1%). One S. succinus subsp. casei isolate was slightly β-hemolytic. SEs and the histidine decarboxylase gene hdcA were not detected, while the tyrosine decarboxylase gene tdcA was detected in four S. xylosus isolates. A blaZ beta-lactamase gene and tetracycline resistance genes tetK (six isolates) and tetA (one isolate also bearing tetK) were found, respectively. However, fewer hazardous and AR traits compared to CNS examined in other studies were found, as a probable consequence of using meat from animals reared in conditions that allow to minimize pathogen circulation and antibiotic use. Therefore, appropriate production conditions can reduce these threats.

BackgroundIt is unclear what underpins the large global variations in the prevalence of fluoroquinolone resistance in gram-negative bacteria. We tested the hypothesis that different intensities in the use of quinolones for food-animals plays a role. MethodsWe used Spearman’s correlation to assess if the country-level prevalence of fluoroquinolone resistance in human infections with Acinetobacter baumannii, Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa was correlated with the use of quinolones for food producing animals. Linear regression was used to assess the relative contributions of country-level quinolone consumption for food-animals and humans on fluoroquinolone resistance in these 4 species. ResultsThe prevalence of fluoroquinolone resistance in each species was positively associated with quinolone use for food-producing animals (E. coli [ρ=0.55; P<0.001], K. pneumoniae [ρ=0.58; P<0.001]; A. baumanii [ρ=0.54; P=0.004]; P. aeruginosa [ρ=0.48; P=0.008]). Linear regression revealed that both quinolone consumption in humans and food animals were independently associated with fluoroquinolone resistance in E. coli and A. baumanii. ConclusionsReducing quinolone use in food-producing animals may help retard the spread of fluoroquinolone resistance in various gram negative bacterial species.

We calculate the hydrodynamic forces exerted on an oscillating circular cylinder when it moves translationally perpendicular to its axis in the infinitely deep water covered by compressed ice. The cylinder can oscillate both horizontally and vertically. In the linear approximation, we find a solution for the steady wave motion generated by the cylinder within the hydrodynamic set of equations for the incompressible ideal fluid. We show that depending on the rate of ice compression, the normal and anomalous dispersion can occur in the system. In the latter case, the group velocity can be opposite to the phase velocity in a certain range of wavenumbers. We investigate the dependences of the hydrodynamic loads (added mass, damping coefficients, wave resistance, and lift force) exerting on the cylinder on the translational velocity and frequency of oscillation. It is shown that there is a possibility of the appearance of negative values for the damping coefficients at the relatively big cylinder velocity; then the wave resistance decreases with increasing of cylinder velocity. The theoretical results are underpinned by the numerical calculations for the real parameters of ice and cylinder motion.

The annual construction and demolition waste (CDW) generated from EU construction sector was 850 million tons, which represented 31% of the total waste generation and about 28% of CDW was ceramics (bricks and tiles). In this study, the feasibility of using CDW brick powder as the precursor of alkali activated mortar (AAM) and extruded polystyrene (XPS) as the lightweight aggregates to form lightweight brick powder AAM (LW-BP-AAM) for non-structural applications was investigated. The thermal conductivity of LP-BPAAM was 0.112 W/m·K with density of about 1,135 kg/m³ which was lower than the counterparts with similar density in literature. The acid resistance of LW-BP-AAM is comparable to conventional fly ash based AAM and superior than ordinary Portland cement. From the scanning electron microscopy with energy dispersive X-ray spectroscopy, there was no severe damage on the surface of LW-BP-AAM but aluminate was removed from the matrix which was further verified in Fourier transform infrared spectroscopy. The mass and strength loss of LP-BP-AAM was 1.5% and 33%, respectively. Although the compressive strength of the LP-BP-AAM was low (about 1.8 MPa), it can be improved by optimising the particle size of the XPS aggregates.

Mucus plugging of the respiratory tract occurs in airway diseases, including asthma, chronic obstructive pulmonary disease and cystic fibrosis. It can cause blockage of airways, leading to breathlessness and lung failure. Here, we demonstrate the effect of BromAc® in dissolving mucus plugs in an novel ex-vivo ovine obstructive lung model using a ventilatory setup. Mucus simulant was filled into the trachea of freshly slaughtered ovine lungs and ventilated via an endotracheal tube (ETT) using Continuous Mandatory Ventilation. Predetermined single or repeated doses of Bromelain, Acetylcysteine (Ac), BromAc® and saline control were administered via an Aerogen® vibrating nebuliser and ventilated for 30 or 60 minutes. Ventilatory recording of resistance, compliance, tidal volume was conducted and rheology pre and post treatment were measured. A significant decline in airway resistance (p&lt;0.0001) compared to saline control was observed when treated with Bromelain, Ac and BromAc®, with the latter showing a stronger mucolytic effect than single agents. The decline in resistance was also effective in shorter timepoint (p&lt;0.05) at lower doses of the drugs. Changes in compliance, peak pressure and tidal volume was not observed post-administration of the drugs. Rheology measurements revealed that BromAc®™ significantly reduced the viscosity of the mucin at the end of 30-minute and 60-minute time points (p&lt;0.001) compared to the saline control. BromAc® showed complete dissolution of the respiratory mucus simulant and improved ventilatory airflow parameters in the ex-vivo ovine model.

The impact of systemic vascular resistance (SVR) in hypertrophic (HCM) and amyloid cardio-myopathies has been seldom investigated. We studied pressure-strain loop derived myocardial work (MW) indices and SVR in patients with either sarcomere HCM or wild type transthyretin cardiac amyloidosis (ATTR), presented with heart failure and preserved left ventricular ejection fraction (HFpEF) at the outpatient cardiology units at Messina and Catania University Hospitals (Italy). Patients were in sinus rhythm and needed to have good transthoracic ultrasound imaging quality to undergo transthoracic strain-echocardiography. Other than conventional parameters, SVR and GWI (global work index) were measured. Based on cross-tabulation (a way to assess the ventricular-arterial coupling), the patients were then classified in 4 classes according to the cut-off values suggested by previous studies of 1,440 dyne/s/cm-5 for SVR (Stefadouros et al., 1973) and 1576 mm Hg% for GWI (Olsen et al., 2022). Sixty patients, 30 in each group, aged 61±16 years, 78% males, were studied. HCM were younger than ATTR patients and in a better clinical status (23% HCM vs 77% ATTR were NYHA class 3, p<0.001). Overall, 51 patients (85%) showed high SVR, of whom 21 were HCM (70%) and 30 ATTR (100%) (p<0.005). Both, SVR and GWI were impaired (the poorest class C) in 43% HCM patients (with greater left ventricular concentric hypertrophy) vs 93% of ATTR patients (in advanced NYHA class) (p<0.001). In conclusion, assessing SVR and GWI in HFpEF patients with HCM or ATTR can help clinicians to interpret the pathophysiological and clinical features of such complex diseases.

Computational rhinology is a specialized branch of biomechanics leveraging engineering techniques for mathematical modelling and simulation to complement the medical field of rhinology. Computational rhinology has already contributed significantly to advancing our understanding of the nasal function, including airflow patterns, mucosal cooling, particle deposition, and drug delivery, and is foreseen as a crucial element in e.g. the development of virtual surgery as a clinical, patient-specific decision support tool. The current paper delves into the field of computational rhinology from a nasal airflow perspective, highlighting the use of computational fluid dynamics to enhance diagnostics and treatment of breathing disorders. The paper consists of three distinct parts – an introduction to and review of the field of computational rhinology, a review of published literature on in vitro and in silico studies of nasal airflow, and the presentation and analysis of previously unpublished high fidelity CFD simulation data of in silico rhinomanometry. While the two first parts of the paper summarize the current status and challenges in the application of computational tools in rhinology, the last part addresses the gross disagreement commonly observed when comparing in silico and in vivo rhinomanometry results. It is concluded that this discrepancy cannot readily be explained by CFD model deficiencies caused by poor choice of turbulence model, insufficient spatial or temporal resolution, or neglecting transient effects. Hence, alternative explanations such as nasal cavity compliance or drag effects due to nasal hair should be investigated.

Long span cable-stayed bridge is the main bridge type with a span of more than 400 meters. It is generally designed as a double tower long-span structure with good spanning capacity and economic performance. Wind resistance safety performance is the main index to control the long-span cable-stayed bridge structure. During the operation of long-span cable-stayed bridge structure, because the service life of the cable is far less than the design life of the structure, the wind resistance performance of the structure will inevitably deteriorate significantly, which will seriously affect the structural service performance of symmetric cable-stayed bridge. Based on symmetric reliability theory, this paper takes flutter and static wind stability of long-span cable-stayed bridge structure as the main design control index, uses positive reliability theory to calculate the reliability index of symmetric cable-stayed bridge structure, uses inverse reliability theory to calculate the safety factor of symmetric cable-stayed bridge structure, and evaluates the wind resistant time-varying performance of long-span cable-stayed bridge structure by comprehensively considering the reliability index and safety factor. Taking a practical project of a long-span cable-stayed bridge as a specific case, the wind resistant time-varying reliability of the bridge during its operation for more than 30 years is analyzed, and the parameter sensitivity is analyzed. The results show that the wind resistance performance of the cable-stayed bridge structure is obviously affected by the cable, and the degradation of the cable performance will have an important impact on the wind resistance time-varying performance of the structure, especially the critical wind speed of the structure has obvious time-varying characteristics. The safety factor and reliability index can objectively evaluate the wind resistance time-varying performance of the long-span cable-stayed bridge structure.

In the last decade, an increasing awareness was directed to the role of Vitamin D in non-skeletal and preventive roles for chronic diseases. Vitamin D is a key hormone involved in the regulation of calcium/phosphorous balance and it has been implicated in the pathogenesis of inflammation, insulin resistance and obesity. Cholecalciferol (Vitamin D3) and Ergocalciferol (Vitamin D2) are the main form of vitamin D: the active form (1,25-dihydroxyvitamin D) is the result of two hydroxylations that take place in liver, kidney, pancreas and immune cells. Some anti-inflammatory cytokines are produced at higher levels by vitamin D, while some pro-inflammatory cytokines are released at lower levels. Toll-Like Receptor (TLR) expression is increased and a pro-inflammatory state is also linked to low levels of vitamin D. Regardless of how it affects inflammation, various pathways suggest that vitamin D directly improves insulin sensitivity and secretion. The level of vitamin D in the body may change the ratio of pro- to anti-inflammatory cytokines, which would impact insulin action, lipid metabolism, and the development and function of adipose tissue. Many studies have demonstrated an inverse relationship between vitamin D concentrations and pro-inflammatory markers, insulin resistance, glucose intolerance, metabolic syndrome, obesity and cardiovascular disease. It's interesting to note that several long-term studies also revealed an inverse correlation between vitamin D level and the occurrence of diabetes mellitus. Vitamin D supplementation in people has controversial effects, in fact while some studies demonstrated improvements in insulin sensitivity, glucose and lipid metabolism, others revealed no significant effect on glycemic control and inflammation. The aim of this review is to provide insight into the molecular basis of the relationship between vitamin D, insulin-resistance, metabolic syndrome, type 1 and 2 diabetes, gestational diabetes, and cardiovascular diseases.

Conjugative transposons in Gram-negative bacteria have a significant role in the dissemination of antibiotic-resistance-conferring genes between bacteria. This study aims to genomically characterize plasmids and conjugative transposons carrying integrons in clinical isolates of Klebsiella pneumoniae. Genetic composition of conjugative transposons and phenotypic assessment of 50 multidrug-resistant K. pneumoniae isolates from Tertiary-care Hospital (SQUH), Muscat, Oman was investigated. Horizontal transferability was investigated by filter- mating conjugation experiments. Whole genome sequencing (WGS) was performed to determine the sequence type (ST), acquired resistome and plasmidome of integron-carrying strains. Class 1 integron was detected in 96% of isolates and among integron-positive isolates, 18 stains contained variable regions. Horizontal transferability by conjugation confirmed the successful transfer of integrons between cells and WGS confirmed their presence in conjugative plasmids. Dihydrofolate reductase (dfrA14) was the most prevalent (34.8%) gene cassettes in class 1 integrons. MLST analysis detected predominantly ST-231 and ST-395. BlaOXA-232 and blaCTX-M-15 were the most frequently detected carbapenems and beta-lactamases in sequenced isolates. This study highlighted the high transmissibility of MDR-conferring conjugative plasmids in clinical isolates of K. pneumoniae. Therefore, the wise use of antibiotics and the adherence to effective infection control measures are necessary to limit further dissemination of multidrug-resistant organisms.

