With the advancement of biomedical research into antimicrobial treatments for various diseases, the source and delivery of antibiotics have attracted attention. In periodontal diseases, antibiotics are integral in positive treatment outcomes; however, the use of antibiotics is with caution as the potential for the emergence of resistant strains is of concern. Over the years, conventional routes of drug administration have been proven to be effective for the treatment of PD, yet the problem of antibiotic resistance to conventional therapies continues to remain a setback in future treatments. Hydrogels fabricated from natural and synthetic polymers have been extensively applied in biomedical sciences for the delivery of potent biological compounds. These polymeric materials either have intrinsic antibacterial properties or serve as good carriers for the delivery of antibacterial agents. The biocompatibility, low toxicity and biodegradability of some hydrogels have favoured their consideration as prospective carriers for antibacterial drug delivery in PD. This article reviews PD and its antibiotic treatment options, the role of bacteria in PD and the potential of hydrogels as antibacterial agents and for antibiotic drug delivery in PD. Finally, potential challenges and future directions of hydrogels for use in PD treatment and diagnosis are also highlighted. The term periodontal disease (PD) is an umbrella term used to describe chronic inflammatory conditions of the soft tissues or supporting tissues surrounding the teeth ,2. In itPD is known to begin with the inflammation of the gingiva. This inflammatory response is often initiated by bacteria in a biofilm surrounding the teeth and dental supporting tissues in the form of plaque ,6. In ciPeriodontal infections are a significant cause of tooth loss and can have negative impacts on overall health. It is not surprising that several studies have identified a bidirectional association between PD and other systemic conditions such as coronary heart disease , cognitiTo prevent irreversible damage to the gingiva, bone, ligament and subsequent tooth loss, several approaches that are aimed at either removing or offsetting the microbiome that makes up the offending plague or ameliorating the inflammatory response have been investigated. The prevention and treatment of PD involve both pharmacological and non-pharmacological options to achieve optimum care.In the pharmacological management of PD, various treatment options are available for medical emergencies in dental practices including odontogenic pain, viral infections, fungal infections and bacterial infection In PD, it is crucial to receive treatment following bacterial infections; failing to do so might result in complicated oral and systemic health problems. In the treatment of periodontal bacterial infections, different antibiotics available as various formulations and dosage forms are used by dental practitioners. Most bacterial infections can be effectively managed by the rational use of antibiotics. However, conventional antibiotics are losing their effectiveness against certain bacterial infections due to increases in antimicrobial resistance (AMR).Challenged by the threat of AMR, researchers have been diligently exploring the potential of advanced antibacterial compounds or materials to address the rising dangers posed by drug-resistant bacteria. Among these, natural extracts, nitric oxide, transition metal dichalcogenides (molybdenum disulfide as an example ) and metSeveral antibacterial polymers were reported approximately 20 years ago ,18. PresThese hydrogels have been proven to have mechanisms of action that are different to most conventional antibiotics and hence have great potential as antibiotic agents ,23. HydrSeveral works have reported on the antibacterial activity of hydrogels in early-stage in vitro experiments using minimum inhibitory concentrations (MIC) and zones of inhibitions (ZOI) with a number of reports on antibacterial effects in vivo ,25,26,27The aetiology of PD is dental plaque that consists of microbial biofilm that adheres to the tooth’s and gingiva’s surfaces . This biPorphyromonas gingivalis, Tannerella forsythia, and Treponema denticola [Aggregatibacter actinomycetemcomitans, has also been implicated in PD as a particularly aggressive form of the disease [Fusobacterium nucleatum, which has been shown to play a significant role in the formation of periodontal biofilm and its association with disease severity and AMR [One of the most well-known groups of bacteria associated with PD is the red complex, which includes enticola ,30. Thes disease ,32. Addi disease . One suc and AMR . Recent  and AMR ,36.Overall, the role of bacteria in the prognosis of periodontal disease is complex and multifaceted. There is also growing evidence that the by-products produced by bacteria in the periodontal pocket may also play a significant role in disease progression and prognosis . A studyFuture research in this area may focus on developing novel therapeutic approaches that target specific bacterial species or their by-products to improve the prognosis and treatment outcomes of PD.PD can be prevented and possibly reversed by good and consistent oral hygiene procedures that remove microbial biofilm. These procedures include daily oral hygiene practices, gingival scaling, surgical procedures and antibiotic therapy. Mechanical oral hygiene practices such as flossing and toothbrushing are highly recommended and common effective methods for preventing PD and maintaining periodontal health ,42.Periodontal examination on a clinical visit is crucial to the choice of treatment in PD . During To eliminate disease-associated pathogens in PD and ameliorate clinical condition, empiric antibiotic treatments are often used in combination with mechanical debridement . VariousLocal antimicrobial treatments such as disinfectants and locally delivered antibiotics have been proposed as an effective way to treat PD . These tBy using local antimicrobials, odontogenic bacteria can be eliminated, leading to improved oral health. In the case of aggressive periodontitis and necrotising ulcerative gingivitis, in patients with comorbidities and in the case of poor response to conventional mechanical therapy, antibiotic therapy provides an effective treatment outcome.Prevotella species isolated from the clinical samples were beta lactamase-producing organisms with 17.1 to 26.3% resistance to amoxicillin; fortunately, these species were susceptible to amoxicillin-clavulanic acid [Prevotella species studied for their antimicrobial resistance to first- and second-line antibiotics in PD treatment, in an in vitro study, a key aspect of the findings revealed that P. nigrescens had the highest amoxicillin, amoxicillin clavulanic acid and clindamycin [The emergence and rapid spread of antibiotic resistance is a threat to public health. A worrying case of AMR was reported by Maestre and colleagues in 2007. In their aim to investigate the susceptibility of clinical periodontitis bacteria isolates to commonly prescribed antibiotics for PD prophylaxis and treatment, an alarming resistance rate from 18.2 to 47.7% to Azithromycin was recorded . In addinic acid . Among tndamycin . In a rendamycin . AMR is ndamycin . Their sDespite the significance of antibiotics in PD treatment, the drug prescribing for dentistry guidelines, has highlighted one of the key drivers of antibiotic resistance in primary care and dentistry to be the indiscriminate use of antibiotics. In the NHS primary care data for Scotland, dental prescription of antibiotics accounts for 9% of oral antibiotics. In a recent clinical audit, about 50% of dental antibiotic prescriptions are inappropriate .A rational antimicrobial treatment, routes of drug delivery and defined treatment goals are essential in enhancing the effectiveness of therapy in PD. Prolonged antibiotic therapy can encourage the development of drug-resistant microbes; hence, the need for surveillance on the selection and prescribing of antibiotics in PD therapy. Previous studies mostly describe hydrogels as soft three-dimensional networks of crosslinked polymers that can accommodate large volumes of water into the polymeric network. This crosslinked network prevents the hydrogel unit from dissolution in spite of its high water affinity ,64.Hydrogels are classified according to a number of parameters, such as the source of polymers, technique of fabrication, crosslinking process as well as their response to environmental stimuli ,66. TheyHydrogels as antibacterial agents can be amenable alternatives to conventional antibiotic therapies . DependiCurrent research on antibacterial hydrogels includes biocompatible polymers such as polyethylene glycol of varied molecular weights, polysaccharides  and polyvinyl alcohol or compounds such as poly  with or without antibiotic substances ,76,77,78Bactericidal and bacteriostatic chemicals and compounds incorporated into hydrogels include nanoparticles  and antibiotics  ,79,80,81Hydrogels that have inherent antibacterial properties could be applied as coatings for surgical or diagnostic instruments in periodontal disease . This coHydrogels are termed smart based on their response to external stimuli, such as temperature, pH, light, ROS or electric fields, which triggers a reversible change in the hydrogel’s structure and properties ,84. For Another category of smart hydrogels for antibiotic therapy in PD is pH-responsive hydrogels. pH-responsive hydrogels alter their swelling dependent on changes in pH. Key characteristics of pH-sensitive hydrogels are the presence of a cationic moiety such as the amine group or an ionic group such as carboxyl acid. The hydrogels are either anionic or cationic. The swelling nature of chitosan hydrogels is dependent on factors such as the pH of the swelling medium, hydrophilicity, polymer concentration, ionic charges and ionizable groups, among others. In a cationic polymer such as chitosan, the protonation of the amino group favours swelling in an acidic medium. On the other hand, for carboxymethyl chitosan, an anionic polymer, a medium with higher pH favours its swelling due to the