Short-term readmission for pediatric pulmonary hypertension (PH) is associated with a substantial social and personal burden. However, tools to predict individualized readmission risk are lacking. This study aimed to develop machine learning models to predict 30-day unplanned readmission in children with PH.This study collected data on pediatric inpatients with PH from the Chongqing Medical University Medical Data Platform from January 2012 to January 2019. Key clinical variables were selected by the least absolute shrinkage and the selection operator. Prediction models were selected from 15 machine learning algorithms with excellent performance, which was evaluated by area under the operating characteristic curve (AUC). The outcome of the predictive model was interpreted by SHapley Additive exPlanations (SHAP).CI: 0.77–0.86), high accuracy for 0.74 (95% CI: 0.72–0.76), sensitivity 0.78 (95% CI: 0.69–0.87), and specificity 0.74 (95% CI: 0.72–0.76). Age, length of stay (LOS), congenital heart surgery, and nonmedical order discharge showed the greatest impact on 30-day readmission in pediatric PH, according to SHAP results.A total of 5,913 pediatric patients with PH were included in the final cohort. The CatBoost model was selected as the predictive model with the greatest AUC for 0.81 (95% This study developed a CatBoost model to predict the risk of unplanned 30-day readmission in pediatric patients with PH, which showed more significant performance compared with traditional logistic regression. We found that age, LOS, congenital heart surgery, and nonmedical order discharge were important factors for 30-day readmission in pediatric PH. Pediatric pulmonary hypertension (PH) is a severe and fatal disease characterized by pulmonary vascular remodeling, which increases pulmonary arterial pressure, and is often associated with high mortality, causing a substantial burden on individuals and society –3. UnplaThere have been some reports of this problem. Some researchers have proposed that the 30-day readmission rate for pediatric PH may be related to several risk factors, such as age, female gender, congenital heart disease, public insurance, use of inhaled nitric oxide, invasive mechanical ventilation, and the number of PH admissions , 8. HoweIn this study, we aimed to develop prediction models and evaluate the risk factors and causes associated with readmission within 30 days for pediatric PH using ML algorithms. This will allow us to clinically target pediatric patients with PH to reduce readmission rates and improve healthcare quality.We retrospectively collected de-identified electronic health record (EHR) data from inpatients at the Chongqing Medical University Medical Data Platform from seven hospitals in Chongqing, China. Pediatric patients (<18 years old) diagnosed with PH according to the International Statistical Classification of Diseases and Related Health Problems, 10th versions (ICD-10) code corresponding to a diagnosis of PH , and discharged between 1 January 2012 and 1 January 2019, were included in this study cohort. The diagnosis of PH was based on clinical findings with echocardiographic confirmation. The first admission and readmission were included when a patient had multiple admissions. Patients who died during admission or were transferred to another hospital or whose discharge status was uncertain were excluded from this study. The present study was approved by the Ethics Committee of Chongqing Medical University. Due to the retrospective observational design, the requirement for informed consent was eliminated. The primary outcome of this study was all-cause unplanned 30-day readmission. The study was reported in accordance with the recommendations of the Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis (TRIPOD) statement , 14.A total of 32 variables associated with readmission were collected according to relevant studies and clinical availability , 15, incIn this study, binary categorical features were encoded as 0 and 1. For instance, the gender of patients was encoded as 0 or 1 . Features related to clinical conditions, such as comorbidities, procedures, and medications, were encoded as 0 or 1 . The primary outcome variable was encoded as 0 or 1 .The least absolute shrinkage and selection operator (LASSO) was applied to identify impactful clinical variables to remove irrelevant and redundant information and improve the discriminative power of ML models . The LASThe entire research process was completed independently by two researchers (MJ Duan and XZ Liu), the final results were checked, and disagreements were discussed with a third researcher (TT Shu) to reach a consensus.This study randomly divided the dataset into a training set (with 70% objects) and a validation set (with 30% objects) by stratified random sampling. The former was used to develop ML models and the latter was used to evaluate the prediction performance of models.This study compared the performance of 15 ML algorithms without hyper-parameters optimization to screen the candidate algorithms for 30-day readmission prediction models. The top four algorithms with excellent performance would be selected according to the accuracy and the area under the receiver operating characteristic (ROC) curve (AUC). In this study, Logistic Regression (LR) was selected as a comparison to the traditional statistical model. The screening process was conducted using the PyCaret package (version 2.3.3), an open-source and low-code ML library in Python.This study constructed five predictive models based on the training set and tuned models with the Bayesian optimization algorithm to select the optimal hyper-parameter configuration. The Bayesian optimization algorithm, an efficient constrained global optimization tool, was performed with the functions of the Bayes_opt Python package (version 1.2.0) and the 10-fold cross-validation method –20. DuriThis study compared the discriminant power among different models calculated in an independent validation set through AUC. Accuracy, sensitivity, and specificity were also calculated. SHapley Additive exPlanations (SHAP) was applied through a SHAP python package (version 0.39.0) to interpret the models to mitigate the black-box nature of ML and help clinicians understand the results provided by models . The impCI), also with the first quartile (Q1) and the third quartile (Q3). Continuous variables with normal distribution were analyzed by Student's t-test and continuous variables with skewed distribution by the Mann–Whitney U-test. A two-sided p < 0.05 was considered to be statistically significant. Statistical analyses were performed with an open-source Scipy python package (version 1.7.1)  and median with 95% confidence interval (n 1.7.1) .Of 6,016 pediatric inpatients diagnosed with PH, 103 patients were excluded due to death, transfer to other hospitals, and uncertain discharge during initial admission. A total of 5,913 pediatric patients with PH were included in the final cohort and divided into a training set with 4,139 patients for model building and a validation set with 1,774 patients for testing. The selection flow chart is shown in The results of 15 algorithms are exhibited in In this study, 12 features with non-zero regression coefficients were selected to construct predictive models through LASSO feature selection analysis shown in CI: 0.7662–0.8551). The AUC of XGBoost model was 0.8067 (95% CI: 0.7657–0.8465), the LightGBM model 0.7992 (95% CI: 0.7560–0.8407), the Random Forest model 0.7817 (95% CI: 0.7335–0.8277), and the LR model 0.7248 (95% CI: 0.6765–0.7723), respectively. This study calculated the accuracy, sensitivity, and specificity of the selected models to evaluate the performance of the models comprehensively, as shown in CI: 0.7198–0.7604), sensitivity 0.7813 (95% CI: 0.6907–0.8660), and specificity 0.7378 (95% CI: 0.7167–0.7585). The hyperparameter search domain and final setting of the CatBoost model are listed in The ROC curves of five constructed models are shown in Feature importance rankings of four prediction models are shown in This study analyzed the independent validation set in the CatBoost model through the Tree-Explainer class imported from the SHAP package, shown in This study displayed two individual samples with prediction and explanation computed by the force plot method of the SHAP package in Previous studies have shown that unplanned readmission of pediatric PH within a short term is potentially preventable . PreventThe present study was the first research to develop a risk stratification model with ML for predicting and explaining the unplanned 30-day readmission in pediatric patients with PH based on the EHRs data collected from a database in Chongqing, China. From the five ML models developed and validated based on 12 relevant clinical variables, the CatBoost model showed the best performance and identified factors strongly associated with unplanned 30-day readmission, such as age, LOS, congenital heart surgery, and nonmedical order discharge in pediatric patients with PH.The prominent etiological type in pediatric patients with PH is CHD, which causes clinical presentation, and outcomes in children differ from those in adults . A previWith advanced medical informatics, ML has become a promising tool for predicting the outcomes of patients. However, the nature of the ML, black box, hinders its application in clinical practice . TranspaThe present study found that decision tree-based gradient boosting ensemble models showed better performance than the traditional logistic regression. For the validation set, although both the CatBoost model and the XGBoost model showed comparable performance, we choose the CatBoost model as our final prediction model due to the following reasons. One important advantage of CatBoost algorithms is that they handle categorical features automatically . AnotherCI. This can be explained by a low representation of patients in this age range in the total validation set (3.5%).Subgroup analysis in this study demonstrated that the CatBoost model performance was comparable in male and female patients. The model prediction power measured by AUC in groups of 0–6 years was consistent with the performance in the total validation set. However, the model did not show a reliable predictive performance in groups of 6–18 years, which was indicated by the high AUC and sensitivity with uncalculated 95% The present study has several limitations. First, the data used in this study are a small-scale dataset collected from the electronic medical records of