Enterococci are gastrointestinal commensals whose hardiness allowed them to colonize very diverse environments, including soils, water, food and feed. This ability to overcome adverse conditions makes enterococci problematic once they colonize hospital niches. Together with the malleability of their genomes, the capacity to acquire and disseminate determinants of antibiotic resistance have contributed to convert what was once just another opportunistic pathogen into a first-class clinical problem. This review discusses the dimension of the emergence of enterococcal resistance to key antimicrobial agents, the dissemination of this resistance and its significance in terms of public health, with the aim of raising the awareness to the need to devise and implement monitoring programmes and effective antibiotic usage guidelines.

The antibiotic or antimicrobial resistance is rapidly spreading in microbes relevant to human health. Two visible major contributory factors have been the indiscriminate overuse of antimicrobials for preventing diseases in human and to enhance the productivity in agriculture sector. To mitigate the potential threat posed by post-antibiotic era, the global health stakeholders have been making extra efforts at a war footing to formulate and implement global and national plans of action. In the current article, an endeavour is made to provide a perspective to look beyond the current focus on just use of the antimicrobials. Attention has been drawn towards various obvious and not-so-obvious self-preservation infection-prevention practices in vogue from the pre-antibiotic era whose usage has been on decline in the antibiotic era for various reasons. Particularly, the practices with a clear potential to effectively decrease the spread of pathogens through contact, curtail the evolution and dissemination of the antimicrobial resistance in local environment and its introduction into the global community, should be Identified and strengthened to make them part of comprehensive hygiene and quarantine practices. Broadly, the suggestions pertaining to the personal and community hygiene including bereavement practices, isolation and quarantine of suspected pathogen carriers, and water and environment security have been made to invoke a constructive debate and discussion among various stakeholders for their evaluation and implementation to effectively delay the development of antimicrobial resistance wherever possible and disrupt its spread to pathogens.

The bean weevil (Acanthoscelides obtectus (Say.)) is one of the main pests of stored beans in the world. Heterogeneous Inbreed Families (HIF) Population of Near Isogenic Lines (NILs) could be an exceptional strategy to study the inheritance of the resistance against A. obtectus. We developed a HIF population of NILs of R-bufa-80-12 (Phaseolus vulgaris) to study the inheritance related to bean weevil resistance and to search NILs with high resistance to the pest within the HIF population. The objective of this research was to study the inheritance in a HIF population and to identify the best lines to provide weevil resistance in bean breeding for commercial genotypes that could reduce pesticide applications. To achieve this objective, we developed a set of 148 NILs which were near-homozygous in the genome, except in the region under study. The HIF were evaluated in two environments under natural infestation with A. obtectus in free choice bioassays in a warehouse highly infested. The population showed wide variability for the traits studied, from 17.2 to 29.2 g for 100 seed weight, 0.0-0.8 for consumption in grams, 2.0-30.0 for consumption in percent and 1.2-9.6 for preference (number of adults in the bottle to the end of the experiments. The heritabilities for resistance traits were from very low to low 0.0 to 0.19. The heritability for 100 seed weight was the highest, with a value of 0.90. All traits studied in this research have a normal distribution, so they are considered to be quantitatively inherited. However, a great variability was found for the traits studied, which allows selecting lines with a high level of resistance within the R-bufa-80-12 HIF population. All traits studied in present research are of quantitative inheritance. The best lines of the HIF population for resistance to A. obtectus were the Line-45, Line-129, Line-124, Line-108 and Line-47.

The main aim of this study was to determine the prevalence of plasmid-mediated colistin resistance mcr-1 to mcr-5 genes among colistin and multi-drug resistant Enterobacterales, Pseudomonas aeruginosa and Acinetobacter sp strains isolated from patients in a tertiary hospital in the city of Toluca, Mexico. 241 strains were included in the study. The presence of mcr genes among these strains was assessed by PCR and sequencing. In the case of mcr-carrying E. coli, further PCR tests were performed to determine the presence of blaCTX-M and whether the strains belonged to the O25b-ST131 clone. Conjugation experiments were carried to assess plasmid-mediated colistin resistance horizontal transmission. 12 strains (5.0%), of which four were E. coli; four, P. aeruginosa; three, K. pneumoniae and one, E. cloacae, were found to be resistant to colistin. Of these strains, two E. coli isolates were found to carry mcr-1. Both mcr-1-carrying E. coli strains were found to co-express blaCTX-M, belong to the O25b-ST131 clone and horizontally transmit their colistin resistance. The results of this study confirm the presence of plasmid-mediated colistin resistance in hospitalized patients in Mexico and demonstrated that the multidrug-resistant O25b-ST131 E. coli clone can acquire mcr genes and transmit such resistance trait to other bacteria.

Resistance training increases myofiber hypertrophy, but the morphological adaptations that occur within myofibers remain largely unresolved. Fifteen males with minimal training experience (24±4 years, 17.9±1.4 kg/m2 lean body mass index) performed 10 weeks of conventional, full-body resistance training (2x weekly). Body composition, the radiological density of the vastus lateralis muscle using peripheral quantitative computed tomography (pQCT), and vastus lateralis muscle biopsies were obtained one week prior to and 72 hours following the last training bout. Fiber typing and the quantification of myofibril and mitochondrial areas per fiber were performed using histology/immunohistochemistry (IHC) techniques. Relative myosin heavy chain and actin protein abundances per wet muscle weight as well as citrate synthase (CS) activity assays were also obtained on tissue lysates. Training increased whole-body lean mass, mid-thigh muscle cross-sectional area, various strength metrics, and mean and type II fiber cross sectional areas (fCSA) (p<0.05). Myofibril areas in type I or II fibers were not altered with training, suggesting a proportional expansion with fCSA increases. Relative myosin heavy chain and actin protein abundances also did not change with training. IHC indicated training increased mitochondrial areas in both fiber types (p=0.018). However, CS activity levels remained unaltered with training. Interestingly, although pQCT-derived muscle density increased with training (p=0.036), suggestive of myofibril packing, a positive association existed between training-induced changes in this metric and changes in type I+II myofibril areas (r=0.600, p=0.018). Shorter-term resistance training seemingly involves a proportional expansion of myofibrils and an accelerated expansion of mitochondria in type I and II fibers. Additionally, histological and biochemical techniques should be viewed independently from one another given the lack of agreement between the variables assessed herein. Finally, the pQCT may be a viable tool to non-invasively track morphological changes in muscle tissue.

Introduction Tuberculosis is common in Pakistan. Due to various factors including socioeconomic factors, compliance is poor to anti-tuberculosis drugs, leading to resistance. We aim to determine the prevalence of Multidrug resistance (MDR) tuberculosis in Pakistani population.Methods A prospective observational study was conducted from April 1, 2019, to December 31, 2019, in the Pulmonology department of a tertiary care hospital in Pakistan. Culture and sensitivity were assessed using a sputum sample or, in cases of an absent sputum sample, from Broncho alveolar lavage.ResultsApproximately 71.3% percent patients who had tuberculosis were found to be resistant to Isoniazid and around 48.6% did not respond to Rifampin. Multi-drug resistant was found in 29.4% participants.ConclusionMulti-drug resistance tuberculosis is very prevalent in Pakistan, which may increase burden on health care system and may lead to various complications of tuberculosis.

Phage therapeutics offer a potentially powerful approach to combat multidrug-resistant bacterial infections. However, to be effective, phage therapy must overcome existing and developing phage resistance. While phage cocktails can reduce this risk by targeting multiple receptors in a single therapeutic, bacteria have mechanisms of resistance beyond receptor modification. A rapidly growing body of knowledge describes a broad and varied arsenal of antiphage systems encoded by bacteria to counter phage infection. We sought to understand the types and frequencies of antiphage systems present in a highly diverse panel of Pseudomonas aeruginosa clinical isolates utilized to characterize novel antibacterials. Using web-server tool PADLOC (Prokaryotic Antiviral Defense Locator), putative antiphage systems were identified in these P. aeruginosa clinical isolates based on sequence homology to a validated and curated catalog of known defense systems. Coupling this host bacterium sequence analysis with host range data for 70 phages, we observed a correlation between existing phage resistance and the presence of higher numbers of antiphage systems in bacterial genomes. We were also able to identify antiphage systems that were more prevalent in highly phage-resistant P. aeruginosa strains, suggesting their importance in conferring the resistance.

Abstract: Vulvovaginal candidiasis (VVC) is a mucous membrane infection, with an increased rate of antifungal resistance of Candida species. The in vitro efficacy of farnesol alone or in combination with traditional antifungals, against resistant Candida strains recovered from women with VVC was assessed. In this study, 80 Candida isolats were identified by multi-plex PCR. Antifungal sus-ceptibility of amphotericin B (AMB), fluconazole (FLU), itraconazole (ITZ), voriconazole (VOR), clotrimazole (CTZ) and farnesol was tested by M27-A3/S4 broth micro dilution method. The combinations of farnesol with each antifungal were calculated based on the fractional inhibitor concentration index (FICI). C. glabrata was the predominant species (48.75%) isolated from vaginal discharges, followed by C. albicans (43.75%), C. parapsilosis (3.75%), mixed infection of C. albicans and C. glabrata (2.5%), C. albicans and C. parapsilosis (1%). C. albicans and C. glabrata isolates had lower susceptibility to FLU (31.4% and 23.0%, respectively) and CTZ (37.1% and 33.3%, respectively). Importantly, there was ‟synergismˮ between farnesol-FLU and farnesol-ITZ against C. albicans and C. parapsilosis (FICI= 0.5 and 0.35, respectively), reverting the original azole resistant profile. These findings indicate that farnesol is able to revert to the resistance profile of azole by enhancing the activity of FLU and ITZ in resistant isolates, which is a promising result.

Dirofilaria immitis infection is one of the most severe parasitic diseases of dogs. Prevention is achieved by the administration of drugs containing macrocyclic lactones (MLs). These products are very safe and highly effective, targeting the third and fourth larval stages (L3, L4) of the parasite. Until 2011, claims of ineffectiveness of MLs, reported as “Lack of Efficacy” (LOE), were generally attributed to owners’ non-compliance, or other reason for inadequate preventative coverage. There was solid argumentation that a resistance problem is not likely to occur because of i) the great extent of refugia, ii) the complexity of resistance development to MLs, and iii) the possible big number of genes involved in resistance selection. Nevertheless, today it is unequivocally proven that ML resistant D. immitis strains exist, at least in the Lower Mississippi region, USA. Accordingly, tools have been developed, to evaluate and confirm the susceptibility status of D. immitis strains. A simple, in-clinic, microfilariae suppression test, 14-28 days after ML administration, and a “decision tree” (algorithm), including compliance and preventatives’ purchase history, and testing gaps, may be applied for assessing any resistant nature of the parasite. On the molecular level, specific SNPs may be used as markers of ML resistance, offering a basis for validation of clinically suspected resistant strains. In Europe, no LOE/resistance claims have been reported so far, and the existing conditions (stray dogs, rich wildlife, majority of owned dogs not on preventive MLs treatment) do not favor selection pressure on the parasites. Considering the genetic basis of resistance and the epizootiological characteristics of D. immitis, ML resistance neither establishes easily nor spreads quickly, a fact confirmed by the current known dispersion of the problem, which is limited. Nevertheless, ML resistance may propagate from an initial geographical point, via animal and vector mobility, to other regions, while it can also emerge as an independent evolutionary process in a new area. For these reasons and considering the current chemoprophylaxis recommendations and increasing use of ML endectoparasiticides as a potential selection pressure, it is important to remain vigilant for timely detection of any ML LOE/resistance, in all continents where D. immitis is enzootic.

Type 2 diabetes mellitus (T2DM) is an endocrine illness associate with various changes in the immune system and adaptor protein levels. Cytokine dependent hematopoietic cell linker (CLNK) is an adapter protein that regulates immune receptor signaling and acts as a regulator of the receptor signaling of T-cells and natural killer T-cell. The role of CLNK in T2DM is not studied previously. In the present study, serum CLNK level was measured and correlated with some sociodemographic and insulin resistance (IR) parameters. This is achieved by performing measurement of CLNK and insulin parameters (glucose, insulin, and HbA1c in addition to the calculation of the functions of IR (HOMA2IR), insulin sensitivity (HOMA%S), and beta-cell function (HOMA%B)) in 60 T2DM patients and 30 controls. The results indicated a significant increase (p=0.025) in serum CLNK in patients group in comparison with the controls. Multivariate generalized linear model (GLM) analysis revealed no significant effect of age, BMI, and sex on the CLNK level. The results of tests for between-subjects showed that the CLNK affects diagnosis significantly (F=7.445, p=0.008, partial η² =0.081) and its effect is approximately the same as the effect of insulin (F=8.107, p=0.006, partial η² =0.087). The correlation study showed a highly significant positive correlation between CLNK and the duration of disease (rho=0.420, p<0.001). It can be concluded that the increase CLNK in T2DM revealing the role of the adaptor proteins level in the nature of disease. Elevation of CLNK level may be used as a predictor for diabetes complications, which needs more investigations.

Background: Obesity and diabetes are two metabolic disorders linked by an inflammatory process named insulin resistance (IR). Various research on the role of gut microbiota in developing obesity and its associated disorders has led to the growing interest in probiotic supplementation. Considering the life-threatening complications of diabesity this mini-review explored the effects of probiotic supplementation on IR in obesity-associated diabetes. Method: This review is based on recent articles from 2005-2020, studying the role of probiotic supplementation on glucose and insulin parameters in healthy and diabetic mouse models. Result: Probiotic supplementation altered the gut microbiota composition, increased short-chain fatty acid production, and decreased pro-inflammatory cytokines. Additionally, they decreased intestinal permeability, circulating lipopolysaccharide, and metabolic endotoxemia hence improved insulin sensitivity and reduced obesity. Although multi-strain probiotic supplementation showed greater benefits than single strain interventions, variations in the concentration of probiotics used and the duration of treatment also influenced the results. Conclusion: Probiotic supplementation could manipulate the gut microbiota by reducing intestinal permeability, inflammation and ameliorate IR and obesity-associated diabetes in animal models which requires further long-term clinical studies in humans.