ionization of acidic groups ,95.Aycan and Alemdar developed a chitosan-based hydrogel reinforced with bone ash for the delivery of amoxicillin . SpecifiBecause smart hydrogels can release drugs in response to specific stimuli, allowing for targeted drug delivery and reduced side effects associated with overt exposure to active pharmaceutical ingredients in conventional drug-delivery methods ,97. ThisE. coli and S. aureus) inhibition by ciprofloxacin-loaded thermo-responsive hydrogel formulations are exhibited in E. coli and 94.71% for S. aureus. See Kang and co-workers  designedPorphyromonas gingivalis without compromising normal healthy tissues. The results indicate that hydrogels can deliver antibiotics over a prolonged period with approaches tuneable techniques to mitigate AMR. An added advantage of using smart hydrogels for the delivery of antibiotics, in particular, is that they can provide sustained release of the antibiotic, ensuring a consistent and controlled dosage over an extended period of time. This can help to prevent the development of antibiotic-resistant strains of bacteria, as a constant and controlled dosage can ensure that all bacterial cells are effectively eliminated. Furthermore, using smart hydrogels for antibiotic delivery can also increase patient compliance. Depending on the fabrication, it removes the need for frequent dosing and reduces the risk of missed doses. In a study reported by Lin et al., a smart hydrogel that contained mesoporous silica on gold nanobipyramids was fabricated for the sustained release of light-thermal antibacterial and drugs against endodontic pathogenic bacteria  The releAn opposing argument could be that the sustained release of antibiotics through smart hydrogels may result in the development of antibiotic resistance, especially sustained suboptimal doses, are delivered . The proAlthough smart hydrogels have great potential for antibiotic delivery, there are some concerns. The main challenges are achieving a high drug-loading capacity while maintaining the hydrogel’s stability and responsiveness and also ensuring that the antibiotic’s release kinetics are consistent and predictable. Additionally, the biocompatibility and toxicity of smart hydrogels must be thoroughly evaluated to ensure their safety for use.Identifying the appropriate drug release model for the hydrogel is key. Responsive hydrogels may also provide a controlled drug release profile of the hydrogel . UnderstDrug release mechanisms can be broadly categorised as either rapid or sustained release. The drug release mechanisms of hydrogels rely heavily on the physicochemical properties of hydrogels. Drugs can be bound to hydrogels through a non-covalent interaction which allows drug molecules to move freely within the hydrogel network . There aThe antimicrobial action of smart hydrogels could be triggered using biological (enzymatic action or pH changes due to the presence of bacteria) or non-biological  stimuli .Due to the desirable characteristics of hydrogels for drug delivery, hydrogels are potentially feasible as matrixes for antibiotics. Dias and team have successfully developed a novel approach to PD treatment by incorporating oxytetracycline in an advanced polymeric system . SimilarHydrogels are good drug-delivery platforms for antibacterial agents that target the inhibition of bacteria biofilm ,126. AntOverall, advantages of hydrogel-infused antibiotics include: potential advantage of localised treatment , advantaAlthough biocompatible hydrogels are appreciated for their high-water content, their ability to hold approximately 70% water in their polymer network is a limitation to their mechanical properties and by extension their applications. There is, therefore, the need to initially establish a database of the target product profile of the intended biomedical device for which the hydrogel is to be used for. Following this, a library of initial starting materials for the hydrogels, fabrication techniques and parameters and physicochemical characterisation are to be considered in developing suitable hydrogel materials for the intended use. For PD treatments where hydrogels are used as drug delivery of antibiotics, considerations such as potential greater offset to the oral microbiome compared to conventional oral therapies, taste effects , and fine-tuning exposure kinetics of the hydrogel device loaded with antibiotics are crucial in positive overall patient experience and treatment outcomes. Drug release models such as Higuchi, Weibull function and Korsmeyer–Peppas could be adopted to enhance the understanding of the release kinetics of hydrogels.First, as this paper is a narrative review, a number of articles may not have been identified and included. Secondly, because this paper attempts to provide details of key considerations for hydrogels in PD diagnostics and management, in-depth discussions of some sections are limited to the search strategy used. However, this paper highlights a heterogenous source of information on PD, strategies for antibacterial treatment using hydrogels and key factors for consideration in POCT, thus assuring the appropriate level of comprehensiveness.This review underscores the need for a multidisciplinary approach to the treatment of periodontal infections, combining innovative technologies and materials with traditional periodontal therapy techniques. Collaboration between dental professionals, researchers and material scientists can facilitate the development of more effective and personalized treatment plans for patients suffering from periodontal infections, ultimately improving the overall standard of care in the field. Furthermore, public health initiatives aimed at promoting oral hygiene and preventative care can play a critical role in reducing the incidence of periodontal infections and the need for antibiotic treatment altogether, further contributing to the fight against AMR. A comprehensive and integrated approach is necessary to effectively address the issue of periodontal infections and antibiotic resistance.Hydrogel-based antibiotic drug-delivery devices have shown promising potential for the treatment of periodontal infections, offering targeted and sustained release of antibiotics. Further research and development in this field could lead to the creation of more effective treatment options for periodontal infections that can ultimately improve patient outcomes and quality of life, while addressing the growing issue of antibiotic resistance. Therefore, it is important to continue exploring the potential of hydrogel-based antibiotic drug-delivery devices and other alternative treatment options for periodontal infections to combat the rise of antibiotic resistance and improve overall oral and systemic health.


In the sample, 70% of the students were unfamiliar with antibiotic stewardship; thus, the analysis revealed a significant difference in their familiarity before and after enrolling in the online course . Conclusion: Medical students experience low confidence in the safe practice of the antibiotic stewardship program. The WHO-online antibiotic stewardship course is considered a valuable resource that can be used in a formative medical curriculum. Thus, educators and the academic curriculum must promote practical strategies to minimize antibiotic stewardship literacy and increase antibiotic prescribing and administration quality. Introducing antibiotic stewardship across the medical curriculum and establishing educational courses are some strategies that can be undertaken to ensure that future doctors are well-educated in the principles and practices of the appropriate use of antibiotic stewardship.Background: Antibiotic resistance is a worldwide health concern that necessitates antibiotic stewardship. Medical students significantly impact future healthcare practices; thus, their trust in antibiotic prescription and administration is crucial. This research aims to assess medical students’ levels of confidence and knowledge in these areas before and after exposure to virtual antibiotic stewardship education. Methods: A one-group pretest-posttest design was conducted with medical students from King Saud bin Abdulaziz University for Health Sciences in Jeddah, Saudi Arabia. Participants were enrolled in the WHO-online antibiotic stewardship course. Results: The group’s baseline confidence and background knowledge were reported to be lower than what was offered after introducing the virtual course. The McNemar–Bowker test showed a significant difference in students’ confidence in pre-course and post-course scores (Z = 20,  Throughout history, substantial advances in managing infectious diseases have occurred, with several discoveries and improvements emerging in recent years . These iAntibiotic resistance is a huge worldwide health concern that occurs when bacteria acquire the capacity to resist antibiotic actions, leaving these medications less effective or completely useless in treating diseases . It has Antibiotic stewardship is an educational program that encourages, educates, and supports safe antibiotic prescription, use, and control . The ultSeveral studies have examined the impact of educational courses on medical students’ knowledge and confidence in antimicrobial stewardship and antibiotic prescribing practices . El-SokkThe World Health Organization (WHO) launched an online antibiotic stewardship course to address the urgent need to control antibiotic resistance through proper surveillance and effective prevention systems . It was It has been alleged that medical students lack specialized expertise and ability in the antibiotic stewardship program . FurtherThirty-three participants were selected to be enrolled in this study. They responded positively to the dispensed survey; 15 (54.1%) were males, while 18 (45.9%) were females. The mean age of the respondents was 22.6 years (SD ± 2.17). The demographic characteristics of the participants are presented in Two-thirds of the participants felt unsure and unconfident in prescribing an antibiotic by themselves and accurately diagnosing an infection that needs antibiotic treatment (36.4%) and (33.3%). Moreover, half of the