Acetyleugenol is a phytochemical compound with broad effect against infectious diseases and tumors. Here, we extracted, characterized and elucidated the structure of acetyeugenol, for the first time, from the leaves of Acacia nilotica (L.)―a well-known medicinal plant. The broad antibacterial potential of acetyleugenol was first confirmed against seven bacterial pathogenic isolates with best activity against Proteus sp., Salmonella typhi, Staphylococcu aureus, and Streptococcus pneumonia, which showed similar or better zone of inhibition to that of the control amoxicillin. To further investigate its effect against Mycobacterium tuberculosis, acetyleugenol and its indole and phenyl analogs were subjected to molecular docking experiments against two potential tuberculosis drug targets―MtPknE and MtPknB Ser/Thr protein kinases. The results reveal that all of the analogs have improved docking scores comparing to the acetyleugenol. The indole analogs EUG-1 and EUG-3 were more effective with better docking scores for MtPknE with –11.08 and –10.05 kcal/mol, respectively. Similar results were obtained for the MtPknB. In contrast, only the EUG-2 phenyl analog has given rise to similar docking scores for both targets. This opens the door for further comprehensive studies on these acetyleugenol analogs with in vitro and in vivo experiments to validate and get more insights into their mechanisms of action.

Resistance to hormone therapy and disease progression is the major challenge in clinical management of prostate cancer (PC). Drugs currently used in PC therapy initially show a potent antitumor effect. Nevertheless, PC gradually develops resistance, relapses and spreads. Most patients develop, indeed, castrate-resistant PC (CRPC), which is almost incurable. The nerve growth factor (NGF) acts on a variety of non-neuronal cells by activating the NGF tyrosine-kinase receptor, TrkA. NGF signaling is deregulated in PC. In androgen-dependent PC cells, TrkA mediates the proliferative action of NGF through its cross talk with the androgen receptor (AR). Epithelial PC cells, however, acquire the ability to express NGF and TrkA, as the disease progresses, indicating a role for NGF/TrkA axis in PC progression and androgen-resistance. We here report that once activated by NGF, TrkA mediates proliferation, invasiveness and epithelial-mesenchyme transition (EMT) in various CRPC cells. NGF promotes organoid growth in 3D models of CRPC cells, and specific inhibition of TrkA impairs all these responses. Thus TrkA represents a new biomarker to target in CRPC.

In California, an average of 41,900 patients are diagnosed annually with Staphylococcus bacterial infection; out of these, 24,090 patients have methicillin-resistant Staphylococcus aureus (MRSA) infection and 17,810 patients have methicillin-sensitive Staphylococcus aureus (MSSA) infection. The aim of this paper is to find out whether there is a significant difference in strain dominancy and in what direction. The paper gathered and analyzed data for period of five years of infection rate due to Staphylococcus aureus. This study indicates that a significant difference in dominancy exists, the MRSA infection rate (an average of five years period) is 1.35 times higher than the MSSA infection rate (P-value < 0.05, CI: 95%), but the gap between the two infection rates is decreasing. The infection rate of both MRSA and MSSA is in a path of decline.

Due to the rapid emergence of multi drug resistant (MDR) pathogens against which current an-tibiotics are no longer functioning, severe infections are becoming practically untreatable. Con-sequently, the discovering of new classes of effective antimicrobial agents with novel modes of action is becoming increasingly urgent. The bioactivity of Cannabis sativa, an herbaceous plant used for millennia for medicinal and recreational purposes, is mainly due to its content in phytocan-nabinoids (PCs). Among the 180 PCs detected, cannabidiol (CBD), Δ8 and Δ9-tetrahydrocannabinols (Δ8-THC and Δ9-THC), cannabichromene (CBC), cannabigerol (CBG), cannabinol (CBN) and some their acidic precursors have demonstrated from moderate to potent antibacterial effects against Gram-positive bacteria (MICs 0.5–8 µg/mL), including methicillin-resistant Staphylococcus aureus (MRSA), epidemic MRSA (EMRSA), as well as fluoroquinolones and tetracycline-resistant strains. Particularly, the not psychotropic CBG was also capable to inhibit MRSA biofilm formation, to eradicate that mature, and to rapidly exterminate MRSA persiters cells. On this scenario, CBG, as well as other minor not psychotropic PCs, such as CBD, and CBC could represent promising compounds for developing novel antibiotics with high therapeutic potential. Anyway, further studies are necessary, needing abundant quantities of such PCs, scarcely provided naturally by Cannabis plants. Here, after an extensive overture on cannabinoids including their reported an-timicrobial effects, aiming at easing the synthetic production of the necessary amounts of CBG, CBC and CBD for further studies, we have, for the first time, systematically reviewed the synthetic pathways utilized for their synthesis, reporting both reaction schemes and experimental details.

The development of multiple drug resistant (MDR) cancer all too often signals the need for alternative toxic therapy or palliative care. Our recent in vivo and in vitro studies using canine MDR lymphoma cancer cells demonstrated that the Anaphase Promoting Complex (APC) is impaired in MDR cells compared to normal canine control and drug sensitive cancer cells. Here, we sought to establish whether this phenomena is a generalizable mechanism independent of species, malignancy type or chemotherapy regime. To test the association of blunted APC activity with MDR cancer behavior, we used matched parental and MDR MCF7 human breast cancer cells, and a patient derived xenograft (PDX) model of human breast cancer. We show that APC activating mechanisms, such as APC subunit 1 (APC1) phosphorylation and CDC27/CDC20 protein associations, are reduced in MCF7 MDR cells when compared to chemosensitive matched cell lines. Consistent with impaired APC function in MDR cells, APC substrate proteins failed to be effectively degraded. Similar to our previous observations in canine MDR lymphoma cells, chemical activation of the APC using Mad2 Inhibitor-1 (M2I-1) in MCF7 MDR cells enhanced APC substrate degradation and resensitized MDR cells in vitro to the cytotoxic effects of the alkylating chemotherapeutic agent, Doxorubicin (DOX). Using cell cycle arrest/release experiments we show that chemo-sensitive and -resistant MCF7 cells progress through the cell cycle at similar rates, but mitosis is delayed in MDR cells with elevated substrate levels. When treated with M2I-1, MDR cells progress through mitosis at a faster rate that coincides with reduced levels of APC substrates. In our PDX model, mice growing a clinically-MDR human breast cancer tumor show significantly reduced tumor growth when treated with M2I-1, with evidence of increased DNA damage and apoptosis. Thus, our results strongly support the hypothesis that APC impairment is a driver of aggressive tumor development and that targeting the APC for activation has the potential for meaningful clinical benefits in treating recurrent cases of MDR malignancy.

Vancomisin resistant enterococcus(VRE), is a resistant microorganism which colonizates and causes infections in hospitalized patients. It was aimed to show the spread of vancomycin-resistant Enterococcus (fVREfm) step-by-step in all intensive care units, which started with the growth of vancomycin-resistant Enterococcus faecium (VREfm) on 02.12.2021 in the blood culture of a patient hospitalized in the anesthesia intensive care unit of our hospital and was found to have reached epidemic size in the surveys. Rectal swab samples were taken from all patients hospitalized in intensive care units, VRE colonization was determined and the VanA and VanB resistance genes associated with vancomycin resistance of VREfm isolates were determined by PCR method, and clonal association analysis was performed by Arbitrarily Primed-PCR (AP-PCR) and Pulsed-Field Gel Electrophoresis. In our study, VRE was detected in 61 of 2601 rectal swab samples. 54 (85.52%) of the VRE isolates were Enterococcus faecium, 3 (4.91%) was Enterococcus faecalis, 3 (4.91%) was Enterococcus gallinorum, 1 (1.63%) was Enterococcus casseliflavus. It was determined that all of the 54 VREfm isolates, which were the most detected among all VRE isolates, carried the vanA gene. In the clonal association analysis of the isolates by AP-PCR and PFGE methods, it was found that they had 12 different genotypes, 48 of them were included in any cluster, the clustering rate was 88.8%, and the largest cluster was genotype 1 cluster with 36 isolates. Of the 54 patients with VREfm isolated recently, 18.51 percent of the clinical samples were isolated before the survey, and 9.24% were isolated after the survey. It was determined that 100% of VREfm isolates were resistant to ampicillin, levofloxacin, ciprofloxacin, high-level gentamicin, trimethoprim-sulfamethoxazole, teicoplanin, 7.4% to tigecycline and 1.85% to linezolid. In our study, in the clonal association analysis performed by isolating VREfm in rectal swab samples, it was found that 88.8% of the samples were indistinguishably similar and the increase in the number of VREfm infections after the index case in our hospital was associated with the epidemic. VREfm infections cause long term hospitalization, costs and also deaths, which shows the seriousness of the event, and the importance of the combination of epidemiological and molecular analysis in epidemic research.

Although the beneficial health effects of prebiotics have been demonstrated in numerous research papers, its incorporation into daily food remains unfamiliar to consumers. This work evaluates the resistant maltodextrin (RMD) addition in the sensory attributes of pasteurized orange juice, together with the physico-chemical properties and the aromatic profile. RMD addition moderately improved almost all sensory attributes evaluated by panellists. It also proportionally increased °Brix together with density and decreased acidity. Colour changes were registered with higher RMD concentrations. Orange pulp presence affected the volume particle size distribution analysis while RMD addition did not exercised any effect. The aroma volatile compounds were also analysed. Pulp-added samples marked higher alcohol and aldehydes quantity, whereas pulp-free samples registered higher terpenes and terpenoids values. Ketones and acids were also quantified. RMD had a moderate impact on volatile compounds quantifications, playing the orange pulp presence a much more decisive role. A correlation analysis was also performed to relate instrumental and sensorial determinations for all samples. This work proves that the addition of RMD to orange juice is technologically feasible while also achieving a good response at the sensory level.

The increased emergence of multidrug-resistant Helicobacter pylori influences the prevention of stomach cancer. Zingiber officinale is a plant usually used in folk medicine to treat a variety of diseases involving infections, nausea, vomiting, peptic ulcer, dyspepsia, and inflammation. This study was conducted to evaluate the ability of Z. officinale extract to combat resistant H. pylori. The disc diffusion, microdilution, and microplate assays were performed to evaluate the susceptibility to antibiotics, and the antibacterial and antibiofilm activities of the Z. officinale extracts. Using the checkerboard method, the combined effects of the gentamicin and Z. officinale extract were investigated. In addition, anti-inflammatory activity and GC-MS analysis were determined by the modified protocol. According to the findings, H. pylori isolates exhibited resistance rates of 56.33, 50.0, and 45.85 for metronidazole, gentamicin, and tetracycline, respectively. The methanolic extract of Z. officinale had the strongest effectiveness against resistant H. pylori isolates with MIC of 20.0 to 50.0 µg/ml against both H. pylori isolates and the stranded strain NCTC 11637. Z. officinale extract suppress the biofilm formed by H. pylori isolates with a percentage of 92.96% at 50.0µg/ml, compared with 97.19% for gentamicin at the same concentration. According to FICI values, combination of methanolic Z. officinale extract to gentamicin increases bacterial sensitivity to such drugs. Moreover, the Z. officinale extract exhibits strong anti-inflammatory activity. The GC-MS analysis of Z. officinale extract exhibits 17 different chemical compounds. Conclusions: The Z. officinale extract contain the anti-inflammatory compound gingerol as the main constituent which inhibits the growth of H. pylori and its biofilm, are a promising natural therapeutic alternative or enhance antibiotics activity

Staphylococcus aureus (S. aureus) is a major human pathogen that requires new antibiotics with unique mechanism. A new pleuromutilin derivative, 14-O-[(4,6-Diaminopyrimidine-2-yl) thioacetyl] mutilin (DPTM), has been synthesized and proved as a potent antibacterial agent using in vitro and in vivo assays. In the present study, DPTM was further in vitro evaluated against Methicillin-resistant Staphylococcus aureus (MRSA) isolated from dairy farms and outperformed tiamulin fumarate, a pleuromutilin drug used for veterinary. Moreover, a murine skin wound model caused by MRSA infection was established and the healing effect of DPTM was investigated. The results showed that DPTM could promote the healing of MRSA skin infection, reduce the bacterial burden of infected skin MRSA and decrease the secretion of IL-6 and TNF-α inflammatory cytokines in plasma. These results provided the basis for further in-depth drug targeted studies of DPTM as a novel antibacterial agent.

