Use of asynchronous store-and-forward (SAF) teledermatology can improve access to timely and cost-effective dermatologic care and has increased during the COVID-19 pandemic. Previous research has found high diagnostic concordance rates between SAF teledermatology and face-to-face clinical diagnosis, but to our knowledge, none have used specific cases to illustrate factors contributing to diagnostic discordance.To identify and illustrate characteristics that may have contributed to diagnostic discordance between store-and-forward teledermatology and in-person clinical diagnosis in a series of patients.We identified 7 cases of diagnostic discordance between teledermatology and in-person visits where the favored diagnosis of the in-person dermatologist was not included in the differential diagnosis formulated by the teledermatologist. Cases were identified from a previously published retrospective chart review of 340 SAF teledermatology consultations, which was previously performed at an academic community health care system in the greater Boston area, Massachusetts, from January 1, 2014, through December 31, 2017. Of 99 patients who completed an in-person dermatology appointment after their teledermatology consultation, 7 had diagnostic disagreement between the teledermatologist and in-person dermatologist where the diagnosis in the in-person consultation was not included in the differential diagnosis in the original teledermatology consult. These 7 cases were examined by 2 author reviewers to identify factors that may have contributed to diagnostic discordance.Factors contributing to diagnostic discordance between SAF teledermatology consultations and in-person visits included poor image quality, inadequate history or diagnostic workup, inability to evaluate textural characteristics, diagnostic uncertainty due to atypical presentations, and evolution in appearance of skin conditions over time.We identified multiple factors that contributed to diagnostic discordance. Recognition and mitigation of these factors, when possible, may help to improve diagnostic accuracy and reduce the likelihood of misdiagnosis. Continuing education of referring providers and implementation of standardized guidelines for referrals may also be helpful in reducing the risk of misdiagnosis due to inherent limitations of teledermatology services. Store-and-forward (SAF) teledermatology systems utilize asynchronous evaluation of clinical images and information to provide diagnostic and management guidance directly to patients or other health care providers. In contrast to real-time telemedicine such as video encounters, SAF encounters involve collecting clinical information from a referring provider to be sent electronically to another site or provider, often a specialist, for review at a later time. SAF teledermatology platforms can increase access to dermatologic care, provide financial savings for patients and health systems, and provide a comparable quality of care to in-person evaluation for numerous dermatologic conditions -8. UtiliEvaluation of diagnostic concordance for patients who receive both a teledermatology and in-person consultation is one method of assessing the diagnostic quality of SAF teledermatology consultations. Complete diagnostic concordance occurs when the first diagnosis matches between the in-person dermatologist and teledermatologist -17. PrevAlthough previously published work has examined rates and patterns of discordance -17, to oPreviously, a retrospective chart review of 340 SAF teledermatology consultations performed at our institution from January 1, 2014, through December 31, 2017, was conducted . All SAFImages from the teledermatology consult were submitted by the referring provider and taken using the Epic Haiku mobile app (Epic Systems Corporation). The teledermatologist was different than the in-person dermatologist in all but the second case reviewed. This project was exempt from full review by our Institutional Review Board.A summary of the cases, teledermatology and in-person differential diagnoses, in-person diagnosis, and factors contributing to diagnostic discordance is provided in A 31-year-old male presented to his primary care provider with a several-year history of well-circumscribed, hyperpigmented, nonpruritic, thin, scaly plaques with skin tightening on his back, trunk, and chest, as well as associated gynecomastia. The patient had tried applying moisturizing lotion without relief. Teledermatology consultation resulted in a broad differential diagnosis including superficial morphea, superficial dermatophyte infection, pityriasis rotunda, psoriasis, parapsoriasis, cutaneous T-cell lymphoma, and Hansen disease. The submitted images showed several sharply demarcated hyperpigmented thin plaques with overlying xerotic scale on the back as well as well-circumscribed tan thin plaques with overlying scale on the collar distribution of the neck and the upper chest  and 2. TA 60-year-old man with 3 weeks of pruritic pink papules on the left forearm next to tattooed skin was referred to teledermatology. Submitted photos showed a 1-2 cm light pink patch containing three discrete 4-6 mm pink papules, and the differential diagnosis included sarcoidosis, atypical mycobacterial infection, hypersensitivity reaction, lichenoid reaction, and pseudolymphoma, as well as arthropod assault and folliculitis. The teledermatologist noted that image quality was compromised by the limited anatomic view provided . The patA 26-year-old male with a 3-day history of a round pink plaque on the left cheek, within which were papules and erosions, was referred to teledermatology. At the time of his referral, the referring provider had prescribed treatment of this plaque with topical clotrimazole. The patient reported that he had worn a mask and participated in paintball and jiujitsu a few days prior to presentation and that his lesions appeared shortly afterwards. He reported that the lesion started as a pimple or vesicle, and then progressed into a plaque. A single submitted clinical image showed a limited view of the left cheek . The telA 63-year-old man was referred to teledermatology for evaluation of a 7-month history of an enlarging nasal lesion. The teledermatologist reviewed the image and described erythematous macules that appeared to have scale or crust on the nasal tip and ala . The difStaphylococcus aureus. He was treated with doxycycline and the fissure healed. The lip erosions subsequently recurred , submission of photos that showed partial views without showing the entire anatomic area involved , and poorly focused images (case 7). These cases demonstrate the importance of education on appropriate image acquisition techniques. Following previously published best practices ,22 and oIn some cases, additional clinical history or diagnostic tests provided by the referring clinician would have been helpful in narrowing the differential diagnosis. For example, diagnostic accuracy may have increased if the referring provider had performed bedside diagnostics such as superficial wound cultures, viral cultures, KOH preps , or dermoscopy (case 7). Use of dermoscopy has previously been shown to be a helpful tool in teledermatology programs, particularly in the evaluation of pigmented lesions . ImproveEven with high-quality images, some morphologic characteristics may be difficult to appreciate with photos given visual limitations and inability to evaluate textural characteristics. For example, in case 4, palpation for detection of scale and induration may have helped the teledermatologist differentiate actinic damage from telangiectasias, and the teledermatologist interpreted the initial submitted image as a lesion with apparent overlying scale or crust, which was not seen in person. Case 6 also highlights that cystic, pustular, and vesicular structures can sometimes be difficult to distinguish from photos alone, depending on the angle and lighting of the photo taken. These cases highlight inherent diagnostic limitations of teledermatology services.Finally, some factors such as atypical presentations and evolution of skin lesions over time were not specific to teledermatology and may have occurred in an initial in-person visit as well. For example, multiple cases remained diagnostically challenging even when patients were seen in person due to atypical presentations . Additionally, cases 2 and 3 highlight how morphology and distribution can evolve over time, leading to changes in suspected diagnosis. Teledermatology may have the highest utility for cases with typical presentations as unusual presentations may be difficult for teledermatologists to manage confidently without in-person evaluation and possible skin biopsy. Recognition of these limitations may also help with appropriate selection of patients more likely to benefit from an in-person encounter rather than a teledermatology visit. Even when patients can be managed with teledermatology, it is important for patients and providers to maintain follow-up to ensure appropriate response to management and ongoing support if the patient’s condition or morphology changes from the time of original teledermatology consultation.Our study has important implications given that the use of asynchronous and other types of virtual care continues to rise ,10, as iIn order to improve the quality of SAF consultations and decrease rates of diagnostic discordance, we advocate for use of a standardized guide to help improve the quality of SAF teledermatology consults, including image quality and appropriate workup. In addition to guidelines already outlined by the American Telemedicine Association ,22, our In addition, the educational value of SAF consults should continue to be emphasized to both referring and consulting providers in order to help improve the quality of consults and ensure the highest level of diagnostic accuracy. Referring providers’ ability to obtain an optimal history and diagnostic testing will also likely improve with increased use of SAF teledermatology and iterative dialogue between providers about patients’ medical management. For example, previous studies have highlighted the educational potential of SAF teledermatology systems on improving referring primary care provider knowledge of dermatologic care . TelederThe strengths of our study include its in-depth analysis of specific cases and side-by-side comparison of teledermatology and in-person consults for the same patients. While several studies have been published on overall rates of diagnostic discordance, which have been estimated at around 39%-67% -17,19, nSome of the limitations of our study include that our sample size limits our ability to generalize across all cases of diagnostic concordance, although we intend for this to be a more in-depth study of fewer cases. In addition, only one teledermatologist reviewed each image submitted by the referring provider, which may introduce the possibility that diagnostic uncertainty may have been due to the individual teledermatologist’s level of comfort with the diagnosis rather than the inherent limitations of teledermatology. The teledermatologist was also different than the in-person dermatologist in all but the second case, and thus some of the differences in experience and comfort level between the teledermatologists and in-person dermatologists may have contributed to the discordant diagnoses.Collectively, these cases highlight factors that can contribute to diagnostic discordance between teledermatologist and in-person dermatologist and the importance of ensuring that teledermatology services are supported by readily available in-person visits when appropriate to achieve the correct diagnosis in these cases. We also highlight the importance of ongoing education of referring providers to ensure optimal history and diagnostic workup and improve quality of consultations and the development of standardized guidelines for submitting referrals.Teledermatology can provide substantial benefits to patients, and recognition of its limitations and mitigation of the factors identified in these cases provide opportunities to improve the quality and diagnostic accuracy of SAF teledermatology services.