local hospitals in Chongqing, China, and each hospital was populated with data to varying degrees. This resulted in significantly missing data for some of the extracted clinical features. Second, for the included pediatrics, the diagnosis of PH was based on echocardiography. That is not the golden and definite diagnosis of PH and may weaken the results. Since we could not derive pictures from the Chongqing Medical University Medical Data Platform, this study lacked some key echocardiographic parameters, such as pulmonary artery systolic pressure. Therefore, these effect indicators were not included in the outcomes of our research. However, the inclusion information was based on discharge diagnosis, so this factor did not affect the overall analysis. Third, the variables included in this study were mainly comorbidities. To ensure the performance of the prediction model and the convenience for clinical application, the objective results, such as vital signs, laboratory tests, and auxiliary examination of patients at admission or discharge were not included as variables for the construction of the model, which may also have important implications for the prognosis of patients. Then, this model was not applied in clinical practice, thus, prospective and external validation was required to further confirm the generalization ability of this model.This study developed a CatBoost model to predict the risk of unplanned 30-day readmission in pediatric patients with PH, which showed more significant performance compared with traditional logistic regression. We found that age, LOS, congenital heart surgery, and nonmedical order discharge were important factors for 30-day readmission in pediatric PH. This study has laid a foundation for further research to improve the accuracy of predicting readmission risk.http://www.xiaozhuliu2021@163.com.The data analyzed in this study is subject to the following licenses/restrictions: due to ethics committee regulations, the dataset supporting the findings of this study is limited and not public. Requests to access these datasets should be directed to XL, The data involving human participants in this study were reviewed and approved by the Ethics Committee of Chongqing Medical University. Written informed consent for participation was not required for this study following the national legislation and the institutional requirements.XL and ZX is the corresponding author who contributed to the conception of the study. MD and BZ performed the model development and drafted the manuscript. TS contributed to manuscript preparation and constructive discussions. TX, HH, and YZ contributed to the collection of data. PX, BZ, and JW contributed in reviewing the manuscript. All authors have read and approved the final manuscript.This study was supported by the Intelligent Medicine Research Project of Chongqing Medical University (Nos. ZHYX2019013 and YJSZHYX202119) and Chongqing Postdoctoral Program (No. 2010010006118105).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The present work established that semi-empirical models accurately predict the output responses in the AWJM of armor steel.Rolled homogeneous armor steel (RHA) with a high tensile strength, toughness, and hardness is often used in military combat vehicles. RHA is a high-strength low alloy steel suitable for all battlefield usage in military vehicles. The present work examines the prediction output responses in the material removal rate (MRR), surface roughness (Ra), and kerf angle (Ka) for the AWJM of armor steel using regression and semi-empirical models. The AWJM trials were performed using an L27 factorial design with each process variable set to three levels, namely, the standoff distance (SOD), jet traversing speed (JT), and jet water pressure (P). A regression model was constructed using the response surface method (RSM) and data from the trials. Through dimensional analysis and with Buckingham’s π-theorem, a semi-empirical model was built using both the experimental data and material property data. Predictions made by the models were proportionate with the results of the experiments under the same conditions. Microscopic investigations on MRR and Ra were performed using a scanning electron microscope (SEM). The optimal values of the output responses of the machined armor steel plate were obtained with higher MRR = 298.92 mm Rolled homogeneous armor (RHA) is often utilized in many armor applications ,2. BecauThe abrasive striking angle and mechanical characteristics of the target material have been critical to the development of each of these mechanisms. AWJM is gaining acceptance as a standard cutting tool in industries such as nuclear, oil, foundry, automotive, aerospace, and construction. This method may be used in conjunction with wire electric discharge machining, plasma flame, and laser cutting. Compared to plasma and laser machining, the cost of AWJM is typically one-quarter that of wire EDM, and it can cut thicker plates with superior dimensional precision ,12. UthaWang  conducteProfile cutting in armor steels is now conducted by fame-cutting. This method generates a large heat affect zone (HAZ) and poor surface quality, which require yet another operation. However, AWJM overcomes these drawbacks and produces minimal distortion in the work material. AWJM provides the following benefits over other conventional machining processes: no heat deformation; good cutting flexibility; and good surface quality. The suggested work may be developed further using this as a starting point. In this study, Buckingham’s The experimental setup used in this work is shown in AWJM trials were carried out on armor steel using M/s. DADRI International makes the DWJ FB-1313 machining center. Throughout the cutting process, the parameters of jet impact angle (90°), garnet abrasive size (80 mesh), nozzle diameter (0.67 mm), and orifice diameter (0.25 mm) were maintained at constant. On the basis of the literature and initial experiments, the AWJM input parameters and their ranges were chosen. AWJM was used to cut a 20 mm straight linear single pass on the armor steel plate. The process parameters were varied at three levels: . The full factorial design was considered to conduct the experiments.tw) and bottom kerf widths (Kbw). Equation (2) was used to calculate the performance parameter kerf angle (Ka).tw + Kbw)/2], Ktw = top kerf width, Kbw = bottom kerf width.The armor steel material is mainly used in battlefield tank body structures and various combat applications in the defense industry. The chemical composition of armor steel consists of various elements . Work on developing semi-empirical models for considering responses was expanded in this study. In this study, four quality requirements were chosen that significantly impact the machining of the material using the AWJM technique. The MRR for abrasive waterjet cutting depends on the penetration depth, kerf width, and JT. It was also observed that the MRR was affected only by the abrasive phase’s power, and not by the water phase. Equation (1) was used to find out the MRR. The kerf characteristics were measured using ImageJ software to find the top kerf widths .tw, and kerf angle. These models were constructed using dimensional analysis and were based on appropriate process parameters such as P, JT, and SOD in the AWJM process. The performance characteristics evaluated in this study are expected to vary depending on the machining parameters used and the material and thermal properties of the workpiece. Dimensional analysis is a technique used to gather a specific set of data on a certain occurrence. A full set of dimensionless parameters may be obtained after the dimensional analysis. The dimensional analysis method is mostly used to make a physical problem easier to solve by cutting down on the number of factors. This may not significantly affect the current problem. Buckingham’s aa = quadratic co-efficient; Aab = interaction co-efficient; The regression analysis method includes experiments, mathematical tools, and statistical analysis. The present investigation’s experimental results given in The machining process parameters and the physical and thermal characteristics of the workpiece material were taken into account while creating the models. According to Equation (7), the MRR performance was calculated. The dimensional analysis was used to determine the relationship between the performance measure MRR and the parameters.The “n” variables are represented as (n − p) non-dimensional groups of the variables, referred to as “π” groups using this approach. This dimensional analysis method is based on Buckingham’s π-theorem. Mass (M), length (L), time (T), and temperature  may be rewritten as Equation (9). The details of the calculated terms are as follows:1, b1, c1, d1 with a, b, c, d; rearranging and rewriting the above phrase as a consequence, the following expression is generated.By replacing aAccording to the power indices on both sides, the dimensionless coefficients are shown in the following way:Thus, Equation (10) is developed by replacing the calculated value of the power index of the Similarly, the values of the following π terms are calculated using the same techniques as for the first term. Equation (8) is given as Equation (6) by rearranging the terms:The machining process parameters and the thermal-physical characteristics of the work material are considered in the semi-empirical MRR model, as stated in Equation (12). In Equation (12), the coefficients  terms, as provided in Equation (11).As in MRR, the solution for Ra is found in the form of a product of six independent dimensionless  is redefined as in Equation (15).1 term as follows:The terms in Equation (12) are rewritten to calculate the The power indices were calculated in the same manner as explained in Using Equation (17), the formula for Ra is produced by replacing all the derived terms. The remaining terms  is provided in Equation (15).The power indices From 2.85 to 3.58 µm, the Ra is directly proportional to JT. P increases the particle’s kinetic energy and substantially increases its MRR, while decreasing Ra ,33.In this study, Ra is initially low as P increases. But the Ra increases as the P increase further. It is an identity that increasing the P (up to 240 MPa) reduces the Ra. Minimizes the chances of plastic deformation and micro-cutting. Increases in P and JT will alter the roughness of the surface. It is due to the size and type. The P and its interaction do not affect the roughness of the character in this case. When P is