Necrotizing pneumonia due to Methicillin-Resistant Staphylococcus Aureus (MRSA) is devastating and difficult to treat in preterm infants. We report a case of severe MRSA necrotizing pneumonia in a preterm infant. As an add-on rescue therapy to vancomycin, linezolid rapidly cured this case after the failure of vancomycin plus rifampicin. This rapid cure suggests that adjunctive rather than rescue linezolid may be considered in such cases.

Once a wheat sheaf has been sealed and tied up, its packed down straws display the same orientation and zero-divergence. This observation brings us to the mathematical notion of presheaf, i.e., a topological structure in which diverging functions are locally superimposed. We show how the concepts of presheaves and the correlated globular sets, borrowed from category theory and algebraic topology, allow a well-founded mathematical approach to otherwise elusive activities of the brain. The mathematical assessment of brain functions in terms of presheaves: a) explains why spontaneous random spikes synchronize; b) leads to the counterintuitive intuition of antidromic effects in neuronal spikes: when an entrained oscillation propagates from A to B, changes in B lead to changes in A. We provide testable previsions: a) we suggest the proper locations of transcranial magnetic stimulation’s coils to improve the clinical outcomes of drug-resistant epilepsy; b) we advocate that axonal stimulation by external sources backpropagates and alters the neuronal electric oscillatory frequency. Further, we describe how the hierarchical information transmission inside globular sets provides fresh insights concerning different issues at various coarse-grained scales, such as object persistence, memory reinforcement in spite of random noise, Bayesian inferential circuits.

Average of 41,900 patients are diagnosed annually with staphylococcus bacterial infection in California, 24,089 patients have Methicillin-resistant Staphylococcus Aureus (MRSA) and 17,810 patients have Methicillin-Sensitive Staphylococcus (MSSA). This paper demonstrates that there is a difference in mortality rate due to staphylococcus infection between males and females (P-value<0.05, CI 95%). Male patient diagnosed with S. aureus has 1.3 chance of mortality incidence than female patient. In addition, MRSA infection rate is 1.4 times MSSA infection (P-value<0.05, CI 95%), but the gap of infection is decreasing; however, mortality of both infections combined are more than threefold greater compared to three decades ago.

Teclistamab (TEC) is the first B-cell maturation antigen-directed bispecific antibody approved by the European Medicines Agency and Food and Drug Administration for triple-class exposed relapsed/refractory multiple myeloma (RRMM). As TEC is increasingly being used in real-world (RW) settings, this study sought to gather existing RW evidence on effectiveness, safety, healthcare resource utilization, and clinical practices associated with TEC. A systematic literature review was performed to identify RW observational studies of adults with RRMM treated with TEC. Sixty-one records representing 41 unique studies were included; sample sizes ranged from 8 to 572 patients. Where reported, median follow-up ranged from 2.3 to 33.6 months and more than 65% of patients would have been ineligible for the pivotal trial of TEC (MajesTEC-1) in all but one study. Across populations with ≥50 patients, overall response rates ranged from 50 to 66% and cytokine release syndrome (CRS) rates ranged from 18 to 64%. Tocilizumab use for CRS management was reported in 14 studies, with two indicating lower CRS rates (13% and 26%) when used prophylactically. Survival and infection outcomes showed wide variability due to short follow-up in most studies. Overall, early RW effectiveness and safety outcomes of TEC were comparable to findings from MajesTEC-1.

Multidrug-resistant-tuberculosis (MDR-TB) patients are treated with a standardised, short, WHO-regimen, which includes clofazimine (CFZ) and bedaquiline (BDQ) antibiotics. These two antibiotics lead to development of QT prolongation in patients, inhibiting potassium (K+) uptake by targeting the Kv11.1 (hERG) channel of the cardiomyocytes (CMs). However, the involvement of these antibiotics on other K+ transporters of the CMs, as potential mechanisms of QT prolongation, has not been explored. This study determined the effects of CFZ and BDQ on the sodium, potassium-adenosine triphosphatase (Na+,K+-ATPase) activity of CMs, using the rat cardiomyocytes (RCMs). These cells were treated with varying concentrations of CFZ and BDQ individually and in combination (1.25 - 5 mg/L). Thereafter Na+,K+-ATPase activity was determined, followed by intracellular adenosine triphosphate (ATP) quantification and cellular viability determination. Both antibiotics demonstrated dose-response inhibition of the Na+,K+-ATPase activity of the RCMs. The greatest inhibition was demonstrated by combinations of CFZ and BDQ, followed by BDQ alone and lastly CFZ. Neither antibiotic, individually or in combination, demonstrated cytotoxicity under the experimental conditions used. The inhibitory effects of CFZ and BDQ individually and in combination, on the activity of the Na+,K+-ATPase pump of the RCMs highlight the existence of additional mechanisms of QT prolongation by these antibiotics.

The safety concerns associated with current lithium-ion batteries are a significant drawback. A short-circuit within the battery's internal components, such as those caused by a car accident, can lead to ignition or even explosion. To address this issue, a polymer shear thickening electrolyte, free from flammable solvents, has been developed. It comprises a star-shaped oligomer derived from a trimethylolpropane (TMP) core and polyether chains, along with the inclusion of 20 wt.% nanosilica. Notably, the star-shaped oligomer serves a dual function as both the solvent for the lithium salt and the continuous phase of the shear thickening fluid. The obtained electrolytes exhibit an ionic conductivity of 10-6 S cm-1 at 20 °C and 10-4 S cm-1 at 80 °C, with a high Li+ transference number (t+ = 0.79). A nearly thirtyfold increase in viscosity to a value of 1187 Pa s at 25 °C and a critical shear rate of 2 s-1 were achieved. During impact, this electrolyte could enhance cell safety by preventing electrode short-circuiting.

New multilayer 3D nanocomposite wear-resistant ion-plasma hard and superhard coatings Avinit [(TiN-AlN)(Mo-Cr-V-Si)]_n have been developed.The introduction of additional alloying elements (Mo, Cr, V, Si) into the Ti-Al-N coating composition, which have a high affinity for nitrogen and are capable of forming strong nitride nanoparticles in the Ti-N and Al-N layers.This makes it possible to obtain hard and superhard hardening coatings.The metallographic and tribological studies carried out indicate the prospects of the developed multicomponent multilayer nano- and microstructured Avinit coatings for increasing wear resistance and reducing friction coefficients.This paper is devoted to the development and implementation of Avinit vacuum plasma technologies for strengthening cutting and forming tools to improve tool performance.Production tests of cutting tools with Avinit's developed multilayer wear-resistant ion-plasma coatings in production conditions at many large machine-building enterprises have shown their high efficiency.In serial production, the wear resistance of tools increases by 3 to 30 times, stamps by 5 to 100 times, and parts rubbing against abrasive materials by 10 to 100 times.Avinit's vacuum plasma technologies have been successfully implemented in production in the aggregate and engine building, transport engineering, and power engineering industries.Positive experience in applying multicomponent coatings has been gained not only when applying hardening coatings to manufactured cutting tools, but also after regrinding to regrindable carbide cutting tools from domestic and foreign manufacturers.

Background/objectives: The health benefits of resistant starch are well known, but there have not been many studies available documenting the effect of basmati rice products containg resistant starch upon blood glucose level and lipid profile in vivo efficacy. Methods: Common cooking methods were used to prepare basmati rice products including two boiling methods viz. boiling 1 (boiling by absorption), boiling 2 (boiling in extra amount of water), frying and pressure cooking. The cooked rice were held at various temperatures and times: it was made fresh (T1), kept at room temperature (20–22°C) for 24 h (T2), kept at 4°C for 24 h (T3), and then reheated after being kept at 4°C for 24 h(T4). Next, the products' proximate composition, total dietary fibre (soluble and insoluble), resistant starch (RS), and In vitro starch digestion rate (rapidly and slowly digested starch) were examined. The effect of RS on blood glucose and lipid profile were measured in humans and rats. Histopathological study of liver and pancreas in rats were also observed. Results: The basmati rice prepared by boiling 1 and stored with T3 was found more effective to control blood glucose and lipid profile. Similarly in rats, the blood glucose level, cholesterol, triglycerides and LDL were reduced about 29.7, 37.9, 31.3 and 30.5% respectively, after consumption of basmsti rice prepared by boiling 1 and stored at T3. Conclusion: Rice products stored at 4⁰C have a high amount of resistant starh, insoluble dietary fibre, slowly digestible starch and low glycemic index. Thus helps to inhibit glycogen and lipid synthesis.

The urgent global health challenge posed by methicillin-resistant Staphylococcus aureus (MRSA) infections demands effective solutions. Antimicrobial peptides (AMPs) represent promising tools of research of new antibacterial agents and LyeTx I mn∆K, a short synthetic peptide based on the Lycosa erythrognatha spider venom, is a good representative. This study focused on analyzing some antimicrobial activities of LyeTx I mn∆K, including minimum inhibitory and bactericidal concentrations, synergy and resensitization assays, lysis activity, the effect on biofilm, and the bacterial death curve in MRSA. Additionally, its characterization was conducted through isothermal titration calorimetry, dynamic light scattering, calcein release, and finally, efficacy in a mice wound model. The peptide demonstrating remarkable efficacy against planktonic cells and biofilms of MRSA, outperforms vancomycin in terms of rapid bactericidal action and anti-biofilm effects. The mechanism involves significant membrane damage. Interactions with bacterial model membranes, including those with lysylphosphatidylglycerol (LysylPOPG) modifications, highlight versatility and selectivity of this compound. Also, the peptide has the ability to sensitize resistant bacteria to conventional antibiotics, showing potential for combinatory therapy. Furthermore, using an in vivo model, was showed that a formulated gel containing the peptide proved superior to vancomycin in treating MRSA-induced wound in mice. Together the results highlight LyeTx I mnΔK as a promising prototype for the development of effective therapeutic strategies against superficial MRSA infections.

Prostate cancer (PCa) is characterised by androgen-dependency. Unfortunately, under anti-androgen treatment pressure, castration-resistant prostate cancer (CRPC) emerges, characterised by heterogeneous cell populations that, over time, lead to the development of different androgen-dependent or -independent phenotypes. Despite important advances in therapeutic strategies, CRPC remains incurable. Context-specific essential genes represent valuable candidates for targeted anti-cancer therapies. Through the investigation of gene and protein annotations and the integration of several published transcriptomic data, we identified two consensus lists to stratify PCa patients' risk and discriminate CRPC phenotypes based on androgen receptor activity. ROC and Kaplan-Meier survival analyses were used for gene set validation in independent datasets. We further evaluated these genes for their association with cancer dependency. The deregulated expression of the PCa-related genes was associated with overall and disease-specific survival, metastasis and/or high recurrence risk, while the CRPC-related genes clearly discriminated between adeno and neuroendocrine phenotypes. Some of the genes showed context-specific essentiality. We further identified candidate drugs through a computational repositioning approach for targeting these genes and treating lethal variants of PCa. This work provides a proof-of-concept for the use of an integrative approach to identify candidate biomarkers involved in PCa progression and CRPC pathogenesis within the goal of precision medicine.

Kluyveromyces marxianus is an attractive thermotolerant yeast species for ethanol production because of its ability to utilize various carbon sources as a fermentation substrate. The use of thermotolerant microbes enables performance of high-temperature ethanol fermentation, which has several advantages including reduction of cooling costs and minimization of contamination risk. To improve K. marxianus for ethanol fermentation under stress conditions, two strains, DMKU 3-1042 and DMKU 3-118, were adapted for heat resistance and toxic substances in pulp wastewater from a paper mill, respectively, resulting in the generation of KMR1042 and KMR118, respectively. Both adapted mutants exhibited clumpy clusters of cells as pseudohyphae and altered colony morphology, and their sedimentation speeds were much faster than those of the corresponding parent strains. The two mutants showed stronger tolerance to various stresses and higher performance for ethanol production than those of the corresponding parent strains at high temperatures or in the presence of toxic substances. Genome sequencing analysis revealed that both mutants had disruption of the same gene, SWI5, despite adaptation under different stress conditions, suggesting that the formation of pseudohyphae is a common strategy of K. marxianus for coping with stresses.