Diabetes mellitus is one of the most common metabolic diseases worldwide, and its long-term complications include neuropathy, referring both to the peripheral and to the central nervous system. Detrimental effects of dysglycemia, especially hyperglycemia, on the structure and function of blood-brain barrier (BBB) seem to be a significant backgrounds of diabetic neuropathy pertaining to the central nervous system (CNS). Effects of hyperglycemia, including excessive glucose influx to insulin independent cells, may induce oxidative stress and secondary innate immunity dependent inflammatory response which can damage cells within the CNS, thus promoting neurodegeneration and dementia. Advanced glycation end products (AGE) may exert similar, pro-inflammatory effects through activating receptors for advanced glycation end products (RAGE), as well as some pattern-recognition receptors (PRR). Moreover, long-term hyperglycemia can promote brain insulin resistance, which may in turn promote Aβ aggregate accumulation and tau hyperphosphorylation. This review is focused on a detailed analysis of the effects mentioned above towards the CNS, with special regard to mechanisms taking part in the pathogenesis of central long-term complications of diabetes mellitus initiated by the loss of BBB integrity.

Epidemics of arboviruses in general, and dengue fever, in particular, are an increasing threat in areas where Aedes (Ae.) aegypti is present. The effectiveness of chemical control of Ae. aegypti is threatened by the increasing frequency of insecticide resistance. The aim of this study was to determine the susceptibility status of Ae. aegypti to public health insecticides and assess the underlying mechanisms driving insecticide resistance. Ae. aegypti eggs were collected in two study sites in the vicinity of houses for two weeks using Gravid Aedes Traps (GATs). After rearing mosquitoes to adulthood, female Ae. aegypti were exposed to the diagnostic doses of permethrin, deltamethrin and bendiocarb, using Centers for Disease Control and Prevention (CDC) bottle bioassays. Unexposed, un-engorged female Ae. aegypti were tested individually for mixed-function oxidase (MFO), glutathione-S-transferase (GST) and esterase activity. Finally, allele-specific PCR (AS-PCR) was used to detect kdr mutations (F1534C, S989P and V1016G) in the voltage-gated sodium channel gene in insecticide-exposed Ae. aegypti. Most traps were oviposition positive; 93.2% and 97% of traps contained Ae. aegypti eggs in the 10ème arrondissement of Cotonou and in Godomey-Togoudo, respectively. Insecticide bioassays assays detected resistance to permethrin and deltamethrin in both study sites and complete susceptibility to bendiocarb. By comparison to the insecticide-susceptibility Rockefeller strain, field Ae. aegypti populations had significantly higher levels of GSTs and significantly lower levels of  and  esterases; there was no significant difference between levels of MFOs. AS-PCR genotyping revealed the presence of the three kdr mutations (F1534C, S989P and V1016G) at high frequencies; 80.9% (228/282) of Ae. aegypti tested had at least one mutation, while the simultaneous presence of all three kdr mutations was identified in 13 resistant individuals. Study findings demonstrated phenotypic pyrethroid resistance, the overexpression of key detoxification enzymes and the presence of several kdr mutations in Ae. aegypti populations, emphasizing the urgent need to implement vector control strategies, targeting arbovirus vector species in Benin.

Background: Monitoring of antibiotic prescription practices in hospitals is essential to assess and facilitate appropriate use. This is relevant to halt the progression of antimicrobial resistance. Methods: Assessment of antibiotic prescribing patterns and completeness of antibiotic prescriptions among out-patients in 2021 was conducted at the University Hospital of Kwame Nkrumah University of Science and Technology in the Ashanti region of Ghana. We reviewed electronic medical records (EMR) of 49,660 patients who had 110,280 encounters in the year. Results: The patient encounters yielded 350,149 prescriptions. Every month, 33-36% of patient encounters resulted in antibiotic prescription, higher than the World Health Organization’s (WHO) recommended optimum of 27%. Almost half of the antibiotics prescribed belonged to WHO’s Watch group. Amoxicillin-clavulanic acid (50%), azithromycin (29%), ciprofloxacin (28%), metronidazole (21%), and cefuroxime (20%) were the most prescribed antibiotics. Antibiotic prescribing parameters (indication, name of drug, duration, dose, route and frequency) were documented in almost all prescriptions. Conclusions: Extending antimicrobial stewardship to the out-patient settings by developing standard treatment guidelines, an out-patient specific drug formulary and antibiograms can promote rational antibiotic use at the hospital. The EMR system of the hospital is a valuable tool for monitoring prescriptions that can be leveraged for future audits.

It is unclear how important it is to reduce fluoroquinolone consumption in the general population to prevent the spread of fluoroquinolone resistance in Neisseria gonorrhoeae (bystander selection). Methods We assessed bystander selection by using Spearman’s correlation to assess if the country-level prevalence of fluoroquinolone resistance in N. gonorrhoeae was correlated with the prevalence of fluoroquinolone resistance in four other gram-negative species - Acinetobacter baumannii, Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa. Results Fluoroquinolone resistance in N. gonorrhoeae was positively associated with homologous resistance in all 4 species - A. baumanii. (ρ=0.61, P=0.0003, E. coli (ρ=0.67, P<0.0001), K. pneumoniae (ρ=0.52, P=0.0004) and P. aeruginosa (ρ=0.40, P=0.0206). Positive associations were also found between the national prevalence of fluoroquinolone resistance and fluoroquinolone consumption in the general population in the preceding year for 4 of the 5 species. Conclusions Gonococcal fluoroquinolone resistance can be productively viewed as being part of a syndemic of fluoroquinolone resistance. Strengthening antimicrobial stewardship programs may help retard the spread of fluoroquinolone resistance in N. gonorrhoeae.

Asians are known to more likely than Westerners develop fatty liver and lifestyle-related diseases despite their weight. However, the relationship between fat accumulation and lifestyle-related diseases in non-obese Asians is unknown. Therefore, this study aimed to analyze visceral fat and hepatic fat in participants with a normal body mass index (BMI) and examine their characteristics during a medical checkup. This cross-sectional study was conducted on 663 of 1,142 patients who underwent abdominal ultrasonography and who had an alcohol intake (converted to ethanol) of <30 g/day for males and <20 g/day for females and a BMI of <25 kg/m2 during a health checkup. Participants were classified into four groups: group A, visceral fat accumulation (VFA) (−) and fatty liver (FL) (−) (n = 549); group B, VFA (+) and FL(−) (n = 32); group C, VFA (−) and FL (+) (n = 58); and group D, VFA (+) and FL (+) (n = 24). The frequencies of lifestyle-related disease complications, liver function tests, and liver fibrosis were evaluated among the four groups. Compared with group A (control), groups B, C, and D had higher number of males; BMI; abdominal circumference, ALT, AST, γ-GTP, triglyceride, uric acid, fasting blood sugar levels; and incidence of hyperlipidemia. Groups C and D had higher ALT, HbA1c, cholinesterase, and triglyceride levels; FIB4 index; and number of patients with diabetes mellitus (DM) than groups A and B; however, there was no difference between groups A and B. FL is a risk factor of DM and liver fibrosis in non-obese Japanese individuals; however, VFA only is not a risk factor of DM and liver fibrosis.

Imatinib became the standard treatment for chronic myeloid leukemia (CML) about 20 years ago, which was a major breakthrough in stabilizing the pathology and improving the quality of life of patients. However, the emergence of resistance to imatinib and other tyrosine kinase inhibitors leads researchers to characterize new therapeutic targets. Several studies have highlighted the role of histone deacetylase 6 (HDAC6) in various pathologies, including cancer. This protein effectively intervenes in cellular activities by its primarily cytoplasmic localization. In this review, we will discuss the molecular characteristics of the HDAC6 protein, as well as its overexpression in CML leukemic stem cells, which make it a promising therapeutic target for the treatment of CML.

Theaflavins, the characteristic and bioactive polyphenols in black tea, possess the potential improvement effects on insulin resistance-associated metabolic abnormalities including obesity and type 2 diebetes. However, the molecular mechanisms of theaflavins improving insulin sensitivity are still not clear. In this study, we investigated the protective effects and mechanisms of theaflavins on palmitic acid-induced insulin resistance in HepG2 cells. Theaflavins could significantly increase glucose uptake of insulin-resistant cells at noncytotoxic doses. This activity was mediated by upregulating the glucose transporter 4 protein expression, increasing the phosphorylation of IRS-1 at Ser307, and reduced the phosphor-Akt (Ser473) level. Moreover, theaflavins were found to enhance mitochondrial DNA copy number through down-regulate the PGC-1β mRNA level and up-regulate PRC mRNA expression in insulin-resistant HepG2 cells. These results indicated that theaflavins could improve free fatty acid-induced hepatic insulin resistance by promoting mitochondrial biogenesis, and were promising functional food and medicines for insulin resistance-related disorders.

Literature is inconsistent as to how coffee affects the features of the metabolic syndrome (MetS), and which bioactive compounds are responsible for its metabolic effects. We aimed to compare the in-vivo effects of unfiltered coffee with a selected mixture of its compounds on diet-induced MetS. 24 male Sprague-Dawley rats were fed a high-fat (35% W/W) food plus 20% W/W fructose in drinking water for 14 weeks, and were randomized into three groups: control, coffee, or nutraceuticals (5-O-caffeoylquinic acid, caffeic acid, and trigonelline). Coffee or nutraceuticals were provided in drinking water in a dosage equal to 4 cups/day in a human. Compared to the controls, only coffee supplementation decreased total food intake, weight gain, and estimated average plasma glucose. Surrogate measures of insulin resistance (fasting insulin, HOMA-IR, and oral glucose tolerance) were improved at endpoint in the coffee group. Circulating triglyceride levels were also reduced by coffee. Histopathological and quantitative measurements indicated lower grades of liver steatosis after long-term coffee consumption. In conclusion, a combination of phenolic acids and trigonelline was not as effective as coffee per se in improving the components of the MetS. This points to the role of other coffee chemicals and a potential synergism between compounds.

Cellular senescence has recently been recognized as a hallmark of cancer, reflecting its association with aging and inflammation, its role as a response to deregulated proliferation and oncogenic stress, and its induction by cancer therapies such as radiation, chemotherapy, and targeted agents. While such therapy-induced senescence (TIS) has been linked to resistance, recurrence, metastasis and normal tissue toxicity, TIS has the potential to enhance therapy response and stimulate anti-tumor immunity. In this review, we examine the Jekyll and Hyde nature of senescent cells (SnCs), with a particular focus on how their persistence while expressing the senescence-associated secretory phenotype (SASP) modulates the tumor microenvironment through autocrine and paracrine mechanisms. Via the SASP, the formation of SnCs may alternately mediate resistance or response to conventional therapy. Further, toward fulfilling the unmet potential of cancer immunotherapy, we consider how SnCs may influence tumor inflammation and serve as a source of antigen to potentiate anti-tumor immunity. This new view suggests treatment strategies based on inducing TIS to enhance immune checkpoint blockade. Finally, we describe strategies for mitigating the detrimental effects of senescence, such as modulating the SASP or targeting SnC persistence, toward enhancing the benefits of cancer treatment.