participants (51.5%) failed to understand not prescribing antibiotics for fever without severe criteria and uncertain diagnosis of infection. Interestingly, a high percentage (94%) of the participants thought they were unconfident and not sure if asked to participate in selecting the appropriate antibacterial agents. Moreover, a similar proportion of the participants (94%) felt unconfident in knowing the suitable dosage for antibiotic treatment for a specific indication such as pneumonia or an exacerbation of COPD, and 90% felt uncertain about establishing treatment duration for any antibiotics. Interestingly, a similar percentage (91%) of the participants thought they were unconfident if asked to participate in prescribing combination therapy and establishing treatment duration, as shown in Regarding participants’ knowledge of administering antibiotics and antibiotic resistance, five case scenarios with two to three multiple-choice questions were used to assess the participant’s knowledge. In the first-case scenario, two-thirds (66.7%) of students correctly identified the best and most appropriate treatment recommendation but could not correctly identify the most appropriate treatment duration. For the second scenario, less than half of the participants (48.5%) were able to select the best treatment recommendation, and a similar percentage (45.45%) were able to figure out the recommended duration for the antibiotic. However, only a few (12.1%) could correctly identify the most appropriate treatment duration. Similarly, for the third scenario, only a third of the participants (33.3%) could select the appropriate treatment choice, appropriate administering time, and best treatment recommendation. For the fourth scenario, more than half of the participants (54.6%) could not select the best initial choice of treatment if the goal was to obtain infection rate control or figure out the recommended treatment based on the patient’s history. However, over two-thirds (84.9%) could not correctly select the recommended prophylactic antibiotic. In the last scenario, more than 70% of the participants could not select the appropriate treatment and management, regardless of their detailed history of overseas travel and anticoagulant medications.In the first scenario, more than two-thirds (81.8%) of students correctly identified the best and most appropriate treatment recommendation, and (42.4%) correctly identified the most appropriate treatment duration. For the second scenario, more than half of the participants (66.67%) were able to select the appropriate initial course of treatment, and 57.6% were able to figure out the recommended duration for the antibiotic. However, only almost a third (39.4%) could correctly identify the most appropriate treatment duration. For the third scenario, more than half of the participants could select the appropriate treatment choice, administering time, and best treatment recommendation. Similarly, for the fourth scenario, more than half of the participants (54.6%) could select the best initial treatment choice if the goal was to obtain infection rate control and determine the recommended treatment based on the patient’s history. However, only a third (33.3%) could not select the treatment recommendation for the dental appointment. More than half (51.5%) of participants could select the most appropriate treatment for the last scenario. At the same time, almost a third could select the appropriate management based on the detailed history of overseas travel and anticoagulant medications  and detaParticipants were asked about their familiarity with “antibiotic stewardship” in the knowledge section. Almost 70% of participants were unfamiliar with antibiotic stewardship, while 30% had heard about it. Thus, all participants (100%) were introduced to the term in the online courses after the course, as shown in p < 0.002). Second, the matched paired t-test was used to compare knowledge scores before and after the course. The table demonstrates a comparison between the mean knowledge scores before and after the courses, and it was found that the mean knowledge score level after the course was higher than the mean knowledge score before the course (M = 7.66 versus M = 5.36 respectively), t = 3.540 and p < 0.001. The association between confidence and knowledge was measured before and after the antibiotic stewardship course. First, the McNemar–Bowker test analysis revealed a significant difference in students’ confidence before and after enrolling in the online educational program , unsure (1.8–2.4), and confident (2.5–3). All participants’ informed consent was duly obtained before participation, and participants were assured that all responses would remain confidential. For students’ knowledge, five case sensations with 15 questions were utilized to evaluate students’ knowledge regarding antibiotic prescribing and administration. The correct selections received one mark, while no points were given to the wrong selections. The overall knowledge score was evaluated as poor <60% or good >60%.t-test was used to compare knowledge scores before and after the course. The significance level was <0.05. The collected data were tabulated and statistically analyzed using JMP Statistics for Windows, version 15.Qualitative data were reported as frequency and percentage, whereas continuous variables were provided as mean, standard deviation (SD), median, minimum, and maximum as appropriate. The McNemar–Bowker Test was performed to compare categorical data and analyze the relationship between confidence levels before and after the course. The matched data paired Infectious disease emerges and reemerges in the community despite considerable progress and achievements in antibiotic discovery and infection control . MalpracIn line with the recent survey, medical students might experience a shallow confidence level about antibiotic options, the right prescription, and dosing treatment . Our datResearchers have also argued that people are still dying of bacterial infection regardless of the availability of several classes and types of antibiotic agents. Dellinger R.P. et al., 2012, found a high incidence of inappropriate antibiotic management in prescribing among medical practitioners . For thep < 0.001, which is significant. The findings of this study are similar to those of David et al., 2017, which indicated that antibiotic stewardship promotes appropriate antibiotic use to reduce the malpractice of antibiotics [p-value = 0.0004, which is considered significant. Knowledge analysis indicates that the course impacts the students’ knowledge. Thus, offering extensive antibiotic stewardship education might help reduce the number. These results agree with Weier et al., 2017, which examined medical students’ attitudes and understanding of antimicrobial stewardship. It emphasized the need for increased education in this area and the possible influence on prescribing confidence [p < 0.001 *).Based on the experimental design, students’ confidence and knowledge were assessed before their enrolment in the online educational course about antibiotic stewardship offered by the WHO, while a similar measure was conducted two weeks after completion . Analyziibiotics . Comparinfidence . The terNot many studies in Saudi Arabia have focused on the depth of medical students’ knowledge and confidence in prescribing antibiotics, which this study has done. This study identified the impact of antibiotic stewardship, online courses, and self-education on medical students’ online expertise and enthusiasm and the need to implement effective online educational programs, curricular activities, and awareness campaigns to augment the learning process effectively. Even though this study was conducted based on non-random selection, it is the only experimental design that can establish cause-and-effect relationships between an independent and dependent variable . SeveralPotential future directions for knowledge gaps and lack of confidence: medical programs can provide more comprehensive training on antibiotic use, emphasize the importance of evidence-based practices, and provide opportunities for students to gain clinical experience and build confidence in their decision-making skills. Furthermore, healthcare education programs should prioritize comprehensive antibiotic use training, including regular guidelines and best practice updates. Additionally, ongoing education and awareness campaigns in clinical rotations and practical experiences should allow students to apply their knowledge in real-world scenarios and help them make more informed decisions regarding antibiotic prescription and administration.Medical students often lack confidence and understanding when regarding antibiotic selection, prescription, and administration. Their understanding of safe practices within antibiotic stewardship programs is often limited. As a result, it is imperative to take proactive measures to ensure that our future physicians receive a comprehensive education in the principles and practical aspects of judicious antibiotic use. Various potential interventions can be employed to enhance students’ knowledge and confidence. Firstly, it is evident that the existing medical curriculum alone does not adequately equip students with the proficiency to understand, prescribe, and interpret antibiotics upon graduation. Thus, it is strongly recommended to integrate antibiotic-related knowledge into their medical education journey. Secondly, this research underscores the pressing need to develop dedicated educational courses on antibiotic stewardship. These suggested courses could significantly bolster students’ comprehension and confidence in antibiotic prescribing within the context of future patient care. By fostering a deeper appreciation for antibiotics, such initiatives can play a pivotal role in minimizing microbial resistance, improving patient outcomes, and curbing the spread of multidrug-resistant organisms. In summary, enhancing medical students’ proficiency in antibiotic usage and stewardship is a critical endeavor, and it holds the potential to bring about substantial positive impacts in healthcare practice.