Infectious illnesses have always posed a threat to human health, with tuberculosis being a major concern. The use of various drugs in the fight against such TB has led to the emergence of drug-resistant tuberculosis, which has become increasingly difficult to manage. While there have been a few studies and proposed conceptual models on how to manage and prevent various drug-resistant TB mutations and lineages, a model aimed at limiting and controlling such mutations in rural areas burdened with tuberculosis is lacking. This study seeks to map a model that is to be used to bridge the gap by facilitating the exchange of knowledge among healthcare professionals in healthcare facilities, diagnostic laboratories, and research institutes, particularly for underprivileged communities in the Eastern Cape. The model information is based on three published manuscripts; therefore, this is a follow-up study. The model will also serve as a practical guide to monitor and evaluate epidemiological TB management plans.

In 2016 northern Nigeria experienced a devastating infestation by the tomato leaf miner, leading to soaring in prices of tomato across the country. Unfortunately, information on the bionomics and resistance status of this pest is lacking in northern Nigeria, hampering appropriate control measures. Here, we identified to species level, and using conventional and synergist bioassays characterised pesticides resistance profile of a field population of a tomato leaf miner from northern Nigeria. Highest resistance was obtained with λ-cyhalothrin (Type II pyrethroid) with a low mortality (18.52% at 56hr) and LD₅₀ of 7461.474ppm. Resistance was also established toward propoxur and chlorpyrifos-methyl with average mortalities each of 56% and LD_50s of 1023.51ppm and 106.351ppm, respectively. Highest susceptibility was seen with abamectin with mortality of 86% and LD₅₀ of 0.034ppm. Pre-exposure to piperonyl butoxide significantly recovered λ–cyhalothrin susceptibility (mortality = 90% and LD₅₀ = 0.92ppm) implicating the P450 monoxygenases in the resistance. No significant changes in mortalities were obtained on pre-exposure to diethyl maleate and triphenyl-phosphate- inhibitors of glutathione S-transferases and carboxylesterases, respectively. The finding of resistance to these agricultural pesticides will sensitize stakeholders across Nigeria to take action to manage the resistance at an early stage before it gets out of hand.

Increased access to highly active antiretroviral therapy (HAART) by HIV⁺ individuals has become a reality worldwide. In Brazil, ART currently reaches over half of the HIV-infected subjects. In the context of a remarkable HIV-1 genetic variability, highly related variants, called quasispecies, are generated. HIV quasispecies generated during infection can influence virus persistence and pathogenicity, representing a challenge to treatment. However, the clinical relevance of minority quasispecies is still uncertain. For this study, we have determined the archived proviral sequences, viral subtype and drug resistance mutations from a cohort of HIV⁺ patients with undetectable viral load undergoing HAART as first-line therapy using next-generation sequencing for near full-length virus genome (NFLG) assembly. HIV-1 consensus sequences representing NFLG were obtained for eleven patients, while for another twelve varying genome coverage rates were obtained. Phylogenetic analysis showed the predominance of subtype B (83%; 19/23). Considering the minority variants, 18 patients carried archived virus harboring at least one mutation conferring antiretroviral resistance; for six patients, the mutations correlated with the current ARVs used. These data highlight the importance of monitoring HIV minority drug resistant variants and their clinical impact, to guide future regimen switches and improve HIV treatment success.

(1) Background: Malaria remains a global public health problem. Unfortunately, the resistance of malaria vectors to insecticides commonly used threatens disease control and elimination efforts. Molecular mechanisms helping some malaria vectors to now survive to greater doses of insecticides remains poorly understood. Here, we elucidated the pattern of resistance escalation in the main malaria vector Anopheles gambiae in a pesticide-driven agricultural hotspot in Cameroon and its impact on vector control tools; (2) Methods: Larval stages and indoor blood-fed females (F0) were collected in Mangoum in May and November and forced to lay eggs; the emerging mosquitoes were used for WHO tube, synergist and cone tests. Molecular identification was done using SINE PCR whereas TaqMan-based PCR was used for genotyping of L1014F/S and N1575Y kdr and the G119S-ACE1 resistance markers. Transcription profile of candidate resistance genes was performed using qRT-PCR methods. Characterization of the breeding water and soil from Mangoum was also performed using HPLC technique; (3) Results: An. gambiae s.s. was the only species in Mangoum with 4.10 % infection with Plasmodium. These mosquitoes were resistant to all the four classes of insecticides with mortality rates &lt;7% for pyrethroids and DDT and &lt;54% for carbamates and organophophates. This population also exhibited high resistance intensity to pyrethroids (permethrin, alpha-cypermethrin and deltamethrin) after exposure to 5X and 10X discriminating doses and Synergist assays with PBO revealed only a partial recovery of susceptibility to permethrin, alpha-cypermethrin and deltamethrin. Only PBO-based nets (Olyset plus and permaNet 3.0) and Royal Guard showed an optimal efficacy. A high amount of alpha-cypermethrin was detected in breeding sites (5.16 fold LOD) suggesting ongoing selection from agricultural pesticides. The 1014F-kdr allele was fixed (100%) whereas the 1575Y-kdr (37.5%) and the 119S Ace-1R (51.1%) are moderately present. Elevated expression of P450s respectively in permethrin and deltamethrin resistant mosquitoes [CYP6M2 (10 and 34-fold), CYP6Z1(17 and 29-fold), CYP6Z2 (13 and 65-fold), CYP9K1 (13 and 87-fold)] supports their role in the observed resistance besides other mechanisms including chemosensory genes as SAP1 (28 and 13-fold), SAP2 (5 and 5-fold),SAP3 (24 and 8-fold) and cuticular genes as CYP4G16 (6 and 8-fold) and CYP4G17 (5 and 27-fold). However, these candidate genes were not associated with resistance escalation as expression level did not differ significantly between 1x, 5x and 10x surviving mosquitoes. (4) Conclusions: Intensive and multiple resistance is being selected in malaria vectors from pesticide-based agricultural hotspot of Cameroon leading to loss of efficacy of pyrethroid-only nets. Further studies are needed to decipher the molecular basis underlying such resistance escalation to better assess its impact on control interventions.

With the increasing use of genome sequencing as a surveillance tool for molecular epidemiology of antimicrobial resistance, we are seeing an increased intersection of genomics, microbiology, and clinical epidemiology. Clear nomenclature for AMR gene families and pathogens is critical for communication. For CARD release version 3.0.3 (July 2019), we updated the entire CARD database to reflect the latest pathogen names. In total, we detected 48 name changes or updates, some of which reflect major changes in familiar names.

Coronavirus disease 2019 (COVID-19) is a potentially serious acute respiratory infection caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Since the World Health Organization (WHO) declared COVID-19 a global pandemic, the virus has spread to more than 200 countries with more than 500 million cases and more than 6 million deaths reported globally. It has long been known that viral respiratory tract infections predispose patients to bacterial infections and that these co-infections often have an unfavourable clinical outcome. Moreover, nosocomial infections, also known as health care-associated infections (HAIs), are those infections that are absent at the time of admission and acquired after hospitalization. However, the impact of coinfections or secondary infections on the progression of COVID-19 disease and its lethal outcome is still debated. The aim of this review was to assess the literature on the incidence of bacterial co-infections and superinfections in patients with COVID-19. The review also highlights the importance of the rational use of antibiotics in patients with COVID-19 and the need to implement antimicrobial stewardship principles to prevent the transmission of drug-resistant organisms in healthcare settings. Finally, alternative antimicrobial agents to counter the emergence of multidrug-resistant bacteria causing healthcare-associated infections in COVID-19 patients will also be discussed.

This study investigates the effects of the antiperspirant aluminum chlorohydrate on the development of antibiotic resistance in commensal Staphylococcus epidermidis isolates. The isolates were exposed to aluminum chlorohydrate for 30 days, respectively. The bacteria that developed resistance to oxacillin, and ciprofloxacin were isolated, and the expression levels of some antibiotic resistance genes were determined by quantitative reverse transcriptase-PCR. Before and after the exposure, the minimum inhibitory concentration (MIC) values of the bacteria were determined by the microdilution method. A time-dependent increase was observed in the number of bacteria that developed resistance and increased the MIC value. Consistent with the ciprofloxacin resistance observed after exposure, an increase in the norA, norB/C, gyrA, gyrB, parC, and parE gene expressions was observed. In addition to aluminum chlorohydrate exposure, oxacillin resistance was observed in all test bacteria in the group subcultured only in the medium, suggesting that phenotypic resistance cannot be correlated with chemical exposure in the light of these data. The increase in mecA gene expressions of selected test bacteria that acquired resistance to oxacillin after exposure compared with control groups suggests that the observed resistance may be related to aluminum chlorohydrate exposure. To our knowledge, this is the first time in the literature that the effects of aluminum chlorohydrate as an antiperspirant on the development of antibiotic resistance in Staphylococcus epidermidis have been reported.

A new picture of the Josephson effect is devised. The radio-frequency (RF) signal, observed in a Josephson junction, is shown to stem from bound electrons, tunneling periodically through the insulating film. This holds also for the microwave mediated tunneling. The Josephson effect is found to be conditioned by the same prerequisite worked out previously for persistent currents, thermal equilibrium and occurence of superconductivity. The observed negative resistance behaviour is shown to originate from the interplay between the normal and superconducting currents.

Transferrin (TF) is a key iron carrier protein. Studies in human cohorts and in cultured adipocytes suggested that decreased transferrin expression and intracellular iron in adipocytes leads to impaired insulin responsiveness and causes differential expression of genes involved in metabolism, insulin action, and obesity. While suggestive, these studies did not definitively prove in an intact organism that altering TF expression in adipocytes is sufficient to affect glucose homeostasis and insulin resistance. In this study we created a mouse model of decreased transferrin expression only in adipocytes (Trf+/-Cre+/-) to test the hypothesis that iron trafficking in adipose tissue is sufficient to affect insulin sensitivity. Area under the glucose curve (AUCg) after intraperitoneal glucose administration was increased in the Trf+/-Cre+/- mice compared to wild type (WT) mice on a normal chow diet, and the mice were slightly heavier (p=0.02 for both). Homeostasis Model of Insulin Resistance (HOMA-IR) values were also significantly higher in the Trf+/- Cre+/- mice (p<0.05). Thus, supporting our hypothesis, analysis of mice with decreased expression of TF restricted to adipocytes showed that a decrease in adipocyte TF is sufficient to affect insulin resistance, weight, and glucose homeostasis.

Geopolymer concrete (GPC) represents an innovative green and low-carbon construction material, offering a viable alternative to ordinary Portland cement concrete in building applications. However, existing studies tend to overlook the recyclability aspect of GPC for future use. Various structural applications necessitate the use of concrete with distinct strength characteristics. The recyclability of the parent concrete is influenced by these varying strengths. This study examined the recycling potential of GPC across a spectrum of strength grades (40, 60, 80 and 100 MPa, marked as C40, C60, C80 and C100) when subjected to freeze-thaw conditions. The cementitious material comprised 60% metakaolin and 40% slag, with natural gravel serving as the coarse aggregate, and the alkali activator consisting of sodium hydroxide solution and sodium silicate solution. The strength of the GPC was modulated by altering the Na/Al ratio. After 350 freeze-thaw cycles, the GPC specimens underwent crushing, washing, and sieving to produce recycled geopolymer aggregates (RGAs). Subsequently, their physical properties and microstructure were thoroughly examined. The findings indicated that GPC with strength grades of C100, C80, and C60 were capable of enduring 350 freeze-thaw cycles, in contrast to C40, which did not withstand these conditions. RGAs derived from GPC of strength grades C100 and C80 complied with the criteria for Class II recycled aggregates, whereas RGAs produced from GPC of strength grade C60 aligned with the Class III level. A higher strength grade in the parent concrete correlated with enhanced performance characteristics in the resulting recycled aggregates.

Tungsten carbide inserts (TCI) and polycrystalline diamond compact (PCD) cutters used in two types of drill bits for drilling oil and gas wells were evaluated by a pin-on-disc test. The morphology of the worn surface was characterized by scanning electron microscopy (SEM). The behavior of corrosion resistance was evaluated with the electrodynamic polarization technique. The polycrystalline diamond compact cutter has a higher hardness, better corrosion, and wear behavior compared to tungsten carbide.

The SiBOC precursor ceramics were fabricated by polymer-derived method SiBOC precursors with different B/Si molar ratios were synthesized by controlling monomer content. The effects of different process conditions on SiBOC ceramics and the oxidation resistance of SiBOC ceramics at a high temperature (1400 ℃) were studied. The SiBOC precursor’s bonds of Si-O-C, Si-O-Si, and Si-O-B were detected by FTIR. The precursor is converted to a rigid ceramic material that has an 85.3 wt % ceramic yield of SiBOC ceramics with B/Si=0.4 by TG-DSC. The results of SEM analysis show that the SiBOC ceramics surface bulges and folds increase with the increase of boric acid content. With the increase of pyrolysis temperature and pyrolysis time, the size and number of pores on the surface of SiBOC ceramics also increase. Static oxidation tests show that SiBOC ceramics with B/Si=0.4 have better oxidation resistance under other conditions being the same.

Background: Worldwide, microbes are becoming more dangerous by acquiring virulent skills to adapt and develop antimicrobial resistance (AMR). This is a concern as this increases morbidity, mortality, and costs. Consequently, physicians need to be trained inappropriate prescribing, starting with medical students. Objective: Evaluate medical students' confidence in antimicrobial agent prescribing and drug resistance Methods: Cross-sectional study assessing medical students' knowledge, perception, and confidence in prescribing antimicrobial agents and drug resistance in a Malaysian University. A universal sampling method was used. Results: Most respondents believe that educational input regarding overall prescribing was sufficient. Regarding the principle of appropriate and accurate prescriptions, female medical students had less knowledge [Odds Ratio (OR)=0.51; 95% Confidence Interval (CI) 0.25-0.99; p=0.050]. Year-IV and Year-V students had more excellent knowledge than Year-III students regarding confidence in antibiotic prescribing. Year-V students also showed appreciably higher confidence in the broad principles of prescribing, including infectious diseases, compared to those in other years. Conclusion: Overall, medical students, gain more excellent knowledge and confidence regarding prescribing, including antimicrobials, as their academic careers progress.