Within the context of sustainable material development for the construction sector, this study explores the viability of panels composed of recycled newspaper-derived cellulose (9%), rice husk (14%), borax (15%), and polyvinyl acetate-based glue (62%). The methods employed involve water absorption and density tests, following ASTM C-1763 and C-303 standards. The fire resistance test conforming to the European standard UNE 23-725-90, and a mold growth test using AOAC 2002.11. The composite is prone to absorbing a significant amount of water when exposed to humid conditions. However, the incorporation of rice husk and borax can provide benefits such as improved moisture resistance compared to other cellulitic insulators, which may be advantageous in specific climates. Also, the developed composite has an intermediate density compared to other polymeric materials. This characteristic presents advantages in applications that demand a balance between strength and lightness. During the fire resistance tests, the samples with borax presented less fire propagation, and superficial damage compared with the specimens without borax. This is important, considering the fireproofing property, required in building materials. The presence of borax in the composite has an inhibitory effect on the growth of fungi and yeasts. These findings are consistent with previous research. Nevertheless, further research and testing are imperative to assess its viability and performance for commercial applications.

The subject of the conducted study was focused on the development of new type of technical blends reinforced with natural fillers. The study was divided into two parts, where in the firsts stage of the research unmodified POM was reinforced with different types of natural fillers: cellulose, wood flour and husk particles. In order to select the type of filler intended for further modification, the mechanical characteristics was assessed. The 20% wood flour (WF) filler system was selected as the reinforcement. The second stage of research involved the use of combination of polyoxymethylene POM and poly(lactic acid) PLA. POM/PLA blend (ratio 50/50 %) were modified with elastomeric compound (EBA) and chain extender as reactive compatibilized (CE). The microscopic analysis revealed that for POM/PLA system the filler-matrix interface is characterized by better wettability, which might suggest higher adhesion. The mechanical performance revealed that for POM/PLA-based composites the properties were very close to the results for POM-WF composites; however, there is still large difference in thermal resistance in favor of POM-based materials. The increase in thermomechanical properties for POM/PLA composites occurs after heat treatment. The increasing crystallinity of the PLA phase allows for an significant increase of the head deflection temperature (HDT), even above 125 °C.

The Reactive Spark Plasma Sintering (R-SPS) method is compared in this work with the two-steps SHS-SPS route, based on combination of the Self-propagating High-temperature Synthesis (SHS) with the SPS process, for the fabrication of dense (Hf0.2Mo0.2Ti0.2Ta0.2Nb0.2)B2-SiC and (Hf0.2Mo0.2Ti0.2Ta0.2Zr0.2)B2-SiC ceramics. A multiphasic and inhomogeneous product, containing various borides, is obtained at 2000°C/20min by R-SPS, from transition metals, B4C and Si. In contrast, if the same precursors are first reacted by SHS, and then processed by SPS under the optimized condition of 1800°C/20min, the desired ceramics are successfully attained. Both High-Entropy-Boride/SiC products display densities > 97%, uniform microstructures and contained only small amounts of residual oxides (<2.4 wt.%). The presence of SiC makes the sintering temperature milder, i.e. 150°C below to that needed by the corresponding additive-free system. Fracture toughness is also markedly improved, particularly when considering the Nb-containing system processed at 1800°C/20min, whereas KIC progressively decreases (from 7.35 to 5.36 MPa m1/2) as the SPS conditions become more severe. SiC addition is found to inhibit the volatilization of metal oxides like MoO3 formed during oxidation experiments, thus avoiding mass loss in the ceramics. The benefits above also likely take advantage of the fact that the two composite constituents are synthesized in parallel, according to the SHS-SPS approach, rather than being produced separately and combined subsequently, so that strong interfaces between them are formed.

To estimate the progressive collapse resistance capacity of a multi-column frame tube structure with the assembled truss beam composite floor (ATBCF), the pushdown analysis, and the nonlinear dynamic analysis as well, are conducted for such a structure by using the alternate load path (ALP) method. The bearing capacities of the remaining structures at three different work conditions, which are the side middle column failure, the edge middle column failure, and the corner column failure, are individually studied, and the collapse mechanism for the remaining structures is analyzed from the aspects of the internal force redistribution and the failure mode of the second defense line. Simultaneously, the influence of the column failure time on the dynamic response of the remaining structure and the dynamic amplification coefficient are discussed. The results show that the residual bearing capacity of the remaining structure with the bottom corner column failure is higher than that of the one with the side or edge middle column failure, while the latter has a stronger plastic deformation capacity. When the ALP method is adopted to operate the progressive collapse analysis, it is reasonable to take the column failure time as 0.1 times of the first-order vertical vibration period of the remaining structure, and it is suitable to set the dynamic amplification coefficient as of 2.0, which is the ratio of the maximum dynamic displacement to the static displacement of the remaining structure under the transient loading condition.

Escherichia coli causes several infections like intestinal diarrhea, urinary tract infections, and pneumonia, which are difficult to treat due to the emergence of antimicrobial resistance. The World Health Organisation (WHO) declared carbapenem-resistant E. coli a critical pathogen and called for the development of new antimicrobial agents. Phage therapy, a century-old technique, has been revitalised recently with many successful applications against multi-drug resistant infections. As such, phage therapy is considered one of the most effective alternatives or adjuvants to antibiotics and is also effective in treating multidrug-resistant (MDR) bacterial infections. However, few phages that can kill pathogenic E. coli strains from Southeast Asia have been studied at a molecular level, although the burden of MDR, particularly carbapenem resistance, is high in this region. In this study, three closely related obligately virulent Escherichia phages (øEc_Makalu_001, øEc_Makalu_002, and øEc_Makalu_003) that could infect uropathogenic E. coli were isolated from sewage samples and characterized using morphological as well as sequence-based analysis. Further, a comparative genomic and phylogenetic analysis was done to predict the functional genes and evolutionary relationships. Electron microscopy and genome-based classification revealed that all three phages belonged Krischvirus genus of Straboviridae family. One-step growth curve showed that the latent period of the phages ranged from 15-20 min, the outbreak period was about 50 min, and the burst size ranged between 74-127 PFU/bacterium. Moreover, the phages could tolerate a pH range of 6 to 9 and a temperature range of 25-37°C for up to 180 minutes without significant loss of phage viability. Spotting the purified phages in different clinical isolates showed a broad host-range of isolated Escherichia phages and could lyse up to 30% of the tested pathogenic clinical isolates, including an intra-genus isolate of Klebsiella pneumoniae. The genome organization of all three phages was almost identical and similar to T4-like phage with a full-length genome of ~163 kb. Around 284 coding sequences (CDS) were predicted in each phage, of which only 40% were functional with an average gene length of 951 bp. The coding density in all phages was approximately 95%, while the gene density was 1.73 gene/kbp. Putative lysin, holin, endolysin, and spanin genes were found in the genomes of all three phages, resembling that of T4-like phages implying their phylogenetic relatedness. Furthermore, various in silico sequence analysis tools confirmed that all three phages were strictly virulent with functional lysis modules but devoid of any known virulence or toxin genes, integron-associated genes and antimicrobial-resistance (AMR) genes. In summary, pre-clinical experimental analysis and exploration of genomic features suggest that all three phages may be suitable candidates for therapeutic applications against uropathogenic E. coli.

Discovery and development of effective strategies to treat emerging and often drug resistant strains of viral and microbial pathogens presents one of the greatest challenges of the 21st century. Despite nearly a century of progress in developments in antimicrobial and antiviral therapies, infectious diseases still account for a substantial proportion of deaths worldwide, including over 100 million globally in the recent pandemic to date. In recent decades, the plague of antimicrobial resistance also represents an additional and alarming signal for both human and animal healthcare and signals a renewed sense of urgency in addressing this issue. This has made the search for novel classes of antibiotics, antivirals and therapeutics found to be capable of bypassing the microbial and viral resistance mechanisms necessary to in order to replenish our current arsenal of antimicrobial and antiviral drugs and update our therapeutic regimens. In addition, the tremendous impact exerted by viral infections and related pathologies on our lives during the recent decade has forced scientists to acknowledge the opportunities and challenges associated with tackling infectious diseases by developing effective antiviral agents endowed with novel mechanisms of action. The discovery of new antimicrobial/antiviral agents, as well as the repurposing of existing drugs and therapeutic options will be crucial to fight the ever-increasing resistance of “superbugs”, pathogenic fungi, viruses, and parasites. Proponents of modern biophoton therapy proposed in this paper can trace its origins to the Russian scientist Alexander Gurwitsch, who a century ago observed ultra-weak emissions of light emerging from an onion root and soon found additional living tissues to be emanating similar energetic phenomena, thus energizing research which continues to the present day and projected toward the development of useful applications of the new-found biological photonic phenomena. The purpose of the present paper is to introduce the past experiences, potential applications and highly successful outcomes of biophotonic therapy as an option to treat infectious diseases including HIV, Hepatitis C, MRSA, and others, with emphasis on efficacy of using biophotonic therapies to treat and ameliorate the drug resistant variants of the above infectious agents, including potential applications for the current COVID-19 pandemic and in preparation for the emergence of the next epidemic or pandemic.

Fly ash cement has rarely been used in Japan, mainly because its strength development is slower than ordinary Portland cement. In this research, the effect of the new fly ash cement with both high alite (C3S) cement and fly ash modified by electrostatic belt separation method on cracking resistance of precast concrete prepared by steam curing was studied. The mechanical and shrinkage properties of the proposed fly ash concrete were compared with those of concrete made using OPC cement without fly ash. In order to study the cracking tendency of precast concrete with the proposed fly ash cement, thermal stress analysis was conducted taking into consideration of the experimental data of concrete properties with the different concrete mix proportions. A standard precast concrete box culvert model was used in this 3D FEM analysis and the distribution of temperature and relative humidity in cross section and induced restraint stress during and after steam curing were discussed. Steam-cured concrete with fly ash and high alite cement developed higher compressive strength on the first day of age than concrete with OPC. The proposed fly ash concrete developed high cracking resistance in the early days. On the other hand, the results showed that the drying shrinkage at later ages was the main cause of cracking.

In this study, deep neural network (DNN) and transfer learning (TL) techniques were employed to predict the viscous resistance and wake distribution based on the positions of flow control fins (FCFs) applied to containerships of various sizes. Both methods utilized data collected through Computational Fluid Dynamics (CFD) analysis. The position of the flow control fin (FCF) and hull-form information were utilized as input data, and the output data included viscous resistance coefficients and components of propeller axial velocity. The base DNN model was trained and validated using a source dataset from a 1000 TEU containership. Grid search cross-validation technique was employed to optimize the hyperparameters of the base DNN model. Then, transfer learning was applied to predict the viscous resistance and wake distribution for containerships of varying sizes. To enhance the accuracy of feature prediction with a limited amount of dataset, learning rate optimization was conducted. Transfer learning involves retraining and reconfiguring the base DNN model, and the accuracy was verified based on the fine-tuning method of the learning model. The results of this study can provide hull designers for containerships with performance evaluation information by predicting wake distribution, without relying on CFD analysis.

A new approach to the treatment of wound lesions, which are complicated by the presence of polyresistant microflora and a possible immunodeficiency background has been proposed. It involves treating the wound surface with high-intensity pulsed optical radiation of a continuous spectrum, continuously covering the entire UV range (from 200 to 400 nm), visible and near infrared region of the spectrum. A pulsed xenon lamp is used as a radiation source. A description of the design and technical characteristics of the developed device for high-intensity optical irradiation "Zarnitsa-A", which implements the proposed medical technology for wound therapy, is represented. The results of preclinical studies of the apparatus in vitro and in vivo are represented hereinafter. The article shows that the apparatus exposure has pronounced bactericidal and wound-healing properties. The apparatus action reliably provides higher rates of wound healing compared to the use of only a typical antibacterial and wound healing agent – “Levomekol” ointment.

Whole-genome sequencing (WGS) was used for genomic characterization of 110 strains of Listeria innocua isolated from 23 cattle farms, 8 beef abattoirs, and 48 retail outlets in Gauteng province, South Africa. In silico multilocus sequence typing (MLST) was used to identify the isolates' sequence types (STs). BLAST-based analyses were used to identify antimicrobial and virulence genes. The study also linked the detection of the genes to the origin (sources and types of samples) of the L. innocua isolates. The study detected 12 STs, 13 resistance genes, and 23 virulence genes. Of the 12 STs de-tected, ST637 (26.4%), ST448 (20%), 537 (13.6%), and 1085 (12.7%) were predominant, and the frequency varied significantly (P<0.05). All 110 isolates of L. innocua were car-riers of one or more antimicrobial resistance genes, with resistance genes lin (100%), fosX (100%), and tet(M) (30%) being the most frequently detected (P<0.05). Of the 23 virulence genes recognized, 13 (clpC, clpE, clpP, hbp1.svpA, hbp2, iap/cwhA, lap, lpeA, lplA1, lspA, oatA, pdgA, and prsA2) were found in all 110 isolates of L. innocua. Overall, diversity and significant differences were detected in the frequencies of STs, resistance, and virulence genes according to the origins (source and sample type) of the L. innocua isolates. This, being the first genomic characterization of L. innocua recovered from the three levels (farm, abattoir, and retail outlets) of the beef production system in South Africa, provides data on the organism's distribution and potential food safety implications..