This study contributes to the multidisciplinary understanding of septal L-strut reshaping and introduces innovative surgical design concepts based on engineering principles of static equilibrium. The objective is to enhance structural strength and stability, ultimately leading to improved surgical outcomes.Finite element analysis is employed to model the three-dimensional septal cartilage in septoplasty. A significant contribution of this work is the introduction of an innovative redesigns for the septal L-strut structure. These redesigns represent the first-ever attempt to incorporate the center of gravity theory into the modeling of the septal L-strut.Our findings emphasize the significance of attaining a lower center of gravity in the design of the septal L-strut, as it contributes to optimal core strength and stability. To achieve this, we recommend widening the caudal septum and shaping the interior fillet corner to its maximum size, taking into account its specific shape. Notably, the utilization of a standard 20x20 mm septal L-strut, the C-shaped technique, and the septal support graft technique provide superior strength due to enhanced basement support.To enhance surgical outcomes in septal L-strut procedures, design modifications are proposed to improve strength and stability, resulting in optimized performance. Recommendations include widening the caudal septum and incorporating fillet shapes in the geometry to lower the center of gravity. The nasal septum, positioned in the middle of the nose, plays a critical role in maintaining the structural integrity and stability of the nose. Structurally, the cartilaginous nasal septum acts as a supporting beam and cantilever, providing essential support for the nose . ComplicSeptoplasty is a surgical procedure aimed at correcting a deviated nasal septum. It offers multiple beneficial improvements, including alleviating nasal obstruction and related conditions, providing nasal support, and enhancing aesthetic outcomes , 9. The Excessive removal of cartilage during septoplasty can lead to the aforementioned complications, necessitating revision procedures . These cThis study combines the expertise of multiple disciplines, including engineering and medicine, to address the challenges in septoplasty. To achieve this, computational modeling techniques using finite element analysis have been employed. This approach allows us to predict and analyze the behavior of the septal L-strut under reaction forces, taking into account its structural characteristics and principles of static equilibrium, such as the center of gravity. Predicting the physical behavior of the septal L-strut in this study provides guidance for surgical procedures and enhances understanding of the internal forces within its structure. Additionally, it offers a visual estimation of the physical stability of the septal L-strut , contribOptimizing surgical outcomes depends on strategically designing the septal L-strut, while employing the principle of center of gravity, which focuses on lowering the center of gravity to enhance strength and stability. This study introduces a groundbreaking approach by applying the center of gravity theory to model the septal L-strut, representing the first attempt to introduce an innovative redesign of its structure. The objectives of this research are as follows: (1) Investigating the impact of structural factors, such as widths, cutting angles, and corner shapes. (2) Proposing a novel surgical design based on engineering principles of static equilibrium, aiming to preserve the integrity and stability of the residual septal L-strut. (3) Reducing the revision rate of surgery. (4) Providing a multidisciplinary understanding of the L-strut structure and its strength, offering insights that can be applied to other design concepts for achieving better outcomes.The septal L-strut is formed through partial removal of the septal cartilage . To enhaThe rule of engineering static equilibrium is taken into account in order to develop septal L-strut design, accordingly. The principle of center of gravity is important for a structure to maintain its stability . The objThe study focuses on design improvement by studying mechanical deformation behavior of varieties of septal L-strut geometry. The numerical model of septal cartilage in rhinoplasty surgery under loading force is performed by COMSOL Multiphysics software with finite element method, with the same condition of tip displacement under loading force of 20 g . The modThe illustration of residual of the septal L-strut structure and its position are presented in F = ma, F is force applied on tissue (N), m is mass (kg), g is the gravitational force (N) and μ is coefficient of friction. In this study, the maximally applied load that septal L-strut can tolerate before deformation for each dimension is measured.σ denotes the stress (Pa), ε is the mechanical strain, E is Young’s modulus (Pa), G is shear modulus (Pa), ν is the Poisson’s ratio and γ is the average displacement (m).The concept of equations in mechanics is applied to describe a deformation behavior in this study. The equations of mechanical deformation  show relTo simplify the problem, the following assumptions are made:Three-dimensional model with the Cartesian coordinate system is assumed.Septal cartilage is assumed to be homogeneous and isotropic incompressible linearized elastic material.The boundary conditions of mechanical deformation analysis are indicated in In order to verify the accuracy of the numerical model in this work, the septal L-strut model is validated against the experimental results performed by Department of Anatomy, Faculty of Medicine, Siriraj Hospital, Mahidol University, Thailand. The process of verification included testing of the warping tolerance of the nasal septum at the different dimensions of septal L-strut in fresh frozen human cadavers. There was no report regarding the patient data in this study. This part was approved by the Ethics Committee of the Faculty of Medicine Siriraj Hospital, Mahidol University, Thailand, protocol number 1012/2564.The maximum forces exerted on nasal tip without causing deformity are compared with the same conditions. The displacement distances of different dimension of septal L-strut  are evidentially paired between computational and experimental results, as can be seen in Three-dimensional models of the septal L-strut with multiple geometries were investigated in this study. The models were subjected to a loading force applied to the nasal tip surface. Mechanical deformation analysis was performed to calculate the Von Mises stress and total elastic strain energy. The study examined the influence of dimensions, cutting angles, and fillet angles on force tolerance and structural integrity. Based on the findings, recommended designs for the septal L-strut and a new design for the septal strut in septoplasty procedures were proposed to improve surgical outcomes.The aim of this study is to analyze the effects of different dimensions of the septal L-strut on its deformation characteristics and supporting ability. When comparing cases with the same septal tip displacement, it was observed that the deformation at point B varied, despite having the same displacement distance at the tip Figs  and 6. TUnder a loading force of 20 g, the widths of the dorsal and caudal septum were found to influence the supporting ability of the septal L-strut. Decreasing the width of either side resulted in increased elastic strain energy and deformation, while wider widths provided better support with reduced strain . Fig 8 iThe von Mises stress distribution demonstrated that different dimensions of the septal L-strut exhibited varying warping tolerance . The modThe cutting angle, defined as the angle between the cutting face of the new shape and the surface of the standard shape of the septal L-strut, had a significant impact on its strength and stability Figs  and 11. A fillet angle refers to the angle formed between two intersecting surfaces or edges, resulting in rounded corners instead of sharp ones. The size of the fillet angle determines the degree of curvature at the corner. The study findings indicate that fillet angles outperformed sharp angles in terms of enhancing the durability of the septal L-strut. Among the different models, the one with a fillet radius of 15°  exhibiteIn septoplasty procedures, there is no standardized approach for the septal L-strut technique, with variations depending on the surgeon’s experience and individual patient characteristics. However, one reliable method involves using a septal extension graft (SEG) to reinforce the nasal septum, aiming to control tip projection and rotation after surgery , 19, 29.The study explored alternative designs based on a previously developed technique in a clinical study. These designs, referred to as C-shaped septal struts : By widening the caudal septum, the center of gravity will shift lower, resulting in improved strength and stability. This adjustment also allows the center of gravity to restore itself more effectively to its original position after temporary deformation, contributing to better overall performance.Modify the geometry: One effective approach is to transform the corner edges into fillet shapes. This alteration also helps to shift the center of gravity to a lower position. As a result, the durability and stability of the septal L-strut can be significantly enhanced.Consider the impact of loading force and septal geometry: The distribution of stress, strain, and deformation within the L-strut is influenced by the location of the loading force and the specific septal geometry. Therefore, relocating the loading force can lead to different outcomes, highlighting the need for careful consideration and analysis.Based on the findings of this study, we propose design modifications for the septal L-strut to enhance its strength and durability. Specifically, we recommend increasing the width of the basement and reshaping the interior corners from sharp angles to fillet angles. In our comparative analysis, Design D and E (It is important to note that the findings of this study are derived from a computational model based on the concept of medical engineering, with a specific focus on the nasal septum structure. Thus, there are limitations in this study to consider. Firstly, the nasal tip support, in fact, is not exclusively from nasal septum, but rather from contributions of many adjacent structures . SecondlThis study aimed to optimize the strength and stability of rhinoplasty procedures by analyzing the geometric properties and gravitational center of the septal L-strut. Our findings suggest that widening the caudal septum and preserving its inherent strength through the use of rectangular-cartilage grafts can enhance the structural integrity of the septal L-strut. Furthermore, adjusting the cutting angle and fillet angle features can significantly influence the center of gravity and overall septal strength. The septal support graft technique demonstrated stronger support compared to other designs. The improved design concepts, involving widening the caudal septum and maximizing the size of the fillet interior corner, exhibited enhanced structural strength and stability. These design principles can be applied to septal L-struts of various dimensions, particularly when a larger septal cartilage size is not necessary. Additionally, it is recommended to prioritize preserving the width of the caudal septum over the dorsal septum during septal cartilage harvest.