Infectious illnesses have always posed a threat to human health, with tuberculosis being a major concern. The use of various medications and antibiotics in the fight against such TB has led to the emergence of drug-resistant tuberculosis, which has become increasingly difficult to manage. While there have been a few studies and proposed conceptual models on how to manage and prevent various drug-resistant TB mutations and lineages, a model aimed at limiting and con-trolling such mutations in rural areas burdened with tuberculosis is lacking. This study seeks to map a model that is to be used to bridge the gap by facilitating the exchange of knowledge among healthcare professionals in healthcare facilities, diagnostic laboratories, and research institutes, particularly for underprivileged communities in the Eastern Cape. The model will also serve as a guide to monitor and evaluate epidemiological TB management plans.

Evidence from large epidemiological studies has shown that obesity may predispose to increased Th2 inflammation and increase the odds of developing asthma. On the other hand, there is growing evidence suggesting that metabolic dysregulation that occurs with obesity, and more specifically hyperglycemia and insulin resistance, may modify immune cell function and in some degree systemic inflammation. Insulin resistance seldom occurs on its own, and in most cases constitutes a clinical component of metabolic syndrome, along with central obesity and dyslipidemia. Despite that, in some cases, hyperinsulinemia associated with insulin resistance has been proven a stronger risk factor than body mass in developing asthma. This finding has been supported by recent experimental studies showing that insulin resistance may contribute to airway remodeling, promotion of airway smooth muscle (ASM) contractility and proliferation, increase of airway hyper-responsiveness and release of pro-inflammatory mediators from adipose tissue. All these effects indicate the potential impact of hyperinsulinemia on airway structure and function, suggesting the presence of a specific asthma phenotype with insulin resistance. Epidemiologic studies have found that individuals with severe and uncontrolled asthma have a higher prevalence of glycemic dysfunction, whereas longitudinal studies have linked glycemic dysfunction to an increased risk of asthma exacerbations. Since the components of metabolic syndrome interact with one another so much, it is challenging to identify each one's specific role in asthma. This is why, over the last decade, additional studies have been conducted to determine whether treatment of type 2 diabetes mellitus affects comorbid asthma as shown by the incidence of asthma, asthma control and asthma-related exacerbations. The purpose of this review is to present the mechanism of action, and existing preclinical and clinical data, regarding the effect of insulin resistance in asthma.

Despite often leading to platinum resistance, platinum-based chemotherapy continues to be the standard treatment for many epithelial tumors. In this study we analyze and validated the cytogenetic alterations that arise after treatment in four lung and ovarian paired cisplatin-sensitive/resistant cell lines by 1-million array-CGH and qRT-PCR methodologies. RNA-sequencing, functional transfection assays and gene-pathway activity analysis were used to identify genes with a potential role in the development of this malignancy. Results were further explored in 55 lung and ovarian primary tumors and control samples and in two extensive in silico databases. Long-term cell exposure to platinum induces the frequent deletion of ITF2 gene. Its expression re-sensitizes tumor cells to platinum and recovers the levels of Wnt/β-catenin transcriptional activity. ITF2 expression was also frequently downregulated in epithelial tumors, predicting a worse overall survival. We also identified an inverse correlation between ITF2 and HOXD9 expression, revealing that NSCLC patients with lower expression of HOXD9 have a better overall survival rate. We define the implication of ITF2 as a molecular mechanism behind the development of cisplatin resistance probably through the activation of the Wnt-signaling pathway. This data highlights the possible role of ITF2 and HOXD9 as novel therapeutic targets for platinum resistant tumors.

Multiple myeloma (MM) is a common type of cancer that unfortunately leads to a significant number of deaths each year. The majority of the reported MM cases are detected in the advanced stages, posing significant challenges for treatment. Additionally, all MM patients eventually develop resistance or experience relapse, therefore advances in treatment are needed. However, developing new anti-cancer drugs, especially for MM, requires significant financial investment and a lengthy development process. The study of drug repurposing involves exploring the potential of existing drugs for new therapeutic uses. This can significantly reduce both time and costs, which is typically a major concern for MM patients. The utilization of pre-existing non-cancer drugs for various myeloma treatments presents a highly efficient and cost-effective strategy, considering their prior preclinical and clinical development. The drugs have shown promising potential in targeting key pathways associated with MM progression and resistance. Thalidomide exemplifies the success that can be achieved through this strategy. This review delves into the current trends, the challenges faced by conventional therapies for MM, and the importance of repurposing drugs for MM. This review highlights a noncomprehensive list of conventional therapies that have potentially significant anti-myeloma properties and anti-neoplastic effects. Additionally, we offer valuable insights into the resources that can help streamline and accelerate drug repurposing efforts in the field of MM.

Objectives: Accumulating evidence suggests that physical activity (PA) is an efficient intervention to maintain functional capabilities and mitigate physiological changes in the older population. However, an attempt has yet to be made to comprehensively investigate the published landscape on the subject. Methods: This study had two aims. The first aim was to perform a bibliometric analysis for two keywords, “aging” and “PA”, to analyze the research trend. Since ‘frailty’ is the most noticeable co-occurring keyword with the two keywords, the second aim was to investigate the effects of PA, particularly resistance training (RT), on frailty via meta-analysis to provide a summary of the current evidence base. Results: Bibliometric analysis revealed that the number of publications on this research topic has gradually increased, highlighting the importance of understanding the role of PA in aging. A meta-analysis found that RT had significant beneficial effects on physical frailty factors, including handgrip strength, lower limb strength, balance, gait speed, and stair climbing ability. Conclusion: These findings demonstrate that RT is an effective intervention for improving physical function in frail populations; thus it has important implications for the development of PA programs for older adults with frailty. Future research is warranted to explore the optimal dose, frequency, and duration of RT programs for older adults, as well as the potential benefits of combining RT with other forms of PA, such as aerobic or balance exercises.

Background: Activation of the immune-inflammatory response system (IRS) and the compensatory immune-regulatory system (CIRS) play a key role in SCZ and treatment resistant SCZ. There are only few data on immune and endogenous opioid system (EOS) interactions in SCZ and treatment resistant SCZ.Aim of the study: We examined serum β-endorphin, endomorphin-2 (EM2), mu-opioid (MOR) and kappa-opioid (KOR) receptors, and interleukin (IL)-6 and IL-10 in 60 non responders to treatment (NRTT), 55 partial RTT (PRTT) and 43 normal controls.Results: Serum EM2, KOR, MOR, IL-6 and IL-10 were significantly increased in SCZ as compared with controls. β-endorphin, EM2, MOR and IL-6 were significantly higher in NRTT than in PRTT. There were significant correlations between IL-6, on the one hand, and β-endorphin, EM2, KOR, and MOR, on the other, while IL-10 was significantly correlated with MOR only. A large part of the variance in negative symptoms, psychosis, hostility, excitation, mannerism, psychomotor retardation and formal thought disorders was explained by the combined effects of EM2 and MOR with or without IL-6 while increased KOR was significantly associated with all symptom dimensions. Increased MOR, KOR, EM2 and IL-6 were also associated with neurocognitive impairments including in episodic, semantic and working memory and executive functions.Conclusion: The EOS contributes to SCZ symptomatology, neurocognitive impairments and a non-response to treatment. In SCZ, EOS peptides/receptors may exert CIRS functions, whereas increased KOR levels may contribute to the pathophysiology of SCZ and EM2 and KOR to a non-response to treatment.

Article contents the analytical model of the drift of a separate ice field under action of wind and current, which velocities and directions can vary during time. Model takes into account the mass of ice, added mass of sea water and the effects of the wind and current on the ice field in form the friction on its upper and underwater surfaces and frontal resistance on its end (forward and backward) surfaces. Results of performed the steady wind drift of the ice fields modelling show the drift velocity exceeds considerable known velocity of a compact ice cover wind drift. Drifting ice field has the certain kinetic energy that should be released when collision with unmovable obstacle and spent on brittle breakdown of part of the ice field. Volume of formed small ice pieces (fragments of ice field) was estimated by comparison of the specific energy of the sea ice brittle destruction and the kinetic energy of drifting ice field. Article presents the results of estimation of possible volume of the ice pieces and the scales of formed piles as result of collision with an obstacle depending on initial dimensions of ice field and wind speed. Developed models and the results of computer modelling can be used to estimate the ice pile sizes near the stationary platforms and terminals on the Arctic seas.

Pseudomonas aeruginosa is an antibiotic-resistant priority pathogen as listed by the World Health Organization. P. aeruginosa, a gram-negative, rod-shaped bacterium, is frequently encountered in hospital settings as an opportunistic pathogen in nosocomial infections. P. aeruginosa has shown high antibiotic resistance, which has been attributed to several mechanisms, such as intrinsic, acquired, and adaptive resistance. This study investigates several genes which may be attributed to the acquisition of antibiotic resistance in the bacteria P. aeruginosa, as it transitions from its planktonic form to the more threatening and resistant biofilm form. Subsequently, the study assesses the comparative efficacy of three antibiotics, Ofloxacin (OFX), Tobramycin (TOB), and Ceftazidime (CAZ), in altering the expression levels of the identified multidrug efflux pump genes associated with the ability to extrude antibiotics from the cell when in the biofilm form. Efflux transporter gene expression in P. aeruginosa was conducted via extraction of total RNA in planktonic and biofilm- both untreated and treated - with Tobramycin (TOB), Ofloxacin (OFX), and Ceftazidime (CAZ). Real-time quantitative reverse transcriptase PCR was employed to analyze alterations in expression levels of the Mex A, Mex B, Mex X, Mex Y, OprM, and RPSL genes in the collected samples. In samples where no antibiotics were administered, an increase in expression of the Mex B efflux pump gene was observed compared to all other efflux pump genes in the biofilm form, providing multidrug resistance when active. The gene of interest, Mex B, was assessed for antibiotic resistance by P. aeruginosa culturing in the planktonic and biofilm forms with simultaneous treatment with TOB, OFX, and CAZ. Of the three antibiotics used, OFX showed more effectiveness in preventing biofilm growth by reducing the expression level of the Mex B efflux pump gene in the biofilm form, making P. Aeruginosa more antibiotic sensitive to OFX. TOB has similar results compared to OFX but was slightly less effective in reducing the expression of Mex B. Conversely, CAZ was not effective in reducing expression of the Mex B gene in the biofilm form or the planktonic form and was determined to be ineffective at eradicating the organism.

For polymicrobial infections, AtbFinder utilizes a novel paradigm of the population response to antibiotics, enabling bacterial growth in the form of a mixed microbial community and selecting the antibiotics targeting not only the principal pathogen, but also those bacteria that support their growth. TGV medium allowed culturing a more diverse set of bacteria from polymicrobial biospecimens, compared with that achieved with the standard media and enabled, already within 4h, accurate selection of the antibiotics that completely eliminated all cultivatable bacteria from clinical samples. In conclusion, AtbFinder system may be a valuable tool in improving antibiotic selection, enabling targeted empirical therapy and accurate antibiotic replacement, which is especially important in high-risk patients.

Drug resistance in tumor cells is a significant roadblock in the clinical management of advanced or recurrent diseases in endometrial cancers. As a part of the tumor-stromal ecosystem, tumor cells are ecologically connected to the cancer-associated fibroblasts (CAFs), which form contributory elements of the tumor microenvironment (TME). We recently reported a novel model of patient-derived CAF-based 2-cell Hybrid Co-Culture (HyCC) to evaluate CAFs' role in developing drug resistance and understanding personalized tumor cell-CAF dialogue. Using our 2-cell HyCC model of patient-derived endometrial CAFs, we present data to demonstrate the direct counter-inhibitory effect of CAFs to combinations of cytotoxic and targeted drugs in developing drug resistance. CAFs derived from resected endometrial tumor samples were first passage-wise characterized before and after freeze-thaw for their positive and negative CAF markers expression pattern. Paclitaxel and its combination with copanlisib, TAK228, lenvatinib, and trametinib were used to test the 3D clonogenic growth of endometrial AN3CA cells on endometrial CAFs. We demonstrate that CAF-mediated resistance to antitumor drugs occurs via direct and indirect contact with CAFs in HyCC. Our data established the strength of the 2-cell HyCC model of patient-derived CAFs in solid tumors and provided a model of resistance to antitumor drugs tailored on a patient-to-patient basis.

When we were working on improving the resistance to deep abrasion of porcelain stoneware tiles, several tiles which had a very high resistance to abrasion were found in the market. The abraded volume of these tiles, measured via ISO 10545-6 method, was conspicuously less than 75 mm³. These values were well below the standard limit (<175 mm³) and reported values in the literature (>110 mm³). We determined the chemical, physical and microstructural characteristics of these tiles and other commercially available ones to find the relationship between the abrasion resistance and the technical specifications. We also characterized the samples by Vickers microhardness (VH), X-ray diffraction (XRD), mercury intrusion porosimetry (MIP) and scanning electron microscopy (SEM). It was observed that the high resistance to abrasion could be due to the presence of an adequate glassy phase capable of wetting all the hard crystalline phases in the matrix such as quartz and mullite. Therefore, the resistance to deep abrasion could be improved by increasing the amount of “vitreous” matrix, without altering the content of "hard" phases considerably well-bonded to the matrix.

Chili peppers (Capsicum annuum L.) are economically important crop worldwide. Pepper yellow leaf cure Thailand virus (PepYLCTHV), a Begomovirus causing yellow leaf mosaic disease of chili pepper has been reported to damage 95% economic loss under favorable epidemic conditions. Thirty-one chili genotypes were screened for resistance to PepYLCTHV disease through challenge inoculation using 10-15 viruliferous whiteflies per plant. We purified two resistant lines (PEP6 and PEP12) through four generations of selfing and selection through challenged inoculations. At the 28 days after inoculations two chili genotypes showed symptoms less based on disease severity and percentage of disease incidence of 30 plants PEP6 showed a disease severity 3.64 with 69.33 % DI and PEP12 showed a disease severity 3.83 with 77.67 % DI. PEP6 and PEP12 were selected for pure-line development for four cycles.Both varieties showed an increase in percentage of the resistant plant 12.78 % and 16.77 %, respectively. These lines have potential for release as resistant lines for improvement chili pepper resistance to PepYLCTHV and for developing maker associated with the resistant trait.