increased, abrasive fragments is also increased along with their enhanced rate. Due to fragmentation, the size of impacting abrasive particles is reduced. Similarly, when P is increased, the kinetic energy of the water jet also increased, affecting the Ra. The JT, second-order terms of P, and JT are identified as significant process parameters for Ra, based on the experimental results. The standoff distance does not have any physical effect on the roughness of the surface, as previously stated in the literature ,35. WithThe semi-empirical modeling is validated by evaluating it to Ra’s experimental data and regression model. The variations for each observation number for semi-empirical, observed, and regression model Ra values are shown in The trial no. 22 is chosen because it provides a lower Ra value than the other experiments. At a higher JT (15 mm/min), the machined surface appears with more microvoids, rough cut, edge pile up, and crater, whereas at a lower JT (5 mm/min), the machined surface appears with a full cut and smooth surface, minimal plowing, less void, and less shearing as shown in tw), and kerf bottom width (Kbw) are determined in this investigation. Ka is calculated using the performance measure of Kbw width. The π1 term for Ktw and Kbw are generated by semi-empirical modelling. Ktw can be expressed in the formula provided in Equation (20).The models of kerf top width .The power indices are calculated similarly to the MRR and Ra model formulations. The dimensionless coefficients a, b, c, and d have values of 0, 1, 0, and 0 respectively. Thus, by replacing the acquired power indices values for the Ktw width produced by replacing all the attained terms is given in Equation (22).The remaining terms The values of the power indices  must be determined. Therefore, an experiment is carried out, and the coefficients and power indices of Equation (18) have been calculated using the nonlinear estimation, respectively.bw must be determined to calculate the Ka model. The performance parameter Ka depends on both Ktw and Kbw, which necessitates a semi-empirical model usage for Kbw. The experiment was carried out to determine the values of Ktw and Kbw. The width of Kbw is directly proportional to the width of the Ktw. As a result, the tw corresponds to the bw as provided in Equation (23).The Ktw and Kbw models. Equation (25) can be used to calculate Ka.The power indices values, bw. The kinetic energy and cutting performance of the particles were enhanced with increased P. As P increased from 240 MPa to 260 MPa, the top kerf increased due to the increase in Ka. At the base of the workpiece, the waterjet kinetic energy decreased. It could not remove the material efficiently and therefore created a narrow Kbw, resulting in a decrease in Ka. A similar trend was seen in armor steel cutting. Ka increased with an increase in SOD. At high speeds, the jet will deviate. The jet increased as it exited the nozzle. The workpiece surface is now exposed to the bottom of the waterjet after the SOD is raised.tw. At the same time, the waterjet thoroughly penetrates the workpiece, maintaining kinetic energy and efficiently cutting the bottom material. The kerf width variation reduces the taper angle. The correct taper was obtained at SOD (1 mm), JT (10 mm/min), and P (220 MPa). The reverse taper was obtained at SOD (3 mm), JT (5 mm/min), and P (240 MPa), as shown in As the water jet diverged, it lost uniformity, which diminished the cutting area seen in Ka immediately after that. Similarly, increasing JT tended to increase Ka. When the JT value is low, the nozzle allows for a high volume of abrasive particles to strike the workpiece. As a result, a larger volume of material is removed, resulting in a higher KThe Ka semi-empirical model was verified by comparing the experimental data and regression model. The confirmation experiments showed that the residuals between the predicted and experimental values were less than 5%. The values of the semi-empirical modeling and regression models were compared with the experimental values. For MRR, Ra, and Ka, the semi-empirical model was proven to be more accurate than the regression model to predict the relationships of the variable.The use of the analysis of variance approach in combination with the dimensional analysis reduced the number of insignificant variables and resulted in simpler models for MRR, Ra, and Ka.The maximum MRR was obtained at SOD = 2 mm, JT = 15 mm/min, and P = 260 MPa. Improved MRR was achieved due to the greater kinetic energy of the jet produced by this combination. These findings demonstrate that a higher surface finish was attained with a higher SOD = 3 mm and lower JT = 5 mm/min. This allows for a more uniform MRR, which resulted in a lower roughness. Ra was determined to be 2.23 µm.The SOD process parameter significantly impacts the response, Ka. The variation in Ka is due to the hardness of the material. The SOD and JT should be kept at the minimum. The lower Ka (0.651°) was obtained at SOD = 1 mm, JT = 10 mm/min, and P = 220 MPa.The microstructural analysis of the machined surfaces revealed three regions: top, middle, and bottom. In the top region, smooth surfaces were obtained, and in the middle region, fewer voids were present, and less ploughing was identified at the bottom.In future, the research may be extended on the comparison of experimental results with numerical modeling studies. The results obtained can be applied in battlefield vehicle applications.The influence of the AWJM process parameters on the MRR, RA, and Ka values while machining an armor steel plate was investigated in this study. Using Buckingham’s π-theorem and the regression equation, a semi-empirical model was created to estimate three key parameters: MRR, Ra, and Ka. ANOVA was used to evaluate the model’s significance and performance. The experimental findings were compared with the predicted values of MRR, Ra, and Ka using the proposed semi-empirical model and regression model, and the following decisions were made:


Oral candidiasis has a high rate of development, especially in immunocompromised patients. Immunosuppressive and cytotoxic therapies in hospitalized HIV and cancer patients are known to induce the poor management of adverse reactions, where local and systemic candidiasis become highly resistant to conventional antifungal therapy. The development of oral candidiasis is triggered by several mechanisms that determine oral epithelium imbalances, resulting in poor local defense and a delayed immune system response. As a result, pathogenic fungi colonies disseminate and form resistant biofilms, promoting serious challenges in initiating a proper therapeutic protocol. Hence, this study of the literature aimed to discuss possibilities and new trends through antifungal therapy for buccal drug administration. A large number of studies explored the antifungal activity of new agents or synergic components that may enhance the effect of classic drugs. It was of significant interest to find connections between smart biomaterials and their activity, to find molecular responses and mechanisms that can conquer the multidrug resistance of fungi strains, and to transpose them into a molecular map. Overall, attention is focused on the nanocolloids domain, nanoparticles, nanocomposite synthesis, and the design of polymeric platforms to satisfy sustained antifungal activity and high biocompatibility with the oral mucosa. Nowadays, oral disease management has become of significant concern in human health and is defined by serious disorders with a life-threatening pattern, affecting over 3.5 billion people worldwide, according to the World Health Organization . GeneralThe development of oral candidiasis is determined by several mechanisms that induce imbalances in the oral epithelium homeostasis. Poor local defense and a delayed immune system response are detrimental to cellular restoration. As a result, pathogenic fungal colonies disseminate and form resistant mixed biofilms by entailing bacterial pathogens and cellular fragments, promoting serious challenges in initiating a proper therapeutic protocol .Candida sp. implied in drug resistance [Multidrug resistance was established as a serious concern that creates unsuccessful results following treatment with classic topical drugs, particularly polyenes and azoles. Enzymes’ structural modifications, efflux pumps, gene regulation, and mutations are the main mechanistic pathways of sistance . One of sistance . Hence, The most studied mechanisms related to the antifungal activity proposed the modification of the cell wall structure, the passage through the inner layers, triggering alterations in the cytoplasmic membrane, and cellular death. It was found that these events can be connected with the presence of genuine surface stabilizers selected in nanocolloids development, particularly micro-/nanoemulsions . IncorpoOverall, attention is focused on the nanocolloids domain, nanoparticles, nanocomposite synthesis, and the design of polymeric platforms to satisfy sustained antifungal activity and high biocompatibility with the oral mucosa. The assessment of molecular targets in the biomaterials domain is considered by creating a molecular map with the most valuable antifungal agents. Candida sp. in oromucosal tissues, overcoming barriers such as antifungal drug resistance, and repurposing new pathways and mechanisms to alleviate resilient infections. The discovery of new targeted therapeutic agents exhibiting intelligent mechanisms of action remains of major concern, especially in the case of chronic and immunocompromised patients [Oral fungal infection is one of the most researched medical challenges today, being critically related to the development of oral candidiasis, the dissemination of patients ,17.Candida can become life-threatening, with a reserved prognosis and a high mortality rate of 71–79%, especially in patients with indwelling catheters or following immunosuppressive treatments [As a part of the gastrointestinal tract, the oral cavity is usually a pleasant environment for commensal microorganisms in the absence of health imbalances . Mycoticeatments ,19. Candida albicans is one of the most encountered types of oral mycosis in 95% of cases [C. glabrata, C. tropicalis, C. pseudotropicalis, C. krusei, C. lusitaniae, C. dubliniensis, C. parapsilosis, or C. stellatoidea [Cryptococcus neoformans were found to produce unexpected tongue lesions in an HIV patient [Infection with of cases  and is kof cases , affectiof cases . Its devof cases . Other slatoidea ,20. In s patient , while m patient ,25, alon patient . The newHence, it can be appreciated that the development of oral candidiasis is influenced by several local and systemic factors, which will be briefly pointed out, as shown in C. albicans related to chemotherapy in acute leukemia was ~90% [C. albicans was encountered as a pathogenic strain in 50.6% of cases from the group of 350 cancer patients included in their study [The development of candidiasis as a result of cytotoxic treatments during chemotherapy and radiotherapy represents a long-term concern that remains one of the main priorities in the palliative care of cancer patients . There iwas ~90% . In a reir study . In the C. albicans may exist in four classic states—yeast, pseudohyphae, hyphae, and chlamydospores, characterized by dynamic morphological switching. However, up to nine morphologies have been described to date, of which the opaque (a/α), grey, and gastrointestinally induced transition yeast-like cells were studied for their behavior in the process of pathogenesis [ogenesis .C. albicans infects the host by two primary mechanisms: specifically, an induction of the receptor-mediated epithelial cell endocytosis, or active penetration [C. albicans in the presence of Flu1 efflux pumps. The efflux pumps protect C. albicans by host defense peptides via SAPs. Subsequently, proteolytic degradation of the intercellular junctions sustains C. albicans passage and completes its invasive character. The affinity of the fungi for bacterial entities and the secretion of toxin-like candidalysin determine the high virulence and an enhanced capacity to invade the epithelial tissue [C. albicans inhabits the lining mucosa, along with other microorganisms, as part of commensal microflora in a calm and friendly environment.etration . Other ml tissue . HoweverThereby, in a normal state, the oral mucosa acts as a physiological barrier against physical and chemical agents due to its well-arranged epithelial structure, which forms the entry lining of the gastrointestinal tract . As wellAt the epithelium level, cells are connected by tight junctions, gap junctions, and anchoring junctions, providing integrity for the entire lining . A rapidC. albicans pathogenesis and invasion, from local development through systemic disease [As exemplified in  disease . Lesions disease . In seve disease ,71.C. albicans is characterized by smart structural behavior. This fact represents the basis of antifungal drug resistance and its ability to interact with the host immune system and invade healthy tissues. Here, the most important mechanisms related to the multidrug resistance and the narrowing of treatment options will be briefly presented, taking into consideration C. albicans morphology.C. albicans grows as yeast—in round to oval structures with an important role in adhesion—and as pseudohyphae or hyphae structures—tubular cells with filamentous patterns [2/O2 tension, and the presence of commensal Gram-positive and Gram-negative bacterial species [C. albicans development, while in reverse, the fungal colonies assure a reduced oxygen tension for living bacteria [Streptococcus mitis, S. oralis, and S. gordoni interact with C. albicans by cell surface proteins, which have an affinity for the cell wall of the fungus containing adhesins [Staphylococcus aureus has an attraction to the hyphal structure of C. albicans, and by default, their interactions increase the virulence of the biofilm [patterns . Their d species ,73. This species . To exembacteria ,75. Stre biofilm . C. albicans will express hypha-specific genes in numerous pathways, namely: the cAMP/PKA primary pathway mediated by the stimulation of CO2 and serum, the chaperone heat shock protein 90 (Hsp90) pathway mediated by temperature, the Rim 101 pathway, specific under the effect of acidic pH [As a mechanistic pathway, the transition through the hyphal state is mediated by multiple transcriptor factors via gene regulation . Under acidic pH , and, incidic pH ,77.C. albicans yeast-like colonization, followed by changes in the oral epithelium under the effect of hyphae invasion. Considering the previously detailed aspects, a concise presentation of the main processes implied in oral candidiasis pathogenesis is rendered and described in C. albicans is presented in The bi-layered cell wall represents a fundamental structure that assures the protection and adhesion of the fungi at the level of the epithelial host cells. Its composition, based on immunogenic elements such as chitin, β (1–3) glucan, β (1–6) glucan, mannan, and mannoproteins, creates an interface to interact with the host immune cells via glycoconjugates, representing the main target of antifungal drugs from the echinocandins’ class . The celC. albicans lysed particles after the action of the immune system, host cells, erythrocytes, epithelial cells, dead cells, neutrophils and polysaccharides [C. albicans biofilm is continued with the dispersion of yeast-like cells under the effect of transcriptional regulators such as Nrg1, Ume6 [The adhesion process of the yeasts at the level of epithelial surfaces or abiotic areas of dental biomaterials with a hydrophobic nature is strengthened by the biofilm generation displayed in the presence of protein-based adhesion regulators, namely Bcr1 via Hwp1 gene , Als1 ancharides ,88. The g1, Ume6 , Pes1 [8g1, Ume6 , Hsp90 [g1, Ume6 , in a sig1, Ume6 .C. albicans to pass from an adhesion-like state of yeast—implied in the attachment at the level of the epithelial cells—through an intermediate pseudohyphal and filamentous hyphal-based morphology [The destructuration of the oral epithelium represents a sign of symptomatic candidiasis, marked by a rapid expansion through the use of extracellular matrix and blood constituents to promote dissemination and invasion . The polrphology ,60. The rphology . This prrphology , along wrphology ,94.C. albicans has for years opened a broad area of research intending to propose specific mechanisms implied in growing fungi cells, discovering their vulnerabilities. According to previous reports, important mechanisms that create a cycle of fungi invasion and interaction with the host immune cellular pathways will be further described. At the contact with the antigen, the innate immune system initiates a defense against the pathogens. Phagocytes are activated and will recognize the pathogen-associated molecular patterns through the pattern-recognition receptor pathways (PAMPs) [C. albicans infection. As a pH-dependent zincophore, it attaches to the immune cells  and deviates their action to reduce the cytokine cascade. Gpd2 targets the epithelial and endothelial cells, while Sap1-Sap3 attaches complement proteins and degrades them via proteolytic reactions [C. albicans development [The immunological pattern of  (PAMPs) ,95, foll (PAMPs) . The imm (PAMPs) . The ada (PAMPs) . Besides (PAMPs) . In the eactions . Subsequelopment . The mecelopment ,100. C. albicans virulence related to hyphal activity, suppress filamentation, and inhibit adhesion [On the other side, another essential component of the oral mucosa sustains the immune cells’ defense. The mucus generated by salivary activity promotes protection against pathogens due to its composition based on mucins . In the adhesion . Generaladhesion . C. albicans favor the epithelial damage and the development of acute, chronic, or chronic mucocutaneous candidiasis [C. albicans development target the commissures of the lips in angular cheilitis or the dorsum area of the tongue, where symmetrical disposal of the lesions determines the shaping of median rhomboid glossitis. The lesions can appear independently or in mixed pathologies associated with pseudomembranous and erythematous candidiasis and constitute a real challenge for an appropriate therapeutic purpose [In a pathological state, when the immune response is weakened, the invasive mechanisms of didiasis . Acute cdidiasis . More frdidiasis . Likewisdidiasis . Other l purpose .C. albicans cells create real challenges in both the topical and systemic delivery of antifungals.Many attempts have been proposed to offer valuable therapeutic solutions for the treatment of oral candidiasis. Local therapy remains essential for the chronic management of fungal lesions. Additionally, here, nystatin as a suspension or tablets, clotrimazole lozenges, miconazole-based gel, or ketoconazole in the form of gel, tablets, or a suspension are the standard choices to alleviate and treat superficial infections . A decreC. albicans with a reduced minimum inhibitory concentration (MIC) of 0.78 μg/mL [® use phospholipidic envelopes, combined with distearoylphosphatidyl glycerol and cholesterol, to retain amphotericin B and deliver it through the ergosterol sites in a targeted manner [Nystatin represents a standard in the local therapy of oral candidiasis, along with amphotericin B, which is kept as a second therapeutic choice for systemic use, due to its nephrotoxic character. Polyene macrolides have an affinity for ergosterol and exert fungicidal action by disrupting the cellular membrane of the fungi ,107. Nys78 μg/mL . In the d manner .As the main representatives of the azoles class preferred for buccal delivery, clotrimazole and miconazole are imidazole compounds that inhibit the 14-α-demethylase enzyme implied in ergosterol synthesis . As an eOther treatments specific to systemic therapy, briefly presented in Considering previous observations, the mechanisms of resistance are closely related to drug action and are mainly attributed to gene alterations for specific catalytic enzymes, which nullify the fungicidal effects, the use of efflux pumps, and the specific adaptive mechanisms of fungi cells, and not least, the generation of complex biofilms, which capture drug molecules and decrease therapeutic action ,113.The key factors to follow in the study of new antifungals for buccal delivery are related to the mechanisms of resistance and fungi cell dynamics, the local activity of the oral epithelium, and the knowledge of substances that can exert mechanistic strategies to efficiently inhibit fungi development and sustain drug passage through the tissue. Transcellular and paracellular routes, in a simple passive diffusion fashion, are the two pathways recognized for drug access at the level of the oral epithelium as a function of drug molecular weight, lipophilicity, electrical charge, pH, and mucoadhesion dynamics . From a C. albicans strains at the level of the oral mucosa, and considering the background focused on the mechanisms of