This article aims to examine the evidence on the relationship between gut microbiota (GM), leaky gut syndrome and musculoskeletal injuries. Musculoskeletal injuries can significantly impair athletic performance, overall health, and quality of life. Emerging evidence suggests that the state of the gut microbiota and the functional intestinal permeability may contribute to injury recovery. Since 2007, a growing field of research has supported the idea that GM exerts an essential role maintaining intestinal homeostasis and organic and systemic health. Leaky gut syndrome is an acquired condition where the intestinal permeability is impaired, and different bacteria and/or toxins enter in the bloodstream, thereby promoting systemic endotoxemia and chronic low-grade inflammation. This systemic condition could indirectly contribute to increased local musculoskeletal inflammation and chronificate injuries and pain, thereby reducing recovery-time and limiting sport performance. Different strategies, including a healthy diet and the intake of pre/probiotics, may contribute to improving and/or restoring gut health, thereby modulating both systemically as local inflammation and pain. Here, we sought to identify critical factors and potential strategies that could positively improve gut microbiota and intestinal health, and reduce the risk of musculoskeletal injuries and its recovery-time and pain. In conclusion, recent evidences indicate that improving gut health has indirect consequences on the musculoskeletal tissue homeostasis and recovery through the direct modulation of systemic inflammation, the immune response and the nociceptive pain. Sports injuries, especially those affecting musculoskeletal structures, are common among endurance athletes The normal function of intestinal permeability refers to the ability of the intestinal barrier to selectively allow for the passage of luminal pathogens, toxins, antigens, nutrients, and water-electrolytes, while maintaining a barrier function against the entry of harmful substances Current literature suggests a relationship between leaky gut syndrome and different factors influencing musculoskeletal homeostasis and healing. Among them, nutrition interventions (including pre- and probiotic intake) promote healthy modulation of the gut microbiota (GM) and have been suggested as a promising novel therapeutic intervention to modulate pain and systemic inflammation 2.Physical exercise is a determinant factor that can alter gut homeostasis and modulate GM and intestinal permeability The GM is the community of microorganisms that inhabit the human digestive tract, including bacteria, fungi, and viruses High-intensive exercise increases both systemic and local acute inflammation, involving musculoskeletal tissues, and increasing the risk of suffering from sports overload/injuries. In addition, it affects gut homeostasis, and promotes adaptive changes in the GM and intestinal epithelium. Previous studies have reported that athletes presenting a previous dysbiosis of the GM had more significant levels of systemic inflammation and a lower capacity for recovery from intensive exercise The intestine exerts a functional barrier with the rest of the body through the epithelium and the mucous layer The intestinal mucosa comprises mucins (glycoproteins) secreted by the intestinal epithelium goblet cells. This layer protects from proteolysis, prevents the attachment of pathogens to the intestinal epithelium, is a niche for commensal bacteria, and retains molecules such as host defense peptides, IgA, and macronutrients The GM acts as an endocrine organ, and promotes protective, homeostatic, metabolic, and immune functions within the other parts of the body The GM ecosystem is highly malleable and rapidly changes according to exposure to intrinsic and extrinsic disruptors such as adverse pathogens, poor nutrition, and different environmental conditions such as hypoxia and/or heat Otherwise, the functions of GM are also essential in the maturation of the innate immune system, producing circulating metabolites, hormones, neurotransmitters, cytokines, and developing lymphoid cells 3.Physical exercise can exert potential health benefits for individuals In the last one, a very high force stimulus is applied to the tissue, above its failure strength threshold, causing its injury. In this situation, the relationship between the microbiota and injuries is questionable. On the other hand, in overuse injuries, motor pattern repetition under injury threshold is presented and induces many adaptive and acute inflammatory changes in bones, muscles, tendons, and joint structures. The critical nature of the body's musculoskeletal structures requires constant homeostatic activation of the innate immune system to restore equilibrium The present work emphasizes the important relationship between systemic inflammation and the higher risk of developing musculoskeletal injuries and impaired recovery and regeneration of connective and muscular structures 3.1.Muscles are highly malleable, plastic tissues that respond to mechanical and physical loading stimuli. However, it has been