Methicillin-resistant Staphylococcus aureus (MRSA) constitutes a serious public health concern with a considerable impact on patients' health and substantial healthcare costs. In this study, patients, and healthcare workers (HCWs)from six public hospitals in Benin were screened for MRSA. Strains were identified as MRSA using conventional microbiological methods in Benin and confirmed using Matrix-Assisted Laser Desorption/Ionization Time of Flight (MALDI-TOF) mass spectrometry in Belgium. Whole genome sequencing (WGS) was used on confirmed MRSA isolates to characterize their genomic content and study their relatedness. In total,304 and 61 samples were collected from patients and HCWs, respectively. The mecA gene was detected in all isolates. The isolates were assigned to five sequence types (STs), with ST8 (55.6%, n=15), ST152 (18.52%, n=5), and ST121 (18.52%, n=5) being the most common. All isolates carried multiple virulence genes, including genes encoding the Panton-Valentine leukocidin toxin (48.15%, n=13) and the test gene (29.63%, n=8) associated with toxic shock syndrome. The presence of strains carrying numerous genomic features associated with antibiotic resistance and virulence in HCWs is a major public health concern. This study highlights the need to implement a multimodal strategy for reducing the risk of cross-transmission of MRSA in hospitals.

Prostate cancer (PCa) is the most commonly diagnosed cancer and the second most common cause of death due to cancer. About 30% of patients with PCa who have been castrated develop a castration-resistant form of the disease (CRPC), which is incurable. In the last decade, new treatments that control the disease have emerged, slowing progression and spread, and prolonging survival while maintaining the quality of life. These include immunotherapies; however, we do not yet know the optimal combination and sequence of these therapies with the standard ones. All therapies are not always suitable for every patient due to co-morbidities or adverse effects of therapies or both, so there is an urgent need for further work on new therapeutic options. Advances in cancer immunotherapy with an immune checkpoint inhibition mechanism (e.g., ipilimumab, an anti-CTLA-4 inhibitor) have not shown a survival benefit in patients with CRPC. Other immunological approaches have also not given clear results, which has indirectly prevented breakthrough for this type of therapeutic strategy into clinical use. Currently, the only approved form of immunotherapy for patients with CRPC is a cell-based medicine, but it is only available to patients in some parts of the world. Based on the experience gained from recently completed clinical research on immunotherapy with dendritic cell-based immunohybridomas, the aHyC dendritic cell vaccine, for patients with CRPC, we highlight the current status, and possible alternatives that should be considered in the future.

The calculation of the collapse load of spherical domes is addressed using a semi-analytical approach under the hypotheses of small displacements and perfect plasticity. The procedure is based on the numerical approximation of the self-stress that represents the projection of the balance equilibrium null space on a finite dimensional manifold. The so obtained self-equilibrated stress span is superimposed to a finite element linear elastic solution to the prescribed loads yielding to the statically admissible set accordingly to Melan’s theorem. The compatibility of the stress with the constitutive law of the material has been enforced using linearized limit domain in terms of generalized stress, namely axial force and bending moment along the local spherical curvilinear coordinates. The procedure has been tested with reference to numerical and experimental data from the literature confirming the accuracy of the proposed method. The comparison with the literature confirms that the buckling load is much greater than the plastic collapse loads both calculated through the proposed procedure and reported in the quoted literature.

Resistant cancer often shows a particular secretory trait such as heat shock proteins (HSPs) and extracellular vesicles (EVs), including exosomes and oncosomes surrounded by lipid bilayers. Lipoproteins are biochemical assemblies that transport hydrophobic lipid (a.k.a. fat) molecules in body fluid and are composed of a single-layer phospholipid and cholesterol outer shell, lipids molecules within the particles, and apolipoproteins embedded in the membrane. However, lipoprotein storage and secretion by cancer cells have not well-investigated yet. We found lipoproteins were stored and abundantly secreted by neuroendocrine, castration-resistant prostate cancer (NEPC / CRPC) cells but barely secreted by colon cancer cells and oral squamous cell carcinoma (OSCC) cells. In addition, large EVs (approx. 300 nm diameter) and potential oncosomes were released by CRPC and OSCC cells. Proteomics revealed that CRPC cells secreted EVs enriched with tetraspanins and extracellular matrices which were reduced upon heat shock stress and alternatively lipoproteins and HSPs were secreted upon stress. Heat shock stress triggered secretion of lipoprotein-EV complexes that contained apolipoprotein A, B, C and E. These data suggested that vesicular assembly composed of EVs and lipoproteins enriched with cholesterols and phospholipids may be stored in resistant cancer cells but released upon cell stress that is increased in cancer therapies.

We report a facile route for the green synthesis of trimethylchitosan nitrate-capped silver nanoparticles (TMCN-AgNPs) with positive surface charge. In this synthesis, silver nitrate, glucose, and trimethyl chitosan nitrate (TMCN) were used as silver precursor, reducing agent, and stabilizer, respectively. The reaction was carried out in a stirred basic aqueous medium at room temperature without the use of energy-consuming or expensive equipment. We investigated the effects of the concentrations of NaOH, glucose, and TMCN on the particle size, zeta potential, and formation yield. The AgNPs were characterized by UV-visible spectroscopy, photon correlation spectroscopy, laser Doppler anemometry, transmission electron microscopy, X-ray diffraction, and X-ray photoelectron spectroscopy. The catalytic activity of the TMCN-AgNPs was studied by the reduction of 4-nitrophenol using NaBH₄ as a reducing agent. We evaluated the antibacterial effects of the TMCN-AgNPs on Acinetobacter baumannii, Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus using the broth microdilution method. The results showed that both gram-positive and gram-negative bacteria were killed by the TMCN-AgNPs at very low concentration (< 6.13 μg/mL). Moreover, the TMCN-AgNPs also showed high antibacterial activity against clinically isolated multidrug-resistant A. baumannii strains, and the minimum inhibitory concentration (MIC) was ≤ 12.25 μg/mL.

The increasing prevalence of multidrug-resistant pathogens (MDR), persistent biofilms, oxidative stress, and cancerous cell proliferation pose significant challenges in healthcare and environmental settings, highlighting the urgent need for innovative and sustainable therapeutic solutions. The exploration of nanotechnology, particularly the use of green-synthesized nanoparticles, offers a promising avenue to address these complex biological challenges due to their multifunctional properties and biocompatibility. Utilizing a green synthesis approach, Mauritia flexuosa Mf-AgONPs were synthesized and characterized exhibiting potent antibacterial effects against both non-resistant and MDR bacterial strains, with minimum inhibitory concentrations (MICs) ranging from 11.25 to 45 µg/mL. Mf-AgONPs also demonstrated significant antifungal efficacy, particularly against Candida glabrata, with a MIC of 5.63 µg/mL. Moreover, the nanoparticles showed strong biofilm inhibition capabilities and substantial antioxidant properties, underscoring their potential to combat oxidative stress. Additionally, Mf-AgONPs exhibited pronounced anti-tumor properties against various cancer cell lines, displaying low IC50 values across various cancer cell lines while maintaining minimal hemolytic activity at therapeutic concentrations. These findings suggest that Mf-AgONPs synthesized via an eco-friendly approach offer a promising alternative for biomedical applications, including antimicrobial, antifungal, antioxidant, and anticancer therapies, warranting further in vivo studies to fully exploit their therapeutic potential.

Introduction: A central role for neuroinflammation in epileptogenesis has recently been suggested by several investigations. This systematic review explores the role of inflammatory mediators in epileptogenesis, its association with seizure severity, and its correlation with drug-resistant epilepsy (DRE). Material and Methods: The study analysed articles published in JCR journals from 2019 to 2024, including retrospective, prospective, case-control, or cross-sectional studies. It combined MESH and free terms for "Epileptogenesis" and "Neuroinflammation" and included searches for biomarkers previously reported in narrative reviews. Results: The study analysed 243 articles related to epileptogenesis and neuroinflammation, with 356 from selective searches by biomarker type. After eliminating duplicates, 324 articles were evaluated, with 272 excluded and 52 evaluated by authors. 21 articles were included in the qualitative evaluation, including 18 case-control studies, 2 case series, and 1 prospective study. This systematic review provides acceptable support for five biomarkers: TNF-a and some of its soluble receptors (sTNFr2), HMGB1 and TLR-4, CCL2 and IL-33. Discussions: Certain receptors, cytokines, and chemokines are examples of neuroinflammation-related biomarkers that may be crucial for the early diagnosis of refractory epilepsy or may be connected to the control levels of epileptic patients. Their value will be better defined by future studies.

Public restrooms are often a hub of microbial contamination, and the examination of bacterial contamination in these facilities can serve as an important indicator of the transmission of infectious diseases. This study was conducted to determine the prevalence of bacterial contamination in public restrooms based on the economic class of the building. Samples were collected from various spots in 32 restrooms found in 10 shopping malls, classifying them into two categories: upper-end restrooms and lower-end restrooms. The findings showed that the level of contamination was higher in the lower-end restrooms, with the seat being the most contaminated area. The most dominant Gram-positive bacteria were coagulase-negative staphylococci species, making up 86% of the identified Gram-positive isolates. The most dominant Gram-negative bacteria identified were Klebsiella pneumoniae and Pseudomonas aeruginosa. The antibiotic sensitivity test results revealed the presence of multi-drug resistant bacteria among the Gram-positive and negative isolates, including Staphylococcus haemolyticus, Staphylococcus kloosi, Acinetobacter baumanii, and Pseudomonas aeruginosa. In conclusion, the study underscores the significance of monitoring bacterial contamination in public restrooms and the need for measures to reduce the spread of infectious diseases. Further research is crucial to gain a complete understanding of the bacterial contamination in public restrooms and their resistance patterns, to ensure the safety and health of the public. The implementation of improved cleaning practices and hands-free designs in restrooms can help reduce the risk of cross-contamination and prevent the spread of diseases.

Methicillin-resistant Staphylococcus aureus (MRSA) infections, in particular biofilm-organized bacteria, remain a clinical challenge and a serious health problem. Rifabutin (RFB), an antibiotic of the rifamycins class, has shown in previous work excellent anti-staphylococcal activity. Here, we proposed to load RFB in liposomes aiming to promote the accumulation of RFB at infected sites and consequently enhancing the therapeutic potency. Two clinical isolates of MRSA, MRSA-C1 and MRSA-C2, were used to test the developed formulations, as well as the positive control, vancomycin (VCM). RFB in free and liposomal forms displayed high antibacterial activity, with minimal inhibitory concentrations (MIC) ranging from 0.009-0.013 μg/mL and MBIC50 values ranging from 0.008-0.012 μg/mL, in planktonic and biofilm bacteria, respectively. Confocal microscopy studies demonstrated the rapid internalization of unloaded and RFB-loaded liposomes in the bacterial biofilm matrix. In murine models of systemic MRSA-C1 infection, Balb/c mice were treated with RFB formulations and VCM at 20 and 40 mg/kg of body weight, respectively. Obtained data proved the superior therapeutic effectiveness of RFB formulations compared to Control and VCM groups even using a two-fold lower therapeutic dose as demonstrated by significantly reduced bacterial burden and growth index values in major organs. In addition, RFB formulations were the only formulations associated with 100% survival. Globally, this study emphasizes the potential of RFB nanoformulations as an effective and safe approach against MRSA infections.

This study investigated the presence, distribution, and antimicrobial resistance profiles of extend-ed-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae in a dairy herd located in Northern Italy. A questionnaire was administered, and the feces of clinically healthy pre-weaned dairy calves, their mothers, and the cows treated for mastitis, waste milk, water, and environmental samples, were collected and inoculated on Chromagar ESBL™ medium. The questionnaire identi-fied several risk factors including administration of waste milk to male calves, lack of routine cleaning of calf feeding and housing equipment, and blanket dry cow therapy. Escherichia coli was identified by MALDI-TOF MS in the feces of 28 of 37 (75.67%) calves, 2 of 3 (66.67%) treated cows, 8 of 14 (57.15%) environmental samples, and the waste milk. Six of 14 (42.85%) environmental samples were also positive for ESBL Acinetobacter baumannii, while all fecal samples were negative. ESBL production was confirmed for all E. coli isolates based on the double disk susceptibility test (DDST), while none were carbapenemase producers. Upon minimal inhibitory concentration (MIC) analysis, all of them showed multiple resistances and were categorized as multi-drug resistant (MDR). This study confirms the widespread presence of MDR, ESBL-E. coli in dairy calves and highlights their diffusion in the farm environment.