pathogenesis and fungi behavior at the epithelial level, this study of the literature aimed to discuss possibilities and new trends through antifungal therapy for the buccal route. A large number of studies explored the antifungal activity of new agents or synergic components that may enhance the effect of classic drugs. For our purposes, it was of major significance to find a strong relationship between smart biomaterials or new compounds and their activity to find molecular responses and mechanisms that can conquer the multidrug resistance of fungi strains and transpose them into a molecular map.Due to the high prevalence of There is no doubt that nanotechnology dominates this research field by repurposing new therapeutic agents from a broad area, specifically the nanocolloids domain, nanoparticle synthesis, and new composites that can be processed as biocompatible, tissue-friendly supports that exhibit superior antifungal activity. Furthermore, polymeric-based systems were found to join this group as new architectural building blocks of new drug delivery systems (DDS), satisfying good adhesion with the tissue, a modified release of the therapeutic agent, and sustained antifungal activity, with intimate mechanisms capable of destroying fungi structure. In another light, interesting reports complete a molecular map of antifungal mechanisms, with the introduction of nanoparticulate and polymer-based formulations as potential therapeutic solutions for oral candidiasis.Biomaterials are designed as biocompatible systems with therapeutic or diagnostic purposes. Tailored to be versatile, these structures are personalized to accomplish various requirements in the biomedical field, including pharmaceutical design. Implantable devices, regenerative scaffolds, and new drug delivery systems based on the use of new natural therapeutic molecules and synthetic compounds, or, more excitingly, traditional compounds modified or appropriately prepared as formulations tailored at the nanoscale level are a couple of actual directions in the development of smart biomaterials. Following the preparation process of a biomaterial and its physicochemical characterization, a second definitory step complies with the interaction with the host immune system, and the molecular signaling that guides therapeutic activity, but also cytotoxicity ,122. Particle size, shape, and surface characteristics are the main variables that guide the cellular dynamics of a biomaterial and are extensively researched in the case of nanocolloids, in both liquid-based formulations or solid states such as nanoparticles . The larC. albicans development on living or abiotic surfaces, Coad, B. et al. described the essence of designing antifungal-coated surfaces to avoid biofilm generation [C. albicans and, by default, a diminished susceptibility to counteract denture stomatitis [The cellular responses are generated by the interactions of the newly synthesized formulation with the extracellular matrix, cell membrane, organelles, or nuclear sites and are oriented through molecular effects that mediate cell adhesion, cell migration, cell proliferation, the inflammation response, antimicrobial activity, cell growth and regeneration, and the reuptake of cellular nutrients ,125. Witneration . They emneration ,127. Polomatitis . NanoparMicroemulsions are known as thermodynamically stable nanodispersions, commonly prepared as transparent mixtures composed of oil, water, a surfactant, and a cosurfactant using spontaneous emulsification. Surfactants and cosurfactants are two key elements implied in the stabilization process of the microemulsions due to a critical reduction in the interfacial tension and an increase in the surface area of the internal drops ,130. TheC. albicans cells was obtained after 110 s [C. albicans inhibition. The addition of fumed silica 7.5% to microemulsions determined a controlled release of clotrimazole but an easily narrowed inhibition zone [Particular knowledge was gained for the mechanistic pathways of microemulsions in the buccal delivery of antifungals to assess local alleviation. Al-Adham, J.S.I. et al. described several molecular actions of microemulsions as direct actives implied in the target of the cytoplasmic membrane of the microorganisms . The altion zone . Furtherion zone . The useion zone . C. albicans, by repurposing semi-synthetic derivates that can interact with fluconazole. Eugenol-tosylate was the starting structure that was grafted with -CH3, -Br, -NO2, -Cl, and -CH2CH3 radicals and exhibited inhibitory effects on the lanosterol 14α-demethylase enzyme. The compounds act at MIC values of 1–62 μg/mL, under the value of 500 μg/mL specific for eugenol [In the study of Monton, C. et al., natural approaches were discovered by accessing microemulsions with Tween 80 and PEG 400 as spray-based vehicles to entrap clove oil 2%. Rich in eugenol, clove oil was considered a natural alternative to antibiotherapy to avoid drug resistance and promote high antimycotic activity. Complementarily, PEG 400 was considered essential to assure an increased release of eugenol from microemulsion-based spray . Eugenol eugenol . On the other hand, Tubtimsri, S. et al. proposed microemulsions as platforms for monolaurin solubilization in a mixture of Imwitor 742 14.38–18.22% and Kolliphor EL 41.23–47.94%. Monolaurin is a natural fatty acid, glyceride ester derivate of lauric acid that may exert antifungal activity in oropharyngeal candidiasis at an MIC of 0.09 μg/mL. To assess a better residence of the compound at the site of administration, the use of gel-based systems was considered a good choice, which was quantified by a release of monolaurin of up to 75% in the first hour. For its part, the fatty acid determined a large inhibition area of 43.7 ± 3.4 mm, as well as miconazole, but with an extended lag time of 2 h. Consequently, the free-drug microemulsions exhibited antifungal activity determined by the action of the surfactants at the level of fungi cell structures .C. albicans, and the possibility to be processed as potential scaffolds for oral applications, as exemplified in the case of clotrimazole-based microemulsions gels processed as nanofibers.Considering the previous examples describing the potential of microemulsions to solubilize and entrap antifungal drugs, Nanoemulsions are accepted as biocompatible systems, designed as an alternative to microemulsions, with a reduced concentration of surfactants but a high susceptibility to instability phenomena, which appear during the storage period. In this way, the reduced amount of the stabilizer enables the formation of droplets with an extended domain up to 200–500 nm. For this reason, high-energy methods are required to optimize the preparation process to obtain tiny droplets ,141. TheC. albicans strains versus 1.56 μg/mL for the free drug [In the study of Fernández-Campos, F. et al., nystatin was examined as part of a nanoemulsion to assess new data concerning antifungal activity and tolerability by the ultrastructural analysis of oral tissue. Labrafac lipophile 25% as the oil phase, Labrasol 35.42% and Plurol Oleique 14.16% as surfactants, and Transcutol P 15.42% and Propylene glycol 10% as cosurfactants formed a suitable nanoemulsion vehicle that may act to aid nystatin solubilization and dispersion up to 138 nm, and then penetration through the mucosal tissue. A sprayable fluid-based system can assure an intimate contact with the mucosa, favoring pronounced antifungal action with an MIC of 0.78 μg/mL on ree drug .In the study of Soriano-Ruiz, J.L. et al., clotrimazole was delivered in a nanoemulsion system prepared more simply than in the anterior case. Thus, Labrafac lipophile 10% was combined with a mixture 4:1 of two stabilizers, namely Labrasol and Capryol 90, in a total amount of 60%. a Lastly, propylene glycol 30% was added as a cosurfactant. It was emphasized that the nanostructured state of the clotrimazole-loaded nanoemulsion exhibits a better antifungal activity, due to a larger surface area of droplets, which creates an extended attachment on fungi cells. Furthermore, it was hypothesized that zeta potential is not only a stability parameter for the formulation process. The low charge values of the drops at pH~6 may determine interactions with the negatively charged phospholipids of fungi cells . Hosny, C. parapsilosis and C. metapsilosis cultures following several pathways, notably the dysregulation of nucleic acid synthesis and the inhibition of cellular adhesion, affecting the development of the biofilms [Flavonoids are other natural compounds that have been studied for antifungal activity. It was proved that kaempferol and quercetin exhibit antifungal activity against biofilms . Moleculbiofilms . To compbiofilms . Oral mubiofilms . The actbiofilms . It can C. albicans development occurred in 24 h. The rapid onset of nystatin activity is favorable for the use of a nanosized formula in oral candidiasis [The particle diameter is considered the main parameter that will influence the therapeutic activity in the case of a pharmaceutical suspension. In this case, the nanosizing process offers important attributes in terms of stability and drug delivery. Firstly, the reduced particle size at the nanometric level opposed the outbreak of drug sedimentation by decreasing the sedimentation rate, followed by the high accessibility of nanoparticles into the area of administration. The application of nanotechnology in the research area of suspensions offers significant advantages for various routes of administration, such as oral, topical, buccal, nasal, or ocular, to solve bioavailability challenges . To assedidiasis . Modern didiasis  and detedidiasis . Nanostructured lipid carriers are the last representatives of the nanocolloids class chosen to serve as reliable models for the antifungal activity enhancement of the old drug molecules. These systems are lipid-based variants of nanoparticles, prepared with solid lipids and surfactants, which act as good solubilization agents and carriers for lipophilic drugs. For buccal delivery, nanostructured lipid carriers were designed for the incorporation of fluconazole or miconazole. In the first case, 17 NSLc with fluconazole 0.03–0.07 g were prepared using glycerol monostearate 1.5–2.5 g as the lipophilic phase, Tween 80 1–3 g as a surfactant, and distilled water up to 100 g. The hot homogenization technique was applied to form solid lipid nanoparticle formulations. The systems were optimized with consideration of physical parameters, and the antifungal activity was studied