Global crop yield and food security are being threatened by phytophagous insects. Innovative methods are required to increase agricultural output while reducing reliance on hazardous synthetic insecticides. It appears to be quite effective at reducing production costs and boosting farm profitability to use the ground-breaking CRISPR-Cas technology to create plants that are insect resistant. In contrast, this new technique can modify an insect's genome to either produce gene drive or get beyond an insect's tolerance to various insecticides. This paper reviews and critically discusses the use of CRISPR-Cas genome editing technology in long-term insect pest management. The emphasis of this review is on the prospective uses of the CRISPR-Cas system for insect stress management in crop production by creating genome-edited crops and insects. The potential and difficulties of using CRISPR-Cas technology to reduce pest stress in crop plants are critically examined and discussed.

Background: Staphylococcus aureus (S. aureus) occasionally threatens the life of the host as a persistent pathogen even though it is normal flora of humans and animals. We characterized drug resistance in S. aureus isolated from animal carcasses and milk samples from the abattoirs and dairy farms in the Eastern Cape Province. Methods: A 1000 meat swab samples and 200 raw milk samples were collected from selected abattoirs and dairy farms in the Eastern Cape Province, South Africa. S. aureus was isolated and positively identified using biochemical tests and confirmed by molecular methods. Antibiotic susceptibility test against 14 different antibiotics was performed against all isolates. Antibiotic resistance genes were also detected. Results: Of the 1200 samples collected, 134 (11.2%) samples were positive for S. aureus. Resistance ranged from 71.6% for penicillin G to 39.2% for tetracycline. Resistance gene (blaZ) was detected in 13 (14.9%), while msrA was found in 31 (52.5%) of S. aureus isolates. Conclusions: The present result shows the potential dissemination of multidrug-resistant S. aureus strains in the dairy farms and abattoirs in the Eastern Cape. Therefore, this implies that the organism may rapidly spread through food and pose serious public health risk

Resistance evolution during exposure to non-lethal levels of antibiotics is influenced by various stress responses of bacteria which are known to affect growth rate. Here, we aim to disentangle how the interplay between resistance development and associated fitness costs is affected by stress responses. We performed de novo resistance evolution of wild-type strains and single-gene knockout strains in stress response pathways using four different antibiotics. Throughout resistance development, the increase in minimum inhibitory concentration (MIC) is accompanied by a gradual decrease in growth rate, most pronounced with amoxicillin or kanamycin. By measuring biomass yield on glucose and whole-genome sequences at intermediate and final timepoints, we identified two patterns of how the stress responses affect the correlation between MIC and growth rate. First, single-gene knockout E. coli strains associated with reactive oxygen species (ROS) acquire resistance faster and mutations related to antibiotic permeability and pumping out occur earlier. This increases the metabolic burden of resistant bacteria. Second, the ΔrelA knockout strain which has reduced (p)ppGpp synthesis, is restricted in its stringent response, leading to diminished growth rates. The ROS-related mutagenesis and the stringent response are vulnerabilities within the fitness of resistant strains that can possibly be targeted to prevent development of resistance.

Skin and soft-tissue infections (SSTI) are common cases of hospital-acquired infections with aetiologic agents exhibiting antimicrobial resistance (AMR). We determined the prevalence, proportion of laboratory-investigated cases, AMR-profiles, and factors associated with SSTI and multi-drug resistance (MDR). This study was based on archived data of patients suspected of SSTI from 2019-2021 at Jinja Regional Referral Hospital. The analysis involved 268 randomly selected patient reports. Prevalence of SSTI was 66.4%. Laboratory-investigated cases were 14.11%. Staphylococcus aureus (n=51) was the most isolated organism. MDR pathogens explained 47% of infections. Methicillin-resistant S. aureus was up to 44%. In addition, 61% of Gram-negatives had the potential to produce extended-spectrum beta-lactamases, while 27% were non-susceptible to carbapenems. Ward of admission was significantly associated with infection (aPR=1.78, 95% CI: 1.003-3.18, p-value=0.04). Age category (19-35) was an independent predictor for MDR infections (aPR=2.30, 95%CI:1.02-5.23, p-value=0.04). The prevalence is relatively high with MDR pathogens responsible for almost half of the infections. Routine use of culture and sensitivity testing should be done for proper infection management. Gentamicin and ciprofloxacin can be considered for empirical management of emergency SSTI suspected of S. aureus. Recognizing SSTI under the Global Antimicrobial resistance Surveillance System would lead to improved preparedness and response to AMR.

Taxanes, particularly docetaxel (DTX), has been widely used for combination therapy of head and neck squamous cell carcinoma (HNSCC). For locally advanced unresectable HNSCC, DTX combined with cisplatin and 5-fluorouracil as a revolutionary treatment revealed an advantage in improvement of patient outcome. In addition. DTX plus immune check inhibitors (ICIs) showed low toxicity and increased response of patients with recurrent or metastatic HNSCC (R/M HNSCC). Accumulating data indicate that taxanes not only function as antimitotics but also impair diverse oncogenic signalings including angiogenesis, inflammatory response, ROS production, and apoptosis induction. However, despite an initial response, development of resistance remains a major obstacle to treatment response. Taxane resistance could result from intrinsic mechanisms such as enhanced DNA/RNA damage repair, increased drug efflux, and apoptosis inhibition, and extrinsic effects such as angiogenesis and interactions between tumor cells and immune cells. This review provides an overview of taxanes therapy applied in different stages of HNSCC and describe the mechanisms of taxane resistance in HNSCC. Through a detailed understanding the mechanisms of resistance may help developing the potential therapeutic methods and the effective combination strategies to overcome drug resistance.

Bacterial resistance to antibiotics is a growing global concern, threatening human and environ-mental health, particularly among urban populations. Wastewater treatment plants (WWTPs) are thought to be “hotspots” for antibiotic resistance dissemination. The conditions of WWTPs, in conjunction with the persistence of commonly used antibiotics, may favor the selection and trans-fer of resistance genes among bacterial populations. WWTPs provide an important ecological niche to examine the spread of antibiotic resistance. We used heterotrophic plate count methods to identify phenotypically resistant cultivable portions of these bacterial communities and charac-terized the composition of the culturable subset of these populations. Resistant taxa were more abundant in raw sewage and wastewater before the biological aeration treatment stage. While some antibiotic resistant bacteria (ARB) were detectable downstream of treated wastewater re-lease, these organisms are not enriched relative to effluent-free upstream water, indicating effi-cient removal during treatment. Combined culture-dependent and culture-independent analyses revealed a stark difference in community composition between culturable fractions and the envi-ronmental source material, irrespective of culturing conditions. Higher proportions of the envi-ronmental populations were recovered than predicted by the widely accepted 1% culturability paradigm. These results represent baseline abundance and compositional data for ARB commu-nities for reference in future studies addressing the dissemination of antibiotic resistance associ-ated with urban wastewater treatment ecosystems.

Increasing HIV drug resistance (DR) among children with HIV (CHIV) on antiretroviral treatment (ART) is concerning. CHIV ages 1-14 years enrolled March 2019 to December 2020 from five facilities in Kisumu County, Kenya were included. Children were randomized 1:1 to control (standard-of-care) or intervention (point-of-care viral load (POC VL) testing every three months with targeted genotypic drug resistance testing (DRT) for VF (&gt; 1000 copies/ml)). A multidisciplinary committee reviewed CHIV with DRT results and offered treatment recommendations. We describe DR mutations and present logistic regression models to identify factors associated with clinically significant DR. We enrolled 704 children in the study; median age was 9 years (interquartile range (IQR) 7,12), 344 (49%) were female and median time on ART was 5 years (IQR 3, 8). During the study period, 106 (15%) children had DRT results (84 intervention and 22 control). DRT detected mutations associate with DR in all participants tested, with 93 (88%) having major mutations, including 51 (54%) with dual class resistance. A history of VF in prior 2 years (adjusted odds ratio (aOR) 11.1; 95% confidence interval (CI) 6.3, 20.0) and less than 2 years on ART at enrollment (aOR 2.2; 95% CI 1.1, 4.4) were associated with increased odds of major DR. DR is highly prevalent among CHIV on ART with VF in Kenya. Factors associated with drug resistance may be used to determine which children should be prioritized for DRT.

The resonance spectrum of surface resistance derivative in quasi-two dimensional layered organic conductors has been calculated numerically for the out-of-plane and in-plane magnetic field. Not all but some of the resonances in a given series of transitions are present in the spectra. They are observed at the positions corresponding to the maxima in the surface resistance derivative curve and are in a good agreement with previously calculated magnetic field resonance positions. For tilted magnetic fields, there are more resonances present in the spectrum than in the case of a non-tilted field. Apart from the resonances corresponding to the transitions between the adjacent surface states there also appear resonances involving the transitions between the more distant surface states. This is correlated with the specific topology of Fermi surface of the organic conductors. The presented calculations will allow correct interpretation of the experimental curves for the resonance spectrum, and also to obtain information on the surface properties of these materials for their possible implementation in fabrication of devices based on organic molecular conductors.

To improve the measurement accuracy of wood density and study the linear correlation between the drill feed resistance and wood density, a new micro drill instrument that can can simultaneously measure the rotation resistance and feed resistance of the drill needle was designed. The test wood samples included hardwood, softwood and conifer. The absolute dry density of each wood sample was measured. The drill resistance data was tested by using self-developed micro drill instrument and Resistogaph 650-SC. 4 linear models between drill resistance and the absolute dry density of wood . The results showed that: the statistical indicators of each model of the self-made micro drill resistance in-strument were better than the corresponding indicators of Resistogaph 650-SC; the coefficient of determination of the linear regression model between the feed resistance of the self-made micro drill resistance instrument and the absolute dry density of wood was 0.946; the statistical indicators of model including rotation resistance and feed resistance, were better than those of the model only including rotation resistance. Therefor, the design proposed in the article is reasonable, and increasing the feed resistance can improve the measurement accuracy of the micro drill resistance instrument for measuring wood density.

Fouling represents a bottleneck problem for promoting the use of membranes in filtration and separation applications. It becomes even more persistent when it comes to the filtration of fluid emulsions. In this case, a gel-like layer that combines droplets, impurities, salts, and other materials form at the membrane's surface, blocking its pores. It is, therefore, a privilege to combat fouling by minimizing the accumulation of these droplets that work as seeds for other incoming droplets to cluster and coalesce with. In this work, we explore the use of the newly developed and novel periodic feed pressure technique (PFPT) in combating the fouling of ceramic membranes upon the filtration of oily water systems. The PFPT is based on alternating the applied transmembrane pressure (TMP) between the operating one and zero. A PFPT cycle is composed of a filtration half-cycle and a cleaning half-cycle. Permeation occurs when the TMP is set at its working value, while the cleaning occurs when it is zero. Three PFPT patterns were examined over two feeds of oily water systems with oil contents of 100 and 200ppm, respectively. The results show that the PFPT is very effective in minimizing the problem of fouling compared to a non-PFPT normal filtration. Furthermore, the overall drops in permeate flux during the cleaning half cycles are compensated by appreciable enhancement due to the significant elimination of fouling development such that the overall production of filtered water is even increased. Inspection of the internal surface of the membrane post rinsing at the end of the experiment proves that all PFPT cycles maintained the ceramic membranes as clean after a 2-hours operation. This can ensure a prolonged lifespan of the ceramic membrane use and a continuous greater permeate volume production. The advantage of the PFPT is that it can be implemented on existing units with minimal modification, ease of operation, and saving energy.

Antibiotic resistance, particularly beta-lactam resistance, is a major problem worldwide. Imipenemase or IMP-type metallo-beta-lactamase (MBL) has become a more prominent enzyme, especially in Asia, since it was discovered in the 1990s in Japan. There are currently more than 91 variants of IMP-type enzymes. The most commonly identified variant of IMP-type enzymes is IMP-1 variant. IMP-type MBLs have been identified in more than 10 species in Enterobacterales. Pseudomonas aeruginosa is the most frequent carrier of IMP-type enzymes worldwide. In Asia, IMP-type MBLs have been distributed in many countries in the region. This work investigated a variety of currently available IMP-type MBLs in both global level and regional level. Out of 88 variants of IMP-type MBLs reported worldwide, only 32 variants were found to have susceptibility profiles. Most of the IMP-type MBLs were resistant to Carbapenems, especially Imipenem and Meropenem, followed by the 3rd generation cephalosporins, and interestingly, monobactams. Our results comprehensively indicated the distribution of IMP-type MBLs in Asia and raised the awareness of the situation of antimicrobial resistance in the region.

Despite available global efforts and funding, Tuberculosis (TB) continues to affect a considerable number of patients worldwide. Policy makers and stakeholders set clear goals to reduce TB incidence and mortality, but the emergence of multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB) complicate the reach of these goals. Drug-resistance TB needs to be diagnosed rapidly and accurately to effectively treat patients, prevent the transmission of MDR-TB, minimise mortality, reduce treatment costs and avoid unnecessary hospitalisations. In this narrative review, we provide a comprehensive overview of laboratory methods for detecting drug resistance in MTB, focusing on phenotypic, molecular and other drug susceptibility testing (DST) techniques. We found a large variety of methods used, with the BACTEC MGIT 960 being the most common phenotypic DST and the Xpert MTB/RIF being the most common molecular DST. We emphasise the importance of integrating phenotypic and molecular DST to address issues like resistance to new drugs, heteroresistance, mixed infections and low-level resistance mutations. Notably, most of the analysed studies adhered to the outdated definition of XDR-TB and did not consider the pre-XDR definition, thus posing challenges in aligning diagnostic methods with the current landscape of TB resistance.