Wheat dwarf virus (WDV) causes an important vector transmitted virus disease, which leads to significant yield losses in barley production. Due to the fact, that at the moment no plant protection products are approved to combat the vector Psammotettix alienus and this disease cannot be controlled by chemical means, therefore the use of WDV resistant or tolerant genotypes is the most efficient method to control and reduce negative effects of WDV on barley growth and production. In this study, a set of 480 barley genotypes were screened to identify genotypic differences in response to WDV and five traits were assessed under infected and non-infected conditions. In total, 32 genotypes showed resistance or tolerance against WDV. Subsequently, the phenotypic data of 191 out of 480 genotypes combined with 34,408 single nucleotide polymorphisms (SNPs) in a genome wide association study to identify quantitative trait loci (QTLs) and markers linked to resistance/tolerance to WDV, using Tassel, GAPIT, and FARM CPU. In total, 1, 3, 2, 2 and 1 significantly associated markers on chromosomes 3H, 4H, 5H and 7H identified by all three methods for ELISA-60, relative performance of total grain weight, plant height, number of ears per plant and thousand grain weight, respectively.

A recent report from the American Heart Association in 2018 shows that over 103 million American adults have hypertension. The angiotensin-converting enzyme (ACE) (EC 3.4.15.1) is a dipeptidyl carboxylase that, when inhibited, can reduce blood pressure through the renin-angiotensin system. ACE inhibitors are used as a first-line medication to be prescribed to treat hypertension, chronic kidney disease, heart failure among others. It has been suggested that ACE inhibitors can reduce the symptoms in mouse models. Despite the benefits of ACE inhibitors, previous studies also have suggested that alterations in the ACE gene are risk factors for Alzheimer’s disease (AD) and other neurological diseases. In mice, overexpression of ACE in the brain reduces symptoms of the AD-model systems. Thus, we find opposing effects of ACE on health. To clarify the effects, we dissect the functions of ACE as follows: (1) angiotensin-converting enzyme that hydrolyzes angiotensin I to make angiotensin II in the renin-angiotensin system; (2) amyloid-degrading enzyme that can hydrolyze beta-amyloid and reduce amyloid toxicity. The efficacy of the ACE inhibitors is well established in humans, while the knowledge specific to AD remains to be open for further research. We provide an overview of ACE and inhibitors that link a wide variety of age-related comorbidities from hypertension to Alzheimer’s disease to aging. ACE also serves as an example of the middle-life crisis theory that assumes deleterious events during the midlife, leading to age-related later events.

(1) Background: Factors reported in literature associated with inappropriate prescribing of antimicrobials, such as physicians with less experience, uncertain diagnosis, and patient caregiver influences on physicians' decisions. Monitoring antimicrobial resistance is critical for identifying emerging resistance patterns, developing, and assessing the effectiveness of mitigation strategies. Improvement in prescribing `antimicrobials would minimize the risk of resistance and, consequently, improve patients' clinical and health outcomes. The purpose of the study is to delineate factors associated with antimicrobial resistance, describe the factors influencing prescriber’s choice during prescribing of antimicrobial, and examine factors related to consequences of inappropriate prescribing of antimicrobial. (2) Methods: Cross-sectional study conducted among healthcare providers (190) in six tertiary hospitals in the Eastern province of Saudi Arabia. The research panel has developed validated and piloted survey specific with closed-ended questions. A value of P &lt;0.05 was considered for statistical significance. All data analysis was performed using Statistical Package for Social Sciences (IBM SPSS version 23.0). (3) Results: 72.7% of the respondents have agreed that poor skills and knowledge are key factors that contribute to the inappropriate prescribing of antimicrobials. All the respondents acknowledged effectiveness and previous experience with the antimicrobial, and reading scientific materials (such as books, articles, and the internet) were key factors influencing physicians’ choice during antimicrobial prescribing. (4) Conclusion: The current study has identified comprehensive education and training needs for healthcare providers about antimicrobial resistance. Using antimicrobials unnecessarily, insufficient duration of antimicrobial use, and using broad spectrum antimicrobials, were reported to be common practices. Further, poor skills and knowledge were a key factor that contributed to the inappropriate use and overuse of antimicrobials and using antimicrobials without physician prescription (self-medication) were the key factors which contribute to AMR from participants’ perspectives. Furthermore, internal policy and guidelines are needed to ensure that the antimicrobials are prescribed in accordance with standard protocols and clinical guidelines.

This study demonstrated that antibiotic residue in milk can be reduced when dairy farmers use Ethno-veterinary Practices (EVP) based on herbal alternatives to prevent and cure common clinical conditions in cattle instead of antibiotics. Of the 220 farmers selected for the study, 140 were trained and motivated to use validated herbal formulations, 80 were kept as control. Milk samples from the selected farmers (except Thirukanurpatti milk society) tested positive for antibiotic residue in the baseline survey. One year after interventions, the milk from 123 (87.86%) farmers out of 140, were without any detectable antibiotic residue, while samples from 11 farmers (7.85%) were low positive for either Beta-lactams or sulphonamides and 6 (4.29%) were positive for Beta lactams and/or sulphonamides. These 17 (11 + 6) farmers had used antibiotics along with herbal formulations. The milk samples from the control groups were positive for beta lactam and sulphonamide. There was suggestive significance of change in knowledge, attitude and practice of EVP among the farmers from Kerala and Tamil Nadu. A progressive reduction in the incidence of mastitis, enteritis, repeat breeding and cowpox were observed from 2016 to 2019 among the cows treated with EVP. Use of herbal alternative also resulted in a significant reduction in health care expenditure of cattle.

Mankind faces a coronavirus pandemic originating from a seafood market in Wuhan, China since December 2019. The pathogen was named novel coronavirus (n-CoV) and bats are the identified key reservoir. The coronavirus disease 2019 (COVID-19) quickly spread over China across the globe, turned into a pandemic with exponentially increasing numbers of cases and significant mortality rate. China reacted with lockdowns and strict control measurements to prevent spreading the virus. The treatment of severe cases was hampered by lack of specific vaccines. Vaccine-development and production is a painstaking process and can only be enforced by international cooperation. Different supportive treatment options surfaced due to combinations of antiviral agents with antibiotic drugs. Elderly, male, immune-suppressed patients with co-morbidities showed a high mortality rate. Health literacy, strong immune system, adequate serum 25-hydroxyvitamin D (25(OH)D) concentrations and healthy life style choices can support fast recovery. Antibiotic resistance needs to be addressed by development of new generation antimicrobials against nosocomial infections in preparation for future outbreaks. Plant-biosynthesis of nanomaterials and antiseptics may help in prevention and recovery rate. Prevalence of COVID-19 maybe inversely related to BCG vaccination, endemicity of malaria, humidy and temperature but directly with latitude. Recommendations to prevent the spread of COVID-19 should be followed strictly.

The Colebrook equation is a popular model for estimating friction loss coefficients in water and gas pipes. The model is implicit in the unknown flow friction factor . To date, the captured flow friction factor can be extracted from the logarithmic form analytically only in the term of the Lambert -function. The purpose of this study is to find an accurate and computationally efficient solution based on the shifted Lambert -function also known as the Wright -function. The Wright -function is more suitable because it overcomes the problem with the overflow error by switching the fast growing term of the Lambert -function to the series expansions that further can be easily evaluated in computers without causing overflow run-time errors. Although the Colebrook equation transformed through the Lambert -function is identical to the original expression in term of accuracy, a further evaluation of the Lambert -function can be only approximate. Very accurate explicit approximations of the Colebrook equation that contains only one or two logarithms are shown. The final result is an accurate explicit approximation of the Colebrook equation with the relative error of no more than 0.0096%. The presented approximations are in the form suitable for everyday engineering use, they are both accurate and computationally efficient.

Very little is known about laboratory confirmed blood stream infections (LCBIs) in neonatal intensive care units (NICUs) in resource-limited settings. The aim of this cohort study was to determine the incidence, risk factors, and causative agents of LCBIs in a level-2 NICU in India. The diagnosis of LCBIs was established using the Centre for Disease Control, USA criteria. A predesigned questionnaire containing risk factors associated with LCBIs was filled-in. A total of 150 neonates (43% preterm) were included in the study. The overall incidence of LCBIs was 31%. The independent risk factors for LCBIs were: preterm neonates (relative risk (RR) 2.23), duration of NICU stay more than 14 days (RR 1.75), chorioamnionitis in the mother (RR 3.18), premature rupture of membrane in mothers (RR 2.32), neonate born through meconium-stained amniotic fluid (RR 2.32), malpresentation (RR 3.05), endotracheal intubation (RR 3.41), umbilical catheterization (RR 4.18), and ventilator-associated pneumonia (RR 3.17). The initiation of minimal enteral nutrition was protective from LCBIs (RR 0.22). The predominant causative organisms were gram-negative pathogens (58%). The results of the present study can be used to design antibiotic interventions to reduce LCBIs in resource-limited settings.

Vinyltriethoxysilane (VTES) was covalently bonded onto graphene oxide. Several methods, including X-ray photoelectron spectroscopy, Fourier transform infrared spectroscopy, and X-ray diffraction, were used to demonstrate the presence of VTES on the surface of graphene oxide and the creation of this covalent link. Following that, different quantities of the resultant vinyltriethoxysilane functionalized graphene oxide (VTESFGO) were mixed with polyvinyl alcohol (PVA) to form VTESFGO/PVA nanocomposite films (NCFs) with a 3-dimensional network structure. The creation of these NCFs and the presence of a three-dimensional network were confirmed by Fourier transform infrared spectroscopy. The three-dimensional network structure provided these NCFs extraordinary characteristics. The mechanical and thermal stability, oxygen transfer rate (OTR), and water resistance pressure (WRP) of the NCFs were investigated. The nanocomposite film (NCF) with the highest weight percentage of VTESFGO (3.0 wt.%) was 47.5% more thermally stable than pure PVA, with an oxygen transmission rate of 0.3 cm3/m2 per day and a water resistance pressure of 780 mm/cm2. However, as the weight percentage of VTESFGO increased, the mechanical strength of the NCFs decreased as a result of silanol self-condensation, resulting in particulate formation, as confirmed by scanning electron microscopy.

Acquired immunodeficiency syndrome (AIDS) is an enormous global health threat stemming from human immunodeficiency virus (HIV-1) infection. Up to now, the tremendous advances in combination antiretroviral therapy (cART) have shifted HIV-1 infection from a fatal illness into a manageable chronic disorder. However, the presence of latent reservoirs, multifaceted nature of HIV-1, drug resistance, severe off-target effects, poor adherence, and high cost restrict the efficacy of current cART targeting the distinct stages of the virus life cycle. Therefore, there is an unmet need for discovery of new therapeutics that not only bypass the limitations of the current therapy but also protect the body health at the same time. The main goal for complete HIV-1 eradication is purging latently infected cells from the patients’ bodies. A potential strategy called “lock-in apoptosis” targeting the budding phase of life cycle of virus leading to susceptibility to apoptosis of HIV-1 infected cells for elimination of HIV-1 reservoirs and ultimately for a complete eradication. The current work intends to present the main advantages and disadvantages of United States Food and Drug Administration (FDA) approved anti-HIV-1 drugs as well as plausible strategies for the design and development of more anti-HIV-1 compounds with better potency, favorable pharmacokinetic profiles, and improved safety issues.