on five optimized systems formulated with Tween 80 2–3%. It was found that Tween 80 promotes a large surface area for lipidic nanoparticles and assures their stabilization. Furthermore, the interaction of the drug with the lipidic domain of nanoparticles influenced antifungal activity. If the drug molecule is highly partitioned in the lipidic content, the release rate into the fungi strain will decrease, and the time to assess a therapeutic effect will be extended. On the other hand, it was presumed that the hydrophobic surface of NSLc had an affinity for fungi cells, determining a localized effect . The attMendes, A.I. et al. chose to encapsulate miconazole into NSLc based on Gellucire 43/01—7%, Mygliol 812—3%, Tween 80—2%, and benzalkonium chloride 0.5%, and obtained systems with particle diameters of 200 nm and sustained antifungal activity in reduced doses. Thus, the initial miconazole dose of NSLc of 0.3% was reduced to 0.12% after imposing the hydrogelling technique and embedding NSLc in a hydrogel prepared with Gelling PFC 1%, glycerin 3%, and benzalkonium chloride 0.01%. The antifungal activity of the prepared hydrogel was expressed as a zone of inhibition of 25.5 mm, similar to that of the commercial product, 24.3 mm . The incC. albicans colonies, the synergism between miconazole and sesame oil in alleviating mucosal ulcerations was proved. This fact can be justified by the antioxidant activity of the natural oil, associated with the molecular action of miconazole [The optimization study of Hosny, K.M. et al. included sesame oil as a second lipophilic agent capable of potentiating miconazole activity as part of an NSLc. One of the strengths of this research included the use of Labrasol surfactant solution, which became a factor in a nanosized dimension of the NSLc and promoted proper drug permeation into the oral tissue. According to the evaluation of the ulcer index on rats treated with conazole .Nanoparticles (NPs) are a group of agents designed to exhibit targeted action against fungi development in all phases of growing, including tolerant biofilms. Several significant research works were dedicated to specific synthesis methods to obtain biocompatible inorganic agents in the nanoparticulate form . Althoug3 determined the generation of nanoparticles with superior antifungal activity. An inhibition of 50% was obtained for the nystatin nanoconjugate and 62% for the fluconazole one, at an MIC value of 300 μg/mL. Thus, it exceeded the initial inhibitory effect of 30–32%, specific for the free drugs. The mechanisms by which nanoconjugates affect the cellular level of C. albicans were suggested to be related to pore formation, in the case of nystatin silver-based NPs, continued with general cellular destructuration under the effect of fluconazole silver-based NPs. Additionally, silver in its nanoparticulate form is recognized for the production of reactive oxygen species and attachment to sulfur-grafted proteins. These effects directly attack fungi cells by inducing alterations and intracellular leakage [3 microcrystals on C. albicans. The oxidative stress produced under the Ag action determined fungistatic and fungicidal effects [The conjugation of nystatin and fluconazole with silver via the borohydride reduction of AgNO leakage . To comp effects .Allium saralicum sp. leaves [+ from AgNO3 to elemental Ag0 in the presence of polyphenols as part of the 2% (w/v) leaves extract. The reaction process ended with the precipitation of silver NPs, and the reaction product was analyzed. Both polyphenols and silver NPs were identified by applying UV–VIS spectroscopy, being defined as polyphenol-specific bands for π→π* transitions at 235 and 305 nm. A silver-specific band was detected at 435 nm. Over the antifungal evaluation of C. albicans strains, an MIC value of 62 μg/mL was obtained. C. krusei and C. guillermondi were found to be more sensitive to silver NPs, being determined to have MIC values of 31 μg/mL [Acorus calamus, Aloe vera, Brassica rapa, Eucalyptus hybrid, Moringa oleifera, Nelumbo nucifera, and Vitex negundo are a few examples of reaction substrates rich in polyphenols that may guide the synthesis of silver NPs [Lotus lalambensis Schweinf and explored for their antifungal potential in oral candidiasis. The research aimed to present the synergism between silver NPs and the leaf extract containing 5′-hydroxy auraptene as an inhibitor of C. albicans development. The synthesized nanoparticles of 6–26 nm resulted in a larger area of inhibition of 19 mm at MIC values of 50 μg/mL, which was superior to the plant extract in the same concentration. At an MIC of 100 μg/mL, the fungal growth was suppressed. In combination with the plant extract, silver NPs determined the largest inhibition area of 24 mm at a concentration of 50/100 μg/mL, explained by the suppression of fungi growth, adhesion, and biofilm formation. The associated molecular events sustained a decrease in C. albicans oxidative enzymes and intracellular glucose and trehalose release. Finally, the ultrastructural analysis using microscopic techniques outlined an invasive effect of the extract–nanoparticle combination, determining pore formation, intracellular content loss, and cell death [Fagus sylvatica L. Nanoparticles synthesis was performed following two pathways that consisted of using two solutions of 1mM, namely AgNO3 and CH3-COOAg solutions. It was revealed that the nanoparticulate products prepared with the acetate solution caused the downregulation of SAP2 expression, which is known to be involved in host cell invasion [C. albicans activity. The central aspect of the study was proposed to be the manner in which silver NPs can counteract fluconazole-mediated resistance, with double significance in terms of both the topical and systemic activity of azoles. Besides the reduced MIC values of AgNPs of 32 μg/mL, compared to the value of 128 μg/mL of fluconazole, the use of the agents in C. albicans isolates caused fungi inhibition only in the early stages of biofilm consolidation up to 6 h, without exerting activity in the maturation stages. The associated agents increased the length of action time up to 12 h, which may define the importance of a proper antifungal therapy initiation as soon as possible in the early stages of diagnosis. Furthermore, it was found that a concentration of 30 μg/mL AgNPs sustained ergosterol depletion by inhibiting the expression of ERG1, ERG11 and ERG25 genes. This effect determines a fluidization of the membrane, affecting the activity of the Cdrp1 and Cdrp2 efflux pumps, responsible for azoles resistance. The in vivo studies on mice were favorable for the use of AgNPs to increase survival rate, without inducing toxicity [Silver NPs are prepared using techniques that assume chemical, photochemical or electrochemical reduction, laser ablation, and lithography. These methods are time-consuming, laborious, and present some disadvantages in the chemical synthesis of pharmaceutically acceptable agents, such as the use of a high number of chemical reagents, obtaining uneven nanoparticles, reduced reaction yield, and environmental drawbacks . Bioinsp. leaves . The pla. leaves . Hence, 31 μg/mL . It can 31 μg/mL . Many atlver NPs . In the ll death . In-deptinvasion . To furttoxicity .Candida species with development into the oral cavity, including C. albicans. The exposure of C. albicans to CuONPs-based polymeric nanofibers at a concentration of 200 mM caused alterations in mycelia integrity, remarked as deformations, distortions, and contractions. CuO NPs have a major effect on fungi destructuration, while the polymer creates a biocompatible platform that sustains contact with the oral mucosa and the release of NPs [2 and ZnO NPs were studied for their antifungal activity as potential alternatives to amphotericin, but their effect was favorable at higher MIC values than the antifungal MIC [Copper oxide NPs are an example of potential antimicrobial agents that can be prepared to create complex nanostructures by using biocompatible and biodegradable polymers. In a recent study, CuO NPs were combined with poly-ε-caprolactone and then electrospinned, resulting in nanofibers with diameters in the range of 925–1080 nm. CuO NPs and their nanofibers were physically described and tested on e of NPs . Similarngal MIC . Based on the knowledge assessed in the studies mentioned above, a molecular map was composed, and is presented in Magnetic NPs of ~4 nm, obtained using the coprecipitation of two iron salts, were studied for their antifungal activity as part of a liquid crystalline system formed with Brij O10 as a surfactant, isopropyl myristate as the oil phase, and distilled water. The complexity of the colloidal system was defined by the use of an ethanolic propolis extract with antimicrobial properties. The formulation was proposed as a delivery system with prolonged release in the treatment of periodontal disease, which was previously described as a predisposing factor for candidiasis development. The fungicidal activity of the system was increased when an alternative external magnetic field was applied .As a final model with valuable older notes that can be regarded in the study of new nanoparticulate formulations for buccal delivery, organic nanoparticles of poly(ethyl cyanoacrylate) were the central subject of antifungal activity assessments. Looked at from a different perspective and compared with anterior examples, polymeric-based nanoparticles were considered appropriate therapeutic agents without being only an entrapment resource. The emulsion polymerization technique was applied, and the antifungal polymeric NPs were generated under the stabilization effect of cationic, anionic, and non-ionic surfactants. Thus, the positively charged NPs characterized by high zeta potentials of +31.3 mV (for cetrimide) and +26.2 mV (for cetylpyridinium chloride) represented the main potential agents for antifungal activity .2 bonds [4 in a concentrated medium of H2SO4, under a rigorous step-by-step temperature control [Graphene was first isolated in 2004 by Andre Geim and Kostya Novoselov. They have drawn attention to the mechanical exfoliation technique of graphite to obtain single sheets of graphene. The new method inspired the research world and was awarded the Nobel Prize in Physics in 2010, paving the way to exciting discoveries in material sciences . Graphen2 bonds . Highly 2 bonds , optical2 bonds , graphen2 bonds , implant2 bonds  and bios2 bonds , and the2 bonds . One of  control ,186,187. control . In the  control . Graphen control  or