The global trend of increasing life expectancy and the growing prevalence of multimorbidity, characterized by the coexistence of two or more chronic conditions, present significant challenges for healthcare systems due to their negative impact on health outcomes –3. LifesArshadipour et al. aimed to determine the prevalence of multimorbidity and common chronic disease combinations, as well as their impact on mortality in men and women aged ≥ 65 years. The authors demonstrated a positive association between multimorbidity and all-cause mortality, and they observed a higher mortality risk in men compared to women. The authors identified hypertension as the most prevalent chronic condition, both in isolation and in combination with other diseases. Notably, the combination of heart disease and diabetes was found to be the most hazardous in both males and females, with a higher risk observed in women compared to men, even when combined with other diseases .The study by de Sousa et al. utilized data from the 2019 National Health Survey, a household survey in Brazil, to examine health patterns and their association with chronic kidney disease (CKD) in the Brazilian general population. A total of 90,846 individuals were assessed, and the authors identified using factor analysis three patterns related to health: metabolic factors, behavioral risk factors, and behavioral protective factors. The presence of arterial hypertension, diabetes mellitus, hyperlipidemia, and cardiovascular diseases, collectively referred to as metabolic factors, was found to be associated with the likelihood of presenting CKD. These noteworthy findings underscore the importance of evaluating these metabolic factors together, as individuals often exhibit interconnected factors, highlighting the role of multimorbidity in the development of CKD .Chen C. et al., the association between multimorbidity and fertility history among middle-aged and older adult women in China was investigated. Data from 10,182 female participants in the China Health and Retirement Longitudinal Study (CHARLS) were utilized. The findings demonstrated that high parity and early childbearing were significantly associated with an increased risk of multimorbidity and a higher number of chronic conditions. Conversely, late childbearing was identified as a significant protective factor against multimorbidity. Moreover, the relationship between fertility history and multimorbidity was influenced by age and the urban-rural dual structure. This study provided valuable data supporting the exploration of sex-specific risk factors for multimorbidity .In the longitudinal study conducted by Gaskell et al. conducted an online pilot study comparing the lifestyle and health-related characteristics of residents in Qatar and the United Kingdom (UK). The study revealed the co-morbidity of psychiatric disorders in individuals with a BMI > 25 in both Qatar and the UK. Interestingly, the study results indicated no statistically significant associations between comorbidity and several predictors, such as drinking habits, smoking status, physical activity, vegetable consumption etc. Nevertheless, a significant association between sleep perception and comorbidity was found within the UK population .Hu et al. conducted a study using data from the Diverse Life-Course Cohort study. The goal was to examine the prevalence of common chronic diseases, identify multimorbidity patterns, and explore their diversity across different age groups and cultural backgrounds among adults in the Guangdong province in China. The findings revealed a prevalence of multimorbidity of almost 40%, with the frequency increasing as age advanced. Dyslipidemia was the most common disease, with a prevalence as high as 45%. The study also identified the top three binary multimorbidity combinations being dyslipidemia and hyperuricemia, dyslipidemia and hypertension, and hyperuricemia and hypertension. This exploration of multimorbidity patterns across different cultural backgrounds provides insights into the diversity of health profiles .Zheng et al. aimed to investigate the association between multiple lifestyle factors and cardiometabolic multimorbidity. The authors found that participants who engaged in two or more high-risk dietary behaviors, such as overeating and drinking water during meals, had a higher risk of developing cardiometabolic multimorbidity. The authors concluded that identifying individuals with specific high-risk lifestyle behaviors and managing their lifestyle may contribute to improved health outcomes for patients with cardiometabolic multimorbidity .The cross-sectional study conducted by Wang et al. conducted a study using the UK Biobank dataset, to investigate the potential influencing factors associated with the Charlson Comorbidity Index (CCI), a widely used measure of multimorbidity. The study suggested that high waist-to-hip ratio (WHR) and high body mass index were statistically significant predictors of elevated CCI, with WHR having a greater impact. Socioeconomic factors, such as income and the Townsend deprivation index, were also found to be associated with CCI. The authors point out that these factors may interact with each other, emphasizing the need for comprehensive, rational, and robust interventions to promote health .Chen M. et al. aimed to investigate the cross-sectional and longitudinal associations between multimorbidity and memory-related diseases (MDs) among middle-aged and older adults in China. The authors utilized data from CHARLS, an ongoing nationally representative study conducted every 2 years, focusing on community-dwelling adults aged 45 years and above. The findings identified significant associations between multimorbidity and MDs, with the strength of the association being more pronounced in middle-aged adults. Specifically, stroke, cancer, heart problems, dyslipidemia, and kidney diseases exhibited stronger cross-sectional relationships with MDs .The study conducted by Shen et al. utilized data from the Chinese Urban Adults Diet and Health Study to investigate the interaction between overweight/obesity and high glycated hemoglobin (HbA1c) status in relation to elevated high-sensitivity C-reactive protein (hs-CRP) levels among adults in the Chinese population. The study revealed that higher HbA1c levels and overweight/obesity, both independently and in combination, were associated with an increased risk of elevated hs-CRP, particularly among females and younger individuals. The authors concluded that implementing intervention strategies aimed at preventing high blood glucose levels and concurrently managing body weight could play a crucial role in reducing the occurrence of hs-CRP-related diseases .Overall, the results of the studies in this Research Topic shed light on the prevalence and impact of multimorbidity in diverse populations. They revealed associations between multimorbidity and increased mortality, identified specific risk factors and disease combinations, and underscored the importance of lifestyle management and early intervention in reducing multimorbidity risk and related diseases. The findings enhance our understanding of multimorbidity and provide valuable insights for the development of targeted interventions and healthcare strategies. We anticipate that this Research Topic will serve as a guide for future researchers to delve further into the intricate nature of multimorbidity, explore novel risk factors, comprehend disease interactions, consider sex-specific and age-specific factors, account for cultural diversity, and conduct more longitudinal and intervention studies. These advancements can contribute to the formulation of effective strategies for preventing, managing, and improving outcomes for individuals affected by multimorbidity.KG drafted and wrote the first draft of the manuscript. All authors reviewed, revised, and approved the final manuscript.


Cardiovascular disease (CVD) and chronic kidney disease (CKD) are the leading causes of mortality and health burden worldwide. Emerging evidence suggests that the gut microbiota plays an important role in the development and progression of CVD and CKD ,2. One oRecent investigations, including one review article of this Special Issue , have deMaternal–fetal crosstalk has been implicated in the long-term control of offspring health, including transgenerational hypertension. Previously, we found that the gut–brain axis via the mother may be a viable strategy for the control of hypertension in offspring . RegardiSpermidine (SPD), a naturally occurring polyamine, which is one of the metabolites of gut microbiota that maintains vascular function, can also be used to explore its potential regulatory effects on the gut microbiota through dietary interventions. In another article of the Special Issue , the autRegarding probiotics, several clinical studies have been conducted to determine the cholesterol-lowering effects of probiotic supplements in people with hypercholesterolemia . LactobaSimilarly, dietary interventions including prebiotics, probiotics and nutrients serve as the first-line treatment for CKD; they affect the development of kidney disease through the gut–kidney axis. A review in the Special Issue  showed tOne of the articles of this Special Issue  designedResistant starch (RS) is a dietary fiber that alters the gut microbial consortium and leads to an increase in the microbial production of SCFAs, which could attenuate inflammatory and oxidative stress pathways, to reduce the progression of diabetic kidney disease (DKD), one of the leading causes of CKD. One review of the Special Issue  evaluateFinally, Immunoglobulin A nephropathy (IgAN) is the leading cause of end-stage renal disease (ESRD) . IdentifThe studies featured in this Special Issue are important in furthering the exploration and application of prebiotics, probiotics, and nutrients. As researchers continue to deepen their understanding of the gut microbiota, the treatment means of targeting the gut microbiota continue to evolve. Complex diet therapy can provide a variety of theoretical support for a better prognosis of CVD and CKD, but more clinical trials are needed to assess its therapeutic potential.