Background: While it is established that intravenous catheter placement duration is strongly linked to the risk of catheter colonization and bloodstream infections, there are still substantial knowledge gaps concerning the varying durations of PICC placement that lead to either infection or colonization by common pathogens, particularly MDR pathogens. The present study aims to compare the dwell time required for MDR pathogens to colonize with the time required to cause Central Line-Associated Bloodstream Infections (CLABSIs) in critically ill patients with PICCs and compares it with non-MDR pathogens, shedding light on the significance of preventive procedures to control MDR infections in clinical settings. Methods: Data from critically ill patients with PICCs admitted consecutively to «Metropolitan» Hospital in Athens, Greece, from May 2017 to May 2020 were retrospectively analysed. Results: In this study, 86 hospitalized patients, consisting of 56 (65.1%) males and 30 (34.9%) females, with a mean age of 55.67±21.1 years (range 16-91 years), presented with both CLABSIs and colonization following PICC placements. Specifically, 42 (48.8%) of them presented with CLABSIs, while 44 (51.2%) presented with colonization. Among the total participants, an MDR pathogen was isolated from 26 (30.2%) PICCs, while other pathogens were isolated from 60 (69.8%). The mean duration of catheter dwell time for all participants was 20.94±14.22 days (range 3-72 days). When analysed separately for each group, the dwell time for PICCs with CLABSIs was 25.73±16.19 days and 16.36±10.28 days for those with colonization (T test, p=0.002). Additionally, the mean dwell time for PICCs infected by non-MDROs was 22.48±15.64 days whereas for PICCs with MDROs, it was 17.38±9.5 days (T test, p=0.005). In PICCs with CLABSIs, the mean indwelling time for MDR pathogens was 21.50±12.31 days, while for non-MDROs, it was 27.73±16.98 days (T test, p=0.417). In PICCs with colonization, the mean dwell time for MDR pathogens was 15.55±7.73 days, while for non-MDROs, it was 16.92±11.85 days (T test, p=0.124). Among PICCs with MDR pathogens (n=26), the mean duration in CLABSIs events (n=18) was 21.5±12.31 days and in colonization events 15.55±7.73 days, (n=8) (T test, p=0.146). Conclusions: The present study reveals that colonization of PICCs exhibited a shorter dwell time compared to those with CLABSIs. Moreover, PICCs infected by MDROs had a shorter mean dwell time than those with non-MDROs. These findings underscore the importance of considering infection status and microbial resistance patterns when evaluating PICC dwell times.

Multiple biological pathways manifest and latent, meant for human survival, become a liability in cancer cure. With an increasing understanding of innumerable complex paths, cancer progression and development of resistance is no surprise. For the three “vasculature-immune-phenotypic” fundamental changes, hypoxia is the maestro orchestrating the whole gamut of changes (through the master manipulator - HIF-1 α), simultaneously transactivating hundreds of pro-angiogenic genes. Such a complex molecular bio-network begs the question, “Is our cancer research caught in such a tangled web that we have lost sight of the Spider?”. Hypoxia is this Spider weaving compensatory webs with every intervention/ obstruction. Anti-angiogenic (AAG) research has been conducted mainly in silos – exploring independent paths. This review conceptualizes a convergence of a multitude of research worldwide to a single theme of normalizing vasculature as a primary baseline for overcoming resistance to AAGs or their combinations.

Staphylococcus aureus bacteremia continues to be associated with significant morbidity and mortality, despite improvements in diagnostics and management. Persistent infections pose a major challenge to clinicians and have been consistently shown to increase the risk of mortality and other infectious complications. S. aureus, while typically not considered an intracellular pathogen, has been proven to utilize an intracellular niche, through several phenotypes including small colony variants, as a means for survival that has been linked to chronic, persistent, and recurrent infections. This intracellular persistence allows for protection from the host immune system and leads to reduced antibiotic efficacy through a variety of mechanisms. These include antimicrobial resistance, tolerance, and/or persistence in S. aureus that contribute to persistent bacteremia. This review will discuss the challenges associated with treating these complicated infections and the various methods that S. aureus uses to persist within the intracellular space.

Mucorales are the causal agents for the lethal disease known as mucormycosis. Mortality rates of mucormycosis can reach up to 90%, due to the mucoralean antifungal drug resistance and the lack of effective therapies. A concerning urgency among the medical and scientific community claims to find targets for the development of new treatments. Here, we reviewed different studies de-scribing the role and machinery of a novel non-canonical RNAi pathway (NCRIP) only conserved in Mucorales. Its non-canonical features are the independence of Dicer and Argonautes proteins. Conversely, NCRIP relies on RNA-dependent RNA Polymerases and an atypical ribonuclease III (RNaseIII). NCRIP regulates the expression of mRNAs by degrading them in a specific manner. Its mechanism binds dsRNA but only cuts ssRNA. NCRIP exhibits a diversity of functional roles. It represses the epimutational pathway and the lack of NCRIP increases the generation of drug resistant strains. NCRIP also regulates the control of retrotransposons expression, playing an essential role in genome stability. Finally, NCRIP regulates the response during phagocytosis, affecting the multifactorial process of virulence. These critical NCRIP roles in virulence and antifungal drug resistance, along with its exclusive presence in Mucorales, mark this pathway as a promising target to fight against mucormycosis.

Background: Blood flow restriction training (BFRT) uses occlusion during low-intensity resistance training (&lt;50% of repetition maximum, 1RM) to reduce arterial blood flow and venous return, imposing greater metabolic stress but similar muscular hypertrophy and strength gains as high-intensity resistance training (HIRT). However, no study, to date, has incorporated BFRT in a collegiate strength and conditioning setting to assess ecological validity. We aimed to investigate the effects of adding 6-weeks of accessory BFRT or HIRT to NCAA Division III soccer players prescribed resistance training regimen on muscle strength and hypertrophy. Methods: Male and female (n=17) athletes were randomly assigned to complete biceps curls 2x/week under BFRT or control (HIRT), following the regularly scheduled strength training. Bicep strength (1RM) and circumference (BC) were assessed at weeks 0, 3, and 6. Results: In men, no significant interaction between time and condition was observed for BC (p=0.861), though condition (BFRT vs Control, p=0.025) and time (p=0.024) were significant. For 1RM, there was no significant interaction between time and condition (BFRT vs HIRT, p=0.067) or of condition (p=0.598), but there was a significant effect of time (p=0.004). In women, there was no significant interaction between time and condition (p=0.765) or of condition (p=0.971) on BC, but time was significant (p=0.045). For 1RM, there was no significant interaction between time and condition (p=0.227) or of condition (p=0.741), but time was (p=0.018). Conclusion: BFRT induced similar increases in muscle strength and hypertrophy as HIRT in soccer players, suggesting that BFRT could be incorporated into collegiate athlete training.

The aim of this study was to evaluate patients' knowledge and perception of the use of systemic antibiotics in the treatment of endodontic infections and to determine the possible contribution of patients to the development of bacterial resistance. Five hundred and fifty patients were asked to respond to a survey on the perception of systemic antibiotic use in the treatment of endodontic infections and antibiotic resistance during January 2022 and March 2023. Data were analyzed using descriptive statistics and Pearson's Chi-square test. 514 patients were included in the study, 65.9% of whom were women. While 34.6% of the population studied thought that it was always necessary to take antibiotics prior to endodontics, 49.4% considered that they were necessary after endodontics, regardless of the clinical symptoms (p&gt;0.05). The prevalence of self-medication was 17.3% and women self-medicate more than men, with significant differences (p&lt;0.05), although they have greater knowledge of antibiotic resistance than men (p&gt;0.05). Forty-four percent of the population expect to take antibiotics when faced with dental pain, mainly women (p&lt;0.05). The general population is contributing to the serious problem of bacterial resistance. It is necessary to promote educational strategies focused on the correct use of antibiotics in the community.

During the bioassay, on leaf sections of the A. roylei species, a significantly higher number of T. tabaci females was recorded compared to the cv. Tęcza of the A. cepa species and the cv. Kroll of the A. fistulosum species, in each observation period. Significantly more thrips settled on cv. Kroll compared to Alibaba and Bila. Regarding the results obtained on A. cepa, significantly fewer females were found on cv. Bila compared to cv. Tęcza. Opposite results were observed in a combination of cvs. Tęcza - Alibaba, where significantly more insects settled on leaves of cv. Alibaba. Statistically significant differences of cultivars/species were found in the number of hatched larvae on the leaves of the tested cultivars/species of onion. The significantly lowest number of larvae hatched from eggs laid on A. roylei compared to A. fistulosum and cultivars of A. cepa, except for Bila.

Obesity affects nearly 660 million adults worldwide and is known for its many comorbidities. Although the phenomenon of obesity is not fully understood, science regularly reveals new determinants of this pathology. Among them, the persistent organic pollutants (POPs) have been recently highlighted. Mainly lipophilic, POPs are normally stored in adipose tissue and can lead to adverse metabolic effects when released into the bloodstream. The main objective of this narrative review is to discuss the different pathways by which physical activity may counteract POPs adverse effects. The research that we carried out seems to indicate that physical activity could positively influence several pathways negatively influenced by POPs, such as insulin resistance, inflammation, lipid accumulation, adipogenesis and gut microbiota dysbiosis that are associated with the development of obesity. This review also indicates how, through the controlled mobilization of POPs, physical activity could be a valuable approach to reduce the concentration of POPs in the bloodstream. These findings suggest that physical activity should be used to counteract the adverse effects of POPs. However, future studies should accurately assess its impact in specific situations such as bariatric surgery where weight loss promotes POPs blood release.

Ultrafast chip nanocalorimetry opens up remarkable possibilities in materials science by allowing samples to be cooled and heated at extremely high rates. Due to heat transfer limitations, controlled ultrafast cooling and heating can only be achieved for tiny samples in calorimeters with a micron-thick membrane. Even if ultrafast heating can be controlled under quasi-adiabatic conditions, ultrafast controlled cooling can be performed if the calorimetric cell is located in a heat-conducting gas. It was found that the maximum possible cooling rate increases as 1/r0 with decreasing radius r0 of the hot zone of the membrane. The possibility of increasing the maximum cooling rate with decreasing r0 was successfully implemented in many experiments. In this regard, it is interesting to answer the question: what is the maximum possible cooling rate in such experiments if r0 tends to zero? Indeed, on submicron scales, the mean free path of gas molecules lmfp becomes comparable to r0, and the temperature jump that exists at the membrane/gas interface becomes significant. Considering the limitation associated with thermal resistance at the membrane/gas interface and considering the transfer of heat through the membrane, we show that the controlled cooling rate can reach billions of K/s, up to 1010 K/s.

The gate resistance is a parasitic element in transistors for RF and millimeter-wave circuits that can negatively impact power gain and noise figure. To develop accurate device models, a reliable measurement methodology is crucial. This article reviews the standard measurement methodology used in the literature and proposes also an additional method, which is evaluated using suitable test structures in a 16nm FinFET process. The advantages and disadvantages of the two approaches are discussed along with their respective application scenarios

This comprehensive review examines the critical issue of antimicrobial resistance (AMR), a growing global concern with profound societal implications. This article presents an overview of the causes of AMR, including the misuse and overuse of antibiotics in healthcare, agriculture, and veterinary practices. Various conventional and advanced detection methodologies have been explored, highlighting the importance of the accurate and timely identification of resistant strains. The challenges associated with tackling AMR, encompassing scientific, economic, and regulatory aspects have been discussed in depth. In addition, this article sheds light on the far-reaching societal implications of AMR, including increased healthcare costs, treatment complexities, and potential disruptions to healthcare systems. This emphasizes the urgency of adopting proactive strategies to combat AMR and underscores the need for global cooperation, policy interventions and public awareness campaigns. By unraveling the multifaceted dimensions of AMR, this review aims to enhance our understanding, stimulate further research, and promote concerted efforts to mitigate the threat of antimicrobial resistance.

Resistance spot welding is an established joining process in the production of safety-relevant components in the automotive industry. Therefore, a consecutive process monitoring is essential to meet the high-quality requirements. Artificial neural networks can be used to evaluate the process parameters and signals to ensure the individual spot weld quality. The predictive accuracy of such algorithms depends on the provided training data set and the prediction of untrained data is challenging. The aim of this paper is to investigate the extrapolation capability of the multi-layer perceptron model. That means, that the predictive performance of the model will be tested with data that clearly differs from the training data in terms of material and coating composition. Therefore, three multi-layer perceptron regression models were implemented to predict the nugget diameter from process data. The three models were able to predict the trained datasets very well. The models, which were provided with features from the dynamic resistance curve predicted the new dataset better than the model with only process parameters. This study shows the beneficial influence of the process signals on the predictive accuracy and robustness of artificial neural network algorithms. Especially, when predicting a data set from outside of the training space.

Carbapenem-resistant Acinetobacter baumannii (CRAB) infections represent the fourth-leading cause of death attributable to antimicrobial resistance globally, but a standardized therapy is still lacking. In this narrative review we focused the antibiotic treatment of CRAB infections in view of newly β-lactam agents (NBLs) like sulbactam/durlobactam and cefiderocol, discussing the main hot points such as the superiority of combination treatment over monotherapy and the best antibiotic partner to use in combination. Sulbactam/durlobactam seems to be the best candi-date to replace current back-bone agents. Cefiderocol, could play a crucial role in combina-tion-regimen. Due to toxicity and the PK/PD limitations, colistin (or polymyxin B) should be used as an alternative agent (when no other options are available). Tigecycline (or minocycline) and fosfomycin could represent suitable partners for both NBLs. Randomized clinical trials (RCTs) are needed to better evaluate the role of NBLs in CRAB infection treatment and to compare the ef-ficacy of tigecycline and fosfomycin as partner antibiotics. Synergism should be tested between NBLs and “old” drugs (rifampicin and trimethoprim/sulfamethoxazole). Huge efforts should be made to accelerate pre-clinical and clinical studies on safer polymyxin candidates with lung im-proved activity, as well as on the i.v. rifabutin formulation.

In recent years, the emergence of cancer drug resistance is one of the crucial tumor hallmarks which is supported by the level of genetic heterogeneity and complexities at cellular levels. Oxidative stress, immune evasion, metabolic reprogramming, overexpression of ABC transporters and stemness are among the several key contributing molecular and cellular response mechanisms. Topo-active drugs, e.g., doxorubicin and topotecan, are clinically active and are utilized extensively against a wide variety of human tumors and often results in the development of resistance and failure to therapy. Thus, there is an urgent need for an incremental and comprehensive understanding of mechanisms of cancer drug resistance specifically in the context of topo-active drugs. This review delves into the intricate mechanistic aspects of these intracellular and extracellular topo-active drug resistance mechanisms and explores use of potential combinatorial approaches by utilizing various topo-active drugs and inhibitors of pathways involved in drug resistance. We believe that this review will help guide basic scientists, pre-clinicians, clinicians, and policymakers toward holistic and interdisciplinary strategies that transcend resistance, renewing optimism in the ongoing battle against cancer.