We found that low MET concentrations exerted no appreciable effect on ADSC proliferation. However, MET was observed to enhance the angiogenic capacity and autophagy of ADSC. MET-induced autophagy was associated with increased vascular endothelial growth factor A production and release, which contributed to promoting the therapeutic efficacy of ADSC. In vivo experiments confirmed that in contrast to untreated ADSC, MET-treated ADSC promoted angiogenesis. Our findings thus indicate that the application of MET-treated ADSC would be an effective approach to accelerate wound healing by promoting angiogenesis at wound sites.Human adipose tissue-derived stem cell (ADSC) derivatives are cell-free, with low immunogenicity and no potential tumourigenicity, making them ideal for aiding wound healing. However, variable quality has impeded their clinical application. Metformin (MET) is a 5′ adenosine monophosphate-activated protein kinase activator associated with autophagic activation. In this study, we assessed the potential applicability and underlying mechanisms of MET-treated ADSC derivatives in enhancing angiogenesis. We employed various scientific techniques to evaluate the influence of MET on ADSC, assess angiogenesis and autophagy in MET-treated ADSC  Non-healing cutaneous wounds represent a crucial global healthcare and societal challenge. Morbidity from diabetes is a major factor for persistent, non-healing wounds that put patients in danger of limb amputation , 2. The Previous research has demonstrated that human adipose tissue-derived stem cells (ADSC), a population of pluripotent mesenchymal cells, are effective for wound healing, as they convey a range of cytokines and growth factors, and influence the biological processes of skin cells implicated in the wound healing process, including fibroblasts, keratinocytes, and endothelial cells. Given the abundance of ADSC sources, they are considered highly advantageous for therapeutic use and are extensively utilized in the field of regenerative medicine . The keyMetformin (MET), a biguanide, is a routinely employed oral antihyperglycemic medication used to treat type 2 diabetes mellitus , the theAutophagy is a cellular process that by selectively degrading dysfunctional organelles and intracellular pathogens, promotes cell survival during both growth and conditions of starvation. These mechanisms serve as protective measures for the cell, ensuring correct cellular function and preventing the accumulation of potentially harmful materials . Autophain vivo and in vitro. Our results revealed that the application of MET-treated ADSC would be a potentially effective approach for accelerating wound healing by promoting angiogenesis at the site of wounding.Our objective in this study was to characterize the influence of MET with respect to enhancing the angiogenic capacity of ADSC-CM. To this end, we investigated the stimulatory effect of MET on ADSC and focussed on whether MET-enhanced autophagy in ADSC is associated with ADSC-related angiogenesis. To assess the changes in cytokine secretion induced by MET simulation, we further compared the angiogenic potential of ADSC-CM with or without treatment with MET The collection and utilization of human ADSC from adipose tissue were approved by the Biomedical Research Ethics Committee of Naval Medical University in Shanghai, China, according to the guidelines of the Declaration of Helsinki. Adipose tissues were procured from three medically fit individuals between the ages of 25 and 45 years, having initially obtained their written informed consent.g for 5 min. The cells were cultured under humidified conditions in a 5% CO2 atmosphere at 37°C, and the medium was refreshed at 72-h intervals. The cells were defined as passage 1 having reached 80% confluence, and were sequentially re-plated until the fourth passage for subsequent experiments. To induce differentiation, the passaged cells were subjected to a 2-week incubation in adipogenic differentiation medium , 3 weeks in osteogenic differentiation medium , or 3 weeks in chondrogenic differentiation medium . The induced cells were subsequently subjected to differentiation assays via staining with Oil Red O for 30 min to evaluate adipogenic differentiation, with Alizarin Red S  for 5 min at room temperature to visualize osteogenic differentiation, or with Alcian Blue (Cyagen) for 1 h at 37°C to visualize chondrogenic differentiation. The stained cells were imaged following a washing step with phosphate-buffered saline (PBS) to eliminate any remaining dye . The pellet comprising cell debris was collected via centrifugation at 100 × ning dye .3/well) in a 96-well plate and treating appropriately, 10 μl of CCK-8 solution was added to each well. The samples were incubated for a period of 1.5 h, after which absorbances were measured at 450 nm using a microplate reader . Cell viability was determined by calculating the difference in optical density values obtained for the experimental and control groups.Cell viability was assessed using a Cell Counting Kit-8 assay , according to the manufacturer’s instructions. After seeding ADSC . Following fixation, the cells were washed with PBS, and CD73 , CD90 , CD105 , CD31 , CD235a , and CD45  were used to label the cells. Flow cytometry was performed to determine the intensity of cell labelling.To prepare the cells for flow cytometry analysis, a single-cell suspension containing 1 × 10For the purposes of cell cycle analysis, 1 × 106 ADSC were collected and washed three times with PBS, and thereafter labelled with propidium iodide  according to the manufacturer’s instructions. The labelled cells were subjected to flow cytometry analysis, and the resulting data were analysed using ModFit software (version 3.1).g for 20 min).Hundred micrometres MET (24 h), 10 nM rapamycin (6 h), and 10 mM 3-MA (6 h) were used respectively to stimulate ADSC for increasing or decreasing autophagy . After tThe migratory capacity of cells was evaluated using human umbilical vein endothelial cells (HUVECs). HUVECs were seeded in six-well plate inserts. After the cells had reached confluence, they were subjected to a 16-h starvation treatment with serum deprivation. For the purposes of the scratch assay, a sterile pipette tip (200 μl) was used to create a straight line on the bottom well, and photographs were captured at 0-, 12-, and 24-h time points. ImageJ software was employed to assess the migratory capacity of cells. The experiment was repeated three times for validation.4 cells/well and incubated for 4–6 h with different groups of ADSC-CM. A phase-contrast microscope was used to observe tube formation, and photographs were taken periodically. Three fields were examined per test condition, and the total number of branching points, tube numbers, covered area (%), and total length of tubes (μm) were calculated using ImageJ software with an installed plugin (https://Image J.nih.gov/ij/plugins/index.html). The experiment was conducted in triplicate.Initially, the wells of a 96-well plate were coated evenly with 60 μl of Matrigel (BD Biosciences), which was then polymerized for 30 min at 37°C. HUVECs were then seeded at a density of 2 × 10Prior to treatment, the wells of six-well plates were seeded with 1 × 106 cells. A protease inhibitor-containing radioimmunoprecipitation assay lysis buffer  was used to lyse the cells. Proteins were separated using sodium dodecyl sulphate–polyacrylamide gel electrophoresis  and subsequently transferred to polyvinylidene fluoride membranes. After washing membranes for 15 min with a quick-blocking reagent , they were incubated overnight with a primary antibody VEGFa , Ang II , LC3 I/II , Beclin-1 , Atg 5 , or GAPDH . Horseradish peroxidase (HRP)-conjugated secondary antibodies  were used to detect the bands using ECL Plus reagent (Bio-Rad Laboratories). The experiment was performed in triplicate.g for 40 min, the concentrated suspension of ADSC-CM was used for analysis. VEGFa and IL-6 levels were measured using commercially available ELISA kits , in accordance with the manufacturer’s instructions. Using a microplate reader, we measured the absorbance of plates at 450 nm (Bio-Rad Laboratories). For each sample, we performed three independent experiments.The different groups of ADSC-CMs were collected as described previously and concentrated using a concentration tube . Following centrifugation at 3400 × ADSC were post-fixed overnight in 2.5% glutaraldehyde , rinsed with PBS, and then fixed in 2% osmium acid for 1 h. Following a series of dehydration steps with ethanol, the ADSC were embedded in Epon resin. After staining for 1 h with uranyl acetate and lead citrate, the specimens were observed under a transmission electron microscope , and images were obtained for random fields of view.Autophagy was assessed using an autophagy detection kit , in accordance with the manufacturer’s protocol. ADSC were placed in the wells of a 96-well plate, treated with 100 μl of Microscope Dual Detection Reagent for 30 min at 37°C, and fixed for 20 min in 4% paraformaldehyde. Three independent researchers used a fluorescence microscope  to capture images of autophagic vacuoles, and ImageJ software was used to calculate the fluorescence intensity of each image.6/well) were seeded in the wells of a six-well plate, to which 5 μl/well VEGFa antibody  was added. The culture supernatant of VEGFa antibody-treated ADSC was used for incubation of HUVECs at 37°C for 24 h, after which they were harvested and examined for further experimentation.To eliminate the influence of the ADSC-secreted VEGFa on HUVECs, ADSC . The Matrigel solution (200 μl) was subcutaneously injected into the dorsal side of the left and right flanks of mice. At the time of injection, the solution was at a temperature of 4°C and formed a plug as it warmed up to the body temperature (37°C). The mice were euthanized after 21 days, and the Matrigel plugs were removed. Depending on the amount of blood vessel ingrowth, the colour of the plugs ranged from white to red.Matrigel plugs were fixed for 12 h in 4% paraformaldehyde at 4°C, and after gradually dehydrating, the specimens were embedded in paraffin blocks and sliced into 4-μm-thick sections. Thereafter, they were then stained with haematoxylin and eosin (H&E) and observed and imaged under a light microscope.To quantify vascular formation in the Matrigel plug, we immunohistochemically examined the expression of CD31 and NSE. The samples were blocked with 5% BSA for 30 min, after which they were incubated overnight with a primary antibody. Following counterstaining the sections with haematoxylin and incubating with an HRP-conjugated secondary antibody, three different researchers used a microscope to observe and photograph the sections. The intensity of CD31 staining was assessed using the ImageJ software IHC Profiler plugin. The intensity with which endothelial cells were stained with