Exosomes are under intense study as a promising means for drug or biomarker discovery, primarily due to their implication in intercellular communication and the emergence of disease states and their potential as a cutting-edge, natural delivery system at a nanoscale level. The proteins and nucleic acid cargo of exosomes has been at the center of exosome bioinformatic analysis in the context of health and disease, towards the hunt for novel biomarkers and diagnostics. However, the exosomal lipid composition has been emerging as an interesting target of study as well. Exosomes derived from different sources exhibit enrichment of specific lipid classes and various lipid compositions under different physiological conditions. Therefore, there is a mounting need for exosome lipidomic studies to build the foundation for novel therapeutic studies that use exosomal components. Bioinformatic pipelines are under development to efficiently identify, quantify and elucidate the exosomal lipids and their roles in disease. Cutting-edge bioinformatic tools, such as LipidXplorer, LUX Score, and LipidHome allow the execution of essential analyses such as shotgun lipidomics, and the detection of systematic differences in lipid composition and metadata processing. In the case of pancreatic cancer, an admittedly prevalent and life-threatening disease, these tools have yielded novel exosome lipid biomarkers. Furthermore, bioinformatic platforms such as “Lipidomics Informatics for Life-Science” enable fast and integrated access to these pipelines in a user-friendly manner.1, allow the prediction of structural components from an input of mass spectrometry data. In addition to the chemical structures, information on the exosomal lipid ontology is readily available. Meta-analysis of the exosomal lipidomics data is also made possible through the platform, which filters the data for non-lipid artifacts and corrects potential errors in the processing of MS spectra before storing the datasets.Modern bioinformatic methods facilitate the processing of exosome lipidomics data stemming from mass spectrometry. A set of bioinformatic tools, developed and provided by the LIPID MAPS consortiumProteins that are secreted by exosomes can have a multitude of effects on the development of pathological conditions. In contrast to eukaryotes, where a signal peptide marks proteins that are to be secreted to allow passage through the ER/Golgi-dependent pathway, the proteins to be secreted by exosomes lack such a signal peptide. Bioinformatic methods can thus bridge the gap toward the effective prediction of protein secretion mediated by exosomes. Intuitive algorithms, such as random forest, can be trained on amino acid sequences of proteins secreted and not secreted by exosomes as a relevant feature, approaching the prediction problem as a classification problem. ExoPred, which implements this method, has been developed to identify proteins secreted by exosomes in vertebrates, marking the potential of cutting-edge algorithmic approaches for predicting and annotating distinct, exosome-secreted proteins and opening new pathways for the subsequent study of their potential role in cell communication.2 enables the extraction of relevant features from a large number of unrelated features. Hence, this modern algorithm can help in the identification of key exosomal miRNAs and mRNAs involved in complex diseases. When combined with adequate cross-validation methods for the strict evaluation of features and parameters, LASSO – and similar feature extraction algorithms – can effectively generate novel information concerning the exosomal RNAs implicated in pathologies.The study of exosomal miRNAs can lead to discovering valuable information concerning the target mRNAs for these miRNAs. Especially in the context of disease and its progression, the differential expression of exosomal miRNAs represents a source of valuable data that can be analysed with bioinformatic tools. With the increase in computational power, machine learning algorithms are gaining popularity in medicine and exosomal analysis. The strength and adaptability of these methods allow the extraction of relevant and helpful information from the vast array of available databases, which are becoming increasingly open to the public and contain large and diverse biomedical data. The development of powerful algorithms, such as LASSO3, have been coupled with fluorescence correlation spectroscopy (FCS) conducted on samples of blood-derived vesicles from cancer patients, with the end goal being the accurate classification of tissue specific extracellular vesicles. In parallel, convolutional neural networks (CNNs), quantum CNNs, and networks such as ResNet4, show promise as supplementary validation tools when trained on the spectral images generated by the FCS. Along with continuously evolving AI algorithms and refined experimental techniques for exosome characterisation, we believe that the future of exosome bioinformatics is very prominent and its role in precision and personalized medicine will prove invaluable in the years to come.In cancer screening and precision nanotherapeutics, extracellular vehicles, such as exosomes, from patients are prime candidates for liquid biopsies. Machine intelligence-driven classification methods are rapidly emerging as a solid support system that, when paired with tried-and-true analytical methods, such as time-dependent spectroscopy, can aid the early and accurate detection of malignancies. An assortment of machine learning approaches such as multilayer perceptrons, support vector machines, and AdaBoost random forest classifiers


Model organisms are non-human species that have long been recognized as one of the crucial pillars in research, particularly in the field of experimental pharmacology and drug discovery . These oModel Organisms in Experimental Pharmacology and Drug Discovery 2022” was established to showcase recent studies that use model organisms with substantial impact on the field of experimental pharmacology and drug discovery. This Research Topic was led by three Research Topic editors and one Research Topic coordinator that managed the whole editorial process, with the help of the Frontiers editorial team, for the submitted papers. This Research Topic was open for submission from 23 March 2022 to 8 August 2022. Of eight submissions, a total of five original articles were successfully accepted, giving promising insights into the use of model organisms and the future direction of experimental pharmacology and drug discovery. Except for Suarez et al. all studies use rodents as model organisms in their studies, illustrating the popularity and continued use to these species in particular, the most used throughout history in the context of drug discovery  and eprinomectin (EPM) as examples. Although this nematode has long been used in the screening of novel anthelmintic candidates, it has not been fully explored for other purposes such as the investigation of anthelmintic dose-response-time and drug-drug interactions. To achieve their purpose, Suarez et al. observed the effects of IVM and EPM on the movement of C. elegans by using an infrared motility assay. They found that the drug effect was increased, according to the exposure time, and worms could not recuperate once paralyzed. They also reported that EPM was less effective compared to IVM; though both drugs exhibited neither synergistic nor antagonistic profiles once combined. Overall, this study implies the pharmacological significance of the exposure time of each drug, rather than the combination of both drugs, to the improvement of their anthelmintic effects.In the first article, Wan et al. confirmed the prospective role of puerarin in the treatment of acute alcoholism-induced oliguria. Using an integrative approach via network pharmacology analysis combined with experimental confirmation, the authors identified potential key targets of puerarin against acute alcoholism-induced oliguria in rats. Following a successful effort to establish a rat model of acute alcoholism, the authors revealed the involvement of cAMP signalling pathway in the puerarin-mediated pharmacological attenuation of oliguria in rats with acute alcoholism. This study has verified not only the potential role of puerarin in the management of acute alcoholism-induced oliguria but also the power of network pharmacology in combination with experimental validation to serve as a comprehensive platform to discover potent drug candidates with less adverse effects to treat human diseases.In the second article, Lu et al. carried out a series of in vitro and in vivo experiments to demonstrate the anti-depressant-like effect of echinacoside (ECH). Using a combination of LPS-induced N9 microglial cells as the in vitro platform and mice with chronic unpredictable mild stress (CUMS) depression signatures as the in vivo model, the authors revealed that ECH could alleviate neuroinflammation-mediated depressive symptoms. Treatment of LPS-induced N9 microglial cells with ECH can reduce the production of NO without any adverse effects on cell viability and can suppress the activation of microglial cells, thus alleviating neuroinflammation. The authors also demonstrated that ECH can downregulate the expression of pro-inflammatory cytokines, such as IL-1β and TNF-α, and slightly upregulated the anti-inflammatory factors of IL-4 and IL-10, supporting the hypothesis that ECH may promote the microglial polarization from M1 to M2 with anti-inflammatory phenotypes. Further, the authors observed that ECH treatment can reverse CUMS-reduced sucrose preference in mice, probably due to suppression of the hippocampal neuronal damage, increased levels of 5-hydroxytryptamine, norepinephrine, and dopamine, and reduced expression of pro-inflammatory cytokines. Thus, their results demonstrated that ECH can alleviate depression-like behaviours, most likely by inhibiting neuroinflammation.In the third article, Crawford et al. investigated the prospective antinociception and anti-allodynia effect of decursinol, the metabolite of its pyranocoumarins contained in the Angelica gigas Nakai (AGN) root alcoholic extract. To do so, the authors used two models of pain in mice: acute model of pain and model of chronic neuropathic pain. The results revealed that decursinol was able to elicit dose-dependent antinociception effect in mice experiencing acute thermal pain and anti-allodynia effect in the cisplatin-induced neuropathic mice. Although decursinol demonstrates promising pharmacological effects, the authors observed the development of tolerance to its pain-relieving properties. They found that full tolerance was detectable to both antinociceptive and anti-allodynia effects of decursinol after prolonged use. Therefore, decursinol demonstrates a promising use in the management of acute and chronic pain. Nevertheless, the authors also raise awareness for its rational use and future applications.In the fourth article, Bervinova et al. studied the activity of the Ficus tikoua Bur. extract in the ethylene glycol-induced urolithiasis model of Sprague-Dawley (SD) rats. The authors used several parameters such as pathological signatures, biochemical and hematological parameters to evaluate the efficacy of treatment on the development of inflammation and urolithiasis. They found that the administration of F. tikoua Bur. extract led to the improvement of diuresis and the reduction of inorganic phosphates concentration as early as 6 weeks after treatment, comparable to Cystone®, a drug currently used to manage urolithiasis. However, different from Cystone®, treatment of the urolithiasis model of SD rats with F. tikoua Bur. extract can restore the level of lymphocytes, sodium, chlorine, and inorganic phosphates in the blood, comparable to the ones shown in the healthy control group. These results suggest that F. tikoua Bur. extract is a promising candidate for pharmacological treatment of urolithiasis with F. tikoua Bur. extract can restore lymphocytes, sodium, chloride, and inorganic phosphates to comparable healthy control group levels in the blood.In the fifth article, In conclusion, this Research Topic has provided recent updates and important findings related to the application of model organisms in experimental pharmacology and drug discovery. Continuous evaluations of reported methods and results are critically required to improve the planforms used in the discovery of new drugs with novel mechanisms of action and less toxicity that will offer better results in the disease management.