Enzalutamide is a second-generation androgen-receptor inhibitor that increases overall survival (OS) rates in patients with metastatic castration-resistant prostate cancer (mCRPC). This study evaluates the efficacy of circulating tumor cell (CTC) status as a prognostic biomarker after enzalutamide administration. A retrospective subgroup analysis and prognostic survey of 43 patients with mCRPC and bone metastases, treated in Juntendo University-affiliated hospitals from 2015–2022, were conducted. Patients were treated with 160 mg enzalutamide daily. CTC analyses on blood samples were performed regularly before and every three months post-treatment. Relationship between the patients' clinical factors and the OS rate was analyzed using the log-rank test; the median OS was 37 months. Patients with no detected CTCs at baseline showed significantly longer OS than those with CTCs at baseline. Furthermore, patients showing negative reversion of CTCs during enzalutamide treatment had significantly longer OS than patients with CTC-positive continuation. Two biomarkers–higher hemoglobin at baseline and achieving negative-reversion of CTCs–were significantly associated with prolonged OS. This study suggests that patients achieving CTC-negative reversion during treatment for mCRPC with bone metastases exhibit improved long-term OS. Chronological measurement of CTC status might be clinically useful in treatment of mCRPC.

Background: About 200 new ovarian cancer cases per year are diagnosed in Armenia, an upper-middle-income country. This study aims to summarize the survival outcomes of relapsed ovarian cancer patients in Armenia based on the type of relapse, risk factors, and the choice of systemic treatment. Methods: A retrospective case-control study including 228 patients with relapsed ovarian cancer from 3 different institutions. Results: The median age of the patients was 55. The median follow-up from the relapse and primary diagnosis was 21 and 48 months. The incidence of platinum-sensitive relapse was 81.6% (186), while platinum-resistant relapse was seen only in 18.4% (42) patients. Median survival of the patients starting from the primary diagnosis in the platinum-sensitive compared to the platinum-resistant group was 54 versus 25 months (p < 0.001), and median survival after relapse: was 25 versus 13 months, respectively 3- and 5-year survival in these groups were: 31.2% vs. 23.8%, and 15.1% vs. 9.5%, respectively (p = 0,113). Conclusions: Overall, despite new therapeutic approaches, ovarian cancer continues to be one of the deadly malignant diseases in women, especially, in developing countries with a lack of resources, where, in fact, the main available systemic treatment for the majority of patients remains chemo-therapy. Low survival rates emphasize the urgent need for more research on this group of patients with poor outcomes.

With the emergence of blockchain and smart contracts, traditional digital applications 1 such as identity management, supply chain management, banking and finance etc. are expected 2 to be transformed into Decentralized Applications (DApps). Blockchain interoperability is a new 3 and exciting aspect of blockchain technology that is quickly gaining popularity in many industries. 4 However, the widespread use of blockchains has not yet been achieved because DApps running on the 5 blockchain using smart contracts require access to authentic off-chain data. Users are more conscious 6 of their personal data privacy and consequently are more reluctant to share their data, posing a 7 challenge in the adoption of DApps. To solve this challenge, we present a novel quantum-resistant, 8 data authentication and zero-knowledge proof scheme named zk-DASTARK. Based on our proposed 9 scheme, we present a novel framework which can be used to feed authenticated off-chain data to 10 DApps without compromising user data privacy. Our proposed framework is quite efficient against 11 well-known off-chain data authentication frameworks. The proposed framework is implemented on 12 state-of-the-art quantum-resistant IOTA Blockchain and is highly efficient as it takes approximately 13 60 ms to generate a proof and approximately 10 ms to verify a proof.

As the control brain of the petrochemical plant, blast resistant performance requirements of the petrochemical control room should be guaranteed when the vapor cloud explosion occurs in the petrochemical production process. 3D-Kagome truss core sandwich structure is a kind of blast resistant material with high energy absorption. Considering the influence factors of the radius of the truss core rod and thickness of the upper and lower panels, in this paper, blast resistant performance of a real steel petrochemical control room with 3D-Kagome truss core sandwich wall is analyzed. With the optimization goal of plastic deformation energy and panel displacement, the optimal wall thickness and radius of the truss core rode are obtained. The optimized blast resistant wall is assembled, and the dynamic response of the steel petrochemical control room with the 3D-Kagome truss core sandwich blast resistant wall is analyzed. The simulation results show that the truss core layer does not dissipate the blast energy effectively when the radius ratio of the truss core rod is larger than 2.7% of the total thickness of the wall; with the increase of the thickness of the upper and lower panels, the proportion of plastic deformation energy of the truss core layer increases gradually and then tends to be a stable proportion value, that is about 90%; When the thickness ratio of the panel is 6.7% of the total one of the wall and the radius ratio of the truss core rod is 2.7% of the total thickness of the wall, the optimal blast resistant 3D-Kagome sandwich wall is determined.

Proxy re-encryption (PRE) is a momentous and widely used cryptographic technique. It enables a proxy to forward ciphertext without the need of decryption. PRE has received significant interest in applications like cloud computing, blockchain, and the Internet of Things. Despite its wide range of uses, PRE has also been subject to new security and privacy regulations. In PKC’19, Cohen $et~al.$~first drew attention to the weakness in PRE's security against chosen-plaintext attacks (CPA) and put up a more stringent security concept known as security against honest re-encryption attacks (HRA). Notably, Cohen provides a beneficial conclusion as well. It is proveded that PRE schemes with re-encryption simulatability property can be elevated from CPA to HRA security. It is also proved that CPA-secure PRE schemes with re-encryption simulatability property can be directly elevated to those satisfying HRA security. However, those PRE schemes with re-encryption simulatability are almost always based on pairings. In this study, to the best of our knowledge, we directly construct HRA-secure PRE with re-encryption simulatability for the first time based on the learning with errors (LWE) assumption, which was widely believed to be quantum-resistant. Based on the re-encryption key generation algorithm and the re-encryption algorithm construction method of the above scheme, we can modify attribute-based conditional proxy re-encryption (AB-CPRE) as well as the corresponding attribute-based proxy re-encryption (AB-PRE) algorithm to make them have re-encryption simulatability properties. Finally, by using this property, We boost the security of AB-CPRE scheme of ESORICS'21 from CPA to HRA and simplify the HRA-security proof for the AB-PRE of ESORICS'21.

This paper presents the experimental and numerical study on a ductile beam-column connection between a composite reinforced concrete truss (CRCT) beam and Concrete Filled Tube (CFT) column subjected to bending and shear loads. Two experimental models with different beam-column joint testing schemes, extracted from the same prototype three-dimensional structure designed according to the rules of the capacity design provided by seismic code, were subjected to quasi-static cyclic tests by applying gravitational loads and the horizontal seismic force. The main objective of this paper is to verify the experimental ductile behavior of both specimens and to simulate the experimental global and local response by nonlinear static analysis considering different modelling approaches. The comparison between the experimental and numerical results highlights, for both models considered, the ductile and dissipative capacity of the connection system, designed following the criterion of the hierarchy of resistances proposed by the current Italian code. Different experimental setup showed similar results demonstrating the repeatability of the test and its reproducibility through the nonlinear numerical analysis.

Background: Carbapenem-resistant Klebsiella pneumoniae (CRKP) is a serious public health issue. Aim of the study was to identify the antimicrobial resistance and accessory genes, the clonal relatedness and the evolution dynamics of selected CRKP isolates recovered in an adult and a pediatric intensive care unit of a tertiary hospital in Greece. Methods: Twenty-four CRKP isolates recovered during 2018-2022 were included in the study. Next-generation sequencing was performed using the Ion Torrent PGM Platform. The identification of the plasmid content, MLST and antimicrobial resistance genes, as well as the comparison of multiple genome alignments and the identification of core genome single-nucleotide polymorphism sites, were performed applying various bioinformatics software. Results: The isolates belonged to eight sequence types 11, 15, 30, 35, 39, 307, 323, and 512. A variety of carbapenemases (KPC, VIM, NDM and OXA-48) and resistance genes were detected. CRKP strains shared visually common genomic regions with the reference strain (NTUH-K2044). ST15, ST323, ST39, and ST11 CRKP isolates presented on average 17, 6, 16 and 866 recombined SNPs, respectively. All isolates belonging to ST15, ST323 and ST39 were classified in distinct phylogenetic branches, while ST11 isolates were assigned to a two-subclade branch. For large CRKP sets, the phylogeny seems to change approximately every seven SNPs. Conclusion: The current study provides insight into the genetic characterization of CRKP isolates in the ICUs of a tertiary hospital. Our results indicate clonal dispersion of ST15, ST323, and ST39 and highly diverged ST11 isolates.

Biosensors have shown great potential in realizing rapid, low cost and portable on-site detection for diseases. This work reports the development of a new bioelectronic sensor called AC electrokinetics-based capacitive (ABC) biosensor, for the detection of genomic DNA (gDNA) of methicillin-resistant Staphylococcus aureus (MRSA). The ABC sensor is based on interdigitated microelectrodes biofunctionalized with oligonucleotide probes. It uses a special AC signal for direct capacitive monitoring of topological change on nanostructured sensor surface, which simultaneously induce dieletrophoretic enrichment of target gDNAs. As a result, rapid and specific detection of gDNA/probe hybridization can be realized with high sensitivity. It requires no signal amplification such as labelling, hybridization chain reaction, or nucleic acid sequence-based amplification. This method involves only simple sample preparation. After optimization of nano-structured sensor surface and signal processing, the ABC sensor demonstrated fast turnaround of results (~10 s detection), excellent sensitivity (a detection limit of 4.7 DNA copies /µL MRSA gDNA) and high specificity, suitable for point of care diagnosis. As a bioelectronic sensor, the developed ABC sensors can be easily adapted for detection of other infectious agents.

Carbapenem resistant Enterobacteriaceae (CRE) has been public health risk in several countries and recent reports indicate the emergence of CRE in food animals. This study was conducted to investigate the occurrence, resistance patterns, and phylogenetic diversity of CRE E.coli from chicken. Routine bacteriology, PCR detection of E.coli species, multiplex PCR to detect carbapenemase encoding genes and phylogeny of CRE E. coli were conducted. The results show that 24.36 % (19/78) were identified as CRE based on the phenotypic identifications of which 17 were positive for the tested carabanemase genes. The majority, 57.99% (11/19) of the isolates harbored multiple carbapenemase genes. Four isolates harbored all blaNDM blaOXA, blaIMP, five and two different isolates harbored blaNDM and blaOXA, and blaOXA and blaIMP respectively. The Meropenem, Imipenem and Ertapenem MIC values for the isolates ranged from 2g/mL to ≥256g/mL. Phylogenetic grouping showed that the CRE E.coli isolates belonged to five different groups; groups A, B1, C, D and unknown. The detection of carbapenem resistant E.coli in this study shows that CRE is has become an emerging problem in farm animals, particularly, in poultry farms. This also implies the potential public health risks posed by CRE from chicken to the consumers.

Background/Objectives: Community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) greatly complicates treatment of skin and soft tissue infections (SSTI). It was previ-ously found that subcutaneous (SQ) treatment with the mononuclear phagocyte (MP)-selective activator, complement peptide-derived immunostimulant-02 (CPDI-02; formerly EP67), increases prophylaxis of outbred CD-1 mice against SQ infection with CA-MRSA. Here, we determined if treatment with CPDI-02 also increases curative protection. Methods: Female CD-1 mice were challenged SQ with CA-MRSA USA300 LAC then CPDI-02 or inactive scCPDI-02 was administered by a topical, SQ, IM, or IV route at 6- or 24-hrs post-challenge. Dermal abscess sizes were compared over 10 days and CA-MRSA burden, neutrophils, MP, and pro-inflammatory cytokines were compared in dermal abscesses. CPDI-02 PK and distribution in female CD-1 mice were compared after IM or IV dosing and CPDI-02 toxicity was determined by IM dose escalation and repeat IM dosing in male and female CD-1 mice. Results: Repeat IM treatment with CPDI-02 starting at 6-hrs post-challenge decreased maximum abscess surface area, CA-MRSA burden, and time to resolu-tion, whereas repeat treatment by the topical, SQ, or IV route had no effect. Starting CPDI-02 treatment at 24-hrs post-challenge was ineffective regardless of route. Single IM treatment with CPDI-02 starting at 6-hrs post-challenge was as effective as repeat IM treatment, increased systemic exposure, and decreased initial levels of IL-1β and increased MP in dermal abscesses. CPDI-02 was tolerated to between 130-170 mg/kg for single IM dosing and 65-130 mg/kg for repeat IM dosing with males being more tolerant. Conclusions: Single early-stage IM treatment with CPDI-02 may increase curative protection against SSTI caused by CA-MRSA or other pathogens controlled by activated MP.