CD31 was classified into following four categories: high positive (HP), positive (P), low positive (LP), and negative (N), with scores being calculated using the following formula:The scores thus obtained were subsequently subjected to statistical analysis. Furthermore, the maximum depth of endothelial cells (µm) was measured using ImageJ software to quantify angiogenesis.5 cells/ml, added to the wells of a 24-well plate at 400 μl/well, and cultivated for 24 h, after which they were fixed with 4% paraformaldehyde and rinsed with PBS. Thereafter, the cells were permeabilized with 0.1% Triton X100 in PBS for 2 min on ice. After washing with PBS, the cells were treated for 60 min at 37°C in the dark with 50 μl of TUNEL test solution, then sealed with an anti-fluorescence quenching solvent, and subsequently inspected using a fluorescence microscope (Leica).Trypsinized ADSC were resuspended in fresh medium at a final concentration of 1 × 10t-tests, and for comparisons among different groups, we used either a one-way or two-way analysis of variance with Tukey’s post hoc test. The statistical significance was determined using GraphPad Prism 8 programme , with the statistically significant threshold set at P < 0.05 .Data are presented as the means±SDs. All experiments were conducted independently in triplicate. For comparisons between two groups, we used Student’s +-FITC, CD235a—PE; 2. CD105+-APC, CD45—FITC; and 3. CD73+-PE, CD31—APC. We accordingly detected no significant difference between untreated and MET-treated ADSC with respect to the proportions of CD90+/CD235a−, CD105+/CD45−, and CD73+/CD31− cells (Cell proliferation tests were performed to determine the appropriate MET concentration for examining the influence of MET on ADSC proliferation. The results indicated that a low MET concentration (0–1000 μM) had no appreciable influence on ADSC proliferation . On the 1− cells . Similar1− cells .in vitro revealed that ADSC-CM promoted tube formation in HUVECs, and MET significantly enhanced this effect in vitro , and 3-methyladenine (3-MA) (an autophagic inhibitor). The findings of an in vitro . Furtherin vitro . An ELISin vitro . Furtherin vitro .To ascertain whether VEGFa secretion contributes to the angiogenesis of HUVECs, a VEGFa antibody was used to neutralize the VEGFa released by ADSC. For this purpose, we used three treatment groups, namely, untreated ADSC-CM (ADSC group), MET-treated ADSC-CM (MET + ADSC group), and MET-treated ADSC-CM with 100 ng/ml VEGFa antibody (MET + ADSC + VEGFa ab group). The different ADSC-CMs were then collected to stimulate HUVECs, after which the HUVECs were collected for western blot and tube formation experiments. The number of tubes formed in the MET + ADSC group was higher than that in the MET + ADSC + VEGFa ab group . Moreovein vivo, we mixed Matrigel with different groups of ADSC-CMs. Matrigel mixed with human ADSC-CM was used as the control group, and as treatment groups, we used Matrigel mixed with untreated ADSC-CM (ADSC group) and Matrigel mixed with the MET-treated ADSC-CM (MET + ADSC group). A total of 200 µl of Matrigel solution was subcutaneously injected into the dorsal surface of mice (P < 0.01)   . In addi 0.0049) . These rAngiogenesis, stimulated by growth factors such as VEGFa, is an essential process for the healing of wounds. ADSC secrete VEGFa, which partially explains the phenomenon whereby the CM of stem cells can promote wound healing. However, given that the variable production of cytokines in ADSC-CM, the clinical application of this medium tends to be limited. To the best of our knowledge, this is the first study to demonstrate how MET enhances autophagy in ADSC, thereby increasing the expression and secretion of VEGFa. On the basis of these findings, we believe that the ADSC-CM derived from MET-treated ADSC may be an effective tool that could be applied to accelerate wound healing by promoting angiogenesis.et al., for example, reported that MET promotes the osteogenic differentiation of stem cells and reduces oxidative stress [et al. have demonstrated that MET can inhibit adipogenic differentiation by downregulating the expression of HSP60 [et al. [in vivo and in vitro. These findings indicate that MET promotes angiogenic capacity by increasing the secretion of VEGFa in ADSC.MET, the most widely prescribed drug for diabetes, has several effects on stem cells. Zhou e stress , whereasof HSP60 . Further [et al.  found thIn this study, we observed that the treatment of ADSC with MET contributed to an increase in the expression of the autophagy-related proteins Atg 5, LC3-II, and Beclin-1, which is consistent with the observed increase in expression of the angiogenesis-related proteins VEGFa and Ang II. In addition, the results of a tube formation assay performed using ELISA revealed that a larger number of tubes were generated in autophagy-enhanced ADSC-CM along with a higher VEGFa expression.et al. [We also found that low MET concentrations (0–1000 μM) had no significant influence on the proliferation of ADSC, which contrasts with previously reported findings  indicatiet al.  found thet al. . These fet al. [et al. [et al. also established that BMSC and MET can enhance cardiac function when used alone, although they detected no synergistic effect on heart protection when these were applied in combination. In addition, they found that MET-mediated AMPK activation led to the abnormal homing and low survival of BMSC in the hearts of diabetic patients [in vivo. We focussed primarily on changes in the secretory capacities of ADSC in response MET stimulation. In addition, it has previously been established that MET can promote cellular autophagy [By performing MSC transplantation for the treatment of myocardial infarction, He et al.  found th [et al.  found thpatients . The resutophagy . Our finutophagy . Howeverin vivo and in vitro, and we demonstrate that this process is mediated via MET-induced autophagy.In conclusion, our findings in this study revealed that ADSC pre-treated with MET are characterized by a more pronounced secretion of VEGFa and enhanced angiogenic capacity rbad043_Supplementary_DataClick here for additional data file.


Pull-out tests were conducted to investigate the effects of corrosion of both the longitudinal bars and stirrups on the bond slip behaviour of reinforced concrete specimens. The main experimental variables include concrete strength  and expected corrosion loss , with a total of 63 specimens fabricated. The results show that the relative bonding strength of specimens under different concrete strengths gradually decreases with increasing corrosion loss, but the higher the concrete strength is, the faster its degradation rate. The influence of stirrup corrosion on the peak slip can be ignored, but it will further aggravate the degradation of the bonding strength of the specimens. This reduction in bonding strength is linearly related to the stirrup corrosion loss. Based on the experimental results of this work and the achievements of other scholars, a modified relative bonding strength degradation model and a bond–slipbond–slip constitutive model of corroded reinforced concrete are presented by accounting for the influence coefficient of concrete strength. The results show that the constitutive model is in good agreement with the relevant experimental results. Reinforced concrete structures are widely used in modern engineering structures because of their high strength, excellent modulability, fire resistance and high-cost performance. Good bonding performance is necessary for steel bars and concrete to work together effectively. The corrosion of steel bars is an important reason for the loss of interface bonding capacity. Many scholars have conducted experimental studies on the bond slip behaviour of corroded reinforced concrete. On one hand, some studies have focused on exploring the bond slip behavior of new types of reinforced concrete, such as fiber-reinforced polymer composites, which can significantly extend the service life of concrete structures . Zhou etOn the other hand, some studies have focused on considering the change in bond slip behaviour under the coupling of various influencing factors. In early studies, the factors considered in models were relatively simple. Zhang et al. , based oMost of the previous studies were based on the corrosion of only the longitudinal reinforcement and rarely considered the effect of concrete strength on the bond–slip behaviour. However, in actual engineering, the longitudinal reinforcement and the stirrup corrode at the same time. Due to the thin concrete cover of the stirrup, the degree of corrosion of the stirrup is often more serious than that of the longitudinal reinforcement . In viewThe variables of this test are concrete strength grade , corrosion loss , and whether the stirrup is rusted, with a total of 21 groups of different working conditions. To obtain more accurate results, 3 specimens were prepared for each working condition, and a total of 63 specimens were poured. The parameters of the specific specimens are shown in The three strength grades of C25, C35 and C45 were prepared for testing. The cement was ordinary Portland cement, the fine aggregate was river sand with a maximum particle size of 3 mm, the coarse aggregate was gravel with a maximum particle size of 20 mm, and the water was tap water. The mix ratios of C25, C35 and C45 concrete were cement:sand:gravel:water = 1:1.68:3.93:0.52, 1:1.26:2.94:0.41 and 1:1.46:3.41:0.45, respectively. After the concrete was prepared, the specimens were poured and cured for 28 days; then, cube compressive strength testing was carried out. According to GB/T 50081, the cube compressive strengths of the three kinds of concrete were 26.7 MPa, 37.7 MPa and 45.2 MPa, respectively.2. The power supply was adjusted daily to ensure the stability of the current.Tian et al.  noted thThe principle of Faraday’s law is that the amount of charge transferred in the electrochemical reaction is equal to the number of electrons transferred in the corroded steel bar, so the charging time of the specimen was calculated according to Faraday’s law:The current needed to initiate the corrosion of each specimen was calculated to be 0.025 A, and the electrification times needed to reach the expected corrosion loss of 4%, 8% and 12% were 15.7 d, 31.5 d and 47.2 d, respectively.