Anthracnose stands as the primary obstacle to lupin cultivation, impeding development despite the considerable agronomic, ecological, and economic potential of such legume crops. This review explores recent efforts to unravel the complexities of anthracnose in domesticated lupins, focusing on both the plant perspective and the causative pathogenic agent, Colletotrichum lupini. Leveraging cutting-edge technologies has yielded crucial insights into various facets of this devastating disease, encompassing plant and pathogen biology, genetic and molecular regulations of the interaction, fungal diversity and population dynamics, and screening of plant genetic resources for anthracnose resistance. The lack of effective disease control measures, relying primarily on the use of disease-free seeds, highlights the need to develop anthracnose-resistant varieties. However, challenges arise from the intricacy of lupin's response to the disease, influenced by polygenic inheritance, in spite of loci with major effects, and environmental factors. The slow pace of genetic improvement underscores the need for more efficient breeding processes, including biotechnological approaches. This review offers a comprehensive overview of current progress and knowledge gaps, stressing the urgent need to further enhance understanding of C. lupini pathogenic mechanisms and lupin‘s resistance. Integrating advanced technologies and accelerated research efforts is paramount for achieving efficient disease management and sustainable lupin cultivation in the face of anthracnose challenges.

The skeletal muscle plays a critical role in regulating systemic blood glucose homeostasis. Impaired skeletal muscle glucose homeostasis associated with type 2 diabetes mellitus (T2DM) has been observed to significantly affect the whole-body glucose homeostasis, thereby resulting in other diabetic complications. T2DM does not only affect skeletal muscle glucose homeostasis, but it also affects skeletal muscle structure and functional capacity. Given that T2DM is a global health burden, there is an urgent need to develop therapeutic medical therapies that will aid in the management of T2DM. Prediabetes is a prominent risk factor of T2DM that usually goes unnoticed in many individuals as it is an asymptomatic condition. Hence, research on prediabetes is essential because establishing diabetic biomarkers during the prediabetic state would aid in preventing the development of T2DM, as prediabetes is a reversible condition if it is detected in the early stages. Literature predominantly documents the changes in skeletal muscle during T2DM, but the changes in skeletal muscle during prediabetes remain unknown. In this review, we seek to review the existing literature on prediabetic and T2DM associated changes in skeletal muscle function.

Barley is an important crop grown on almost 49 Mha worldwide in 2021 and is particu-larly significant in Europe where powdery mildew is the most frequent disease on sus-ceptible varieties. The most suitable way for protecting crops is exploiting genetic re-sistance. However, the causal agent Blumeria hordei is an extremely adaptable pathogen. The aims of this research were to increase our knowledge of the rapidly changing path-ogen population and detect rare virulences. Random samples of the pathogen were ob-tained from the air by means of a mobile spore sampler. Spores were collected by driv-ing across the Czech Republic in 2019, 2021 and 2023 and 299 isolates were analyzed on 121 host varieties. No infection occurred on 35 differentials, rare virulence was recorded on 31 varieties and a higher virulence frequency was found on 55 differentials. A core set of differentials along with four additional varieties distinguish 295 pathotypes (Simple Index = 0.987) and virulence complexity of isolates varied from 4 to 19 with an average 10.39. The detection of new virulences, the increasing frequency of previously rare viru-lences and high pathotype diversity as well as high virulence complexity confirm that using nonspecific durable resistance is crucial for successfully breeding commercial va-rieties.

Background: Misconceptions and knowledge gaps about antibiotic use contribute to inappropriate antibiotic use and antimicrobial resistance. Aim: Identifying and prioritizing misconceptions and knowledge gaps about antibiotic use from a healthcare professionals’ perspective. Methods: A modified Delphi study of two rounds with an expert meeting. A literature search was conducted to create statements about misconceptions and knowledge gaps about antibiotic use. These were rated by healthcare professionals from five EU countries representing general practice, out-of-hour services, nursing homes, and pharmacies. Consensus was achieved if ≥80% of the participants rated 4+ on a five-point Likert scale during the second Delphi round. Results. In total, 44 misconceptions were identified through the literature search within four themes: 1) antimicrobial resistance in general, 2) use of antibiotics in general, 3) use of antibiotics for respiratory tract infections, and 4) use of antibiotics for urinary tract infections. Consensus was reached for more than half of the statements within each setting. Conclusions. Experts from different settings and nationalities acknowledge that multiple misconceptions and knowledge gaps can contribute to inappropriate use of antibiotics in the community. These results provide valuable information to use in educational campaigns for patients and healthcare professionals to improve the use of antibiotics.

Helicobacter pylori is a gastric pathogen that infects nearly half of the global population and is recognized as a group 1 carcinogen by the Word Health Organization. The global rise in antibiotic resistance has increased clinical challenges in treating H. pylori infections. Biofilm growth has been proposed to contribute to H. pylori’s chronic colonization of the host stomach, treatment failures, and the eventual development of gastric diseases. Several components of H. pylori have been identified to promote biofilm growth, and several of these may also facilitate antibiotic tolerance, including the extracellular matrix, outer membrane proteins, the coccoid morphology, modulated metabolism, efflux pumps, and virulence factors. Recent developments in therapeutic approaches targeting H. pylori biofilm have shown that synthetic compounds, such as small molecule drugs and plant-derived compounds, are effective at eradicating H. pylori biofilms. These combined topics highlight the necessity for biofilm-based research in H. pylori, to improve current H. pylori targeted therapeutic approaches and alleviate relative public health burden. In this review we discuss recent discoveries that have decoded the life cycle of H. pylori biofilms and current biofilm targeted treatment strategies.

The lungs of tuberculosis (TB) patients contain a spectrum of granulomatous lesions ranging from solid and well vascularized cellular granulomas, to avascular caseous granulomas. In solid granulomas, current therapy kills actively replicating (AR) intracellular bacilli, while in low vascularized caseous granulomas the low oxygen tension stimulates aerobic and microaerophilic AR bacilli to transit into non-replicating (NR), drug-tolerant, extracellular stages. These stages, which do not have genetic mutations and are often referred to as persisters, are difficult to eradicate due to low drug penetration inside caseum and mycobacterial cell walls. The sputum of TB patients contains also viable bacilli called differentially detectable (DD) cells that, unlike persisters, grow in liquid, but not in solid media. This review provides a comprehensive update on drug combinations killing in vitro AR and drug-tolerant bacilli (persisters and DD cells), and sterilizing Mycobacterium tuberculosis-infected BALB/c and caseum-forming C3HeB/FeJ mice. These observations have been important for testing new drug combinations in noninferiority clinical trials, in order to shorten duration of current regimens against TB. In 2022, the World Health Organization, based on one of this trial, supported the use of a 4-month regimen for treatment of drug-susceptible TB as a possible alternative to the current 6-month regimen.

Introduction: The reduced implementation of surveillance programs and limited bedside infectious diseases consultations due to the pressure of COVID-19 pandemic in healthcare systems led to increased rates of irrational use of antimicrobials and incidence of infections by multidrug-resistant microorganisms. The aim of the present study is to evaluate the incidence of antimicrobial resistance and the management of bloodstream infections before and during COVID-19 pandemic at the University General Hospital of Alexandroupolis (Greece). Material-Methods: This is a retrospective study conducted from January 2018 to December 2022. Data were collected from the University Microbiology Laboratory per semester regarding the isolated strains of Gram positive and negative bacteria in blood cultures and respiratory samples in hospitalized patients in medical and surgical wards and in the Intensive Care Unit (ICU). Additionally, bloodstream infections with requested infectious diseases consultation were reported (n=400), determining whether these were carried out via telephone contact or at the patient's bedside. Demographic data, comorbidities, focus of infection, antimicrobial regimen, duration of treatment, length of hospitalization and clinical outcome were analysed. Results: A total of 4569 strains of Gram positive and negative bacteria were isolated. An increasing trend was reported compared to the pre-pandemic period in the incidence of resistant Gram-negative bacteria, particularly in ICUs. Prior antimicrobial use and the rate of hospital-acquired infections were increased significantly during the pandemic. In the pre-pandemic period 2018-2019, a total of 246 infectious diseases consultations were carried out, while during the period 2020-2022 154, with the percentage of telephone consultations 15% and 76% respectively. Detection of the source of infection and timely administration of appropriate antimicrobial agents were more frequently recorded before the pandemic and 28-day mortality was significantly reduced in cases with bedside consultations. Conclusion: Empowering of infectious diseases surveillance programs and committees, rational use of antimicrobials agents and bedside infectious diseases consultations are vital in order to reduce the impact of infections caused by multidrug-resistant strains.

Background: Multi-drug resistance organisms (MDRO) often cause increased morbidity, mortality, and length of stays (LOS). However, there is uncertainty whether the infection of MDRO increase the morbidity, mortality, and ICU-LOS. Objective: This study performed to determine the prevalence of MDRO in ICU, site of infection and the association of MDRO or site of infection with mortality. Secondary outcome was determined by ascertaining the association of MDRO or site of infection with (ICU-LOS). Methods: A retrospective cohort study was performed with adult sepsis patients in ICU. Univariate and multivariate (MVA) logistic regression with cox regression modeling were performed to compute the association of MDRO on ICU-mortality. MVA modelling was performed for ICU-LOS predictors. Results: Out of 228 patients, the isolated MDRO was 97 (42.5%) of which 78% were gram-negative bacteria. The mortality rate among those with MDRO was 85 (37.3%). The hospital acquired infection (HAI) was significantly predictor for ICU-LOS in univariate linear regression (R² = 0.034, P=0.005). In MVA linear regression, both Enterococcus faecalis infection and acinetobacter baumannii (AC) -MDRO were predictors for ICU-LOS with (R² = 0.478, P<0.05). In the univariate cox regression, only the infection with AC- MDRO was a risk factor for ICU-mortality with [ HR =1.802 (95% CI: 1.2 – 2.706; P = 0.005)]. Conclusions: Identifying risk factors for MDRO highlight the appropriate administration of empirical antibiotics and effectively control of source of infection which would reduce mortality and ICU-LOS. The usage of broad- spectrum antibiotics should be limited for those having substantial risk factors to acquire MDRO.

Concrete is the most commonly used construction material due to its various advantages, such as versatility, familiarity, strength and durability and it will continue to be in demand far into the future. However, with today’s sensitivity to the environmental protection, this material is facing unprecedented challenges due to its high greenhouse gas emission mainly during cement production. This paper investigates one of the promising cement replacement materials, alkali activated cement (AAC) concrete. Being produced mainly from byproduct materials and having a comparable structural performance to conventional concrete, AAC concrete has a potential to transform the construction industry. Mechanical properties such as compressive and flexural strength and the relationship between them are studied. Different source materials such as fly ash (FA), ground granulated blast furnace slag (GGBS), silica fume (SF) and Metakaolin (MK) are used. The effect of the source materials and the activator solutions on the concrete performance is studied. Furthermore, the freeze-thaw resistance of the concrete is studied. The results of the study showed that the behavior of AAC depends highly on the source material combinations as well as type used. The effect of the alkaline solution is also dependent on the source material used. Mixes with higher GGBS content in general showed the highest strength while mixes with MK showed the highest flexural strength. The results from the freeze-thaw test showed that proper design of AAC concrete with a lower water content is critical to achieve a good resistance.