Scanning edentulous arches during complete denture fabrication is a crucial step; however, the quality of the resulting digital scan is still questionable. The purpose of this study is to systematically review studies  and determine whether intraoral scanners have clinically acceptable accuracy when recording completely edentulous arches for the fabrication of removable complete dentures. An electronic search in medical databases like PubMed, Scopus, and Web of Science (WOS), using a combination of relevant keywords, retrieved 334 articles. After full-text evaluation, twelve articles fulfilled the inclusion criteria for this review . A quality analysis of the included studies was carried out using the QUADAS-2 tool. The accuracy values varied between different intraoral scanners. Different regions of the edentulous arches showed differences in trueness and precision values in both in vitro and clinical studies. Peripheral borders, the inner seal, and poorly traceable structures like the soft palate showed maximum discrepancies. The accuracy of intraoral scanners in recording clear anatomic landmarks like hard tissues with attached mucosa was comparable to conventional edentulous arch impressions. However, higher discrepancies were recorded when digitizing mobile and poorly traceable structures. Intraoral scanners can be used to digitize denture-bearing areas, but the interpretation of the peripheral border and the soft palate should be carefully carried out. The optimum function of a complete denture depends on the tight fit of the intaglio surface of the complete denture and the peripheral seal area, with the cohesive forces of saliva adding to the retention . DiffereNevertheless, scanning reduces patient discomfort as no impression material is placed on the tissues, and the tissues are not deformed during the impression. Moreover, it allows for the easy transfer of information to the laboratory technicians and the archiving of data related to prosthesis fabrication . The denThe capabilities of the IOS in scanning denture-bearing areas were previously investigated; however, the resulting accuracy of these scans is still inconclusive. This systematic review aims to determine whether intraoral scanners have clinically acceptable accuracy when recording completely edentulous arches to fabricate removable complete dentures.The protocol for this systematic review was registered in the International Prospective Register of Systematic Reviews (PROSPERO) with the registration number CRD42021289821. It was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.The PICO format for the current study is as follows: (P) the population is a completely edentulous patient, (I) the intervention is an impression made using an IOS, (C) the comparison is a conventional impression technique used for the completely edentulous arch, and (O) the outcome assessed is accuracy in the form of trueness and precision. The inclusion criteria consisted of studies comparing the accuracy of intraoral scanners for recording completely edentulous arches. Studies that compared digital scans with conventional impressions, in in vitro or in clinical studies, were included. The studies were clinical nonrandomized studies. There were no restrictions on the publication date or languages of the included studies. Studies that included complete arch implant impressions, case reports/series, and studies where accuracy was not determined were excluded. Review articles were also excluded.Two independent reviewers  performed the initial search in online databases like PubMed, Scopus, and Web of Science using the relevant keywords in different combinations. The risk of bias for all included studies was evaluated by two independent reviewers using the Quality Assessment Tool for Diagnostic Accuracy Studies-2 (QUADAS-2). This tool is specifically designed to assess the quality of primary diagnostic accuracy studies. It consists of four domains that cover patient selection, index test, reference standard, and flow and timing. The relevant questions from QUADAS-2 were applied to the eligible studies, and a scoring system was used, where a score of 1 was assigned for “yes” answers and a score of 0 for “no” or “unclear” answers. The maximum score achievable was 13, indicating a low risk of bias .The following outcome variables were extracted from the included studies: year of publication, type of study, country, sample size, type of intraoral scanner, experimental method, accuracy evaluation method, and mean deviation from the conventional impression expressed in mm (precision or trueness).n = 144, Scopus n = 128, Web of Science n = 62). After removing the duplicates, 238 articles were screened for eligibility. Based on the title and abstract screening, 211 articles were excluded. Further, 27 full texts were assessed, and based on the inclusion and exclusion criteria, 12 studies were included in the review  was the most used, with six clinical studies ,25,26,27Due to the heterogeneity of outcome variables reported in the studies, a meta-analysis could not be conducted. Some studies reported mean average deviations, while others reported root mean square deviations. The accuracy of the intraoral scan was primarily evaluated by superimposing it against a 3D model obtained from a lab scanner in most studies ,22,26,27The superimposition of virtual models was performed using Geomagic, a 3D aligning software, with best-fit alignment. However, it is worth noting that different versions of the same software were utilized in six separate studies. In one study , 3D ReshZarone et al. described the three scanning techniques. The buccopalatal technique (BP) first scans the edentulous ridge top starting from the left maxillary tuberosity, then moving along the buccal aspect and with an anticlockwise movement along the palatal surface and completing at the midline of the palate; in the S-shaped technique, the scanning started from the palatal side of the left maxillary tuberosity by moving the scanner tip with alternate palatobuccal and buccopalatal S-shaped movements along the ridge, from the left to the right side; finally, the area along the palatal midline was recorded. In the palatobuccal technique, the scanning advanced from the left maxillary tuberosity along the top of the ridge, ending at the right side, then covered the palatal side and terminated on the buccal side .The IOS used were Trios3  ,29,30 anTwo studies evaluated the accuracy by superimposing an intraoral scan against a 3D model obtained from a laboratory scanner ,30. AnotThe included studies indicate that the accuracy of an edentulous mucosa scan depends on soft tissue features such as flexibility, mobility, and dimension ,24,27, aZarone et al.  assessedMost of the included studies used the best-fit algorithm software that stitches together the images acquired by the IOS. The studies that assessed the trueness and precision of the digital scans employed different aligning software, some of which were custom-made for the specific study ,29. TherThe assessment of best-fit alignment and color-coded comparisons of the maxilla revealed that maximum deviations were present at the soft palate, peripheral borders, or the inner seal in an intraoral scan. The highest variation was found in sublingual areas and the vestibule in the mandibular arch. The authors reported that lips and cheeks must be considerably retracted during the scanning procedure ,24, whicLo Russo et al.  found thIn a dimensional measurement study on the mandibular arch, Braian and Wennerberg calculated the distance between five markers in pairwise comparison and cross-arch comparison. They reported that complete arch scans had low precision, although short distances of about 22 µm presented better accuracy. The study showed an inversely proportional relation between scan distance and 3D data accuracy .Osnes et al.  describeUsing custom-made software, Kalberer et al.  evaluateThe influence of the operator’s experience on scan accuracy and operating time was studied by Schimmel and Deferm et al., indicating that the operator’s experience and shorter scanning time improved the accuracy of the digital scan ,35. A fuWith technological advances, new-generation IOSs show higher accuracy and shorter scan times. Software and hardware updates over the years have been implemented to improve data acquisition. Although the accuracy of an IOS depends on the precision of each image captured, it also relies on the accuracy of superimposition, which is determined by the mathematical models and algorithms used to reconstruct the image . The limitations of this study include clinical studies comparing digital scan data to the conventional impression with constraints. Conventional impressions needed to be digitized by a laboratory scanner, which could introduce some known or unknown distortion. Additionally, in some studies, the cast was made and digitized, leading to variations in results. Nonetheless, this method was a valid approach to revealing the shortcomings of an evolving technology and providing recommendations to clinicians. Most of the included studies could not compare the effect of the digital scan on the retention and stability of complete dentures. However, one of the included studies by Chebib et al.  assessedWithin the limitations of the current systematic review, intraoral scanners provide clinically acceptable digital scans. However, some improvement should be implemented when recording the mobile mucosa surfaces. Studies should standardize the quantification methods of discrepancies and explore the clinical significance of those deviations on the clinical fit and comfort of resulting complete dental prosthesis. Digital intraoral scanning is not recommended when facing unfavorable ridge anatomy and when denture retention may require the compression of the tissues.When scanning the vestibule, the entire area should be scanned in one shot, as rescanning later to capture the missed area may result in error. Additionally, the intraoral scanner can be used to digitize edentulous arches, although case selection is still required.