η is the corrosion loss of the longitudinal reinforcement, m1 is the mass of the steel bar after rust removal in the anchoring section (g).The corrosion loss of the longitudinal reinforcement can be calculated using Formula (2):The corrosion loss of the stirrup can be calculated using Formula (3):The pull-out testing was completed with an electrohydraulic servo universal testing machine with a measuring range of 1000 kN, and a force sensor with a measuring range of 400 kN was used to measure the pull-out force. Two displacement sensors with a measuring range of 25 mm were set at the loading end and the free end of the concrete. The loading rate of the test was 0.5 mm/min, and the end was marked by the stability of the pull-out force or the failure of the specimen. The test site is shown in s is the average slip value of the specimen, The slip value is expressed as the average of the displacement data of the free end and the loaded end:During the process of energized corrosion (rusting), most of the samples showed rust overflow, as shown in The pull-out test results of the A-series and M-series specimens are summarized in Lin et al.  proposedA formula for calculating the relative bonding strength considering the corrosion of longitudinal reinforcement is established above. However, stirrup corrosion is widespread in building structures in natural environments, so it is necessary to further study its influence. The results of the D-series pull-out tests are summarized in Based on the data of Zheng et al.  and Lin han 0.68  because n et al.  are insuThe revised relative bonding strength g et al. , as showIAE is used to quantify the accuracy of the two models. The smaller the IAE is, the better the predicted value of the model fits the actual value. The IAE can be obtained with Equation (14). The calculated IAE of the model in this paper is 0.08, and that of Equation (13) is 0.12. This is because the database on which this model is based not only includes references [Formulas (10) and (13) were used to calculate the relative bonding strengths of the corroded specimens described in this paper and in reference  in Figurferences , but alsIAE is the error index, Here, The bond–slip curve of the specimen obviously shows a rising section, falling section and a section in which the curve relatively slowly approaches a residual stress. In this paper, the piecewise constitutive model is used to describe the bond–slip behaviour of the specimen. In the constitutive model previously proposed in reference , the ascReference  points oTo verify the rationality of the constitutive model, several groups of corroded specimens were selected, and the test bond–slip curves and predicted curves are shown in (1)With increasing corrosion time, different degrees of pitting and regional corrosion of the longitudinal bars are observed. The corrosion of the inner stirrup of a specimen with both longitudinal bar and stirrup corrosion is generally more serious than that of the longitudinal reinforcement, and the distribution of surface cracks is more complex than that of a specimen with only longitudinal reinforcement corrosion, showing a pattern of interlacing cracks, and the phenomenon of rusting during the corrosion process is more serious.(2)Steel bar corrosion in a specimen will reduce the bonding strength of the specimen. The higher the concrete strength grade of the specimen is, the faster the bonding strength deteriorates with increasing corrosion loss. In addition, under the same longitudinal reinforcement corrosion loss, the bonding strength of the longitudinal reinforcement- and stirrup-corroded specimens is significantly lower than that of the longitudinal reinforcement-corroded specimens only. In severe cases, the bonding strength of the longitudinal reinforcement-corroded specimens is only 75% of that of the longitudinal reinforcement- and stirrup-corroded specimens. Moreover, the reduction effect caused by stirrup corrosion can change approximately linearly with stirrup corrosion loss.(3)Based on the experimental results and previous work, a relative bonding strength degradation model and a bond–slip constitutive model of corroded reinforced concrete are established, accounting for many factors, such as concrete strength and longitudinal bar and stirrup rust. The empirical formula of peak slip and the values of each parameter are given, and the constitutive model is in good agreement with the relevant experimental results.(4)The model proposed in this paper is only applicable to the case of steel bars that do not yield. In future research, the bond–slip constitutive model of corroded reinforced concrete under the yield state of steel bars could be explored.Three reinforced concrete specimens with concrete strengths of 26.7 MPa, 37.7 MPa and 45.2 MPa were tested, and the degradation of the bond–slip behaviour of corroded reinforced concrete was studied by conducting electrochemically accelerated corrosion tests and pull-out tests. The following conclusions were obtained:


Escherichia coli is a frequent aetiological agent of uncomplicated UTIs, causing 75% of cases, associated with recurrence of infection (40%) and a major source of bacteraemia (∼40%). Trimethoprim and nitrofurantoin are currently recommended as first-line antibiotics for the treatment of uncomplicated UTIs. However, 48700 deaths in Europe in 2019 have been associated with antimicrobial-resistant UTIs and resistance to trimethoprim in community-acquired UTIs caused by E. coli is high (33.4%). With little to no antimicrobial development in recent years, new strategies are therefore required to maintain efficacy in currently available antibiotics. One such strategy is to use evolutionary principles to understand how antimicrobial resistance (AMR) to one antibiotic can affect the activity and probability of resistance development to a second antibiotic. Effect on antimicrobial activity can be assessed through collateral susceptibility, where prior resistance to one antibiotic either increases or decreases susceptibility to a second, unrelated class of antibiotic. While the probability of resistance development can be assessed by the mutant selection window (MSW), an antibiotic concentration range where AMR mutations can be selected for. This ranges from the MIC (the lowest concentration to select for resistance) to the mutant prevention concentration . In this study, we aimed to determine the effect trimethoprim resistant derivatives of three clinical strains of uropathogenic E. coli on collateral susceptibility and MSWs to nitrofurantoin. We found that trimethoprim-resistant mutants conferred the expected decrease in susceptibility to trimethoprim and an increase in the MSW. This suggests prior selection with trimethoprim increases the probability of treatment failure and the selection of further mutations conferring high-level resistance to trimethoprim. We also observed collateral resistance to nitrofurantoin in the trimethoprim-resistant mutants. Importantly, however, there was a reduction in the MPC, and therefore a narrowing of the MSW, reducing the probability of selection of higher levels of nitrofurantoin resistance. This suggests that using nitrofurantoin after trimethoprim may reduce the probability of developing nitrofurantoin resistance compared with using nitrofurantoin first. These data provide a potential evidence base to use evolutionary principles when designing antimicrobial regimens to limit AMR development and improve treatment success.Urinary tract infections (UTIs) are a common infection in healthy adult women and as such account for 1%–3% of all medical consultations and the second most common reason for prescribing antimicrobials in the UK.


This article presents the results of a study of the physical and mechanical properties of fine-grained fly ash concrete based on a combined reinforcement with steel and basalt fibers. The main studies were conducted using mathematical planning of experiments, which allowed the experiments to be algorithmized in terms of both the amount of experimental work and statistical requirements. Quantitative dependences characterizing the effect of the content of cement, fly ash binder, steel, and basalt fiber on the compressive strength and tensile splitting strength of fiber-reinforced concrete were obtained. It has been shown that the use of fiber can increase the efficiency factor of dispersed reinforcement (the tensile splitting strength to compressive strength ratio). To increase the resistance of basalt fiber, it is proposed to use fly ash in cement systems, which reduces the amount of free lime in the hydrating cement environment. An increase in concrete strength leads to increased fragility and deterioration of the deformation properties. This concrete is characterized by almost immediate destruction under short- and long-term loads when it reaches its ultimate stresses ,2,3,4. ODispersed reinforced concrete, or fiber concrete, is a group of composite materials that include short lengths of various fibers in a cement matrix. Different types of materials, such as steel, glass, synthetic materials, carbon, etc., can be used as fiber ,12,13,14The most popular are Portland cement steel fiber-reinforced concrete. This type of fiber can have a different cross-sectional profile, size, and surface ,16,17,18Due to its higher crack resistance, steel fiber concrete is characterized by an increase in frost and heat resistance by 1.5 to 2 times. Important indicators of steel fiber concrete are increased resistance to abrasion, impact and dynamic resistance, and shrinkage .Several authors have shown ,27,28 thAt the same time, an important problem with the use of steel fiber in concrete is the possibility of the formation of so-called “hedgehogs”, increased “clumping” in the concrete structure, and uneven distribution of fiber, which requires the use of special devices to evenly add fiber to the concrete mixture.Although steel fiber is used to improve the mechanical properties of concrete, it is still susceptible to corrosion , and itsOne of the most effective types of mineral fibers for dispersed concrete reinforcement is basalt fiber . It is c3, the increase in compressive and flexural strength at the age of 28 days is 25% and 84% higher compared to concrete without fiber. An appropriate fiber content can optimize the internal microstructure of concrete, but an excessive fiber content will lead to agglomeration, causing a decrease in strength.The results of many studies show that basalt fiber has a small effect on the compressive strength of concrete, but there is a significant increase in the tensile splitting strength . With a The authors ,38 note Conflicting results have been reported in the literature on the effect of basalt fiber on the compressive strength of concrete. Li et al.  noted thHowever, basalt fiber has a significant disadvantage. In the alkaline environment of hardening Portland cement, the fiber surface is destroyed by the formation of shells . In thisAn important area of concrete research and development is minimizing the use of cement by partially replacing it with various active mineral additives, including those obtained from production waste. Many production wastes have been sufficiently studied to be used as structural components of binders and concretes, which also helps to solve the environmental problem and accompanies a reduction in the cost of concrete and