This paper investigates the effect of shot peening on the strength and corrosion properties of EN AW 6082-T651 aluminium alloy. Surface roughness, microhardness, residual stresses and corrosion performance were investigated and compared with the untreated aluminium alloy. Cracks and delaminations in the surface layer can only be seen on the treated specimens at a working pressure of 4 bar and 8 bar, while no such effect was observed at a working pressure of 1.6 bar. The effect of dislocation densification was confirmed by the microhardness measurement of the hardened layer, where microhardness increased by up to 23 % compared to the untreated aluminium alloy. Shot peening also results in a deeper layer with higher compressive residual stresses compared to untreated specimens. With higher working pressure, surface roughness increases, which can promote localized pitting corrosion. However, all treated specimens improve the corrosion resistance and have a lower degree of anodic dissolution. The current density of the shot peened specimen with the lowest surface roughness was more than twice lower than that of the untreated specimen.

Inspired by the process of bone formation in living organisms, many studies have been conducted to develop organic-inorganic composite materials by generating calcium phosphate crystals within solutions or dispersions of polymers with appropriate functional groups. Bones are composite materials consisting of organic polymers (mainly Type I collagen), carbonated apatite, and water, with volume fractions 35-45%, 35-45%, 15-25%, respectively. Carbonated apatite in bone contributes to rigidity, while organic polymers and water contribute to toughness. The inorganic crystal, carbonated apatite, is a plate-shaped crystal with dimensions of 50 nm × 25 nm × 1-4 nm, generating a significant organic-inorganic interface due to its nanoscale size. This interface is believed to absorb externally applied forces to dissipate mechanical energy to thermal energy. Creating such nanometer-scale structures using top-down approaches is challenging, making bottom-up methods like co-precipitation of polymer and inorganic crystals more suitable. In this account, efforts to develop eco-friendly mechanical materials using biomass such as cellulose and starch based on the bottom-up approach to bone-like composites are described.

To achieve a micro-destructive and rapid measurement of the wood density of standing trees, this study investigated the feasibility of using the micro-drilling resistance method, formulated a mathematical model, explored the potential for a unified model across multiple tree species, and analyzed the influence of moisture content on measurement accuracy. First, 231 tree cores and drill resistance data were sampled from Pinus massoniana, Cunninghamia lanceolate, and Cryptomeria fortunei. The basic density and moisture content of each core were measured, and the average value of each resistance data record was calculated. Second, the average drill resistance, the natural logarithm of average drill resistance, and absolute moisture content were used as independent variables, while the wood basic density was used as the dependent variable. Third, the total model of the three tree species and sub-model for each tree species were established through a stepwise regression method. Finally, the accuracy of each model was compared and analyzed with that of using the average basic density of each tree species as an estimated density. The results revealed that the estimation accuracy of the sub-model for each tree species was 1.670 percentage points higher than the average value of each tree species used as the density estimation value for these tree species. Additionally, except for Cryptomeria fortunei, the natural logarithm of drill resistance significantly influenced the wood density model at a significance level of 0.05. Moreover, moisture content significantly affected the total model and sub-models of Pinus massoniana at a significance level of 0.05. The estimation accuracy of the total mathematical model was 2.125 percentage points lower than that achieved using the average basic density of each tree species to predict their density. The results indicated the feasibility of using the micro-drilling resistance method to measure the wood density of standing trees. Moreover, the relationship between wood density and drill resistance did not follow a linear pattern, and moisture content slightly influenced the drill needle resistance. Furthermore, the establishment of a mathematical model for each tree species was deemed essential. This study provides valuable guidance for measuring the wood density of standing trees through the micro-drilling resistance method.

Identification of recurrent driver mutations in genes encoding tyrosine kinases has resulted in the development of molecularly targeted strategies designed to improve the outcomes for patients diagnosed with acute myeloid leukemia (AML). The receptor tyrosine kinase FLT3, is the most commonly mutated gene in AML, with internal tandem duplications within the juxtamembrane domain (FLT3-ITD) or missense mutations in the tyrosine kinase domain (FLT3-TKD), present in 30%-35% of AML patients at diagnosis. An established driver mutation and marker of poor prognosis, the FLT3 tyrosine kinase has emerged as an attractive therapeutic target, and thus has encouraged the development of FLT3 tyrosine kinase inhibitors (TKIs). However, the therapeutic benefit of FLT3 inhibition, particularly as monotherapy, frequently results in the development of treatment resistance and disease relapse. Commonly, FLT3 inhibitor resistance is induced by the emergence of secondary lesions in the FLT3 gene, particularly in the second tyrosine kinase domain at residue Asp835 (D835) to form a ‘dual mutation’ (ITD-D835). Individual FLT3-ITD and FLT3-TKD mutations influence independent signaling cascades however, currently little is known which divergent signaling pathways are controlled by each of these FLT3 specific mutations, particularly in the context of patients harboring dual ITD-D835 mutations. This review provides a comprehensive analysis of the known discrete and cooperative signaling pathways regulated by each of the FLT3 specific mutations, as well as the therapeutic approaches that hold the most promise for development of more durable and personalized therapeutic approaches targeting mutant FLT3, to improve the treatment of AML.

The hydrodynamic results obtained from the permeability of porous materials not only affect the assessment of the stream of the gas flow through those materials but they also refer to the loss of pressure energy in that flow. The direct measure of that loss is flow resistances.The results of experimental research upon the assessment of the flow resistances of porous materials with respect to gas flow. The research conducted applied to natural materials with an anisotropic gap-porous structure. The tests were carried out on a gas permeability measuring system, adapted to different shapes of porous material samples. The process issue of the total pressure drop on a porous deposit was considered in the Reynolds number category. The coefficient of flow resistance for anisotropic materials was defined and the value of this coefficient was compared to the gas stream and the total pressure drop on the porous bed was experimentally evaluated.

The article describes the study of the properties of polytetrafluoroethylene, modified using natural layered silicates—serpentinite. It is shown that the introduction of a small amount of layered silicates significantly increases the tribological characteristics of the material. The additional introduction of magnesium nano-spinels facilitated the formation of an intercalated polymer-silicate nanocomposite.

Enterococci are commonly found in the environment and humans as a part of the normal micro-biota Among these, Enterococcus faecalis and Enterococcus faecium can convert into opportunistic pathogens, making them a major cause of nosocomial infections. The rapid diffusion of vanco-mycin-resistant strains and their impact on nosocomial settings is of considerable concern. Ap-proximately one-third of the E. faecium infections in Italy are caused by vancomycin-resistant strains. This study explored the hypothesis that the oral cavity could represent a silent reservoir of virulent enterococci. A sample of 862 oral flora specimens collected from healthy human volun-teers in Central Italy was investigated by real-time PCR to detect E. faecalis and E. faecium, as well as the genetic elements that most frequently determine vancomycin resistance. The prevalence of E. faecalis was 19%, a value that was not associated with alcohol consumption, tobacco smoking, or age of the subjects. Less frequently detected, with an overall prevalence of 0.7%, the E. faecium was more common among people older than 49 years of age. The genes conferring vancomycin resistance were detected in only one sample. Results indicate that the oral cavity can be considered a reservoir of clinically relevant enterococci; however, our data suggest that healthy individuals rarely carry vancomycin-resistant strains.

Hyperlipidemia and insulin-resistance are often associated with Non Alcoholic Fatty Liver Disease (NAFLD) thereby representing a true issue worldwide, due to increased risk of developing cardiovascular and systemic disorders. Although clear evidence suggests that circulating fatty acids contribute in pathophysiological mechanisms underlying NAFLD and hyperlipidemia, further studies are required for better identify potential beneficial approaches for counteracting such a disease state. Recently, several artichoke extracts have been used for both reducing hyperlipidemia, insulin-resistance and NAFLD, though the mechanism is unclear. Here we used a wild type of Cynara Cardunculus extract (CyC), rich in sesquiterpens and antioxidant active ingredients, in rats fed and High Fat Diet (HFD) compared to Normal Fat Diet (NFD). In particular, in rats fed HFD for four consecutive weeks, we found a significant increase of serum cholesterol, triglyceride and serum glucose. This effect was accompanied by increased body weight and by histopathological features of liver steatosis. The alterations of metabolic parameters found in HFD were antagonised dose-dependently by daily oral supplementation of rats with CyC 10 and 20 mg/Kg over 4 weeks, an effect associated to significant improvement of liver steatosis. The effect of CyC (20 mg/Kg) was also associated to enhanced expression of both OCTN1 and OCTN2 carnitine-linked transporters. Thus, present data suggest a contribution of carnitine system in the protective effect of CyC in diet-induced hyperlipidemia, insulin-resistance and NAFLD.

The aim of this study was to verify the effects of blood flow restriction on movement velocity and muscle activity during the back-squat exercise. Methods: Twenty-four university students participated in this study. In two randomized 72-hours apart sessions, participants performed a 4-set protocol consisting of 30-15-15-15 repetitions performed at 30% of their one-repetition maximum in the back-squat exercise. In both sessions, neuromuscular function was monitored by surface electromyography (EMG) and movement velocity (mean propulsive velocity [MPV], peak concentric velocity [Vmax] and the effort index [EI]). Blood flow restriction (BFR) was applied during exercise in one of the experimental sessions with 80% of full arterial occlusion pressure over lower limbs. Results: BFR condition showed higher (p&lt;0.05) EI, peak and rooted mean square normalized EMG in set 1 compared to set 2. Similar MPV and Vmax were observed at each set for both BFR and control conditions. No significant differences were observed between conditions at any set. Conclusions: BFR did not imply changes in neuromuscular performance during low-intensity resistance training, but it might induce greater intra-series velocity loss and less activation of the muscles involved.

The high mutation rate of human immunodeficiency virus type 1 (HIV-1) plays a major role in treatment resistance from the development of vaccines to long-lasting drugs. In addressing the crux of the issue, various attempts to estimate the mutation rate of HIV-1 resulted in a large range of 10-5 - 10-3 errors/bp/cycle due to the use of different types of investigation methods. In this review, we discuss the different assay methods, their findings on the mutation rates of HIV-1 and how the location of these mutations can be further analyzed for their potential allosteric effects to reveal potentially new inhibitors with different pharmacodynamics that can be used to circumvent fast occurring HIV drug resistance. Given that HIV is one of the fastest mutating viruses, it is a good model for comprehensive study of its mutations that can give rise to much horizontal understanding towards overall viral drug resistance as well as emerging viral diseases.

The whitefly leads extensive damage to plants through direct feeding, honeydew secretion, plant physiological disorders, and vectoring plant viruses. This study aimed to evaluate the physiological characteristics of susceptible and resistant soybean cultivars to B. tabaci. The experiments were conducted in a greenhouse. Eleven soybean cultivars were selected and infested with 100 adults of B. tabaci at the V3 stage. The evaluation of photosynthetic parameters, such as photosynthetic rate, leaf transpiration, stomatal conductance, and internal CO2 concentration, revealed that B. tabaci infestation influenced gas exchange in soybean plants. The photosynthetic rate was higher in cultivars AS3810 and M8349 during the V6 stage. Infestations led to alterations in photosynthetic parameters, suggesting increased energy demand to maintain photosynthetic activity. However, the response to infestation varied among different cultivars, indicating varying levels of resistance and tolerance to the whitefly's damage. Additionally, the impact of infestation was more significant during the vegetative phenological. In conclusion, B. tabaci infestation affects soybean plants' physiology, leading to changes in gas exchange parameters and water use efficiency. The response to infestation varied among soybean cultivars, suggesting potential differences in resistance to the pest. The study highlights the importance of evaluating the physiological impact of whitefly infestations on soybean.

The choice of antibiotic regimens to use in patients presenting with diabetic foot osteomyelitis and their duration differs according to the situation. Antibiotics play a more important role in the medical option where no infected bone has been resected while their role is reduced but not negligible in the case of surgical options. Some studies have reported the presence of biofilm structures in bone samples taken from patients with diabetic foot osteomyelitis which raises the question of the place of anti-biofilm antibiotic regimens in this setting. During the last two decades, clinical studies have suggested a potential benefit for anti-biofilm antibiotics, mainly rifampicin against staphylococci and fluoroquinolones against gram-negative bacilli. No data from randomized controlled studies have however been reported so far. The present work provides a summary of the available data on the question of the place of anti-biofilm antibiotics for the treatment of diabetic foot osteomyelitis but also the potential limitations of such treatments.

Growing resistance is reported to carbamate insecticides in malaria vectors in Cameroon. However, the contribution of acetylcholinesterase (Ace-1) to this resistance remains uncharacterised. Here, we established that the G119S mutation is driving resistance to carbamates in Anopheles gambiae populations from Cameroon. Insecticide bioassay on field collected mosquitoes from Bankeng, a locality in southern Cameroon, showed high resistance to the carbamates bendiocarb (64.8 ± 3.5 % mortality) and propoxur (55.71 ± 2.9 %) but a full susceptibility to the organophosphate fenithrothion. The TaqMan genotyping of the G119S mutation in field-collected adults revealed the presence of this resistance allele (39%). A significant correlation was observed between the Ace-1^R and carbamate resistance at allelic [(bendiocarb; OR = 75.9; P<0.0001) and (propoxur; OR= 1514; P<0.0001)] and genotypic [RR vs SS (bendiocarb; OR = 120.8; P<0.0001) and (propoxur; OR= 3277; P<0.0001) levels. Furthermore, the presence of the mutation was confirmed by sequencing an Ace-1 portion flanking codon 119. The cloning of this fragment revealed a likely duplication of Ace-1 in Cameroon as mosquitoes exhibited at least three distinct haplotypes. Phylogenetic analyses showed that the predominant Ace-1^R allele is identical to that from West Africa suggesting a recent introduction of this allele in Central Africa from the West. The spread of this Ace-1^R represents a serious challenge to future implementation of IRS-based interventions using carbamates or organophosphates in Cameroon

Antimicrobial resistance (AMR) is one of the top 10 threats affecting global health. AMR defeats the effective prevention and treatment of infections caused by microbial pathogens including bacteria, parasites, viruses and fungi (WHO). Microbial pathogens have natural tendency to evolve and mutate over time resulting in AMR strains. The set of genes involved in antibiotic resistance also termed as “antibiotic resistance genes” (ARGs) spread through species by lateral gene transfer thereby causing global dissemination. While this biological mechanism is prevalent in the spread of AMR, human methods also augment through various mechanisms such as over prescription, incomplete treatment, environmental waste etc. A considerable portion of scientific community is engrossed in AMR related work trying to discover novel therapeutic solutions for tackling resistant pathogens. Comprehensive inspection of the literature shows that diverse therapeutic strategies have evolved over recent years. Collectively, these therapeutic strategies include novel small molecules, newly identified antimicrobial peptides, bacteriophages, phytochemicals, nanocomposites, novel phototherapy against bacteria, fungi and virus. In this work we have developed a comprehensive knowledgebase by collecting alternative antimicrobial therapeutic strategies from literature data. We have used subjective approach for datamining new strategies resulting in broad coverage of entities and subsequently add objective data like entity name, potency, safety information etc. The extracted data was organized KOMBAT (Knowledgebase Of Microbes’ Battling Agents for Therapeutics). A lot of these data are tested against AMR pathogens. We envision that this database will be noteworthy for developing future therapeutics against resistant pathogens. The database can be accessed through http://kombat.igib.res.in/.