Low alloyed martensitic resistant steels could become a solution for material saving and components lightweighting in the industrial activity due to the combination of high strength and good weldability and toughness characteristics. However, it is known that martensitic resistant steels are susceptible to temper embrittlement (TE), which can cause undesirable brittle fracture during service of components. In this investigation the influence of the cooling rate after a high temperature tempering (650 ºC) on TE of a low alloyed martensitic Mn-Cr-Ni steel was studied. Charpy impact tests and metallurgical analysis using emission Scanning Electron and Transmission Electron Microscopy were carried out on specimens cooled in different cooling media after the tempering to stablish a relation between the microstructures and the TE. Obtained results shown a considerable influence of the tempering-carbides location at grain boundaries at low post-tempering cooling rates on the TE of the selected steel.

This study investigated the characteristics and outcomes of drug-resistant tuberculosis patients in selected rural healthcare facilities in the Eastern Cape, South Africa. A retrospective review of clinical records from 456 patients, covering the period from January 2018 to December 2020, revealed that a statistically significant relationship between DR-TB types and age groups (Chi-square statistic: 30.74, p-value: 0.015). Younger adults (19-35 years) and middle-aged adults (36-50 years) are more frequently affected by RR-TB and MDR-TB, which are the most prevalent forms of DR-TB. Less common types, including Pre-XDR, XDR, and INH TB, were observed in smaller numbers. The study suggests that DR-TB imposes a heavy burden on the working-age population. Gender analysis shows that while the frequency of DR-TB differs between males and females, the percentage distribution of DR-TB types is relatively equal. Both genders are predominantly affected by RR-TB and MDR-TB, which together account for nearly 90% of cases. Pre-XDR, XDR, and INH-resistant TB are much less common, comprising only a small percentage of cases in both males and females. High-risk behaviors such as smoking and drinking are linked to a wider diversity of DR-TB types, while occupations like mining and prison work show higher rates of RR-TB and MDR-TB. In HIV-positive individuals, DR-TB is more common, but the distribution of DR-TB types between HIV-positive and negative groups shows no statistically significant difference. However, HIV-positive individuals have a 20% lower survival rate (65%) compared to HIV-negative patients (85%). Financial stability and comorbidities also significantly influence outcomes, with patients having stable income and fewer high-risk comorbidities experiencing better survival and treatment outcomes. The findings underscore the importance of addressing socioeconomic disparities and strengthening healthcare infrastructure to improve DR-TB treatment outcomes in rural Eastern Cape.

A tritium resistant coating on the surface of materials is one of the main methods to reduce tritium permeability. In actual operating processes, mechanical damage such as spalling and scratches will occur on the surface of tritium resistant coatings. These mechanical damages will affect the hydrogen permeability resistance of the coatings. It is an important engineering problem that evaluate the effect of these damage on the tritium resistance of the coating. In this experiment, the mechanical damage of FeAl/Al2O3 tritium resistant coating on 316L stainless steel was simulated by scratching, debonding and thermal shock, and the gas hydrogen isotope permeation (GDP) test was carried out. The influence of mechanical damage degree on the tritium permeation behaviour of the coating was evaluated and discussed.

Background/Objectives: Boscia senegalensis (BS) Pers.) Lam. Ex Poir (Capparaceae), is an important local famine food plant in Africa and widely exploited by healers for its seeds in Sahelian region to reduce hyperglycaemia. Purpose: We studied the efficacy of commercial dosage form of BS namely Boscisucrophage (BSP) on type 2 diabetes (T2DM) patients with Oral antihyperglycemic drugs resistant. Study Design: Clinical benefits of BSP, were evaluated in multicentre cohort observational study on naïve patients (43) or diabetic patients resistant of oral antidiabetic drugs (289). All patients received capsules of the fixed dose containing 350 mg of BSP twice daily for 12 weeks and overactive control on vein blood sugar, glycosylated haemoglobin (HbA1c), urine glucose excretion (UGE), aspartate aminotransferase, alanine aminotransferase, creatinine, and clinical examination of functional symptoms. Results: In clinical study, BSP induced the reduction of glycaemia, HbA1c, and increase UGE, with removal of side effects functional symptoms of T2DM. Conclusions: In clinical studies, our findings lend support to use of BSP to reduce glycaemia, and HbA1c in T2DM patients with Oral antihyperglycemic drugs resistant without over adverse effects. BSP supressed clinical examination of functional symptoms.

A 70-year-old female with a significant medical history of hypertension, hypothyroidism, chronic back pain, and a left hip prosthetic joint infection experienced complications following a total hip replacement. After multiple revisions and eventual discharge to a rehabilitation facility, she developed surgical site bleeding and a femoral head dislocation extending into the pelvis. At our hospital, imaging revealed a failed hip arthroplasty with extensive damage and infection, necessitating complex revision surgery and an antibiotic regimen. During her treatment, she developed a diffuse rash diagnosed as vancomycin-induced hypersensitivity reaction (DRESS), prompting a switch to oral linezolid and systemic corticosteroids. Despite transient eosinophilia and elevated inflammatory markers, her condition stabilized, and she was discharged with instructions for follow-up. This case underscores the importance of vigilant monitoring and timely intervention in managing complex postoperative infections and drug reactions.

Blood stream infections (BSI) due to carbapenem-resistant gram-negative bacilli (CR-GNB), especially Klebsiella pneumoniae carbapenemase (KPC) and New-Delhi metallo-β-lactamase (NDM) producers, are a major concern of public health, as they are associated with high morbidity and mortality. We conducted a single-center, retrospective, observational study at a tertiary-care, teaching Greek hospital, to determine the incidence, 30-day and overall, in-hospital, crude mortality, risk factors and efficacy of best available treatment options in patients with BSIs from KPC- or NDM-producing GR-GNB. During the one-year study period, from 1st January to 31st December 2023, we recorded 133 episodes of BSIs in 118 unique patients; 79 episodes were due to KPC-producing and 54 to NDM-producing CR-GNB. Our study showed relatively high incidence of BSIs by both KPC- and NDM-producing CR-GNB (0.49 and 0.31 episodes per 1000 patient-days respectively). We found high 30-day crude mortality rates for patients with BSIs due to KPC- producing CR-GNB (26.4 %), and NDM-producing CR-GNB (37%), while BSIs due to NDM-producing P. aeruginosa had the highest 30-day (47.1%) and overall (70.6%) in-hospital, crude mortality. Beta-lactam/beta-lactamase inhibitors as monotherapy or in combination with other active agents used to treat KPC-producing CR-GNB were associated with improved survival rates (p=0.009).

Musculoskeletal infections (MIs) are among the most difficult-to-treat staphylococcal diseases. The limited availability of effective antibiotics has encouraged the development of innovative strategies such as combinatory therapy to combat MI. The aim of this study was to investigate the in vitro antistaphylococcal activity of anti-inflammatory and the antimicrobial combinatory effect of celecoxib with oxacillin. The minimum inhibitory concentrations (MICs) of 17 anti-inflammatory drugs were determined for standard strains and clinical isolates of S. aureus strains, counting methicillin-resistant strains (MRSA), by the broth microdilution method. The fractional inhibitory concentration indices (FICIs) were evaluated by the checkerboard assays. Celecoxib produced the most potent antistaphylococcal effect against all the tested strains (MIC ranging from 32 to 64 mg/mL), followed by diacerein against MRSA3 and MRSA ATCC 33592 (MIC 64 mg/mL). Several synergistic effects were observed for tested S. aureus strains, including MRSA (FICI ranging from 0.087 to 0.471). The strongest synergistic interaction (FICI 0.087) was obtained against MRSA ATCC 33592 at a celecoxib concentration of 2 mg/mL with a 19-fold oxacillin MIC reduction (from 512 to 26.888 mg/mL). This is the first report on the antistaphylococcal combinatory effect of celecoxib with oxacillin. Our findings suggest celecoxib and its combination with oxacillin as perspective agents for research focused on the development of novel therapies for MI caused by S. aureus. Thus, this study presents novel findings that celecoxib could, in some cases, resensitise MRSA strains to become susceptible to certain β-lactams (e.g., oxacillin) not previously tested.

Background: Number of joint infections caused by Vancomycin-resistant pathogens is emerging. Currently no PMMA cement is commercially available to cover VRE. Daptomycin shows promising results in infection treatment, offers a good safety profile and reduced risk for resistance development. Purpose of this in vitro study is to investigate the mechanical stability, handling properties, elution behavior and antimicrobial effectiveness of PMMA cement loaded with three different Daptomycin concentrations in comparison to commercially available ALBC; Methods: Mechanical properties and handling characteristics (ISO 5833, DIN 53435), HPLC elution, antimicrobial effectiveness with proliferation assay (DIN 17025) and inhibition zone testing were investigated; Results: All tested Daptomycin concentrations fulfilled ISO and DIN mechanical strength. Dosage of 0.5. g added Daptomycin did not show any antimicrobial effectiveness in contrast to 1.0 g and1.5 g. Cement with 1.5 g Daptomycin was best in elution and effectiveness, showed good mechanical ISO strength, ISO doughing was a little longer sticky and setting was faster as Vancomycin containing reference cement; Conclusion: PMMA cement containing 0.5 g Gentamicin and 1.5 g Daptomycin could be a good alternative to the already established COPAL® G+V for PJI treatment of VRE.

Obesity is a complex disease increasing risk of other pathologies. Its prevention or long-term weight loss maintenance is problematic. Gut microbiome is considered a potential obesity modulator. The objective of the present study was to summarize recent findings regarding relationships between obesity, gut microbiota and diet, with emphasis on dietary fiber and resistant starch. Composition of the human gut microbiome and methods of its quantification are described. Products of the gut microbiome metabolism, such as short-chain fatty acids and secondary bile acids including their effects on the gut microbiota, intestinal barrier function and immune homeostasis are discussed in the context of obesity. Importance of dietary fiber and resistant starch is emphasized as far as effects of the host diet on the composition and function of the gut microbiome are concerned. Complex relationships between human gut microbiome and obesity are finally summarized.

Accumulating psychedelic research has demonstrated potential for improving mental health and wellbeing, yet studies in the context of eating disorders (EDs) are limited. This study explores the subjective effects of psychedelic experiences to gain insight into the benefits and risks for people with EDs. Semi-structured interviews were conducted with 11 eligible adults. A purposive sample of eight adults aged 25-54 (M =  36.9) with chronic EDs, diagnosed (N = 7) and undiagnosed (N = 1) were thematically analysed. Reports of cessation or reduction of ED symptoms were unanimous, with two participants reporting recovery, attributed to psychedelic use. Thematic analysis resulted in two superordinate themes, each comprising three subordinate themes. The first superordinate theme, ‘Exploring’ via the ‘gateway to healing’, illustrates mental, emotional, and transcendental elements of psychedelic experiences. The second superordinate theme, ‘Transformation’ and being ‘able to do the work’, illustrates cognitive and behavioural outcomes, with retrospective safety perceptions. This research presents an account representative of the ED population for the therapeutic potential for psychedelic experiences to reduce symptoms and improve wellbeing. Findings provide evidence of therapeutic feasibility to support larger scale research, emphasising the therapeutic use of psychedelics as a potentially promising avenue for chronic and treatment resistant EDs.

Indigo leaves form various plant species are sources of dyes/pigments, not fully exploited for making sustainable textiles. Blue indigo vat dye extracted from indigo leaves, yields high wash colorfastness but fades slowly with light, and is not easily used for direct printing. Indigo leaves can be used to produce textiles of various color shades, while light resistant Mayan-inspired hybrid pigments have not yet been used for textile coloring. Using blue indigo dyes from 3 plant species, with exhaustion dyeing, intense wash resistant blue colored textiles are produced, and in the case of Indigofera Persicaria tinctoria, textiles have antibacterial activity against S. Epidermis and E. Coli.100% Natural Mayan-inspired blue indigo pigment, made from Sepiolite clay and indigo dye, was used both in powdered and paste forms to perform pigment textile dyeing by pad cure process, and direct screen printing on textiles. A water-based bio-binder (40%) was used efficiently for both padding and printing. Bio-based Na Alginate thickener allowed color fast printing on both polyester and cotton fabrics, while bio-based glycerin allowed good print color fastness on polyester only, yielding prints with excellent color fastness to wash (5/5), to dry and wet rubbing (5/5) and light (7/7).