Recently, advances in stem cell engineering to differentiate desired cell types and produce multicellular structures in vitro have enabled the derivation of limb-like tissues from pluripotent stem cells. However, in vitro recapitulation of limb morphogenesis is yet to be achieved. To formulate a method of building limbs in vitro, it is critically important to understand developmental mechanisms, especially the modularity and the dependency of limb development on the external tissues, as those would help us to postulate what can be self-organized and what needs to be externally manipulated when reconstructing limb development in vitro. Although limbs are formed on the designated limb field on the flank of embryo in the normal developmental context, limbs can also be regenerated on the amputated stump in some animals and experimentally induced at ectopic locations, which highlights the modular aspects of limb morphogenesis. The forelimb-hindlimb identity and the dorsal-ventral, proximal-distal, and anterior-posterior axes are initially instructed by the body axis of the embryo, and maintained in the limb domain once established. In contrast, the aspects of dependency on the external tissues are especially underscored by the contribution of incoming tissues, such as muscles, blood vessels, and peripheral nerves, to developing limbs. Together, those developmental mechanisms explain how limb-like tissues could be derived from pluripotent stem cells. Prospectively, the higher complexity of limb morphologies is expected to be recapitulated by introducing the morphogen gradient and the incoming tissues in the culture environment. Those technological developments would dramatically enhance experimental accessibility and manipulability for elucidating the mechanisms of limb morphogenesis and interspecies differences. Furthermore, if human limb development can be modeled, drug development would be benefited by in vitro assessment of prenatal toxicity on congenital limb deficiencies. Ultimately, we might even create a future in which the lost appendage would be recovered by transplanting artificially grown human limbs.Building limb morphogenesis  Engineering limb morphogenesis should require recapitulating the developmental environment of the limbs in vitro. Importantly, the modularity of limb development, namely, independence from the development of other organs, might potentially facilitate the self-organization of patterns and structures without external guidance in culture  such as embryonic stem cells (ESCs) or induced pluripotent stem cells (iPSCs) . Those f culture . TherefoLimb development initiates as epithelial-mesenchymal transition of the lateral plate triggered by FGF-signaling from ectoderm . The mesOnce the limb bud is established, the morphogenesis of the limb proceeds in a semi-independent manner, as shown by the fact that limb bud morphogenesis could happen in an unusual part of the body in experimental and regenerative situations. In 1995, Cohn et al. showed that when a bead soaked with FGF or WNT is implanted into the flank region between the forelimb and hindlimb, an ectopic limb bud is induced and the established bud then independently develops into a complete additional limb . These sRegeneration of the limbs in urodele amphibians and larval anurans is another example showing the modularity of limb formation, as it can be interpreted as ectopic and heterochronic limb development. When the limb is amputated in those animals, the stump is immediately covered by the wound epidermis and the wound epidermis then serves as the signaling center called apical ectodermal cap (AEC), which functionally corresponds to AER of the developing limb bud . UnderneInterestingly, ex vivo culture of chick limb bud fails to develop properly , to the anterior margin of another limb bud, the mirror-duplicated pattern of three digits is induced along the anteroposterior axis . It was Shh established and how does the anteroposterior axis of limbs correspond to that of the body? The axial expression of Hox9 paralogous group genes is restricted to the posterior portion of the forelimb-forming region and Hox9 genes activate the expression of Hand2 in the posterior forelimb, which then activates Shh in ZPA . StrikiBlood vessels are the incoming tissues that substantially affect the morphogenesis of the limb skeleton. Vascularization of the limb bud is initiated as angiogenesis from the dorsal aorta . ConcomiHif1a, for its development and maintenance (The failure of proper cartilage morphogenesis in avascular culture does not seem to be simply due to the lack of oxygen and nutrient supply. Cartilage morphogenesis is associated with vascular remodeling since cartilage requires a hypoxic environment and hypoxic gene regulator, ntenance . While bntenance . Althougntenance , vasculantenance . Furtherntenance .Unlike cartilage, bone requires vascularization. Limb bone formation occurs via endochondral ossification, in which cartilage anlagen is replaced by bone minerals. At the center of the cartilage anlagen of long bones, the chondrocyte becomes hypertrophic chondrocyte and secretes VEGF to attract invasion of blood vessels . Bone minAG, Fgf, Bmp, and Nrg1 are considered to be “nerve factors” which are secreted from peripheral nerves and induce blastema formation at a stump (Peripheral nerves are critically important for limb regeneration. It has long been known that if a limb of urodele amphibians is denervated, the amputated limb will fail to regenerate . Convers a stump . However a stump . Further a stump . Thus, tIn this section, we argued that besides limb bud mesenchyme, tissues such as blood vessels, muscles, and peripheral nerves come into the limb bud and contribute to limb morphogenesis . Musculoin vitro, is it necessary to direct the morphogenesis of those incoming tissues separately? Since limb morphogenesis is dependent on the interaction of multiple different tissues in the limb, it would be important to establish methods for co-culturing and integrating multiple cell lineages, including limb mesenchyme and the incoming tissues. However, the modular aspect of limb development and regeneration suggests that the incoming tissues as well as limb mesenchyme do not rely on continuous input of morphogenetic information from the external environment. Therefore, in the next section, we will discuss how to achieve the derivation of limb progenitor cells, introduce the positional identities of limb mesenchyme, and integrate them with the incoming tissues.In the context of engineering limb morphogenesis in vitro (Recently, Chen et al. reported that three-dimensional culture of mouse iPSCs successfully induced the differentiation of cells with limb bud identity in vitro  (Figure in vitro . Due to in vitro . Chen etin vitro . Furtherin vitro . Thus, tin vitro .Strikingly, the limb bud-like aggregates stimulated the regeneration of a mouse digit. Chen et al. transplanted the limb bud-like aggregates derived from iPSCs together with a cocktail of growth factors, FGF8, WNT3a, Thymosin β4, and BMP2 onto the amputated second phalange of an adult mouse digit. While the adult mouse is unable to regenerate the digit after amputation without any manipulation, the grafted digit showed the outgrowth of distal phalange tissues which were composed of both graft-derived and host-derived cells .in vitro, in which Hand2-positive mesenchyme is covered by E-cadherin-positive ectoderm (Later, it was reported that another three-dimensional culture method of mouse ESCs successfully recapitulated the differentiation of early limb bud-like structure ectoderm  (Figure ectoderm . Essentiectoderm . While wectoderm , a high ectoderm . Thus, tectoderm .After the primitive streak is established, mesodermal cells from the posterior part of the primitive streak migrate laterally more robustly than those from the anterior part, and thereby the anteroposterior identities of the primitive streak are converted into the mediolateral axis of mesoderm at the later embryonic stage. At this stage, BMP4 that is secreted from the lateral plate and NOGGIN, a BMP antagonist secreted from the notochord, constitute a BMP gradient along the mediolateral axis, specifying the subtypes of mesoderm . Thus, iWnt7a and ventral Bmp. Hence, the third fate decision by BMP was to grant ventral identity to the limb bud-like aggregates. Indeed, local inhibition of BMP signaling created a portion with dorsal identity in the aggregate and induced the formation of AER-like structure at the dorsoventral border.Although it is not very clear how the aggregate with lateral plate identity is differentiated into limb bud mesenchyme in the culture of Is it possible to recapitulate more complex limb morphogenesis with cultures from PSCs? To achieve this goal, it seems essential to induce proper organization of the proximo-distal, dorso-ventral, and anteroposterior axis and to induce vascularization into the limb bud organoid. In fact, these are two of the current major challenges in the field of organoids in general: to provide morphogen gradients that are not self-organized in the aggregate and to induce vascularization.To establish morphogen gradient in the culture environment of organoids, methods are selected based on the scale and duration of the gradient to be maintained. One commonly used method relies on diffusion from two reservoir chambers. Organoids are embedded in hydrogels and placed between the two chambers . Using tWhen a smaller scale of the gradient is required, local administration of signaling molecules can be utilized. As mentioned above, When a larger scale of the gradient is desired, a 4 mm scale of the gradient can be achieved by embedding organoids on the confluent of two parallel streams . An evenAlternatively, the organoid assembly approach might be utilized. In this approach, two organoids with two different positional information are differentiated separately and combined into one “assembloid” . This apin vitro (in vitro. This goal will likely be achieved by identifying culture environments which allow integration