Fusarium wilt caused by Fusarium oxysporum f. sp. cubense (Foc) is one of the most destructive diseases in banana farming worldwide. Knowledge of the factors of genetic diversity and virulence of the pathogen contributes to the development of resistant cultivars and in management strategies based on exclusion. In this study, phenotypic traits such as virulence and aggressiveness in a sample of 52 Foc isolates, were analyzed and their relationship to the presence of putative effectors of gene SIX (Secreted in Xylem) pathogenicity homologues, verified. According to the dissimilarity matrix, there were three isolates closest to the standard Foc race 1 strain. Isolates 229A and 218A, were selected according to their aggressiveness profile in 'Grand Naine' and 'Prata-Anã', respectively, I order to replace the standard isolate of race 1 in the resistance screening process carried out by the breeding program. Two homologues of the SIX8 gene, SIX8a and SIX8b, are present in isolates of Foc from Brazil and the SIX8b gene correlates with avirulence in the cultivar ‘Grand Naine’ (Cavendish). These results are important to support the banana genetic breeding program by identification of sources of resistance to Foc and contribute in the establishment of the function of SIX effector proteins.

Genetic engineering technology offers opportunities to improve many important agronomic traits in crops, including insect-resistance. However, genetically modified (GM) exogenous proteins in edible tissues of transgenic crops has become an issue of intense public concern. To advance the application of GM techniques in maize, a Cre/loxP-based strategy was developed for manipulating the transgenes in green tissues while locking it in non-green tissues. In the strategy, the site-specific excision can be used to switch on or off the expression of transgenes at specific tissues. In this work, two basic transgenic maize named KEY carrying the Cre gene and LOCK containing the Vip3A gene with a blocked element, were obtained based on their separate fusion gene cassettes. The expression level and concentration of Vip3A were observed with high specific accumulation in green tissues (leaf and stem), and only a small amount in root and kernel tissues in the KEY × LOCK hybrids. The insect-resistance of transgenic maize against two common lepidopteran pests, Ostrinia furnacalis and Spodoptera frugiperda, was assessed in the laboratory and field. The results indicated that the hybrids possessed high resistance levels against the two pests, with mortality rates above 73.6% and damage scales below 2.4 compared with the control group. Our results suggested that the Cre/loxP-mediated genetic engineering approach has a competitive advantage in GM maize. Overall, findings from this study are significant for providing a feasible strategy for transgenes avoiding expression in edible parts and exploring novel techniques toward the biosafety of GM plants.

Multiple myeloma (MM) is a genetically heterogenous disease that includes a subgroup of 10-15% of patients facing dismal survival despite most intensive treatment. The aim of this review article is to provide an integrated clinical and biological overview on the high-risk MM discussing the novel therapeutic perspectives aimed to target the neoplastic clone and its microenvironment. The dissection of the molecular determinants of the aggressive phenotypes and drug resistance can foster a better tailored clinical management of high-risk profile and refractoriness to therapy. Among the current clinical difficulties in MM, patient’s management manipulating the tumor niche represents a major challenge given the limited knowledge about the MM-milieu interaction. The angiogenesis and bystander infiltrate constitute pivotal mechanisms of mutual collaboration between MM and the non-tumoral counterpart. Immuno-modulatory and anti-angiogenic therapy hold great efficacy but variable and unpredictable responses in high-risk MM. Therefore, it would be worth to better select the population and the MM stage that could profit to a dual immune/vasculogenesis targeting. The comprehensive knowledge of the genetic heterogeneity and MM high-risk ecosystem enforce a systematic bench-to-bedside approach. Despite significant improvements in the biology knowledge, MM is still a chronic and incurable neoplasia and therapeutic options able to overcome the relapsing/refractory behavior represent an unmet clinical need. Here, we corroborate previous biological findings providing a synthetic outlook of novel druggable targets. We also summarize the existing multi-omics-based risk profiling tools, in order to better personalize the patient-oriented clinical management.

Periodic assessment of bacterial contamination is necessary as it allows proper guidance in cases of eye infections through the use of appropriate antibiotics. Due to the extensive use of antibiotic treatment, most of the contamination flora is resistant to the usual ophthalmic antibiotics. The present study shows an updated picture of the susceptibility of Gram-positive and Gram-negative bacteria found on the ocular surface to the most commonly used antibiotic agents in patients undergoing cataract surgery. A total of 993 patients were included in the study with ages between 44 and 98 years old. Conjunctival culture was collected 7 days before cataract surgery. The response of Gram-positive and Gram-negative bacteria to various antibiotic classes like glycopeptides, cephalosporins, carbapenems, fluoroquinolones, aminoglycosides, phenicols, tetracyclines, rifamycins, macrolides and penicillins was assessed. From the tested antibiotics, vancomycin had 97.8% efficacy on Gram-positive bacteria. In the cephalosporin category, we observed an increased resistance of the cefuroxime for both Gram-positive and negative bacteria. Antibiotics that have more than 90% efficacy on Gram-positive bacteria are: meropenem, imipenem, netilmicin, amikacin and rifampicin. On Gram-negative bacteria, we found 100% efficacy of all tested fluoroquinolones, aminoglycosides (except for tobramycin), doxycycline, azithromycin, clarithromycin and chloramphenicol. The current study illustrates patterns of increased resistance of certain bacteria present on ocular surface to some of the commonly used antibiotics in ophthalmological clinical practice. One such revealing example is cefuroxime, which has been highly used as an intracameral antibiotic for the prevention of bacterial endophthalmitis after cataract surgery.

Let G[F,Vk, Huv] be the graph with k pockets, where F is a simple graph of order n ≥ 1,Vk= {v1,v2,··· ,vk} is a subset of the vertex set of F and Hvis a simple graph of order m ≥ 2,v is a specified vertex of Hv. Also let G[F,Ek, Huv] be the graph with k edge pockets, where F is a simple graph of order n ≥ 2, Ek= {e1,e2,···ek} is a subset of the edge set of F and Huvis a simple graph of order m ≥ 3, uv is a specified edge of Huvsuch that Huv− u is isomorphic to Huv− v. In this paper, we derive closed-form formulas for resistance distance and Kirchhoff index of G[F,Vk, Hv] and G[F,Ek, Huv] in terms of the resistance distance and Kirchhoff index F, Hv and F, Huv, respectively.

The aim of our work was to check if one of the products of natural origin, namely honey bee propolis may be an alternative or supplement to currently used antifungal agents. The activity of 50 ethanolic extracts of propolis (EEPs), harvested in Polish apiaries, was tested on a group of 69 clinical isolates of C. albicans. Most of the EEPs showed satisfactory activity, with minimum fungicidal concentrations (MFC) mainly in the range of 0.08-1.25% (v/v). Eradication of biofilm from polystyrene microtitration plates in 50% (MBEC50) required concentrations in the range of 0.04% (v/v) to more than 1.25% (v/v). High activity was also observed in eradication of biofilm formed by C. glabrata and C. krusei on the surfaces of PVC and silicone catheters. EEPs at subinhibitory concentrations inhibited yeast-to-mycelia morphological transformation of C. albicans in liquid medium and mycelial growth on solid medium. A synergistic effect was observed for the action of EEPs in combination with fluconazole (FLU) and voriconazole (VOR) against C. albicans. In the presence of EEP at concentration as low as 0.02%, the MICs of FLU and VOR were 256 to 32 times lower in comparison to those of the drug alone. Evidences for the fungal cell membrane as the most probable target of EEPs are presented.

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. Although prognosis continually improved along years, a significant proportion of patients still relapse from the disease due to leukemia resistance to therapy. Methotrexate (MTX), a folic acid antagonist, is a chemotherapy agent commonly used against ALL and a immune-system suppressant for rheumatoid arthritis, that presents multiple and complex mechanisms of action and resistance. Previous studies have shown that MTX modulates the nuclear factor kappa B (NF-κB) pathway, an important family of transcription factors involved in inflammation, immunity, cell survival, and proliferation, frequently hyperactivated in ALL. Using gene set enrichment analysis (GSEA) on publicly available gene expression data from 161 newly diagnosed pediatric ALL patients, we found “TNF-α signaling pathway” to be the most enriched Cancer Hallmark in MTX poor responder patients. Transcriptomic analysis in a panel of ALL cell lines (6 BCP-ALL and 7 T-ALL) also identified the same pathway as differentially enriched among MTX resistant cell lines, as well as in slowly dividing cells. To better understand the crosstalk between NF-κB activity and MTX resistance, we genetically modified the cell lines to express luciferase under a NF-κB biding site promoter. We observed that the fold change in NF-κB activity triggered by TNF-α (but not MTX) treatment correlated with MTX resistance and proliferation across the lines. At the individual gene level, NFKB1 expression was directly associated with a poorer clinical response to MTX, and with both an increased TNF-α-triggered NF-κB activation and MTX resistance in the cell lines. Despite these results, pharmacological inhibition (with BAY 11-7082 and parthenolide) or stimulation (with exogenous TNF-α supplementation) of the NF-κB pathway did not alter MTX resistance of the cell lines significantly, evidencing a complex interplay between MTX and NF-κB in ALL.

Chinese pepper rust is a live parasitic fungal disease caused by Coleosporium zanthoxyli, which seriously affects the cultivation and industrial development of Z. armatum. Cultivating and planting resistant cultivars is considered the most economical and environmentally friendly strategy to control this disease. Therefore, the mining of excellent genes for rust resistance and analysis of the mechanism of rust resistance are the key strategies to achieve the targeted breeding of rust resistance. However, there is no relevant report on pepper rust resistance at present. The aim of the present study was to further explore the resistance mechanism of pepper by screening the rust-resistant germplasm resources in the early stage. Combined with the analysis of plant pathology, transcriptomics, and metabolomics, we found that the genes and metabolites related to phenylpropanoid metabolism were highly enriched in resistant varieties after pathogen infection, which indicated that phenylpropanoid metabolism might mediate the resistance of Z. armatum. This finding was further confirmed by real-time quantitative polymerase chain reaction analysis, which revealed that the expression levels of core genes involved in phenylpropane metabolism in disease-resistant varieties were high. In addition, the difference in flavonoid content in the leaves between resistant and susceptible varieties further supported the conclusion that the flavonoid pathway is one of the main pathways involved in resistance formation in Chinese pepper, and MeJA is involved in the formation of resistance. Our research results not only help to better understand the resistance mechanism of Z. armatum rust but also contribute to the breeding and utilization of resistant varieties.

This study entailed the design and analysis of a 400 m-class underwater glider operated by a bladder-type buoyancy engine. The underwater glider was designed for high-speed movement with a maximum velocity of 2 knots. The shape of the hull was designed to reduce water resistance using the Myring hull profile equation. The reliability was verified by performing simulations using resistance coefficients. The relationship between the control value of the ballast discharged from the buoyancy engine and the glider's speed according to the path angle was analyzed. Further, the relationship between the optimal glide angle and the design control value of the ballast was derived, and the optimal glider speed was estimated accordingly. Based on the analysis results, a bladder-type buoyancy engine was developed, and the maximum speed of the tested underwater glider was measured via sea trials.

Antibiotic resistance currently considered as a global concern mostly impacting low- and middle-income nations and it can be accelerated by antibiotic abuse and other forms of excessive antibiotic use. There is little data on community practices and understanding in Somaliland on antibiotics and antibiotic resistance. To provide evidence-based communication intervention techniques for safer antibiotic use the qualitative study was done from November 1st to December 1st, 2023, and consisted of in-depth semi-structured interviews with adult heads of households in Hargeisa, Somaliland, using purposive and snowball sampling strategies. Participants were chosen from a variety of medical and educational backgrounds. Thematic analysis was used to investigate community knowledge and antibiotic use in the sampled population. To investigate the level of awareness on antibiotic use, 20 respondents (households) were questioned (Table 1). Of these, 17 (85%) became aware of the term antibiotic itself, with 7 (35%) being prescribed by a physician, 9 (45%) receiving laboratory diagnosis when using antibiotics, and 6 (30%) becoming aware of the potential risks associated with improper antibiotic use. This study highlighted the community's lack of understanding about antibiotic use. The majority of the study participants knew the phrase "antibiotic" but had no idea what it meant, the side effect of the antibiotics and other medical science related information regarding how to safely use antibiotics. According to the findings, initiatives for antibiotic stewardship should focus on community education to prevent antibiotic misuse or abuse.

To examine the hydrophobicity of torrefied wood fuel, the water resistances of torrefied pellets prepared by two different methods were evaluated using exposure tests under indoor and outdoor conditions. Torrefied pellets from the xylem of Japanese cedar (Sugi, Cryptomeria japonica) and oak (Konara, Quercus serrata) were prepared by two methods: the torrefaction of wood chips followed by pelletization and the pelletization of wood chips followed by torrefaction. It was found that the pellets prepared by pelletization followed by torrefaction had much lower moisture levels than those prepared by the other method and they showed almost no change in diameter after an outdoor weathering test. These characteristics are unique and indicate that the pellets can be applied not only for industrial use but also for residential and commercial purposes.