adhes control .Likewise, novel platforms for the delivery of antimicrobials and regenerative agents are of major significance to conducting medicine at a safer, high-quality, and modern level . The antC. albicans and C. tropicalis fungi cells, and the loss of intracellular content after prolonged contact with the nanoscrolls. GO-based nanoscrolls were considered reliable models of the slow release of silver NPs, thus avoiding the undesirable cellular toxicity produced by silver accumulation [3, Ag NPs of 12 nm were formed with a uniform distribution in the GO structure. The antifungal activity was quantified as the complete inhibition of fungi growth at the same concentration of 50 μg/mL as in the case of GO-based Ag NPs, and the diameter of inhibition was 21 ± 4 mm. Furthermore, the inclusion of Ag NPs into the GO structure increased cell viability and reduced apoptotic and necrotic events, as was proved in experiments on HacaT cells [Graphene oxide nanocomposites are versatile candidates to sustain local antifungal activity for gynecological purposes, wound regeneration, and the targeting of specific infections in mucocutaneous tissues. In this regard, Li, C. et al. studied nanocomposites prepared with graphene oxide and silver nanoparticles as carbon nanoscrolls. Elongated structures were obtained from graphene oxide sheets filled with silver NPs by applying sonication. The antifungal activity was studied for GO, GO-based silver NPs and the nanoscrolls. It was observed that GO-based nanoscrolls exhibited superior antifungal activity at an MIC of 0.125 μg/mL, compared with the simple GO-based silver NPs which achieved doubled MIC values of 0.5 μg/mL. At the same time, GO itself did not induce any action on fungi strains. SEM images proved the lysis process of mulation . In a siaT cells .C. albicans due to pore formation on the yeast cell surface and apoptotic action. On the other hand, the PEG-GO composite has a superior antifungal effect compared with PEG-EGO, GO, and EGO, but under the activity of Cu NPs. This is why a synergism of PEG-GO and CuNPs promoted high adhesion on the yeast spores and hyphae, followed by their deformation. From a physical point of view, the antifungal effect of the PEG-GO derivate was correlated with the zeta potential value of −41.9 mV. In this regard, these structures have powerful aggregative stability, maintaining their properties over time. As a final result, a reduced C. albicans cell viability was obtained at a concentration of 500 μg/mL of PEG-GO and CuNPs in a ratio of 30:70 [When polymers enrich graphene oxide, new valuable physiologically acceptable composites are created to combat the dissemination of fungal infections. Cheong, Y.-K. et al. used a chemical conjugation reaction for amide bond formation to produce PEGylated graphene oxide (PEG-GO) and PEGylated expanded graphene oxide (PEG-EGO). It was demonstrated that copper NPs are efficient against of 30:70 .C. albicans colonies was obtained at MIC values of GO/fluconazole of 400/9 μg/mL. The mechanism was proposed to act in multiple directions, implying fungi cell lysis and chemical oxidation via GO, followed by DNA damage. The GO/fluconazole system was found to interfere with the adhesion step of fungi cells, promoting gene downregulation [In another light, the entrapment of antifungals in the structure of GO can be a real opportunity to enhance antimycotic activity. Few but promising research works have studied azoles as active molecules for GO binding. The advantages of these formulations are described as attempts to assure high stability, a modified release of the active ingredient, and a synergism created with the aid of GO as a substrate of release ,196. AsaC. albicans inhibition to 17.1 mm. This aspect was suggested to be sustained by the interactions between the polymers and GO, and then between GO and clotrimazole [The large surface area of GO represented a new beginning for the design of biocompatible GO-based oral films. Thus, Huang, J. et al. projected GO-based polymeric films for the local delivery of clotrimazole, using chitosan and alginate as proper mucoadhesive polymers that modulate the antifungal activity of clotrimazole via electrostatic interactions. There was a graphical explanation of the chemical interactions between rimazole . In theirimazole .To conclude, graphene oxide has a high potential for drug delivery and can be successfully integrated into novel antifungal platforms. The association between inorganic nanoparticles, antifungal drugs, and mucoadhesive polymers promotes synergistic actions and favors fungi cell death. In Mucoadhesive polymers are studied as functional biomaterials that can enhance the therapeutic activity of drugs in buccal delivery. By adequate processing, these structures assure the attachment of the pharmaceutical formulation to the mucosa without being removed through the salivary flow or enzymatic processes . PolymerFirstly, at the level of the oral mucosa, the salivary glands permanently ensure a proper level of saliva, which is based on the proportion of water being 99% and organic substances 1%. Saliva assures the troficity of the oral tissues and maintains adequate hydration and protection via immune defense. On the other hand, it participates in the initial biochemical reactions of the first phase of digestion. Thus, the presence of enzymes such as lipases, proline-based proteins, peroxidases, amylases, and glycoprotein-based mucins, as well as pH changes, influence the activity of a drug molecule ,199,200.Consequently, mucoadhesion describes the capacity of a material to adhere at the level of the epithelium and interconnect with the mucosal film to sustain prolonged retention, but also a modification of cellular permeability . This inC. albicans and other fungi strains. Nylon-3-copolymers containing AMP structural groups were synthesized by the route of the anionic ring-opening polymerization of β-lactams and were codified as MM-TM, DM-TM, and NM. However, in-depth studies are required to assess valuable data concerning their antifungal activity because their action was considered limited to yeasts only [C. albicans, exerting fungicidal activity at 3 μg/mL, with minimal toxicity on fibroblasts. Hemolytic activity and the discovery of derivates with selective toxicity on fungi cells represent a challenge to finally conclude that these polymers can be safely integrated into formulations with clinical efficacy [There is a need to develop new antifungal agents to avoid multidrug resistance to classic antibiotherapy. Thus, polymers are promising biomaterials that can be processed to exhibit antifungal activity. Recent pursuits proposed various manners in which polymers may be adapted to these requirements by the modification of the polymeric structure with specific moieties derived from antifungal drugs, the modification of polyenes and echinocandins, the synthesis of composites with the inclusion of inorganic or organic compounds, or designing polymers as inclusion agents for various drug molecules . Groups sts only ,207. In efficacy . ConsidePolymeric micelles are interesting complex nanovehicles for drug delivery, designed to solve the major drawbacks of lipophilic agents, specifically solubility, inadequate drug size, or drug passage through mucosal tissues . Such a C. albicans by the inclusion of cationic polyethyleneimine (PEI) [50 and MIC80 values in both planktonic and biofilm states of C. albicans [Zhou, L. et al. created nano-inspired micelles to load luteolin as a natural active compound for oral candidiasis. Their study proposed the creation of a tri-block copolymer satisfying two main actions, namely luteolin solubility enhancement, promoted by a diblock polymer of monomethoxy polyethylene glycol–poly-ε-caprolactone (MPEG-PEC), but also an inhibitory action on ne (PEI) ,212. Thealbicans . New antifungal solutions for resistant oral candidiasis were proposed by Mady, O.Y. et al. They developed polymeric oral films based on carboxymethylcellulose and polyvinyl alcohol to support the antifungal synergism of a combination based on a miconazole base and urea. The synergism was quantified and accepted due to a miconazole MIC reduction from 32 to 0.0625 μg/mL, when combined with urea, followed by high inhibition diameters of 30–40 mm. Their activity led to mycotic cellular death and necrosis, with cytoplasm rupture and intracellular content release. In this case, mucoadhesive polymers sustained the adhesion and release of the antifungals .Kraisit, P. et al. merged the film properties of chitosan with the inclusion of solid lipid nanoparticles as NSLc for fluconazole delivery at the oral level. The inclusion of fluconazole into NSLc prepared with glyceryl monostearate and stabilized with Tween 80 solved its solubility problems, while its release to the oral mucosa was hypothesized to occur due to the hydrophilic character of chitosan. The addition of NSLc into chitosan films can affect the mucoadhesive properties of the polymer. The bioadhesive effect was considered to be enhanced in high levels of Tween 80 and chitosan, which form hydrogen bond interactions with the mucus. Considering the antifungal activity, the nanosized level of NSLc of 63.73–265.8 nm may determine a facile penetration of the fungi cell membrane and attenuate antifungal drug resistance . From anC. albicans biofilms was suggested by Al-Ani E. and Heaselgrave W. Hence, thymol was considered a powerful antifungal agent for oral candidiasis when combined with Poloxamer 407 as a polymeric surfactant. Subsequently, the polymeric carrier effect was compared with a second thymol formulation based on hydroxypropyl methylcellulose. Remarkable results were obtained when Poloxamer 407 was combined with thymol. The surface activity of the polymer determined the solubilization of the active compound and supplementary inhibitory effects on C. albicans biofilms were proved at higher concentrations of thymol and lower concentrations of Poloxamer 407. The inhibitory effect related to Poloxamer 407 activity was considered to be based on the suppression of the aggregative activity of the proteins of the biofilm [The polymer contribution to the antifungal activity on  biofilm . Poloxam biofilm . Further biofilm ,222.Lactobacillus paracasei 28.4. To protect and preserve probiotic activity, a biocompatible polysaccharide was proposed as an encapsulating agent. Gellan gum (1.0–0.6%) was considered appropriate to sustain the formulation process. The use of gellan gum 1% was favorable to permit probiotic remanence in the oral