Many cellular functions important for tumor initiation and progression are mediated by members of the integrin family, a diverse family of cell adhesion receptors. With recent studies emphasising on the role of the tumor microenvironment (TME) in tumor initiation and progression, it is not surprising that a lot of attention is being given to integrins. Several integrins are under trial with many demonstrating appealing activity in patients with different cancers. A deeper knowledge of the functions of integrins within the tumor microenvironment is still required, and might lead to better inhibitors being discovered. Integrin expression is commonly dysregulated in many tumors with integrins playing key roles in signaling as well as promotion of tumor cell invasion and migration. This review report new data on the differential expression of integrins within solid tumors using two publicly available resources: The Cancer Genomic Atlas (TCGA) and Gene Expression Profiling Interactive Analysis (GEPIA). In this analysis, I investigated the expression of integrin alpha 2 (ITGα2), ITGα3, ITGβ4 and ITGβ6 in tumor tissues versus adjacent normal tissues. This analysis showed that integrins were differentially expressed in cervical squamous cell carcinoma (CESC), head and neck squamous cell carcinoma (HNSC), esophageal carcinoma (ESCA) and lung adenocarcinoma (LUAD). This analysis showed that ITGα2 and ITGβ6 expression are upregulated in CESC and ESCA, ITGα3 is upregulated in HNSC and ESCA whilst ITGβ4 is highly expressed in CESC, HNSC, ESCA and LUAD tumor tissues compared to adjacent normal tissues. Integrins also play a major role in adhesion of circulating tumor cells to new sites and the resulting formation of secondary tumors. Furthermore, integrins have demonstrated the ability to promoting stem cell-like properties in tumor cells as well as drug resistance. Anti-integrin therapies rely heavily on the doses or concentrations used as these determine whether the drugs act as antagonists or as integrin agonists. This review offers the latest synthesis in terms of current knowledge of integrins functions within the tumor microenvironment and potential targets for different cancers.

Stress Granules formation is a pro-survival mechanism helping cells to cope with environmental challenges. Stress Granules have been studied for two decades in fundamental research, and are now being examined in the context of human pathogenesis. Here, we review studies highlighting stress granules’ involvement in cancer development through translational pattern modification.

1. Heterospecific pollen interference has recently been proposed as a mechanism contributing to the success of alien invaders, as heterospecific pollen of alien plants interferes with the reproduction of natives by reducing fruit and seed set. However, no study has looked at the opposite interaction. Moreover, few studies have considered the roles of phylogenetic and trait distances between pollen donors and recipients. 2. We did a large multi-species experiment in which we used alien and native species both as pollen recipients and as pollen donors, and included phylogenetic as well as trait distance as explanatory variables. 3. We found that both alien and native recipients suffered from heterospecific pollen from donors of the opposite status in terms of seed and fruit set. Phylogenetic distance and trait distance both affected heterospecific pollen interference, but the effect depended on recipient and donor statuses. 4. We conclude that heterospecific pollen interference affects both native and alien recipients, thus indirectly altering community composition and increasing biotic resistance against invaders.

Pasmo is one of the most widespread diseases threatening flax production. To identify genetic regions associated with pasmo resistance (PR), a genome-wide association study was performed on 370 accessions from the flax core collection. Evaluation of pasmo severity was performed in the field from 2012 to 2016 in Morden, MB, Canada. Genotyping-by-sequencing has identified 258,873 single nucleotide polymorphisms (SNPs) distributed on all 15 flax chromosomes. Marker-trait associations were identified using ten different statistical models. A total of 692 unique quantitative trait nucleotides (QTNs) associated with 500 putative quantitative trait loci (QTL) were detected from six phenotypic PR datasets (five individual years and average across years). Different QTNs were identified with various statistical models and from individual PR datasets, indicative of the complementation between analytical methods and/or genotype × environment interactions of the QTL effects. The single-locus models tended to identify large-effect QTNs while the multi-loci models were able to detect QTNs with smaller effects. Among the putative QTL, 67 had large effects (3-23%), were stable across all datasets and explained 32-64% of the total variation for PR in the various datasets. Forty-five of these QTL spanned 85 resistance gene analogs including a large toll interleukin receptor, nucleotide-binding site, leucine-rich repeat (TNL) type gene cluster on chromosome 8. The number of positive effect QTL (NPQTL) in accessions was significantly correlated with PR (R²=0.55), suggesting additive effects. NPQTL was also significantly associated with morphotype (R²=0.52) and major positive effect QTL were present in the fiber type accessions. The 67 large effect QTL are suited for marker-assisted selection and the 500 QTL for effective genomic prediction in PR molecular breeding.

Today, Colebrook’s equation is mostly accepted as an informal standard for modeling of turbulent flow in hydraulically smooth and rough pipes including transient zone in between. The empirical Colebrook’s equation relates the unknown flow friction factor (λ) with the known Reynolds number (R) and the known relative roughness of inner pipe surface (ε/D). It is implicit in unknown friction factor (λ). Implicit Colebrook’s equation cannot be rearranged to derive friction factor (λ) directly and therefore it can be solved only iteratively [λ=f(λ, R, ε/D)] or using its explicit approximations [λ≈f(R, ε/D)]. Of course, approximations carry in certain error compared with the iterative solution where the highest level of accuracy can be reached after enough number of iterations. The explicit approximations give a relatively good prediction of the friction factor (λ) and can reproduce accurately Colebrook’s equation and its Moody’s plot. Usually, more complex models of approximations are more accurate and vice versa. In this paper, numerical values of parameters in various existing approximations are changed (optimized) using genetic algorithms to reduce maximal relative error. After this improvement computational burden stays unchanged while accuracy of approximations increases in some of the cases very significantly.

The current work is dedicated to the search for new high-energy materials (HEMs) with improved characteristics which are gained through agglomeration with salts. The research was performed by Becke’s three-parameter hybrid functional approach with non-local correlation provided by Lee, Yang, and Parr and cc-pVTZ basis set. The geometry, total energy, and heat of formation of the most stable compounds forming due to 3-amino-5-[(2, 4, 6-trinitrophenyl) amino]-1H-1, 2, 4-triazole (APATO) within salts selected were obtained to foresee its influence on resistance to shock stimuli, detonation pressure, and velocity of the materials under study. Results obtained allow us to foresee that only agglomeration with precise salts could lead to significant improvement in the stability of the specific high-energy materials and the resistance to shock stimuli. We also show that the agglomeration leads to better energetic properties of the above compound, although the improvement could be insignificant in some cases.

The infections caused by various bacterial pathogens both in clinical and community settings represent a significant threat to public healthcare worldwide. The growing resistance to antimicrobial drugs acquired by bacterial species causing healthcare-associated infections has already become a life-threatening danger noticed by the World Health Organization. Several groups or lineages of bacterial isolates usually called ‘the clones of high risk’ often drive the spread of resistance within particular species. Thus, it is vitally important to reveal and track the spread of such clones and the mechanisms by which they acquire antibiotic resistance and enhance their survival skills. Currently, the analysis of whole genome sequences for bacterial isolates of interest is increasingly used for these purposes, including epidemiological surveillance and developing of spread prevention measures. However, the availability and uniformity of the data derived from the genomic sequences often represents a bottleneck for such investigations. In this dataset, we present the results of a comprehensive genomic epidemiology analysis of 17,546 genomes of a dangerous bacterial pathogen Acinetobacter baumannii. Important typing information including multilocus sequence typing (MLST)-based sequence types (STs), intrinsic blaOXA-51-like gene variants, capsular (KL) and oligosaccharide (OCL) types, CRISPR-Cas systems, and cgMLST profiles are presented, as well as the assignment of particular isolates to nine known international clones of high risk. The presence of antimicrobial resistance genes within the genomes is also reported. These data will be useful for researchers in the field of A. baumannii genomic epidemiology, resistance analysis and prevention measure development.

Chronic kidney disease (CKD) is a progressive condition of kidney dysfunction due to diverse causes of injury. In healthy kidneys, protein-bound uremic toxins (PBUTs) are cleared from the systemic circulation by proximal tubule cells through the concerted action of plasma membrane transporters that facilitate their urinary excretion, but the endogenous metabolites are hardly removed with kidney dysfunction and may contribute to CKD progression. Accumulating evidence suggests that senescence of kidney tubule cells influences kidney fibrosis, the common endpoint for CKD with an excessive accumulation of extracellular matrix (ECM). Senescence is a special state of cells characterized by permanent cell cycle arrest and limitation of proliferation, which promotes fibrosis by releasing senescence-associated secretory phenotype (SASP) factors. The accumulation of PBUTs in CKD causes oxidative stress and increases the production of inflammatory (SASP) factors that could trigger fibrosis. Recent studies provide some clues that PBUTs may also promote senescence in kidney tubular cells. This review provides an overview on how senescence contributes to CKD and the involvement of PBUTs in this process, and how kidney senescence can be studied, Finally, some suggestions for future therapeutic options for CKD while targeting senescence are given.

Bacteria’s ability to withstand the detrimental effects of antimicrobials may take the form of resistance or tolerance with the minimum inhibitory concentration (MIC), the mutant prevention concentration (MPC), and the mutant selection window as salient concepts. Isolates exposed for 30 days to different concentrations of selected antibiotics, biocides, and heavy metals, singly and in combination, were additionally exposed to very high (15 × MIC) concentrations of ampicillin., and their tolerance was calculated the time to kill 99.9% of the isolate population (MDK99.9). These values were increased by 30 to 50% in test isolates compared to the untreated control. BAC 10-exposed isolates had the highest tolerance increase, and the tolerance appeared to originate from two sources, i.e., stochastic persistence and genetic-induced persistence, involving multiple genes using diverse mechanisms. The mutant selection window of the isolates to ampicillin, amoxicillin, and oxytetracycline also slightly increased compared to the control, indicating the amplification of persister cells during the 30-day exposure. These findings indicate that bacterial exposure to sub-inhibitory concentrations of environmental chemical stressors may not always result in the development of antimicrobial resistance but could initiate this process by selecting for persisters that could evolve into resistant isolates.

Abstract: Background: The diagnosis of nasal airway disorders relies on questionnaires, subjective data, and objective data. Interpretation of objective data obtained from measurement technology is not well understood by providers and researchers who use the equipment to test nasal airway function, justifying the need to cre-ate a new clinical tool. The Davidson Airway Function & Nasal Evaluation (DAFNE) Scoring System is a web-based scoring system that allows healthcare providers (MDs, PAs, PTs, APRNs, DMDs, DDSs, SLPs, and DCs) and researchers who treat nasal obstruction and breathing disorders to make more accurate diagnostic decisions, select the appropriate treatment for individualized patient care, monitor treatment progression and outcomes, and show how to approach a collaborative care model with other healthcare professionals. The current technologies, such as 4-phase rhinomanometry, use a simple approach that relies on a measurement tracing intersecting a color-coded y-axis on a four-quadrant graph with diagnostic numeric data output de-scribing nasal airflow and resistance. This is a good source of biofeedback demonstrating abnormal nasal breathing patterns but lacks interpretation guidelines to describe the severity of disease. The more sophisti-cated proprietary DAFNE approach uses multiple parameters which include airflow restriction, speed, vol-ume, and patient characteristics to identify patients’ disease progression much more accurately. Additionally, it explains how to segregate patients into appropriate treatment options which minimizes risks and compli-cations associated with sleep and breathing disorders while improving patient outcomes. Methods: Electronic searches of PubMed, MEDLINE, EMBASE Cochrane Library, and Scopus of publications between 1988-2022 were necessary to identify studies which determined the ranges of nasal function measurement parameters among three airway measurement technologies used in writing the DAFNE Score algorithm. The performance of DAFNE was evaluated compared to the research data and patient demographics used in previous studies. Results: By using primary outcome measurements from the literature, we were able to create a reliable, re-peatable, and validated tool to facilitate patient identification, treatment stratification, and collaboration for sleep and nasal breathing dysfunction. Subsequently, we found DAFNE could be used to identify the appro-priateness of a sleep study. Conclusions: DAFNE Scoring System has demonstrated the ability to detect high risk patients in the pediatric and adult populations susceptible of sleep apnea and breathing dysfunction needing a sleep study and treatment to improve nasal airway function and sleep. DAFNE Scoring System should be used as an adjunct tool in routine clinical practice and research to further understand the technol-ogy data output, identify patients at risk, stratify treatment options, progress, and stabilization after treatment, and how to collaborate with other healthcare providers to improve patient outcomes.