Pneumonia kills over two million children under-age of five every year. Oral amoxicillin was recommended by WHO as the first drug of choice for treatment of non-severe pneumonia. The study aimed to determine the clinical failure rate of amoxycillin for the treatment of childhood non-severe pneumonia at Primary Health Care Centers (PHCCs). A randomized controlled multicenter-trial study was conducted in Sana’a. IMCI strategy was used to enrollments the cases where randomly allocated to receive amoxicillin or co-trimoxazole orally for five days. Multivariate logistic regression was used for identified risk factors associated with clinical failure. A total of 254 children were enrolled, of whom 128 cases were treated with amoxicillin while 126 with co-trimoxazole. The clinical failure for amoxicillin was significantly more than co-trimoxazole (30% vs 10%) p value > 0.001. the most risk factor which significantly associated to amoxicillin failure were pre-infection in the last 6 months, while abnormal CBC and literate mothers were associated with clinical failure of co-trimoxazole (p value > 0.05). The use of co-trimoxazole as an alternative to amoxicillin for the treatment of non-severe pneumonia in the PHCCs and conducting further studies to determine the appropriate antibiotic as the first line of defense are recommended.

Buckground: Although ceftazidime/avibactam (CAZ/AVI) has become important option for treating adults and children, no recommendations exist for neonates. We report a neonatal sepsis case due to CAZ/AVI-resistant KPC-2 producing-Klebsiella pneumoniae carrying blaVEB-25 and the use of a customized active surveillance program in conjunction to infection control measures. Methods: The index case was an extremely premature neonate hospitalized for 110 days that had been previously treated with multiple antibiotics. Customized molecular surveillance was implemented at hospital level and enhanced infection control measures were taken for early recognition and prevention of outbreak. Detection and identification of blaVEB-25 was performed by next-generation sequencing. Results: That was the first case of a bloodstream infection caused by KPC producing K. pneumoniae that was resistant to CAZ/AVI without the presence of a metalo-β-lactamase in the multiplex PCR platform in a neonate. All 36 additional patients tested (12 in the same NICU and 24 from other hospital departments) carried wild-type blaVEB-1 but they did not harbor blaVEB-25. Conclusion: The emergence of VEB-25 is signal for horizontal transfer of plasmids at hospital facilities and it is of greatest concern for maintaining a sharp vigilance for surveillance of novel resistance mechanisms. Molecular diagnostics can guide appropriate antimicrobial therapy and early implementation of infection control measures against antimicrobial resistance.

Candida glabrata has thoroughly adapted to successfully colonize human mucosal membranes and survive in vivo pressures prior to and during antifungal treatment. Out of all the medically relevant Candida species, C. glabrata has emerged as a leading cause of azole, echinocandin, and multidrug (MDR: azole + echinocandin) adaptive resistance. Neither mechanism of resistance is intrinsic to C. glabrata, since stable genetic resistance depends on mutation of drug target genes, FKS1 and FKS2 (echinocandin resistance), and a transcription factor, PDR1, which controls expression of major drug transporters, such as CDR1 (azole resistance). However, another hallmark of C. glabrata is the ability to withstand drug pressure both in vitro and in vivo prior to stable ‘genetic escape’. Additionally, these resistance events can arise within individual patients, which underscores the importance of understanding how this fungus is adapting to its environment and to drug exposure in vivo. Here, we explore the evolution of echinocandin resistance as a multistep model that includes general cell stress, drug adaptation (tolerance), and genetic escape. The extensive genetic diversity reported in C. glabrata will be highlighted.

Recently Cold Bitumen Emulsion (CBE) mixture technologies have been developed to lower the pavement construction temperatures to reduce the environmental costs and control the gas emissions. Due to its poor early mechanical strength, active fillers (i.e. cement) have been used to obtain high early stiffness in order to have the potential for timely construction of the next layer. There is, however, a lack of understanding about the impact of active fillers nature on viscoelastic behaviour and fatigue damage resistance of CBE mastics. This study, therefore, aims to identify the influence of active fillers on the rheological properties and the resulted fatigue behaviour of CBE mastic, supported by chemical analysis for the filler-bitumen emulsion. For this aim, bitumen emulsion was mixed separately with seven fillers/blended fillers to prepare the CBE mastics. Various experiments include continuous pH monitoring tests (chemical reactivity of filler-bitumen emulsion), Strain sweep (SS) tests, Temperature-Frequency Sweep (TFS) tests, Time Sweep (TS) tests, and Linear Amplitude Sweep (LAS) tests were conducted on the CBE binder and the prepared mastics. Results show that the rheological performance and the fatigue damage resistance is not only dependent on the filler inclusions, but it significantly relies on filler type and chemistry. Based on that, the raise in complex shear modulus and the decrease in viscous components were associated with a significant enhancement in fatigue performance for specific filler.

Data on the seasonally dry tropical forests of Mexico have been examined in the light of statistical mechanics. The results suggest a division into two classes of species. There are drifting populations of a cosmopolitan class capable of existing in most dry forest sites; these have a statistical distribution previously only observed (globally) for populations of alien species. A high proportion of species found only at a single site are endemic and these prefer sites comparatively low in species richness.

Alopecurus myosuroides (blackgrass) is a problematic weed of Western European winter wheat and its success is largely due to widespread multiple-herbicide resistance. Previous analysis of F2 seed families derived from two distinct blackgrass populations exhibiting equivalent non-target site resistance (NTSR) phenotypes shows resistance is polygenic and evolves from standing genetic variation. Using a CIDER-seq pipeline we show that herbicide resistant (HR) and herbicide sensitive (HS) F3 plants from these F2 seed families as well as the parent populations they were derived from carry extra-chromosomal circular DNA (eccDNA). We identify the similarities and differences in the coding structures within and between resistant and sensitive populations. Although the numbers and size of detected eccDNAs varied between the populations, comparisons between HR and HS blackgrass populations identified shared and unique coding content, predicted genes, and functional protein domains. These include genes related to herbicide detoxification such as Cytochrome P450s, ATP-binding cassette transporters and glutathione transferases including AmGSTF1. eccDNA content was mapped to the Alopecurus myosuroides reference genome, revealing genomic regions at distal end of chromosome 5 and the near center of chromosome 1 and 7 as regions with high number of mapped eccDNA gene density. Mapping to 15 known herbicide-resistant QTL regions showed the eccDNA coding sequences match 12 with four QLT matching HS coding sequences one region only contained HR coding sequences. These findings establish that like other pernicious weeds, blackgrass has eccDNAs that contain homologs of chromosomal genes, and these may contribute genetic heterogeneity and evolutionary innovation to rapidly adapt to abiotic stresses including herbicide treatment.

Pulmonary infections with Mycobacterium avium occur in susceptible individuals following exposure to the bacterium in the environment, where it often persists in biofilms. Many methods have been used to generate biofilms of M. avium, and it is unknown whether different approaches generate similar structures and cell phenotypes. To make a parallel comparison of in vitro biofilm ultrastructure, extracellular matrix (ECM) composition, and drug susceptibility of biofilm resident bacteria, we used two published methods to generate M. avium biofilms: four week incubation in M63 medium or 24 hour exposure to dithiothreitol (DTT). Scanning electron microscopy revealed differences in biofilm ultrastructure between the two methods, including variation in appearance of ECM materials and morphology of resident cells, while light microscopy and staining with calcofluor white indicated that both biofilms contained polysaccharides characteristic of cellulose. Measuring susceptibility of biofilms to degradation by enzymes suggested differences in structurally important ECM molecules, with DTT biofilms having important protein and, to a lesser extent, cellulose components, and M63 biofilms having moderate protein, cellulose, and DNA components. Both biofilms conferred resistance to the bactericidal effects of amikacin and clarithromycin, with resident cells being killed at &gt;10-fold lower rates than planktonic cells at almost all concentrations. Though these comparisons indicate differences in biofilm responses by M. avium under differing conditions, they also suggest common features of biofilm formation including cellulose production and antimicrobial resistance.

The rise of antibiotic-resistant strains of clinically important pathogens is a major threat to global health security. The World Health Organization (WHO) has recognized the urgent need to develop alternative treatments to address the growing list of priority pathogens. Antimicrobial peptides (AMPs) rank among the various suggested options with proven activity and a high potential to be developed into effective agents. Many AMPs are naturally produced by living organisms and protect the host against pathogens as a part of their innate immunity. Various mechanisms associated with their antimicrobial actions include cell membrane disruption, cell wall weakening, protein synthesis inhibition, and interference in nucleic acid dynamics that can induce apoptosis and necrosis. Acinetobacter baumannii is considered a critical pathogen, and severe clinical problems have appeared with isolates resistant to current antibiotic treatments and conventional control procedures such as UV light, disinfectants, and drying. Here, we review the natural AMPs representing the primary candidates for new anti-A. baumannii drugs in a post-antibiotic era and present the use of computational tools to develop the next generation of AMPs with greater microbicidal activity and reduced toxicity.

Tomato is the highest-value fruit/vegetable crop worldwide. However, the quality and yield of tomatoes are severely affected by late blight. MicroRNA482s (miR482s) are involved in plant immune system. In this study, miR482c was transiently and stably overexpressed in tomatoes in transgenic plants to explore its mechanism in tomato resistance against late blight. Tomato in transgenic plants transiently overexpressed miR482c displayed larger lesion area than the control plants upon infection. Furthermore, compared with the WT tomato plants, the transgenic tomato plants stably overexpressing miR482c displayed decreased expression of target genes accompanied by lower POD, SOD, and PAL activity activities and higher MDA content, thereby leading to a decline in the ROS scavenging ability and aggravating the damage of lipid peroxidation product accumulation on the cell membrane, eventually enhancing plant susceptibility. This finding indicates that miR482c may act as a negative regulator in tomato resistance by regulating NBS-LRR expression levels and ROS levels.

Companion animals are increasingly being recognized as important contributors to the spreading of antimicrobial resistant bacteria. The present work aimed to measure the antimicrobial drug prescribing in dogs and cats in the Campania region, Italy by analyzing the Veterinary Electronic Prescriptions (VEPs) between 2019 and 2020. The medical records associated with antimicrobial drug prescription were collected considering the drug delivery (systemic or local) and the rationale for the treatment chosen. In the period under investigation, 166879 drugs were prescribed of which 129116 (73.37 %) were antimicrobial. A total of 83965 (65.03 %) antibiotics were prescribed to dogs, 40477 (31.35 %) to cats, and 4674 (3.62 %) to other companion animals. In dogs the 90.48 % of VEPs prescribed for systemic treatment included an antimicrobial Critically Important or Highly Important or Important for human medicine (WHO, 2018). The most widely commonly prescribed class were fluoroquinolones. The main prescribed antimicrobials were the metronidazole-spiramycin (29.71%), amoxicillin-clavulanic (19.58%), enrofloxacin and cephalexin in dogs (16.52 %) and enrofloxacin (22.64%) and amoxicillin-clavulanic acid (21.37 %) in cats. Based on the results the wide use of broad-spectrum or second-line antibiotics is emerged together with the use of the critically important antimicrobials for human medicine.

Background: Across the world, antibiotic resistance is a critical challenge. To address such a problem, it has to be done to investigate new antibiotic sources. Aim of the study: Study of the antibacterial activity of Corallopyronin A in preclinical animal testing and randomized human clinical trials stages 1/2, as well as investigating the purification of Corallopyronin A from different soil conditions in Egypt. Type of the study: Screening experimental study. Methodology: Egypt's various soil conditions were tested to develop bacterial isolates that produced the antibiotic compound Corallopyronin A. Reversed phase HPLC was used to purify Myxopyronin A. The broth microdilution method and the paper disc diffusion assay determined the test antibiotic's minimum inhibitory concentration( MIC) and in vitro antibacterial activity. Moreover, in vivo antibacterial spectrum, adverse medication responses, and pharmacokinetics were found in phases 1/2 of randomized clinical studies involving humans and animal models. Results: Corallopyronin A was generated from the culture supernatant of the soil bacterial isolate Corallococcus coralloides M2, cultivated on a Casein yeast peptone( CYP) plate. The test antibiotic prevented the growth of several Gram-ve bacteria, including Escherichia coli, at MICs higher than 100 mcg/ ml; while blocking the development of many Gram +ve bacteria, with MICs ranging from 3 to 15 mcg/ ml. However, eukaryotic cells—such as those found in fungi and humans—were unaffected. A bactericidal consequence of the test antibiotic was detected in the inhibition of prokaryotic DNA-dependent RNA polymerase( RNLP). Conclusion: The synthesis of the bactericidal antibiotic Corallopyronin A from Corallococcus coralloides M2 isolated from different soil settings in Egypt intrigued the current investigation.

Primary lymphoma of the middle ear is rare in cats, and little information has been accumulated on the treatment and course. An 11-year-old spayed female mixed-breed cat was brought to our hospital with facial nerve paralysis, which had been stable using prednisolone for 3 months. She was diagnosed with B-cell lymphoma of the right middle ear after otoscopic sampling, which showed evidence of filling of bilateral tympanic bullae on computed tomography. Hepatic metastasis was suspected and she was treated with multidrug chemotherapy, resulting in clinical remission. On day 176, magnetic resonance imaging and computed tomography was performed as a checkup, revealing tumor invasion into the nasopharyngeal region and recurrence of hepatic lesions without any brain abnormality. Nasal congestion then worsened and the patient died on day 228 after presenting with generalized seizures. Clinicians should be aware of the possibility of invasion to surrounding tissues and hepatic metastasis in cases of feline primary middle ear lymphoma.

Background. The European Centre for Disease Prevention and Control describes the community pharmacist as gatekeeper to the quality of antibiotic use. The pharmacist has the responsibility to guard safe and effective antibiotic use; however, little is known about how this is implemented in practice. Aims. To assess the feasibility of a method to audit the quality of antibiotic dispensing in community pharmacy practice and to explore antibiotic dispensing practices in Greece, Lithuania, Poland, and Spain. Methods. The Audit Project Odense methodology to audit antibiotic dispensing practice was adapted for use in community pharmacy practice. Community pharmacists registered antibiotic dispensing on a specifically developed registration chart and were asked to provide feedback on the registration method. Results. Altogether twenty pharmacists were recruited in four countries. They registered a total of 409 dispenses of oral antibiotics. Generally, pharmacists were positive about the feasibility of implementing the registration chart in practice. The frequency of checking for allergies, contraindications and interactions differed largely between the four countries. Pharmacists provided little advice to patients. The pharmacists rarely contacted prescribers. Conclusion. This tool seems to make it possible to get a useful picture of antibiotic dispensing patterns in community pharmacies. Dispensing practice does not seem to correspond with EU guidelines according to these preliminary results.