Methicillin-resistant Staphylococcus aureus (MRSA) exerts a considerable concern in healthcare and the community. Globally MRSA strains cause numerous infections with high morbidity and mortality rates. The success of MRSA is a result of the extensive production of virulence factors. With the limited treatment options for the MRSA infection and growing resistance problem, an urgent call is needed to search for an alternative to antibiotics. One of the promising strategies is targeting the quorum sensing (QS) system, of the MRSA, by using a dendrimer loaded with kinase inhibitor peptide. This study formulates a poly-amidoamine dendrimers (PAMAM) G4 dendrimers loaded with Quorum Quencher (QQ), QQ3 peptide which is a Histidine Kinase inhibitor. The physicochemical properties of the formula were characterized using different in-vitro analysis method such as Zetasizer and transmission electron microscope (TEM). The antibacterial activity and anti-virulence effect of the formula was tested against MRSA and different mutant stains using growth assay, haemolysis assay and biofilm assay. Overall, QQ3-G4 complex showed antibacterial and anti-virulence activity and it can be a potential alternative treatment to overcome antimicrobial resistance and treat MRSA infection.

Pathological aseptic calcification is the most common form of structural valvular degeneration (SVD), leading to premature failure of heart valve bioprostheses (BHVs). The processing methods used to obtain GA-fixed pericardium-based biomaterials determine the hemodynamic characteristics and durability of BHVs. This article presents a comparative study of the effects of several processing methods on the degree of damage to the ECM of GA-fixed pericardium-based biomaterials as well as on their biostability, biocompatibility, and resistance to calcification. Based on the assumption that preservation of the native ECM structure will enable the creation of calcinosis-resistant materials, this study provides a soft biomimetic approach for the manufacture of GA-fixed biomaterials using gentle decellularization and washing methods. It has been shown that the use of soft methods for preimplantation processing of materials, ensuring maximum preservation of the intactness of the pericardial ECM, radically increases the resistance of biomaterials to calcification. The data obtained are of interest for the development of new calcinosis-resistant biomaterials for the manufacture of BHVs.

Combining Matrix-Assisted Laser Desorption/Ionization Time-of-Flight (MALDI-TOF) spectra data and artificial intelligence (AI) has been introduced for rapid prediction on antibiotic susceptibility test (AST) of S. aureus. Based on the AI predictive probability, the cases with probabilities between low and high cut-offs are defined as “grey zone”. We aimed to investigate the underlying reasons of unconfident (grey zone) or wrong predictive AST. A total 479 S. aureus isolates were collected, analyzed by MALDI-TOF, and AST prediction, standard AST were obtained in a tertiary medical center. The predictions were categorized into the correct prediction group, wrong prediction group, and grey zone group. We analyzed the association between the predictive results and the demographic data, spectral data, and strain types. For MRSA, larger cefoxitin zone size was found in the wrong prediction group. MLST of the MRSA isolates in the grey zone group revealed that uncommon strain types composed 80%. Amid MSSA isolates in the grey zone group, the majority (60%) was composed of over 10 different strain types. In predicting AST based on MALDI-TOF AI, uncommon strains and high diversity would contribute to suboptimal predictive performance.

In this study, global response analysis was performed to explore the mechanism of action of Usnic acid and its synergy with Norfloxacin, a well-known quinolone antibiotic to which MRSA clinical isolates showed resistance (MIC, 500 µg/mL). Microdilution assay, growth kinetics, microscopic analysis, and cell-based assays consistently showed that Usnic acid possess strong anti-staphylococcal activity (MIC, 7.8 µg/ml), causes cell leakage, modulates efflux pump activity, and synergizes with Norfloxacin against multi-drug resistant clinical isolate MRSA 2071. Whole cell proteome profiling using gel-free based nano-LC-ESI-QTOF-MS/MS revealed several proteins whose expression was significantly modulated by Usnic acid and Norfloxacin alone or in combination. Usnic acid downregulated the abundance of RNA polymerase subunits (RpoB, RpoC), carbamoyl phosphate synthase large subunit (PyrAB), chaperone (GroEL), and adenylosuccinate synthetase (PurA). Interestingly, proteins found to be upregulated in the presence of Usnic acid and Norfloxacin included oxidative stress-related proteins such as peroxidase (Tpx), alkyl hydroperoxide reductase (AphC), and general stress protein (UspA). This study clearly showed that Usnic acid affects numerous cellular targets and can potentiate the action of Norfloxacin. Furthermore, an in-vivo study emphasized the use of Usnic acid to develop as a safe phytopharmaceutical to repurpose old antibiotics through combination therapy against MRSA infections.

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.

Keywords: Agrobacterium 1; Xenorhabdus 2; NR-AMP 3 T-DNA keyword 4; TI-plasmid 5; Intact/Cured/T-DNA Deleted 6 Sensitive/Resistant 7; EMA_PF2 8; HPLC 9

Due to slow progression and susceptibility to radical forms of treatment low-grade PC is associ-ated with high overall survival (OS). With the clinical progression of PC the therapy is getting more complex. The immunosuppressive tumor microenvironment (TME) makes PC a difficult target for most immunotherapeutics. Its general immune resistance is established by i.e. immune evasion through Treg cells, synthesis of immunosuppressive mediators, and defective expression of surface neoantigens. The success of sipuleucel-T in clinical trials initiated several other clinical studies that specifically target the immune escape of the tumor and eliminate the immunosuppres-sive properties of TME. In the settings of PC treatment, this can be commonly achieved with radi-ation therapy (RT). Also, focal therapies usually applied for localized PC, such as high-intensity focused ultrasound (HIFU) therapy, cryotherapy, photodynamic therapy (PDT), or irreversible electroporation (IRE) were shown to boost anti-cancer response. Nevertheless, the present guide-lines restrict their application to localized and low-grade PC. This review explains how RT and focal therapies enhance the immune response. We also provide data supporting the combination of RT and focal treatments with immune therapies.

We conducted a retrospective evaluation of the clinical outcomes and prognostic factors in patients with non-metastatic castration-resistant prostate cancer (nmCRPC) treated with first-line androgen receptor signaling inhibitors (ARSI) in real-world clinical practice in Japan. Between 2012 and 2023, a total of 127 consecutive patients with nmCRPC received ARSI treatment. Overall survival (OS), metastatic-free survival (MFS), and prostate-specific antigen progression–free survival (PSA-PFS) from ARSI initiation were assessed using Kaplan–Meier methodology. Clinical factors associated with OS in nmCRPC were analyzed using the Cox proportional hazards model. Among the patients, 72, 26, 12, and 17 received enzalutamide (ENZ), abiraterone (ABI), apalutamide (APA), and darolutamide (DARO) as first-line therapy. The median OS and MFS for all patients were 79.0 and 42.0 months, respectively. Median PSA-PFS was 27.0, 20.0, 10.0, and 14.0 months for patients treated with ENZ, ABI, APA, and DARO, respectively (p = 0.33). Multivariate analysis revealed that a baseline PSA level ≥3.67 ng/ml at ARSI initiation was significantly associated with poorer OS (p = 0.002). ARSI demonstrated favorable efficacy in nmCRPC patients. There were no significant differences in clinical outcomes among different types of ARSI therapy for nmCRP. Elevated baseline PSA at ARSI initiation was significantly associated with poorer OS.

The prevalence of multidrug-resistant Gram-negative infections, particularly carbapenem-resistant strains, has become a significant global health concern. Ceftazidime-avibactam (CZA) has emerged as a promising treatment option. However, data on its efficacy and safety in children are scarce, necessitating further investigation. We conducted a retrospective study at a tertiary hospital in Spain from February 2019 to January 2022. Pediatric patients (<16 years) treated with CZA for confirmed or suspected multidrug-resistant Gram-negative infections were included. Clinical and microbiological characteristics, treatment approaches, and outcomes were examined. Eighteen children received CZA treatment. All had complex chronic conditions, with the most frequent underlying main diseases being liver transplantation (n=8) and biliary atresia (n=4). The predominant type of infection for which they received CZA was intra-abdominal infections caused or suspected to be caused by OXA-48-producing Klebsiella pneumoniae. CZA was generally well tolerated. Within the first month of starting CZA therapy, 2 patients died, with one case directly linked to the infection’s fatal outcome. Some patients needed repeated courses of therapy due to recurrent infections, yet no resistance development was noted. In summary, the use of CZA showed effectiveness and safety, while the lack of resistance development highlights CZA’s potential as a primary treatment option against OXA-48-producing infections.

The current globally dominant SARS-CoV-2 variants are showing immune escape and reduced susceptibility to antiviral drugs. Therefore, agencies responsible for drug evaluation and regula-tion such as the FDA and EMA are revising their emergency authorization use of several COVID-19 neutralizing antibodies. These NAbs proved to be unlikely effective against new variants espe-cially Omicron descendants and several pharmaceutical companies are pursuing the development of more potent neutralizing antibodies. To address the issue of using in silico prediction for the rapid assessment of anti-SARS-CoV-2 MAbs neutralization power, we used a computational method we developed previously, to evaluate 10 SARS-CoV-2 antibodies propensity to neutralize the new Omicron’s subvariants Eris (EG.5) and Pirola (BA.2.86) based on comparative binding affinity and previous experimental and clinical observations. Nine of these MAbs were once granted emergency use authorization, and one is currently under clinical investigation. The rapid, cost-effective in silico evaluation provided reliable predictions consistent with published clinical and experimental data. Furthermore, our data showed new potential therapeutic MAbs combi-nation that could be effective for the treatment countermeasure of the new Omicron’s subvariants Eris (EG.5) and Pirola (BA.2.86).

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.

The demand for efficient processes through a comprehensive understanding and optimization of welding conditions continues to grow in the manufacturing industry. This study involves heat-resistant 2.25 Cr-1 Mo V-groove steel welding using the square-waveform alternating cur-rent. Experiments were conducted to build the relationship between input variables—such as current, frequency, electrode negativity ratio, and welding speed—and process performance, such as penetration, bay area, deposition rate, melting efficiency, percentage dilution, flux–wire ratio, and heat input. The process was analyzed in light of the defect-free high-deposition weld groove weld, the sensitivity to process parameters, and the optimization and development of the process map. The study proposes an innovative approach to reducing the cost and time of optimizing the one-pass-each-layer V-groove welding process using bead-on-plate welds. Square waveform welding creates a metallurgical notch in the form of a bay at the fusion boundary that can be minimized by selecting appropriate welding conditions. The square waveform submerged arc welding is more sensitive towards changes in current and welding speed than the frequency and electrode negativity ratio; however, the electrode negativity ratio and frequency are minor but helpful parameters to achieve optimal results. The proximity of the planned and experimental results to within 3% confirms the validity of the proposed approach. The investigation shows that 90% of the maximum deposition rate is possible for one-pass-each-layer V-groove welds within heat input and weld width constraints.

The purpose of this study is to examine the relationship between the institutional investors which can affect financial performance for corporate sustainability on the income smoothing. Therefore, this study focus on the connection between the nature of stock rights and income smoothing in China. For this study, hypotheses were established on the relationship each state-controlled companies, income smoothing, and information equilibrium of individual investors, and empirical analysis was conducted through related variables. The analysis results are summarized in three categories as follows. First, this research finds that state-controlled firms (CONTs) prefer income smoothing activities compared to non-state-controlled firms for the long-term sustainable development of firms using data from 2011 to 2019. Second, this study found out that Institutional investors support the behavior of CONTs to smooth their earnings because this behavior is seen as an attempt by CONTs to convey valuable private information to other investors. Third, we was able to discover that institutional investors' monitoring effect is predominantly driven by pressure-resistant institutional investors. This research complements the lack of empirical research on income smoothing and enable to give a guideline that the type of stock rights is a critical key determinant of participation in income smoothing activities for stable growth and sustainability in the future.

The RSA cryptosystem has long been a fundamental component of contemporary public key in- frastructure. However, recent developments in quantum computing and mathematical theory have introduced signicant challenges to its security. A fully operational quantum computer would allow for the application of Shor's algorithm, enabling the ecient factoring of large integers, thereby com- promising the integrity of RSA and other cryptographic methods dependent on discrete logarithms. Although Grover's algorithm poses a comparatively smaller threat to symmetric encryption systems, it still presents a vulnerability by accelerating key search processes. The looming threat from quan- tum technologies has driven a surge in research aimed at developing quantum-resistant cryptography. These eorts focus on cryptographic techniques grounded in error-correcting codes, lattice structures, and multivariate public key systems, all of which leverage the complexity of NP-hard problemssuch as solving multivariate quadratic equationsto preserve security in a post-quantum world. This pa- per reviews the current progress in quantum-resistant encryption methods, particularly emphasizing the role of robust trapdoor functions. Additionally, it provides a comprehensive analysis of critical multivariate cryptosystem frameworks, such as Matsumoto-Imai, Oil and Vinegar, and Polly Cracker schemes. It also examines advances in lattice-based systems like Kyber and Crystals-Dilithium, which are undergoing assessment by NIST for potential standardization. As quantum computing continues to evolve, the demand for cutting-edge cryptographic solutions to safeguard digital communications grows increasingly pressing.