Background: The Davidson Airway Function &amp; Nasal Evaluation (DAFNE) Scoring System was developed as an intuitive and research-based scoring system that could be validated through beta testing and easily introduced to healthcare providers of several subspecialties who treat nasal obstruction and breathing disorders (MDs, PAs, PTs, APRNs, DDSs, and DCs). This scoring system was shown to increase the knowledge of airway function, nasal measurement parameters, and identification of proper treatment options for sleep and breathing disorders. The basis for the DAFNE score was developed from a systematic review of nasal measurement data. Methods: Electronic searches of PubMed, MEDLINE, EMBASE Cochrane Library, and Scopus of publications between 1988-2022 were used to identify studies validating nasal function measurement parameters to create the algorithm for the DAFNE Score™. The systematic review was accomplished using the 2020 ‘Preferred Reporting Items for Systematic Reviews’ (PRISMA) guidelines. Results: Twenty studies met the inclusion criteria for systematic review. Primary outcomes measurements demonstrated reliability, repeatability and validity of the DAFNE measurement technologies, data and output. Conclusions: The data analysis and systematic review uncovered a need and framework to develop and validate a web-based software algorithm for global access to improve the understanding of data interpretation of nasal measurements from three nasal measurement technologies. DAFNE Scoring should be used as an adjunct tool in routine clinical practice and research to further understand the technology data output and how to collaborate with other healthcare providers to improve patient outcomes.

The three-armed cluster-randomized trial ARena (Sustainable reduction of antibiotic-induced antimicrobial resistance) aimed to foster appropriate antibiotic use and reduce overprescribing in German ambulatory care to counter antibiotic resistance. Multi-faceted interventions targeted primary care physicians, teams and patients. This study examined effectiveness of the implementation program. ARena was conducted in 14 primary care networks with 196 practices. All arms received data-based feedback on antibiotics prescribing and quality circles. Arms II and III received different add-on components each. Primary outcome examined is the prescribing rate for systemic antibiotics for cases with non-complicated acute infections (upper respiratory tract, bronchitis, sinusitis, tonsillitis, otitis media). Secondary outcomes refer to prescribing of quinolones and guideline-recommended antibiotics. Based on pseudonymized quarterly claims data, mixed logistic regression models examined pre-post intervention antibiotic prescribing rate changes and compared to matched standard care. A significant rate reduction (arm I 11.7%; arm II 9.9%; arm III 12.7%) and significantly lower prescribing rates were observed for all arms (20.1%, 18.9% and 23.6%) compared to matched standard care (29.4%). Fluoroquinolone prescribing was reduced in all intervention arms and rates for recommended substances generally increased. No significant post-interventional difference between intervention arms was detected. Findings indicate implementation program impact compared to standard care. Trial registration: ISRCTN, ISRCTN58150046

As Chronic Non-Communicable Diseases (CNCD) increase, preventive approaches become more crucial. In this review, Calorie Restriction (CR) effects on human beings were evaluated, comparing benefits and risks of different CR diets: classic CR vs ketosis-inducing diets, including Intermittent Fasting (IF), Classic Ketogenic Diet (CKD), Fasting Mimicking Diet (FMD), Very-Low-Calorie Ketogenic Diet (VLCKD) and Spanish Ketogenic Mediterranean Diet (SKMD). Special emphasis on Insulin Resistance (IR) was placed, as it mediates Metabolic Syndrome (MS), a risk factor for CNCD, and predicts MS diagnosis. CR is the most robust intervention known to increase lifespan and health span, with high evidence and known biochemical mechanisms. CR improves cardiometabolic risk parameters, boosts exercise insulin sensitivity response, and there may be benefits of implementing moderate CR on healthy young and middle-aged individuals. However, there is insufficient evidence to support long-term CR. CKD is effective for weight and MS management, and may have additional benefits such as prevention of muscle loss and appetite control. SKMD has extreme significance benefits for all the metabolic parameters studied. Studies show inconsistent benefits of IF compared to classic CR. More studies are required to study biochemical parameters, reinforce evidence, identify risks, and seek effective and safe nutritional CR approaches.

This review paper gives Excel functions for highly precise Colebrook’s pipe flow friction approximations developed by users. All shown codes are implemented as User Defined Functions – UDFs written in Visual Basic for Applications – VBA, a common programming language for MS Excel spreadsheet solver. Accuracy of the friction factor computed using nine to date the most accurate explicit approximations is compared with the sufficiently accurate solution obtained through an iterative scheme which gives satisfying results after sufficient number of iterations. The codes are given for the presented approximations, for the used iterative scheme and for the Colebrook equation expressed through the Lambert W-function (including its cognate Wright ω-function). The developed code for the principal branch of the Lambert W-function has additional and more general application for solving different problems from variety branches of engineering and physics. The approach from this review paper automates computational processes and speeds up manual tasks.

An evaluation of emerging issues in One Health (OH) in Sub-Saharan Africa was undertaken to map the existing OH initiatives in Sub-Saharan African (SSA) countries. Desk review, expert opinions survey, limited interviews and wider consultations with selected OH stakeholders were conducted. The strengths, weaknesses, opportunities and threats to OH initiatives were identified. OH influence, interest and impacts were evaluated. One Health is transiting from multidisciplinary to transdisciplinary concepts and OH viewpoint should move from ‘proxy for zoonoses’, to include issues of climate change, nutrition and food safety, social sciences, geography, policy and planning, economics, welfare and well-being, antimicrobial resistance (AMR), vector-borne diseases, toxicosis and pesticides issues. While the identified major strengths should be boosted, the weaknesses should be addressed.OH Networks in SSA were spatially and temporally spread across SSA and stakeholders were classified as key, latent, marginal and OH defenders. Imbalance in stakeholders’ representation led to hesitation in buying-in from stakeholders who are outside the main networks. Theory of change, monitoring and evaluation frameworks, and tools to standardized evaluation of OH policies is needed for sustained future of OH and the future OH engagement should be outputs and outcomes-driven and not activity-driven.National roadmap for OH implementation and institutionalization is necessary and proofs of concepts in OH should be verified and scaled-up. Dependence on external funding is unsustainable and must be addressed. Necessary policy and legal instrument to support OH nationally and sub-nationally should be implemented taking cognizance of contemporary issues like urbanization, endemic poverty and other emerging issues. Utilizing current technologies and OH approach to address ongoing pandemic of COVID-19 and other emerging diseases is desirable. Finally, OH implementation should be anticipatory and not reactive to significantly benefit budgeting and contain disease outbreaks in animal sources before the risk of spillover to human can be envisaged.

Pasmo (Septoria linicola) is a fungal disease causing major losses in seed yield and quality, and stem fibre quality in flax. Pasmo resistance (PR) is quantitative and has low heritability. To improve PR breeding efficiency, the accuracy of genomic prediction (GP) was evaluated using a diverse worldwide core collection of 370 accessions. Four marker sets, including three defined by 500, 134, and 67 previously identified quantitative trait loci (QTL) and one of 52,347 PR-correlated genome-wide single nucleotide polymorphisms, were used to build ridge regression best linear unbiased prediction (RR-BLUP) models using pasmo severity (PS) data collected from field experiments performed during five consecutive years. With five-fold random cross-validation, GP accuracy as high as 0.92 was obtained from the models using the 500 QTL when the average PS was used as the training dataset. GP accuracy increased with training population size, reaching values >0.9 with training population size greater than 185. Linear regression of the observed PS with the number of positive-effect QTL in accessions provided an alternative GP approach with an accuracy of 0.86. The results demonstrate the GP models based on marker information from all identified QTL and the 5-year PS average is highly effective for PR prediction.

Interviews from strength and conditioning coaches across all levels of athletic competition identified their two biggest concerns with the current state of wearable technology: (a) the lack of solutions that accurately capture data "from the ground up" and (b) the lack of trust due to inconsistent measurements. The purpose of this research is to investigate the use of liquid metal sensors, specifically Liquid Wire sensors, as a potential solution for accurately capturing ankle complex movements such as plantar flexion, dorsiflexion, inversion, and eversion. Sensor stretch linearity was validated using a Micro-Ohm Meter and a Wheatstone bridge circuit. Sensors made from different substrates were also tested and discovered to be linear at multiple temperatures. An ankle complex model and computing unit for measuring resistance values were developed to determine sensor output based on simulated plantar flexion movement. The sensors were found to have a significant relationship between the positional change and the resistance values for plantar flexion movement. The results of the study ultimately confirm the researchers' hypothesis that liquid metal sensors, and Liquid Wire sensors specifically, can serve as a mitigating substitute for inertial measurement unit (IMU) based solutions that attempt to capture specific joint angles and movements.

The comprehensive anabolic effects of insulin throughout the body, in addition to the control of glycemia, also include ensuring lipid homeostasis and anti-inflammatory modulation, especially in adipose tissue (AT). The prevalence of obesity, defined as a body mass index (BMI) ≥ 30 kg/m2, has been increasing worldwide on a pandemic scale with accompanying syndemic health problems, including glucose intolerance, insulin resistance (IR) and diabetes. Impaired tissue sensitivity to insulin or IR paradoxically leads to diseases with an inflammatory component despite hyperinsulinemia. Therefore, an excess of visceral AT in obesity initiates chronic low-grade inflammatory conditions that interfere with insulin signaling via insulin receptor (INSR). Moreover, in response to IR, hyperglycemia itself stimulates a primarily defensive inflammatory response associated with the subsequent release of numerous inflammatory cytokines and a real threat of organ function deterioration. In this review, all components of this vicious cycle are characterized with particular emphasis on the interplay between insulin signaling and both the innate and adaptive immune responses related to obesity. Increased visceral AT accumulation in obesity should be considered the main environmental factor responsible for the disruption in the epigenetic regulatory mechanisms in the immune system, resulting in autoimmunity and inflammation.

Studies have previously described the occurrence of multidrug-resistant (MDR) Escherichia coli in human and veterinary medical settings, livestock, and, to a lesser extent, in the environment and food. While they mostly analyzed foodborne E. coli regarding phenotypic and sometimes genotypic antibiotic resistance and basic phylogenetic classification, we have limited understanding of the in vitro and in vivo virulence characteristics and global phylogenetic contexts of these bacteria. Here, we investigated an E. coli strain (PBIO3502) isolated from a pork sausage in Germany in 2021 in-depth. Whole-genome sequence analysis revealed sequence type (ST)58, which is an emerging international high-risk clonal lineage. In addition to its MDR phenotype that mostly matched the genotype, PBIO3502 demonstrated pronounced virulence features, including in vitro biofilm formation, siderophore secretion, serum resilience, and in vivo mortality in Galleria mellonella larvae. Along with the genomic analysis indicating close phylogenetic relatedness of our strain with publicly available, clinically relevant representatives of the same ST, these results suggest the zoonotic and pathogenic character of PBIO3502 with the potential to cause infection in humans and animals. Also, our study highlights the necessity of the One Health approach while integrating human, animal, and environmental health, as well as the role of meat products and food chains in the putative transmission of MDR pathogens.

Animal products, in particular dairy and fermented products, are natural, major sources of lactic acid bacteria (LAB). Due to their antimicrobial properties, LAB are used in humans and in animals, with beneficial effects, as probiotics or in the treatment of a variety of diseases. In livestock production, LAB contribute to animal performance, health, and productivity. In the food industry, LAB are applied as bioprotective and biopreservation agents, contributing to improve food safety and quality. However, some studies have described resistance to relevant antibiotics in LAB, with the concomitant risks associated to the transfer of antibiotic resistance genes to foodborne pathogens, their potential dissemination throughout the food chain, and the environment. Here, we summarize the application of LAB in livestock and animal products, as well as the health impact of LAB in animal food products. In general, the beneficial effects of LAB on the human food chain seem to outweigh the potential risks associated with their consumption as part of animal and human diets. However, further studies and continuous monitorization efforts are needed to ensure their safe application in animal products and in the control of pathogenic microorganisms, preventing the possible risks associated with antibiotic resistance and, thus, protecting public health.