mortars.Fly ash is one of the most common mineral fillers, the effectiveness of which has been confirmed by practical experience ,46. Ther2, which is released during the hydrolysis of cement clinker minerals. Due to the pozzolanic activity, the addition of fly ash to cement–water systems not only increases the volume of hydrate formation but also accelerates the hydrolysis process and increases the degree of cement hydration, which ultimately has a positive effect on the strength of cement stone [Fly ash, due to its aluminosilicate phase, has pozzolanic activity and chemically interacts with Ca(OH)nt stone ,47.2 formed in fly ash concrete and mortars as a result of the hydration of C3S and C2S is lower compared to mixtures without fly ash, since Ca(OH)2 together with silicates contained in fly ash form calcium hydrosilicates. Additionally, the amount of ettringite decreases as a result of a decrease in the concentration of Ca(OH)2 in hardening concrete [Fly ash contributes to the sulfate resistance of cement concrete in the same way as other active mineral additives. This can be explained by the fact that the content of the Ca(OH)concrete . Paper [concrete  reports The study of the properties of concrete and concrete mixtures using combined reinforcement is also reported in several works ,50. ConcThe study of the properties of concrete and concrete mixtures using steel and basalt fibers is reported in several papers. This concrete has improved physical and mechanical characteristics. However, there is a significant disadvantage to using basalt fiber in concrete. In the alkaline environment of Portland cement curing, the fiber surface is destroyed, leading to the formation of defects. In this regard, as shown in this study, when reinforcing concrete with basalt fiber, it is necessary to use additives that bind CaO  and consequently reduce the alkalinity of the curing environment. Therefore, to achieve superior physical and mechanical properties of concrete, it is recommended to study fine-grained fly ash concrete based on combined reinforcement with steel and basalt fibers.3S—57.10%; C2S—21.27%; C3A—6.87%; C4AF—12.19% (EN 196-2). The specific surface area of Portland cement SCem = 300–320 m2/kg (EN 196-6). The chemical composition of Portland cement  is shown in Portland cement CEM I 42.5R from the “Dyckerhoff” Wiesbaden, Germany, cement plant in Ukraine. Mineralogical composition of clinker: CA = 250–280 m2/kg (EN 196-6). The chemical composition of the fly ash is shown in Fly ash from “Burshtyn” TPP , which is a type II category B ash with a 45 μm sieve particle size of no more than 25% (class 2) (EN 450-1:2012). The specific surface area of the fly ash SQuartz sand with a fineness modulus FM = 2.05. Dust and clay particle content up to 1.5% (EN 12620+A1); particle size distribution of sand is shown in Granite aggregate of a 2–5.6 mm fraction. Dust and clay particle content up to 0.5% (EN 12620+A1);Polycarboxylate superplasticizer with 30% water reduction effect (EN 934-2);Steel fiber (StF) with a wavy shape. The standard tensile strength is 1350 MPa (EN 14889-1). Fiber dimensions: length—60.0 ± 5.0 mm; thickness—1.0 ± 0.1 mm, wave width—6.0 ± 0.1 mm. A photo of the steel fiber is shown in Basalt fiber (BF). Fiber dimensions: length—24 mm, diameter—16 µm. Tensile strength 2800 MPa and elastic modulus 85 GPa. A photo of the basalt fiber is shown in The materials used for the study of fine-grained fly ash concrete based on combined reinforcement with steel and basalt fibers were:In the study of fine-grained fly ash concrete based on combined reinforcement, physical and mechanical research methods, and methods of mathematical planning of experiments were combined. In the course of research to evaluate the effect of fly ash, steel, and basalt fiber on the properties of concrete mixtures and concrete, standard cubes (10 × 10 × 10 cm) and prisms (10 × 10 × 40 cm) were made, which were cured under normal conditions (EN 12390-2). The flowability of the concrete mixture was tested immediately after mixing all components using the fall cone method according to EN 12350-2. The compressive strength was tested on 4 specimens at 7 and 28 days of age (EN 12390-3), and the tensile splitting strength on 3 specimens at 7 and 28 days of age (EN 12390-6). The main studies were conducted using mathematical planning of experiments , which aThe theory of experiment planning is based on probabilistic and statistical methods that allow for a theoretically grounded determination of the minimum number and composition of experiments, as well as the order of their conduct, to obtain quantitative dependencies between the parameter under study and the factors affecting it.y is the optimization parameter, that is, the output parameter of the system, and iX are the variable factors of the same system.The task of planning mathematical experiments is to get an idea of the response surface of the factors , which can be analytically represented as a function:X1, X2, …, kX are independent variables (factors) that can be varied in the experiments; β0, iβ, ijβ, iiβ are theoretical regression coefficients.The most convenient way is to represent the unknown function as a polynomial:n rows and m columns, which contains a set of combinations of factors varied relative to some origin or zero (baseline) level. The allowable area of variation of factors (factor space) is selected on the basis of a preliminary study of the object in accordance with the purpose. To simplify the recording of experimental conditions and processing of experimental data, the upper level of factors is coded +1, the lower level −1, and the main level corresponds to 0.The experiment was planned according to a typical matrix, that is, a table with ib-regression coefficients was evaluated by finding the experimental value of the t-test (it) and comparing it with the tabulated value. The regression equations, being quadratic in nature, allow one to trace the individual and joint influence of factors on the studied output parameters to establish the necessary and optimal values of the factors.To build quadratic models, a full factorial experiment was used, which provides all possible combinations of factors at three levels. For the technological analysis and selection of significant factors, along with checking the adequacy of the equation, the significance of the regression coefficients was also assessed. The significance of the k factors.The results of the experiments were processed using mathematical statistics methods, obtaining, in general, quadratic regression equations for B3 was implemented [In order to study the influence of composition factors on the strength characteristics of fine-grained fly ash fiber concrete as well as establish optimal parameters for the manufacture of such concrete, the main studies were performed using mathematical planning of experiments. For this purpose, a three-level, three-factor plan lemented , the plaThe cement–ash binder was obtained by thoroughly mixing Portland cement with fly ash in an amount of 30% by weight of the binder. To reduce the water consumption of the mixture, a polycarboxylate-type superplasticizer was added in an amount of 0.7% by weight of the binder (Portland cement + fly ash). The choice of fiber content was based on the optimal amount of fiber, according to previous studies and a review of the literature .The flowability of the mixtures at all points of the plan was constant and amounted to 12–15 cm, according to the slump of a standard Abrams cone. For this purpose, the amount of water was determined separately for each mixture. The matrix for the planning of experiments and compositions of fly ash concrete mixtures is given in After processing and statistical analysis of the experimental results obtained, experimental and statistical models of the compressive and tensile strengths of fine-grained fly ash-containing, fiber-reinforced concrete were constructed, which are given in X1 >> X2 >> X3 and X2 > X3 > X1, respectively.Analysis of constructed models (3–6) confirms that the most significant effect on compressive strength is exerted by the cement–ash binder content, which in turn is associated with the water–binder ratio, and on tensile splitting strength, by dispersed reinforcement. According to the significance of the influence of variable factors on the compressive and tensile splitting strength of concrete, they can be organized in the following descending order: It should be noted that, In order to achieve the required flowability, concrete mixtures require more water to mix with an increase in fiber content. The decrease in concrete plasticity is explained by the larger surface area, which requires more cement paste, while the effect of basalt fiber is more significant.Based on experimental and statistical models, graphical dependences of compressive strength  and tens3 to B = 600 kg/m3, led to an increase in strength of 35–45% at 7 days and 30–40% at 28 days, respectively. This is mainly due to a decrease in the water binding ratio from W/B = 0.38–0.4 to W/B = 0.21–0.24. An increase in steel fiber content within a variable range in a constant water–binder ratio increased compressive strength by 12–16%. The effect was more significant in the absence of basalt fiber and binder volume consumption of up to 500 kg/m3. In turn, the effect of basalt fiber at a rate of up to 2 kg/m3 did not lead to an increase in compressive strength as occurred at the ages of 7 and 28 days. Further increasing the basalt fiber content to 4 kg/m3 yielded a slight increase in compressive strength of up to 10%. As in the case of steel fiber, it is more significant with minimal use of another type of fiber and binder consumption.The analysis of the results and the graphical dependencies  allowed 3 to 120 kg/m3 and basalt fiber to 4 kg/m3 led to an increase in tensile splitting strength at 7 days from 8.2–10.5 Mpa to 13.1–15.2 Mpa, depending on the variation of other factors within the experimental plan.The effect of dispersed reinforcement on tensile splitting strength was somewhat different and had a more significant impact . IncreasX1 with X2 and X2 with X3 was also observed. It should be noted that the positive effect of increasing the fiber content of both types gradually faded as the content approached maximum within the range of variation. This allowed us to assert the so-called optimum zone (the extremes of the graphs), which is in the range of 80 to 100 kg and 2 to 3 kg for steel and basalt fiber, respectively. Under these conditions, the tensile splitting strength reaches 15–17 Mpa at the minimum binder consumption and 17–20 Mpa at the maximum binder consumption.At the same time, the effect on tensile splitting strength at the age of 28 days was somewhat different, whereby, along with the fiber content , the cement–ash binder content had a significant impact. The influence of