The increasing emergence of multidrug resistant (MDR) pathogens, due to antibiotics misuse, translates in obstinate infections, with high morbidity and high-cost hospitalizations. To oppose these MDR superbugs, new antimicrobial options are necessary. Although both quaternary ammonium (QASs) and phosphonium salts (QPSs) possess antimicrobial effects, QPSs have been studied at lesser extent. Recently, we have successfully reported on the bacteriostatic and cytotoxic effects of a triphenyl phosphonium salt against MDR isolates of Enterococcus and Staphylococcus genus. Here, aiming at finding new antibacterial devices possibly bactericidal towards a broader spectrum of clinically relevant bacteria, responsible for severe human infections, we synthesized a water-soluble, sterically hindered quaternary phosphonium salt (BPPB). It encompasses two triphenyl phosphonium groups linked by a C12 alkyl chain, thus embodying the characteristics of molecules known as bola-amphiphiles. BPPB was characterized by ATR-FTIR, NMR and UV spectroscopy, FIA-MS (ESI), elemental analysis and potentiometric titrations. Optical and DLS analyses evidenced BPPB tendency to self-forming spherical vesicles in solution (45 nm by DLS), having a positive zeta potential (+18 mV). The antibacterial effects of BPPB were for the first time assessed against fifty clinical isolates of both Gram-positive and Gram-negative species. Excellent antibacterial effects were observed on all strains tested, involving all the most worrying species included in ESKAPE bacteria. The lowest MICs were 0.250 µg/mL, while the highest ones (32 µg/mL) were observed on MDR Gram-negative metallo-β-lactamase-producing bacteria and/or species resistant also to colistin, carbapenems, cefiderocol, so that intractable with current available antibiotics. Moreover, when administered to HepG2 human hepatic and Cos-7 monkey kidney cell lines, BPPB showed selectivity indices &gt; 10 for all Gram-positive isolated and for clinically relevant Gram-negative superbugs such as those of E. coli species, thus being very promising to be clinically developed.

Candidiasis is one of the global public health problems. In fluconazole resistant Candida spp. (FRCS), mutations in ergosterol biosynthesis gene 11 (ERG 11) have been commonly found. This study aimed to determine the profile of FRCS isolates and to detect mutations in part of ERG 11 gene in fluconazole resistant Candida albicans (FRCA) isolates. Study was conducted on 150 isolates of FRCS obtained from patients admitted in a tertiary care hospital, South India from September 2019 to December 2021. Candida spp. was identified by MALDI-TOF MS and fluconazole resistance was detected by VITEK 2 system. Following which a part of the ERG 11 gene of the FRCA isolates were amplified, purified, sequenced and a phylogenetic tree was constructed. Out of the 150 FRCS, the most common FRCS was C. auris followed by C. glabrata, C. krusei, C. parapsilosis, C. albicans, C. tropicalis and C. guilliermondii. Sequencing of amplicons detected a single missense mutation and 44 silent mutations. We opined that fluconazole resistance in FRCA isolates may be due to mecha-nisms other than the studied one in our region. Phylogenetic analysis of amplified sequences of 12 FRCA isolates observed three clusters and all 12 sequences showed relatedness to Malaysian 2019 isolates.

In interepidemic periods, a sapronoses typically employs a variety of mechanisms for maintaining viability of its causative agent in terrestrial parasitic systems, associated with different adaptive strategies utilized by its populations to survive. Unlike spore-forming bacteria, causative agents of sapronoses use resistant cell forms, which is a viable but nonculturable (VBNC) state, and persistence. Implementation of these strategies is conditioned by effects of various stress factors of the habitat and is characterized by decreased metabolism, alteration of the morphology and physiology of bacterial cell, and cessation of its replication. It is important that the resistant forms of cells retain virulence and, as favorable conditions come, turn back into the active vegetative form again. The discovery of the genetic modules of bacterial toxin–antitoxin systems in recent years has made it possible to identify a number of complicated regulatory molecular mechanisms responsible for maintaining the pathogenic potential of resistant forms of causative agents of natural-focus sapronoses in interepidemic periods.

Multidrug resistant organisms (MDROs) outbreaks have been steadilyincreasing in Intensive care units (ICUs). Still, healthcare institutions and workers (HCW) reached no unanimity on how and when implementing infection prevention and control (IPC) strategies. We aimed to provide a pragmatic, physician practice-oriented, resume of strategies towards different MRDOs outbreaks in ICU. We performed a narrative review on IPC in ICUs, investigating patient-to-staff ratios, education, isolation, decolonization, screening and hygiene practices, outbreak reporting, cost-effectiveness, reproduction-number(R0), and future perspectives. The most effective IPC strategy remains unknown. Most studies focus on a specific pathogen or disease, making the clinician losing the big picture. IPC strategies proved their cost-effectiveness regardless typology, country, or pathogen. A standardized, universal, pragmatic protocol for HCW education should be elaborated. Likewise, a rapid outbreak recognition tool elaboration (i.e., an easy-to-use mathematical model) would improve early diagnosis and spreading prevention. Further studies are needed to express in favor or against MDROs decolonization. New promising strategies are emerging and need to be tested in the field. The lack of IPC strategies application has made, and still makes ICUs a major MDROs reservoir into the community. In a not-too-distant future genetic engineering and phage therapies could represent a plot-twist in MDROs IPC strategies.

The lung microbiota is a complex community of microorganisms that colonize the respiratory tract of individuals from or even before birth. Although the lungs were traditionally believed to be sterile, recent research has shown that there is a diversity of bacterial species in the respiratory system. Knowledge about the lung microbiota in the newborn and its relationship with bacterial infections is of vital importance to understand the pathogenesis of respiratory diseases in neona-tal patients undergoing mechanical ventilation. In this article, the current evidence on the compo-sition of the lung microbiota in the newborn will be reviewed, as well as its role in the develop-ment of bacterial infections in mechanically ventilated neonates. Although advances in many as-pects of the neonatal intensive care unit care have significantly improved the survival of preterm infants, the diagnosis and treatment of ventilator-associated pneumonia has not progressed in recent decades. Avoiding dysbiosis caused by inappropriate use of antibiotics around birth, as well as avoiding intubation of patients or promoting early removal of endotracheal tubes are among the most important preventive measures for ventilator-associated pneumonia. The use of probiotics and prebiotics to prevent infectious, allergic or metabolic complications in the short or long term constitutes a very important field of research in perinatal medicine.

Seed germination and seedling growth represent two vulnerable stages in a plant life cycle and it is important to determine how they will be affected by environmental changes associated with climate change. This study examines the impact of salinity levels (0, 50, 100, and 150 mM) at each of three temperatures (15, 25, and 35˚C) on seed germination and radicle growth for three dormant and three non-dormant varieties of conventional, glyphosate resistant, or reduced lignin alfalfa. The genetic basis and phenotypic plasticity for seed germination and seedling growth in response to salinity and temperature were determined. Both traits were phenotypically plastic with respect to temperature and salinity. Seed germination was 87.0% ± 1.7 at 25˚C, 0mM (no salinity), but decreased to 33.9% ± 3.9 germination at 35˚C and 150mM. Radicle length went from 36.7 ± 1.5 mm after four days at 25˚C, 0mM, to 10.5 ± 0.7 mm at 35˚C, 150mM. The phenotypic response brought seed germination and radicle length away from their optimum, but we detected standing genetic variation for both seed germination and radicle length. Selection to increase both traits at high temperature and salinity would facilitate alfalfa establishment under climate change.

Transparent materials used for facial protection equipment provide protection against microbial infections caused by viruses and bacteria, including multidrug-resistant strains. However, transparent materials used for this type of application are made of materials that do not possess antimicrobial activity. They just avoid direct contact between the person and the biological agent. Therefore, healthy people can get infected through contact of the contaminated material surfaces and this equipment constitute an increasing source of infectious biological waste. Furthermore, infected people can transmit microbial infections easily because the protective equipment do not inactivate the microbial load generated while breathing, sneezing, or coughing. In this regard, the goal of this work consisted of fabricating a transparent face shield with intrinsic antimicrobial activity that could provide extra-protection against infectious agents and reduce the generation of infectious waste. Thus, a single-use transparent antimicrobial face shield composed of polyethylene terephthalate and an antimicrobial coating of benzalkonium chloride has been developed for the next generation of facial protective equipment. The antimicrobial coating was analyzed by atomic force microscopy and field emission scanning electron microscopy with elemental analysis. This is the first facial transparent protective material capable of inactivating enveloped viruses such as SARS-CoV-2 in less than one minute of contact, and the methicillin-resistant Staphylococcus aureus and Staphylococcus epidermidis. Bacterial infections contribute to severe pneumonia associated with the SARS-CoV-2 infection, and their resistance to antibiotics is increasing. Our extra protective broad-spectrum antimicrobial composite material could also be applied for the fabrication of other facial protective tools such as such as goggles, helmets, plastic masks and space separation screens used for counters or vehicles. This low-cost technology would be very useful to combat the current COVID-19 pandemic and protect health care workers from multidrug-resistant infections in developed and underdeveloped countries.

Background: This study provides a comprehensive analysis of Acinetobacter baumannii in aquatic environments and fish microbiota by integrating culture-dependent methods, 16S metagenomics, and antibiotic resistance profiling. Methods: A total of 83 A. baumannii isolates were recovered using culture-dependent methods from intra-hospital infections (IHI), wastewater (WW) and surface water (SW) samples from two southern Romanian cities in august 2022. The antibiotic susceptibility was screened using disc diffusion, microdilution, PCR and Whole Genome Sequencing assays. Results: The highest microbial load in the analyzed samples was found in Glina, Bucharest for both WW and SW samples across all investigated phenotypes. For Bucharest isolates, the resistance levels corresponded to fluoroquinolones &gt; aminoglycosides &gt; β-lactam antibiotics. In contrast, A. baumannii from upstream SW samples in Targoviste showed the highest resistance to aminoglycosides. The blaOXA-23 gene was frequently detected in IHI, WW, and SW isolates in Bucharest but was absent in Targoviste. Molecular phylogeny revealed presence of ST10 in Târgoviște isolates and ST2 in Bucharest isolates, while other minor STs were not specifically correlated with a sampling point. Using 16S rRNA sequencing, significant differences in microbial populations between the two locations was identified. The low abundance of Alphaproteobacteria and Actinobacteria in both locations suggests environmental pressures or contamination events. Conclusions: These findings indicate significant fecal contamination and potential public health risks, emphasizing the need for improved water quality monitoring and management.

Purpose: We aimed to develop a nomogram able to predict treatment failure, skeletal events and overall survival (OS) in patients with castration-resistant prostate cancer with bone metastases (CRPC-BM) treated with Radium-223 dichloride (223Ra). Patients and Methods: Patients from Castilla-La Mancha Spanish region was prospectively included in ChoPET-Rad multicenter study, from January 2015 to December 2022. Patients underwent baseline, interim, and end-of-treatment bone scintigraphy (BS) and 18F-Fluorocholine PET/CT (FCH PET/CT) scans, obtaining multiple imaging radiomics as well as clinical and biochemical variables during follow-up and studying their association with the previously defined end-points. Survival analysis was performed using Kaplan-Meier method and Cox regression. Multivariate logistic and Cox regression models were calculated, and these models were depicted by means of nomograms. Results: Median progression-free survival (PFS) and OS for our population were 4 and 14 months (mo), respectively. The variables that showed the most robust independent significant association with therapeutic failure were baseline alkaline phosphatase (AP) levels (p=0.022) and the characteristics of BM on CT portion of PET/CT (p=0.017). In the case of OS, the significant variables were therapeutic failure (p=0.038), the number of lines received after 223Ra (p

Recently Candida auris has emerged as a multi-resistant fungal pathogen, with a significant clinical impact, and has become a critical issue in WHO fungal priority list, due to its unique ability to persist for long time on human skin and hospital environments. It is therefore fundamental to reinforce hospital surveillance protocols to limit nosocomial outbreaks. The study purpose was the Fourier-Transform Infrared Spectroscopy (FT-IR) application to investigate the phylogenetic relationships between isolated strains within the C. auris outbreak at the university Intensive Care Unit of a Tertiary University hospital in Turin (Italy). In order to calculate a clustering cut-off, intra- and inter-isolates distance values were analysed. Data showed the presence of a major cluster Alfa and a minor cluster Beta with a defined C. auris clustering cut-off. The results were validated by an external C. auris strain and Principal Component and Linear Discriminant Analysis. The application of FT-IR technology had allowed to obtain important information about the phylogenetic relationships between the analysed strains, defining for the first time a “not WGS-based” clustering cut-off with a statistical-mathematical approach. FT-IR could represent a valid alternative to molecular methods for rapid and cost saving typing of C. auris strains with important clinical implications.