of a microfluidic device with a vascular bed and vascularized organoids (To vascularize organoids, one of the approaches is co-culturing with endothelial progenitor cells. For example, in a brain organoid, human iPS-derived endothelial cells formed a vascular network and improved the survivability and maturation of the organoid . Similarin vitro . Howeverrganoids .in vitro models of three-dimensional limb development, manipulability to elucidate the mechanisms of morphogenesis will be dramatically enhanced. Furthermore, since iPSCs have been established in many non-traditional model organisms, molecular and genetic mechanisms of mammalian limb diversities, including specific features of human limbs, are expected to be studied using organoids from PS cells. For instance, the extensive growth of the proximal hindlimb is one of the remarkable differences between the bodies of modern humans and any other extant animals. It has enabled our upright bipedalism and presumably allowed us to have a heavy brain and has released our hands from their roles for walking. Thus, it would be exciting to have an opportunity to unravel the genetic and developmental mechanisms of the evolution of our limb proportions. Finally, models of human limb development would bring about medical benefits, such as drug screening to assess prenatal toxicity causing congenital limb defects and ultimately rescuing lost appendages by transplanting in vitro-derived human limb bud tissues.It is becoming technically feasible to introduce appropriate morphogen gradients exogenously and to introduce blood vessels and other tissues to limb bud organoids. If engineering a more complex limb bud could be achieved, it would substantially open up avenues for research and applications of appendage development. If we can create


A steady, incompressible, two-dimensional Sisko-nanofluid flow towards the horizontal direction with no movement in the vertical direction is considered on a stretching/shrinking surface. The power law component (Sisko model) is incorporated under the regime of the porous medium. A magnetic impact is included coming from the MHD in the surface normal direction. In addition, thermal radiation, Brownian diffusion, and thermophoresis are involved in the governing system of equations obtained from the Navier–Stokes model in two-dimensional flow systems. The PDEs are converted into the one-dimensional system using suitable transformations and solved by Galerkin weighted residual method validated with the spectral collocation method. The optimization analysis is performed on heat transfer and skin-friction factors using response surface methodology. The impact of the parameters involved in the model has been testified and is provided in graphical forms. The outcomes indicate that for the values of the porosity factor fluctuating between , the velocity profile and corresponding boundary layer thickness are lesser towards the maximum value of the parameter, and the results are opposite as the parameter approaches zero. The optimization and sensitivity analysis shows that the transport of heat sensitivity towards thermal radiation, Brownian diffusion, and thermophoresis declined whenever the Nt and Nb increased from low to high and at the medium level of thermal radiation. An increment in the Forchheimer parameter increases the sensitivity of the rate of friction factor, whereas increasing the Sisk-fluid parameter has the reverse effect. Elongation processes like those of pseudopods and bubbles make use of such models. The idea is also widely used in other sectors, such as the textile industry, glass fiber production, cooling baths, paper manufacture, and many more. One notable piece in this area is Crane’s2 description of the boundary layer flow phenomenon, which depends on the stretching of the surface, moves within the plane, and implements the idea of relevant velocity towards a fixed point. Reading Hassanien et al.3 explanation of how micro-polar fluids behave when they flow through a stretching surface utilizing the varied temperature distribution on the surface is crucial to getting a firm grasp on this phenomenon. The effect of a magnetic field on the motion of a viscoelastic and electrically conducting fluid based on a stretching surface was studied by Anderson et al.4. The reader is directed to10 for further information on related topics.Fluid flow analysis on stretching and shrinking surfaces are well-researched in the literature. To be sure, there are two distinct types of stretching phenomena: linear and non-linear. While both have their uses in real-world challenges, the simplicity of linear stretching makes it more trustworthy than non-linear. Stretching surfaces has several significant applications, particularly in boundary layer formulations of fluid problems. Elongation processes like those of pseudopods and bubbles use shrinking/stretching surfaces. The idea is also widely used in other sectors, such as the textile industry, glass fiber production, cooling baths, paper manufacture, and many more. The research of Sakaidis11 focused on the fluid dynamics of lubricating greases. With the addition of a superscript (j = 1), the fluid reverts to its Newtonian form, losing its Sisk-property. Therefore, in the power law model, the values (j > 1 or j < 1) play a crucial role. After Khan et al.13 described the model of nanofluids based on sisko-fluid features, Nadeem, and Akbar14 expanded the concept in peristaltic flow by merging the sisko model with the inclined tube surface. Later works incorporated the idea of boundary layer formulations and reported noteworthy discoveries; for instance, Khan and Shehzad15 established boundary layer approximations for sisko-fluid models using a stretching surface. It was shown that the wall drag force varies noticeably between linear and non-linear stretching situations. According to the sisko flow model described by Hayat et al.16, porous media with blowing or suction capabilities may be used to create the flow. Using the sisko-model and other characteristics including heat production, heat absorption, and thermal radiation, Eid et al.17 and Eid and Mahny18 developed similar ideas.Sisko-fluids is a catch-all term for power-law fluids that describes the commonalities amongst, for example, biofluids, greases, cement pastes used in drilling fluids, waterborne fluids, and cement slurries. For his first modelling of siskofluids, Sisko20 presented mixed convection analysis of visco-elastic fluid using a stretching velocity coupled with porous medium characteristics, which increases the porosity factor. Sometimes it's necessary to regulate flow by manipulating the fluid's motion, and this is where MHD comes in. The behavior of non-Newtonian fluids was studied by Eid and Mishra21 using a porous, non-linear stretching surface. In their investigation of fluid flow, Eid & Mahny22 considered the role of multi-scale heat dynamics (MHD) and heat absorption/production. Using boundary layer approximations, Hayat et al.23 examined the effect of MHD on a sisko-model-based, three-dimensional flow issue. Researchers have also considered the effects of a number of other models all at once, including the Jeffrey model, the Casson model, the micropolar fluids model, and the sisko-model (see for example27). Furthermore, the significant improvement in the thermophysical properties of nanofluids subject to various parameters including inclined as well as surface normal MHD, porosity factor, and stretching surfaces has been reported categorically in39 and cross references cited therein.Recent years have seen a rise in the importance of MHD (magnetohydrodynamic) research in many practical engineering and industrial uses of fluids. Because MHD has such a dramatic effect on fluid motion and generates different retardational and supporting forces depending on where a magnetic field is applied to a particular surface, it may be used with surprising swiftness to regulate a wide range of conditions. Induction flow meters are a prime example of this since they measure the velocity of a fluid in relation to the direction of a magnetic field's potential difference. Hundreds of researches have been published on the role of MHD in fluid flow issues, and the results have vastly improved. The occurrence of MHD in non-Newtonian fluids is indicative of real-world engineering applications, such as in the production of electricity, the operation of nuclear reactors, the purification of crude oil, and many other areas. Several research have been recorded, indicating that the idea of MHD participation in fluid mechanics has been given considerable attention. HsiaoThe online literature on this subject is a significant source of inspiration for our inquiry. We have studied this fluid flow model in the context of boundary layer formulations on a stretched surface to enhance the thermophysical characteristics of a nanofluid subject to various parameters. The rules on governing heat and mass transfer equations are therefore included in the flow model. The governing non-linear Navier–Stokes equations, which are expressed in two dimensions, have the Darcy-Forchheimer components and MHD together with the power law rule (Sisko model) in the momentum equation and thermal radiation in the energy equation, such that the fluid model responds to a stretching rate at the solid surface due to stretching/shrinking properties of the surface and exhibits the governing equations in PDEs format, which are constructively transformed into ODEs using suitable transformations, and subsequently solved by Galerkin weighted residual method (GWRM) validated with spectral collocation method (SCM). The optimization analysis is performed on heat transfer and skin-friction factors using Response Surface Methodology (RSM). The governing model's significant components are porosity, magnetohydrodynamics (MHD), power law rule (Sisko model), and thermal radiation. To our knowledge, however, there is no research on the subject matter. Therefore, the article can be very handy in different fluid mechanics applications, especially