the interaction of factors The results obtained indicate that an increase in fiber content in the entire range of variation leads to an increase in the tensile splitting strength at all curing times and has an extreme character. This indicates a certain optimal consumption of steel fiber (80 to 100 kg) in a composition with basalt fiber (2 to 3 kg), which would ensure the achievement of a maximum tensile splitting strength of 18 to 21 Mpa.The increase in strength is explained by the increased resistance to the development of microcracks present in the concrete matrix b,d due tThus, as a result of experimental studies, it was established that fine-grained fly ash concrete is possible using steel and basalt fiber characterized by a compressive strength of more than 80 Mpa and a tensile splitting strength of more than 17 Mpa. Combined concrete reinforcement increases the strength of concrete, especially the tensile splitting strength, which can be explained by the improvement of the concrete pore structure.Given that there is no protective layer on the dispersed reinforcement, the corrosion resistance of fibers in fiber-reinforced concrete is determined mainly by the crack resistance and protective properties of the concrete itself, including permeability, which depend on its pore structure. Improvement in the pore structure and increased crack resistance are more evident when using a finely dispersed basalt fiber.2O3 and SiO2, crystals of calcium hydrosulfoaluminate 3CaO·AI2O3·3CaSO4·32H2O were formed on the surface of sand particles  [c.tnf/c.mf from 0.17 to 0.23 and from 0.24 to 0.31 was caused by an increase in the content of fiber, both basalt and steel, at a binder consumption of 400 kg and 600 kg, respectively. However, this tendency was observed at the optimal fiber content. For steel fiber, this is 80–120 kg/m3, and for basalt fiber, 2–4 kg/m3. This parameter increases significantly with minimum consumption of ash-containing binder in the studied area of variation of the given factor.The deformability of concrete is closely related to its crack resistance. Various criteria have been proposed to characterize the deformability of concrete. One of the simplest is the ratio of tensile splitting, or flexural strength to compressive strength (tn/fc.m) ,41. ThisIt should be noted that unreinforced, fine-grained concrete samples had a brittle fracture pattern. Fiber-reinforced concrete specimens fractured differently, as evidenced by the nature of their destruction. This observation shows that even after crack formation, the fiber-reinforced concrete sample had the ability to carry a certain load. This is due to the fact that some of the fibers did not break at the crack but in the concrete matrix and, after that, were pulled out of the concrete. In addition, there were some fibers anchored on one side of the crack to a small depth. Such fibers were also not cut off but were pulled out of the matrix. The effect described above was enhanced by an increase in the volume content of fiber.Based on the analysis of a complex of experimental and statistical models of the strength parameters of efficient fly ash concrete using steel and basalt fiber, the effectiveness of its application for fine-grained concrete has been determined. Quantitative dependences characterizing the effect of the content of the ash-containing binder, steel, and basalt fiber on the tensile splitting strength and compressive strength of fiber-reinforced concrete were obtained.An increase in fiber content over the entire range of variation leads to an increase in tensile splitting strength at all curing times and has an extreme character, indicating a certain optimal consumption of steel fiber (80–100 kg) in a composition with basalt fiber (2–3 kg), which would ensure the achievement of a maximum tensile splitting strength of 18–21 MPa. The strength at 28 days of the efficient, fine-grained fly ash fiber concrete obtained is within the characteristic limits of high-strength concrete and amounts to 83–98 MPa in compressive strength.The use of fine-grained concrete on the fiber types studied has been shown to increase the efficiency factor of dispersed reinforcement (the ratio of tensile splitting strength to compressive strength) from 0.15–0.2 to 0.23–0.31.The replacement of Portland cement with fly ash leads to a slight decrease in compressive and tensile splitting strength, but the addition of composite reinforcement makes it possible to eliminate this deficiency and increase strength properties.To increase the resistance of basalt fiber in cement systems, it is effective to use fly ash, which reduces the amount of free lime in the hydrating cement environment.


Nitrofurantoin (NF), a wide-spectrum antibiotic accessible since 1953, is utilized widely to treat urinary tract infections as it usually stays active against drug-resistant uropathogen. The use of Nitrofurantoin has increased exponentially since new guidelines have repositioned it as first-line therapy for uncomplicated lower urinary tract infection (UTI). To, although fluoroquinolones are usually used to re-evaluate the first- and second-line therapies for treating uncomplicated UTI, their level of utilization is thought to be inappropriately excessive and will eventually have a detrimental impact; thus, we hypothesize that NF might be the best choice for this condition, because of its low frequency of utilization and its high susceptibility in common UTI pathogens. It can be concluded from this review that NF can be considered as the most effective drug in the treatment of acute urinary infection, but due to the long-term side effects of this drug, especially in elderly patients, it is essential to introduce some criteria for prescribing NF in cases of chronic UTI. NF is o2®  Capsules Product Information. Cincinnati, OH, USA: Procter & Gamble Pharmaceuticals, 2009; 1–12.)  Figure 1; 1–12.) . Table ; 1–12.) .3Most absorption of NF is done in the duodenum, so the presence of food in GI tract leads to an increase in the time of gastric emptying. Therefore, more NF dissolves in gastric juice before it reaches the duodenum .The dissolution time hypothesis is supported by the results of Naggar and Khalil, who showed that absorption increased when the solubility of NF was increased by the addition of Mg2O8Si3 .4UTI is one of the most common bacterial infections and has two complicated and uncomplicated forms which are differentiated by symptoms and causative agents Figure 2The uncomplicated form of UTI is often caused by uropathogenic Escherichia coli (UPEC) strains in 80% of cases , followeConventional antibiotic therapy for acute uncomplicated UTI includes trimethoprim-sulfamethoxazole, Cefpodoxime, Cephalexin and Cefuroxime, Ciprofloxacin, Cefepime, Ampicillin, Imipenem/Cilastatin and Trimethoprim-Sulfamethoxazole are suitable choices for acute complicated form . The emeTwenty-seven trials consisting of 4807 patients have been conducted to analyze NF as a remedy for UTIs. NF was determined to be clinically and microbiologically effective, with clinical cure rates between 79% to 92% and microbiological eradication rates of 80%–92%.5In addition to the greatest effect on uropathogens, NF has an inhibitory effect on a wide range of Gram-positive bacteria such as Staphylococcus and Enterococcus and Gram-negative bacteria such as Klebsiella and Citrobacter . It seem6Following the activation of the nitro group in its molecular structure by the cytochrome P450 reductase Figure 3E. coli which attributed to the presence of a mutation in the gene coding for nitrofurantoin (nfsA), an oxygen-insensitive enzyme. This mutation prevents the reduction of NF and the subsequent production of toxic compounds , Amoxicillin (76%), Tetracycline (71%), Trimethoprim-Sulfamethoxazole (64%), Cephalexin (61%) and Cephalothin (60%), respectively. Also, this strain has the highest antibiotic sensitivity to Imipenem (86%), NF (82%), Amikacin (79%) and Ciprofloxacin (72%) . Accordi7Antibiotic resistance is considered as one of the possible side effects of any antimicrobial agents. This issue has been reported in long-term prophylaxis cases for UTI and elderly patients with renal failure. Generally, NF is considered as a safe antimicrobial drug, but, in 1 per 100,000 patients  in long-in vitro studies, long-term consumption of NF damages DNA by inhibiting DNA synthetase and chromosomal mutations. Moreover, Tumorigenicity of NF has not yet been precisely proven, but there is no doubt that NF has the ability to produce toxic metabolites (According to abolites . Further7.1Drug-induced liver injury (DILI) can result in an acute or chronic hepatitis-like syndrome. The acute form is usually associated with 1 to 2 weeks of NF treatment and is rare . Acute liver injury usually occurs within weeks of starting treatment with NF and may occur within weeks of completing a defined course of treatment. The more common form of hepatotoxicity is due to chronic prophylactic use, occurring in 1 in 1,500 people . A wide 7.2Drug-induced fevers are independent-infection conditions which are classified as the miscellaneous group and may induce fever which is known as fever of unknown origin (FUO). FUO is characterized as temperatures higher than 38.3°C which will elapse more than two weeks after they appear . Accordi8As shown in 9As shown in 10in vitro than the sum of each drug ]. There is growing evidence that the use of these substances enhances the antibacterial properties of conventional antibiotics, repurposing them instead of replacing them . CombinaGenerally, understanding the mechanism of action of antibiotics, AgNPs, plants and combined treatments allows predicting more feasible treatments or designing new ones more efficiently. Even if some aspects of the mechanism of action remain unknown, these results provide a more effective way to fight infectious diseases .11In this review, our goal was to obtain a comprehensive picture by considering the clinical use of nitrofurantoin and its adverse effects to inform physicians to manage UTI patients under long-term nitrofurantoin therapy. Nitrofurantoin should not be recommended for long-term prophylaxis in patients with UTI, especially elderly patients. The intention is not to discard nitrofurantoin prescription, but urologists must use nitrofurantoin as the most effective drug on acute UTI. Therefore, a series of supervisions and criteria regarding the prescription of nitrofurantoin in cases of chronic UTI are needed.AD and RG conceived, designed and supervised the study. AD and MM contributed to data collection, interpretation and final approval of data for the work. SD and FG developed the first and final draft of the manuscript. SS and PK developed the second draft of the manuscript. All figures and tables were designed and checked by MM, EB and TD. All authors reviewed and contributed to the revisions and finalized the drafts.