The increasing emergence of multidrug resistant (MDR) pathogens causes difficult-to-treat infections, with long-term hospitalizations and high incidence of death, thus representing a global public health problem. To manage MDR bacteria bugs, new antimicrobial strategies are necessary, and their introduction in practice is a daily challenge for scientists in the field. An extensively studied approach to treat MDR infections consists in inducing high levels of reactive oxygen species (ROS) by several methods. Although further clinical investigations are mandatory on the possible toxic effects of ROS to mammalian cells, clinical evaluations are extremely promising, and their topical use to treat infected wounds and ulcers, also in presence of biofilm, is already clinically approved. Biochar (BC) is a carbonaceous material obtained by pyrolysis of different vegetable and animal biomass feedstocks, at 200−1000 °C in limited presence of O2. Recently, it has been demonstrated that BC capability of removing organic and inorganic xenobiotics is mainly due to the presence of persistent free radicals (PFRs), which can activate oxygen, H2O2 or persulfate in the presence or not of transition metals by electron transfer thus generating ROS, which in turn degrade pollutants by advanced oxidation processes (AOPs). In this context, the antibacterial effects of BC containing PFRs have been demonstrated by some authors against Escherichia coli and Staphylococcus aureus, thus giving birth to our idea of the possible use of BC-derived PFRs as a novel method capable of inducing ROS generation for antimicrobial oxidative therapy. Here, the general aspects concerning ROS physiological and pathological production and regulation, and the mechanism by which they could exert antimicrobial effects have been reviewed. The methods currently adopted to induce ROS production for antimicrobial oxidative therapy have been discussed. Finally, for the first time, BC-related PFRs have been proposed as a new source of ROS for antimicrobial therapy via AOPs.

The use of acoustic and magnetic methods of non-destructive testing to detect zones of stable localization of deformation in order to assess and predict the performance of long-term equipment is of scientific and practical interest at present. A structural-mechanical criterion has been developed, that reflects the revealed relationships between the structural and substructural states, internal stress fields and stable localization of deformations with the characteristics of non-destructive tests in the metal of long-term equipment made of structural 0.2 С steel and heat-resistant 0,12C-1Cr-1Mo-1V steel. The values of the structural-mechanical criteria Ks.-m for structural 0.2 С steel and for heat-resistant 0,12C-1Cr-1Mo-1V steel, corresponding to the moment of stable localization of deformation, are established. At the same time, it is recommended to replace the checked equipment nodes due to the exhaustion of the resource. The proposed and justified approach to assessing and predicting the performance and residual life of long-term power equipment, based on the identified relationships between the structural and substructural states, internal stress fields and stable localization of deformations with the characteristics of non-destructive tests and the calculation of the structural-mechanical criterion, was applied at a number of power plants in the Kemerovo region – Kuzbass. A methodology has been developed for evaluating the residual life, based on the identification and use of relationships between structural and substructural states, internal stress fields and stable localization of deformations with the characteristics of non-destructive tests and the calculation of a structural-mechanical criterion.

This study investigates the emergence of ertapenem-resistant, meropenem-susceptible (ErMs) among non-carbapenemase producing (NCP) and carbapenemase producing (CP) Escherichia coli and Klebsiella pneumoniae. As mutations for ertapenem resistance establish the genetic background for non-carbapenemase meropenem resistance, there is a great need for antibiotic stewards and researchers to understand the determinants of a strain’s propensity to become resistant. Whole genome sequencing was conducted on clinical carbapenem-resistant E. coli (CREC) and K. pneumoniae (CRKP) across 5 hospitals in San Antonio, U.S. from 2012-2018. The majority of carbapenem resistant Enterobacterales (CRE) were NCP (54%; 41/76). The blaCTX-M was found to be most prevalent among NCP isolates (p = 0.02). LC-MS/MS analysis of carbapenem hydrolysis revealed that blaCTX-M-mediated carbapenem hydrolysis, indicating the need to reappraise the term, “non-carbapenemase (NCP)” for quantitatively uncharacterized CRE strains harboring blaCTX-M. Antimicrobial susceptibility results showed that 56% of all NCPE isolates had an ErMs phenotype (NCPE vs. CPE, p &lt; 0.001), with E. coli driving the phenotype (E. coli vs. K. pneumoniae, p &lt; 0.001). ErMs strains carrying blaCTX-M, had approximately 4-fold more copies of blaCTX-M than ceftriaxone-resistant but ertapenem and meropenem susceptible (EsMs) isolates (3.7 v. 0.9, p &lt; 0.001). ErMs also carried more mobile genetic elements (MGEs), particularly IS26 composite transposons, than EsMs (37 vs. 0.2, p &lt; 0.0001). Immunoblot analysis demonstrated the absence of OmpC expression in NCP-ErMs E. coli, with 92% of strains lacking full contig coverage of ompC. Overall, this work provides evidence of a collaborative effort between blaCTX-M and OmpC in NCP strains that confer resistance to ertapenem but not meropenem. To thwart potential mismanagement of CRE infected patients, future efforts should focus on understanding the mechanism(s) underlying OmpC loss, developing rapid methods to detect blaCTX-M copy number variants, and targeted antimicrobials for NCPE and ErMs strains.

Multiple myeloma (MM) accounts for about 10 to 15% of all diagnosed hematologic malignancies and about 1-2% of all cancer cases. Approximately 80-90% of MM patients develop bone disease and the changes rarely regress. It is only possible to stop or slow their progression. A major role in bone destruction in MM is attributed to the Wnt signaling pathway, and its action can be modified by various types of interventions including training and diet. Therefore, the aim of this project was to evaluate the effects of a Nordic Walking (NW) training cycle and intermittent fasting (IF) on the levels of selected bone turnover markers associated with the Wnt pathway in patients with MM. Results from 35 patients divided into training (NW and IF NW) and non-training (IF and control) groups were included in the analysis. A 6-week training cycle involving 60-minute workouts 3 times a week was conducted. Body mass and composition and the levels of: vitamin D, calcium and phosphorus, beta2-microglobulin and albumin were examined before and after completion of training cycle. Markers of bone turnover were also determined: sclerostin (SOST), Dickkopf-related protein 1 (DKK-1), osteoprotegrin (OPG), osteopontin (OPN) and Tartrate-resistant acid phos-phatase 5b (TRACP 5b). There was no negative effect of IF or combined training and fasting on the nutritional status of the patients (the level of albumines was unchanged). Both training groups showed an increase in serum concentrations of the active metabolite of vitamin D (IF NW and NW: p=0.001 and p=0.022, re-spectively). The change in the concentration of this vitamin negatively correlated with the con-centration of TRACP 5b (r=-0.413, p=0.014). Evaluating the concentrations of markers related to bone turnover, a reduction in the concentrations of SOST (time: p=0.026, time vs. group: p=0.033) and TRACP 5b (time: p

Background: Infections caused by S. aureus strains encoding Panton-Valentine leukocidin (PVL-SA) have become increasingly relevant in community settings and can cause severe conditions in pediatric populations. We present a pediatric case of invasive disease caused by PVL-SA and provide a literature review of severe manifestations caused by these strains in children. Methods: A PubMed search (February 2024) evidenced studies that included relevant clinical outcomes, diagnostics, and treatments, excluding cases of asymptomatic infection or adult populations. Logistical multivariate analysis was used to find predictors of the need for intensive care. Results: A 10-year-old boy came to the attention of our Pediatric Infectious Diseases Unit with fever, chest pain, and tachypnea. A rapid worsening of his clinical conditions was observed, with the development of necrotizing pneumonia, osteomyelitis, deep vein thrombosis (DVT), and multiple abscesses. Blood cultures confirmed the presence of PVL-producing methicillin-resistant S. aureus (MRSA). The initial treatment included linezolid and ceftaroline and was later adjusted to clindamycin, daptomycin, and fosfomycin, with clinical improvement. Discussion: Our review collected 36 articles, including 156 pediatric cases of severe PVL-SA infection. Bacteremia was present in 49% of cases, lung infection in 47%, and osteomyelitis in 37%. The presence of pulmonary localization was predictive of the need for intensive care, O.R. 25.35 (7.46 - 86.09; p&lt;0.001). Anti-toxin molecules were used in about half the cases where information on treatment was reported. Our report highlights the capacity of PVL-SA to cause life-threatening complications in children, while also discussing the full range of its clinical spectrum and the most effective therapeutic approaches.

Understanding of the molecular mechanisms of prostate cancer has led to development of therapeutic strategies targeting androgen receptor (AR). These androgen-receptor signaling inhibitors (ARSI) include androgen synthesis inhibitor- abiraterone and androgen receptor antagonists- enzalutamide, apalutamide, and darolutamide. Although these medications provide significant improvement in survival among men with prostate cancer, drug resistance develops in nearly all patients with time. This could be through androgen-dependent or androgen-independent mechanisms. Even weaker signals and non-canonical steroid ligands can activate AR in the presence of truncated AR-splice variants, AR overexpression, or activating mutations in AR. AR splice variant, AR-V7 is the most studied among these and is not targeted by available ARSIs. Non-androgen receptor dependent resistance mechanisms are mediated by activation of an alternative signaling pathway when AR is inhibited. DNA repair pathway, PI3K/AKT/mTOR pathway, BRAF-MAPK and Wnt signaling pathway and activation by glucocorticoid receptors can restore downstream signaling in prostate cancer by alternative proteins. Multiple clinical trials are underway exploring therapeutic strategies to overcome these resistance mechanisms.

Despite recent improvements in the methods used to eradicate and minimize mosquito populations, they still pose severe threats to human health. This study aimed to investigate the Larvicidal potentials of silver nanoparticles of Ocimum gratissimum on wild Anopheles larvae from Lagos. The plant used in this study was collected from the southeastern part of Nigeria, Ibite-Olo in Ezeagu Local Government Area of Enugu State. Wild Anopheles mosquito larvae were collected from a field at Kosofe Local Government Area of Lagos State, Nigeria where resistant Anopheline populations have been reported in and around Lagos State were brought to the laboratory and kept under standard insectary conditions (25–29 °C;78–82% relative humidity). Aqueous extract of Ocimum gratissimum was made and subsequently into the silver nanoparticles. A bioassay test was performed according to WHO guidelines, with six different concentrations to assess the larvicidal activity and values obtained were subjected to log prohibit regression analysis to obtain LC₅₀ and values with 95% confidence limit. The results of the larvicidal activities of the silver nanoparticles of Ocimum gratissimum showed that the mortality rate was dose-dependent with the percentage mortality increasing at a direct proportional rate as with dose and time of exposure. Ocimum gratissimum gave LC₅₀ at 0.5 ppm and LC₉₅ at 2.5 ppm respectively. The biosynthesized silver nanoparticles augmented the larvicidal activity of the silver nanoparticles of Ocimum gratissimum on wild Anopheles larvae from Lagos. Therefore, this study showed that the silver nanoparticles of Ocimum gratissimum have the potency to be used against an insecticide-resistant mosquito vector and are a suitable candidate for the development of novel natural insecticides.

Neuroendocrine neoplasms (NENs) comprise a heterogeneous group of rare malignancies mainly originated from hormones secreting cells, which are widespread in human tissues. The identification of mutations in ATRX/DAXX genes in sporadic NENs, as well as the high burden of mutations scattered throughout MEN-1 gene in both sporadic and inherited syndromes, provided new insights into the molecular biology of tumour development. Other molecular mechanisms, such as the NOTCH signaling pathway, have shown to play an important role in the pathogenesis of NENs. NOTCH receptors are expressed on neuroendocrine cells and generally, act as tumour suppressor proteins, but in some contexts can function as oncogenes. The biological heterogeneity of NENs suggests that to fully understand the roles and the potential therapeutic implications of gene mutations and NOTCH signaling in NENs, a comprehensive analysis of genetic alterations, NOTCH expression patterns and their potential roles across all NEN subtypes is required.