biofluids, greases, cement pastes used in drilling fluids, waterborne fluids, and cement slurries.Using the concept of nanoparticles' molar concentration, what physical model can be realistically adapted to predict boundary layer flows of sisko-fluids?How could a magnetic field in terms of MHD act on fluid flow?Given that the Darcy medium enhances the frictional impact on fluid flow analysis, how can we predict the resulting skin friction?Which scientific approach yields reliable findings?What is the significance of applying Optimization analysis to the current model? How can it be fruitful in analyzing the crucial fluctuations in heat transfer rate and wall drag force?How can we enhance the nanofluidic medium's thermal performance?"How can we reduce the magnitude of the forces exerted by friction at the surface?How does the suggested nanofluid flow issue manifest hydrothermally?The present study incorporates Buongiorno’s model utilizing the Sisko-fluid properties adopting a laminar, steady, two-dimensional flow in the positive plane of xy-coordinate system subject to zero movement in vertical direction. The only fluid motion is taken in the x-direction for both shrinking and stretching cases of the surface depending on the stretching/shrinking rate of the surface taken as mentclass2pt{minim29). Hence, in the present model, we have emphasized the development of fluid flow using a porous medium. Referring to Khan et al.40 and Prasannakumara et al.41, we can write the complete governing model as follows:The detailed study of available published literature regarding nanofluid flow shows that porous structures are highly applicable in many industrial applications , are listed below:The relevant governing boundary conditions :The following transformations, highly suitable to power law models, are introduced in the governing PDEs to resolve them into ODEs for subsequent solutions via numerical scheme , re, re12), A significant number of parameters are involved in the systems 1)–(12); therefore, a complete nomenclature of the parameters is necessarily provided below in the Table –(12); thSignificantly, the dimensionless expressions of the total viscous frictional factor Moreover, the involved shear stress components The finaly simplified version of system (15)–(16) is given in (17)–(18), as follows:GWRM, also known as Galerkin weighted residual method, is used to solve the final ODEs. The method can be called a modification case of the Least Squares method. It prioritizes the approximating function derivative over the residual function derivative for the relevant unknown In the governing differential equations, the initial guesses are assumed to be combinations of trial functions with unknown coefficients.These solutions are incorporated in the equations which contain residuals.The easiness of handling BVPs,High precision, fast convergence, and efficiency,The minimized range within 0 to The errors are restricted to a low ratio. In addition,GWRM is an effective technique for finding BVP solutions for the following reasons:The approximate solutions are sought out as follows:Table A comparative analysis was performed for the spectral collocation method (SCM) and Galerkin weighted residual method (GWRM). Figure The impact of various parameters named as magnetic field, thermal radiation, Forchheimer number, porosity number, Sisko-fluid parameter, and power law index represented here with notation j, Brownian diffusion, thermophoresis & Prandtl number on all the three main profiles of fluid flow are analyzed by finding numerical data which is subsequently plotted in graphical forms. A dual analysis is performed within the same frame of reference for each parameter for shrinking and stretching surfaces. Solid lines in the graph represent shrinking surfaces, while dashed lines represent the stretching surface. Specifically, the diagram in Fig. mentclass2pt{minimFigure mentclasspt{minimamentclass2pt{minimTo determine the optimal response of heat transfer rate and the skin friction coefficients for the efficiency of specific components, a recently developed statistical method known as Response Surface Methodology (RSM) is used. The current simulation is dependent on thermal radiation, Brownian motion, and thermophoresis variables for the local Nusselt number, and the simulation is dependent on the magnetic field parameter, Sisk-fluid parameter, and Forchheimer parameter for the skin friction coefficient, respectively. The simulation process is carried out within the allowed range of these parameters. These factors are considered when determining the heat transfer rate as We then reach the following response functions by removing the insignificant components from the response function and calculating the regression coefficients.The regression coefficients are obtained via the Design of Experiments with RSM.A statistical instrument that is reliable. Analysis of Variance (ANOVA) is used to assess the regression models and the different statistical tests with F-values, p-values, lack of fitting, error, and total error for the simulated outcomes of Nusselt number and the skin friction coefficient is deployed via Tables Similarly, the model of skin friction is provided by excluding the interaction variables in the manner directed in Table The normal plot for the distributions of the data with the fitting values is shown in Figs. Figure Furthermore, at a middle level of Modeling and simulating the suggested design relies heavily on sensitivity analysis. The present study investigates the sensitivity of the heat transfer rate and the shear force rate to modest changes in parameters under controlled settings. It is defined as the partial derivative of the responses, which are the local Nusselt number and the shear rate, concerning the characterizing parameters Displayed here is the sensitivity of the rate of heat transfer as well as the friction factor in Fig. Similarly, the lowest sensitivity value (-0.00056) of heat transport is at the coded values of The influence of the involvement of porous medium in fluid flow analysis is prominent. Forchheimer number results in an inevitable decline in fluid flow. And so is the case with values of porosity parameter fluctuating between Temperature distribution receives enhancement for larger thermal radiation, Brownian diffusion, and thermophoresis, which is quite logical from their constituency; however, a more significant Prandtl number results in a low thermal profile.For both the cases, shrinking & stretching, we have noticed that the concentration of the particles shows specific rising behavior for the range The involvement of Darcy-medium is quite helpful in controlling the fluid movement and balancing the fluid's thermal state for various manufacturing procedures while maintaining the nanofluid's low viscosity and higher thermal conductivity.The coefficient of heat transfer is significantly achieved at higher levels of thermophoresis and lower levels of thermal radiation and Brownian motion factors. The surface friction rate at the plate boundary is dominant at higher values of Sisk-fluid parameter and Forchheimer parameter factors and lower levels of magnetic field parameter.The transport of heat has the highest sensitivity value at the levels of The transport of heat sensitivity The current study provides numerical approximations for a steady, incompressible, two-dimensional Sisko-nanofluid flow on a stretching/shrinking surface equipped with power-law component (Sisko model), magnetic impact, thermal radiation, Brownian diffusion, and thermophoresis. In addition to boundary layers formulations, optimization analysis of the heat and mass transfer attributes is performed using Response Surface Methodology. The followings are the key outcomes of the study:


Hematopoiesis is the intricate process responsible for all blood cell formation and maintenance, and is tightly regulated by a myriad of intrinsic and extrinsic factors . This orNonetheless, the fragile balance of normal hematopoiesis often succumbs to a spectrum of genetic and epigenetic aberrations. These deviations may disrupt the self-renewal, differentiation, proliferation, or survival of HSCs, ultimately leading to the malignant transformation of specific hematopoietic cell populations. Moreover, disruptions within the bone marrow niche that supports the requisite number and functionality of HSCs can further facilitate oncogenesis . ConsequAt the core of comprehending leukemia pathogenesis lies the precise unraveling of the roles played by genetic and epigenetic regulatory mechanisms . GeneticNPM1 mutations. High VISTA levels at diagnosis serve as a predictor of disease recurrence in specific AML subgroups. The potential of VISTA blockade as an immunotherapeutic strategy against AML with the aim of boosting antitumor immune responses and modulating the inflammatory microenvironment is discussed. Furthermore, our contributing authors provide comprehensive reviews concerning the impact of mutations or dysregulation of key proteins such as TET proteins [In this Special Issue, we proudly present a compilation of one original research article and seven reviews that delve into the diverse facets of the molecular mechanisms driving hematologic malignancies, including leukemia. In a research article by Pagliuca et al. , the expproteins , IKAROS proteins , S100A8/proteins , NPM1 [8proteins  on hematproteins .Comprehending the fundamental molecular basis that governs both normal and malignant hematopoiesis is essential for more rational and effective therapeutic interventions. While a substantial amount of work remains, this compilation of cutting-edge research will contribute to unraveling the complexities of the diseases, improving patient outcomes, and advancing fundamental knowledge, ultimately granting safer and more effective personalized treatments for this neoplasm. Finally, the Guest Editor extends their deep appreciation to the dedicated authors whose invaluable contributions have enriched this endeavor, as well as to the Editorial Board for their unwavering support.