Extracellular vesicles (EV) released by tumor cells are a major aspect of the resistance-associated secretory phenotype (RASP), by which immune evasion can be established. Heat shock proteins (HSPs) are an evolutionarily conserved family of molecular chaperones, which stabilize proteins, minimize protein misfolding and aggregation within the cell, besides facilitating protein translocation, refolding and degradation. (i) Releases of extracellular HSPs (ex-HSP) and EV-associated HSPs (EV-HSP) are essential in RASP, by which molecular cotransfer of HSPs with oncogenic factors into recipient cells can promote cancer progression and resistance against stress such as hypoxia, radiation, chemicals, and immune system. (ii) RASP of tumor cells can eject anticancer drugs, molecularly targeted therapeutics, and immune checkpoint inhibitors with EVs. (iii) Cytotoxic lipids can be also released from tumor cells as RASP. Nevertheless, ex-HSP and EV-HSP can play immunostimulatory and immunosuppressive roles by binding to receptors such as LRP1/CD91/A2MR, scavenger receptors, and toll-like receptors expressed on recipient cells. Liquid biopsy of HSPs in body fluids may be useful in diagnosis, prognosis, and treatment in cancer. Regarding HSP90-targeted therapeutics, we summarize the pros, cons, and problem solutions in this review. Although production of HSPs are canonically induced by heat shock factor 1 (HSF1) and hypoxia-inducible factor 1 (HIF-1), recent studies discovered that production of HSPs is also regulated by matrix metalloproteinase 3 (MMP3) and heterochromatin protein 1 (HP1) and production of cochaperone CDC37 is reciprocally regulated by myeloid zinc finger 1 (MZF1) and SCAN-D1.

Biofilm-associated bacterial infections are the major reason for treatment failure in many diseases including burn trauma infections. Uncontrolled inflammation induced by bacteria leads to materiality, tissue damage and chronic diseases. Specialized proresolving mediators (SPMs), including maresin-like lipid mediators (MarLs), are enzymatically biosynthesized from omega-3 essential long-chain polyunsaturated fatty acids, especially docosahexaenoic acid (DHA) by macrophages and other leukocytes. SPMs exhibit strong inflammation-resolving activities, especially inflammation provoked by bacterial infection. In this study, we explored the potential direct inhibitory activities of three MarLs on gram-positive (Staphylococcus aureus) and gram-negative (Pseudomonas aeruginosa and Escherichia coli) bacteria in their biofilms that are leading bacteria in burn trauma related infections. We also examined the effects of MarLs on the bactericidal activities of a typical broad-spectrum antibiotics carbenicillin on these bacteria in their preformed biofilms. The results revealed that MarLs combined with carbenicillin can inhibit the survival of gram-positive and gram-negative bacteria in their biofilms although MarLs alone did not exhibit bactericidal activity. Thus, our findings suggest that the combination of MarLs and carbenicillin can lower the antibiotic requirements to kill the bacteria in preformed biofilms.

Cardiovascular diseases (CVDs) and type 2 diabetes mellitus (T2DM) are two of the four major chronic non-communicable diseases (NCDs), representing the leading cause of death worldwide. Several studies demonstrate that endothelial dysfunction (ED) plays a central role in the pathogenesis of these chronic diseases. Although it is well known that systemic chronic inflammation and oxidative stress are primarily involved in the development of ED, recent studies have shown that perivascular adipose tissue (PVAT) is implicated in its pathogenesis, also contributing to the progression of atherosclerosis and to insulin resistance (IR). In this review we describe the relationship between PVAT and ED, and we also analyse the role of PVAT in the pathogenesis of CVDs and T2DM, further assessing its potential therapeutic target with the aim of restoring normal ED and reducing global cardiovascular risk.

One of the leading causes of death worldwide, in both man and woman, is cancer. Despite the significant development in therapeutic strategies, the inevitable emergence of drug resistance limits the success and impedes the curative outcome. Intrinsic and acquired resistance are common mechanisms responsible for cancer relapse. Several factors crucially regulate tumourigenesis and resistance, including physical barriers, tumour microenvironment (TME), heterogeneity, genetic and epigenetic alterations, the immune system, tumour burden, growth kinetics and undruggable targets. Moreover, transforming growth factor-beta (TGF-β), Notch, epidermal growth factor receptor (EGFR), integrin-extracellular matrix (ECM), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), phosphoinositol-3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR), wingless-related integration site (Wnt)/β-catenin), Janus kinase/signal transducers and activators of transcription (JAK/STAT) and RAS/RAF/mitogen-activated protein kinase (MAPK) signalling pathways are some of the key players that have a pivotal role in drug resistance mechanisms. To guide future cancer treatments and improve results, a deeper comprehension of drug resistance pathways is necessary. This review will cover both intrinsic and acquired resistance and give a comprehensive overview of recent research on mechanisms that enable cancer cells to bypass barriers put by treatments, and like “satellite navigation”, find alternative routes to carry on their “journey” to cancer progression.

Background: The burden of resistant fungal infection is rising in patients with pulmonary disease. Options for antifungal therapy are limited, and the only orally-available antifungals, the triazoles, demonstrate inter and intra-patient variability, non-linear kinetics, toxicity, drug interactions and increasing antifungal resistance. Therapeutic drug monitoring (TDM) of itraconazole, voriconazole and posaconazole has been necessary to ensure their safety and efficacy, but is considered unnecessary for the newest triazole isavuconazole, use of which is increasing. Aims: To characterise isavuconazole susceptibility of Aspergillus fumigatus isolates in a tertiary respiratory referral centre to understand prevalence of isavuconazole antimicrobial resistance. To retrospectively review experience of isavuconazole use in this setting, assessing tolerability and therapeutic drug monitoring. Methods: A retrospective observational analysis of adult patients with respiratory disease in a tertiary hospital setting between Sept 2016 and Aug 2021. Clinical cultures were collected and triazole Minimum inhibitory concentration (MIC) were recorded (based on Clinical &amp; Laboratory Standards Institute (CLSI method)). Isavuconazole trough drug levels were carried out as part of the standard of care. Clinical outcomes of treatment were evaluated, along with drug tolerance and TDM. Results: During the study period, isavuconazole susceptibility testing was performed on 26 Aspergillus spp isolates. 80.8% of Aspergillus fumigatus isolates were non-wild type and had isavuconazole MIC &gt; 1mg/L, and 73.0% had MIC above the EUCAST (European Committee on Antimicrobial Susceptibility Testing) epidemiological cut-off (ECOFF) of 2mg/L. There was good correlation between isavuconazole MIC and voriconazole MIC (r =0.7, p=0.0002). 54 patients had isavuconazole therapy over the study period with a median duration of 7.7 months (IQR 0.79 - 16.42). 67% of patients were able to tolerate isavuconazole, despite toxicity with prior azole treatment being the primary indication for use (in 61.8%). Increased age (r=0.29; p=0.03 (95%CI 0.02,0.52)) and gender (r for female sex=-0.31; p=0.027 (95%CI -0.52,0.036) were associated risk factors for development of adverse events (AEs). 127 Isavuconazole TDM levels were performed over the study period with 90% &gt;1mg/L and 72% &gt;2mg/L. Dose change from manufacturer’s dose recommendation, however, was required in 15% of patients to achieve a serum drug concentration above the EUCAST ECOFF or Area of technical uncertainty (ATU) value of 2mg/L. Conclusion: In our study, we show use of Isavuconazole as salvage therapy in chronic pulmonary fungal disease setting with high prevalence of azole resistance. Isavuconazole MICs demonstrated good correlation with voriconazole MICs suggesting the latter could be a useful surrogate marker for isavuconazole susceptibility. Although Isavuconazole achieved excellent serum drug concentrations at standard dose compared to other azole drugs, we highlight the importance of antifungal stewardship and TDM monitoring to optimise therapy in this setting.

In the context of improving aircraft safety, this study focuses on the development and evaluation of a graphene-based ice detection system using an environmental chamber. The research is driven by the need for more accurate and efficient ice detection methods, crucial in mitigating in-flight icing hazards. The methodology employed involves testing flat graphene-based sensors in a controlled environment, simulating a variety of climatic conditions that could be experienced in an aircraft during its entire flight. The environmental chamber enabled precise manipulation of temperature and humidity levels, thereby providing a realistic and comprehensive test bed for sensor performance evaluation. The results were significant, revealing the graphene sensors’ heightened sensitivity and rapid response to the subtle changes in environmental conditions, especially the critical phase transition from water to ice. This sensitivity is the key to detecting ice formation at its onset, a critical requirement for aviation safety. The study concludes that graphene-based sensors, tested under varied and controlled atmospheric conditions, exhibit a remarkable potential in enhancing ice detection systems for aircraft. Their lightweight, efficient and highly responsive nature makes them a superior alternative to traditional ice detection technologies, paving the way for more advanced and reliable aircraft safety solutions.

In the past decade, targeted therapies for solid tumors, including non-small cell lung cancer (NSCLC), have advanced significantly, offering tailored treatment options for patients. However, individuals without targetable mutations pose a clinical challenge, as they may not respond to standard treatments like immune-checkpoint inhibitors (ICIs) and novel targeted therapies. While the mechanism of action of ICIs seems promising, the lack of a robust response limits their widespread use. Although the expression levels of programmed death ligand 1 (PD-L1) on tumor cells are used to predict ICI response, identifying new biomarkers, particularly those associated with the tumor microenvironment (TME), is crucial to address this unmet need. Recently, inflammatory cytokines such as interleukin-1 beta (IL-1β) have emerged as a key area of focus and hold significant potential implications for future clinical practice. Combinatorial approaches of IL-1β inhibitors and ICIs may provide a potential therapeutic modality for NSCLC patients without targetable mutations. In this review, we discuss the role of IL-1β in NSCLC, its involvement in inflammatory pathways, and explore its potential role in the treatment of NSCLC.

We previously described a model of deep intrinsic resistance of breast cancer wherein we used a function-based approach to selection of cancer cells that can survive a variety of challenges in prolonged but reversible quiescence. Our experimental results suggested that resistant cancer cells possess a variety of mechanisms, including modifications of the epigenome and transcriptome, for generating a high degree of cellular heterogeneity. In the present study, we evaluated JIB-04, a small-molecule epigenetic inhibitor initially discovered to inhibit cancer growth, to determine its ability to affect deep intrinsic resistance in our breast cancer model. We found that long pretreatment with JIB-04 sensitized resistant triple-negative inflammatory breast cancer cells and their parental cell line SUM149 to the chemotherapeutic drugs doxorubicin and paclitaxel. Resistant cancer cells derived from another inflammatory breast cancer cell line, FC-IBC02, were considerably more sensitive to JIB-04 than was the parental cell line. Investigating a mechanism of sensitization, we found that JIB-04 exposure increased the expression of PD-L1 in resistant cells, suggesting that JIB-04 may also sensitize resistant breast cancer cells to anti-PD-L1 immune therapy. Finally, these results support the usefulness of our experimental strategy for evaluating anticancer agents such as JIB-04 that may halt cancer evolution and prevent development of cancer resistance to currently used therapies.

The emergence of acquired resistance to EGFR-TKIs is almost inevitable even after a remarkable clinical response. Secondary mutations such as T790M and C797S are responsible for the resistance to 1st/2nd generation (1/2G) TKIs and 3G TKIs, respectively. To overcome both the T790M and C797S mutations, novel 4G EGFR-TKIs are now under early clinical development. In this study, we evaluated the efficacy of a 4G EGFR-TKI in the treatment of lung cancer with EGFR mutation as well as explored resistance mechanisms to a 4G TKI. First, we compared the efficacies of seven TKIs including a 4G TKI, BI4020, against Ba/F3 cell models that simulate resistant tumors after frontline osimertinib treatment failure because of a secondary mutation. We also established acquired re-sistant cells to BI4020 by chronic drug exposure. Ba/F3 cells with an osimertinib-resistant secondary mutation were refractory to all 3G TKIs tested (alflutinib, lazertinib, rezivertinib, almonertinib, and befotertinib). BI4020 inhibited the growth of C797S-positive cells; however it was not effective against L718Q-positive cells. Erlotinib was active against all Ba/F3 cells tested. In the analysis of resistance mechanisms of BI4020 resistant (BIR) cells, none harbored secondary EGFR mutations. HCC827BIR cells had MET gene amplification and were sensitive to a combination of capmatinib (MET-TKI) and BI4020. HCC4006BIR and H1975BIR cells exhibited epithelial to mesenchymal transition. This study suggests that erlotinib may be more suitable than 4G TKIs to overcome sec-ondary mutations after front-line osimertinib. We found that off-target mechanisms that cause re-sistance to earlier generation TKIs will also cause resistance to 4G TKIs.