cavity for up to 10 days. Thereby, a study on murine models demonstrated the antifungal activity of polymeric-based probiotics. The inhibition of C. albicans activity in the oral mucosa was correlated with the probiotic effects upon the downregulation of several genes implied in biofilm architecture, namely ALS3, HWP1, EFG1, and CPH1 [Lastly, a natural alternative to support the antifungal activity in the oral mucosa was presented in the study of Ribeiro, F.C. et al. Their study was based on the assessment of the antifungal activity of probiotics, namely and CPH1 ,224. In To support a therapeutic activity in the oral cavity and a sustained release, the selection of biocompatible polymers is of major significance, being generally discovered in the development of mucoadhesive nanocolloids, nanoparticle delivery, or the design of nanocomposites and mucoadhesive scaffolds. Polymers are versatile supports that enhance the antifungal properties of natural or synthetic agents, and have been documented as valuable biomaterials that may complete the mechanistic pathways of old and new drugs.C. albicans are recognized to be of high emergence and need an early diagnosis for a favorable prognosis. The development of oral candidiasis is based on multifactorial mechanisms concerning local tissue imbalances and poor local immune defense. These events culminate with real changes in the oral metabolism, mediated via gene regulation. The challenges of drug delivery research present a unique invitation to develop new strategies to overcome the multidrug resistance of fungi strains. Classic drugs cope with the most sophisticated mechanisms of resistance of fungi, which target catalytic enzymes and gene regulation. Biomaterials are promising carriers to enhance the antifungal activity of classic drugs by improving mucoadhesion in oral tissue. Nanocolloids are ideal formulations to solve the solubility problems of lipophilic drugs, exerting destructuration effects on fungi cells.Oral candidiasis remains a complex pathology with a high power of dissemination through a systemic state. Mainly occurring in immunocompromised patients, mucocutaneous infections with Furthermore, newly synthesized inorganic nanoparticles from vegetable resources are considered eco-friendly and easy-to-synthesize systems that can interfere with biofilm development and gene regulation. Subsequently, organic composites based on graphene oxide are demanded as versatile platforms that may covalently interact with drug molecules and polymers. It was pointed out that graphene-oxide-based materials such as silver nanoparticle-decorated graphene oxide have superior antifungal activity, protecting cellular lines from cytotoxicity in the same manner. As the final representatives discussed here, polymers are tunable agents that can sustain the generation of new architectural platforms for antifungal drugs, the incorporation of nanoparticles, or the synthesis of nano-sized micellar systems. Their intrinsic mucoadhesive qualities led to antifungal activity for both synthetic and natural antimycotic agents, completing an authentic molecular map of antifungal mechanisms.


Our findings confirmed the alterations of several elements among Saudi females with obesity. The toenail elemental analysis may become a useful diagnostic technique in monitoring the nutritional status, predicting some metabolic disorders, and environmental exposure.Elemental homeostasis is essential for maintaining normal metabolic processes. Elements in the toenails are now considered in the diagnosis or screening and used as biomarkers of several metabolic disorders. The incidence of obesity is more prevalent in females than males globally. At the same time, females appeared more susceptible to elemental alterations than males. This study aimed to evaluate the variation in the levels of several elements in toenails as possible biomarkers of health conditions associated with obesity in young Saudi females. A cross-sectional study was performed, between February–November 2019. The study enrolled 79 young females divided into two groups: participants with obesity (n=39) and non-obese (n=40). The toenail was analyzed to estimate Fe, I, K, Na, Cd, Cr, Mn, Ca, Mg, Cu, Co, and Se levels. The study showed a significant elevation in the levels of Fe, Ca, K, and Na in the toenail sample of female participants with obesity compared to the non-obese group. The levels of Mn, Cd, Co, Cu, and Cr, were significantly decreased in the toenail of participants with obesity. Moreover, other elements ( The participants were divided into females with obesity (OG) BMI>30 kg/m5 kg/m2) .The free edge of the nail from the two great toes was taken by a stainless-steel nail clipper  on the same day for each participant. Toenail specimens (5 mg) from each participant were collected in a polyethylene bag either from naturally non-polished or after removing the nail polish before cutting the nails.All samples of toenails underwent the washing procedure according to the protocol by Blazewicz et al. and Ishak et al. , 18. Eac2O2 (30%), acetone, HNO3 (65%), Triton-X 100 . Afterward, the sample digestion and dilution procedures were carried out following the method described by Ishak and his colleagues in 2015  were carried out in the laboratory of Saudi Food & Drug Authority (SFDA) with simultaneous Inductively Coupled Plasma Emission spectrometers . The spectrometer was optimized daily with a 10µg/L solution of the study elements in a blank solution (1% HNOGermany) . Procedui.e., anthropometric data and age, were presented as mean and standard error of mean (SEM), whereas data with non-parametric distribution were expressed as median and 25–75 percentile boundaries. Statistical significance was considered at p<0.05.Data were analyzed using IBM SPSS, version 24. The normality of continuous variables was assessed using the Shapiro-Wilk test. Mean analysis was performed using the Mann-Whitney U test. Normally distributed data, 2, and for NOG, it was 22.8±1.6 kg/m2. The mean age of participants in NOG and OG were 20.5±1.6 and 21.3±1.8 years, respectively.Descriptive data of the study participants are shown in The levels of Ca (p<0.001), Fe (p<0.001), K (p<0.001), and Na (p<0.001) in the toenail of participants with OG were significantly higher as compared to participants in NOG. In contrast, Cd, Co, Cu, Cr, and Mn levels were significantly lower in the OG than in NOB (p<0.001). Furthermore, the levels of the other studied elements  were lower in OG as compared to NOG; however, those differences were not significant .We found high levels of Fe, Ca, Na, and K and low levels of Cr, Cd, Co, Cu, and Mn in the toenail of females with obesity in Saudi Arabia. Alteration in the levels of these elements might play a vital role in the appearance and/or progression of several diseases. For example, reduced or elevated elements  may indicate the presence of depression in young people , 20.The high level of serum ferritin is associated with the accumulation of adipose tissues independent of dietary iron intake . ObesityIn this study, the obese females showed a higher level of Ca than the non-obese females. Previous studies suggested some explanations for this metabolic disruption, including volumetric dilutional, physiological sequestration of vitamin D in adipose organs, adaptation to the need for more bone mass to support weight gain , and secThis study revealed a significant increase in the level of Na in the toenail of females with obesity. Earlier data reported an anomaly in the hormone mechanism associated with Na homeostasis that may contribute to the development of hypertension and hypernatremia in participants with obesity . A previIn addition, the level of K in the toenail was significantly much higher among females with obesity than those in the NOG. K is an intracellular element necessary for the normal function of all living cells. Many researchers have investigated the associations between K and obesity. However, these observational results are considered controversial . This maIn this study, Cr, Cd, Co, and Mn were significantly lower in OG participants. These data are in accordance with earlier experimental reports , 34. TheIt was reported that blood Cr was reduced in obese participants. Vice versa, Cr supplementation could be a promising agent in modulating obesity . HoweverUnfortunately, little is known about the effect of Co level on obesity in general. In the present study, the Co level in toenails from the OB group was lower than in NOB. The same finding was observed in another study using a plasma sample .i.e., “deficiency in one element may impair the absorption of another”, [There is evidence of direct interaction between the elements. nother”,  which conother”, .The lower level of Se in the toenail of females with obesity was in agreement with a previous report that showed an inverse association between obesity and Se levels in nails . HoweverMoreover, despite the absence of statistically significant differences, the observed decrease in levels of Mg and I are generally consistent with findings from previous studies where it was reported that obesity increases the incidence of Mg  and I deThe present data added new information on the elements from the toenails of young Saudi females with obesity. The elemental analysis of the nail may become a useful diagnostic technique in monitoring nutritional status, predicting some metabolic disorders, and environmental exposure in the future. However, further studies are needed with a representative sample size to precisely elaborate reference ranges of elements in the nail and formulate universal guidance on methodology considering age, gender, and lifestyle. The medical care plan for obese individuals should include behavioral counseling to reduce their exposure to high-calorie foods with low nutritional value. To the best of our knowledge, this is the first study that reports elemental alterations in the toenail of females with obesity in Saudi Arabia. Expert lab technicians used a very advanced automated instrument for the elemental analysis in a qualified and specialized governmental institute (SFDA).There were some limitations in our study. Firstly, the study did not correlate the results with demographic variables of other health and lifestyle data of the study sample, which are essential in future data collection. Secondly, there was a small sample size, and the focus was on only one gender and a specific age group. Third, we did not correlate the elemental levels in toenails with blood levels.