reported that the persistence of a chronic proinflammatory state impairs the capacity of satellite cell regeneration and tissue repair Additionally, the gut-muscle axis has been a growing area of research in recent years Longer and more intense exercise loads increase the risk of producing muscle injuries As we reported, an acute inflammatory response in muscles is usually coupled with regeneration and repair following injury A local and systemic inflammatory state has been shown to decrease insulin sensitivity and glucose supply to the muscle It was shown how the composition of the GM affects muscle function, and how certain bacteria increase under optimal conditions of muscle anabolism , unlike others, which were described with sarcopenia  A dysbiosis of the GM associated with gut barrier dysfunction increases proinflammatory cytokines, oxidative stress 3.2.Tendinopathies are the overuse mechanical injuries with the highest proportion among total musculoskeletal injuries (30–50%) Tendons require constant remodeling to maintain their tissue architecture and strength levels Previous studies have reported how the gut microbiota state correlates with tendon injury regeneration and the healing process 3.3.Joint structures are affected by many factors, such as mechanical overloads, age, gender, intensity and volume, increasing the risk of degeneration and the lack of healing during inflammatory processes. Osteoarthritis (OA) is a degenerative joint disease with a prevalence in adults of 20% that increases with aging up to 50% Bacterial antigens  within the synovial fluid demonstrate the translocation of intestinal bacteria into the joints Traditional treatments for joint injuries include the administration of medication to modulate the inflammatory processes. However, the chronic and/or regular consumption of analgesics and anti-inflammatory medications promotes adverse effects on gut health, thereby impairing GM balance 3.4.In all bone tissues, the acute inflammatory response is positive and enhances the regulated processes of remodeling, healing, and regeneration. Bone remodeling depends on the balance between the actions of osteoblasts, osteocytes, and osteoclast. However, under conditions of proinflammatory chronicity, it can be detrimental to healing In a normal condition, regular exercise with mechanical impact loads increases musculoskeletal stress and promotes bone microdamage The intake of nutritional prebiotics and supplemental probiotics has been proven effective in preventing bone loss and improving recovery after fractures 4.As this review noted, gut health is related to microbiota and intestinal permeability and can influence sports injuries' development and/or recovery It was reported that well-trained athletes present a higher diversity and abundance of GM than sedentary or sick subjects Pain is a primary factor limiting physical performance, reducing regular exercise practice, and impairing athletes' moods. Pain is an unpleasant sensation related to tissue inflammation and damage It has been hypothesized that positive daily routines, including specific diet interventions, may reduce systemic inflammation and promote a lower activation of nociceptors signaling pain Additionally, some neurotransmitters and hormones synthesized in the gut are essential for modulating neural pain and mood. Directly, GM synthesizes high proportions of total neurotransmitters in the body. Dopamine regulates inflammation and the immune response and it's a crucial modulator of chronic pain and behavior Intestinal hormones such as ghrelin and leptin have anti-inflammatory properties that participate in nociceptive regulation and immunometabolic inflammation, which are characteristics of chronic pain conditions Cortisol is the key stress hormone in humans and influences the GM composition 5.Several studies have shown how some pathologic bacteria may be related to leaky gut syndrome. However, most of them are observational studies in which it's not proven that there's a direct cause-and-effect relationship between bacteria and leaky gut syndrome. For example, a significant positive association was found between the presence of microorganisms such as Fusobacterium or Prevotella and the risk of musculoskeletal injuries 6.There are several limitations to the current evidence on the relationship between gut microbiota, leaky gut syndrome and musculoskeletal injuries. First, most of the studies are observational, which limits the ability to establish causality. Further randomized controlled trials are needed to confirm the findings of the observational studies. Second, the studies are heterogeneous regarding the participants studied, the interventions examined, and the outcomes measured, making it difficult to compare the results across studies. Third, based on different exercise practices and nutritional routines, it is unclear if the findings included here are generalizable to elite, recreational athletes or general populations. Fourth, the mechanisms underlying the relationship between gut microbiota, intestinal permeability, and sports injuries are not fully understood.However, we hypothesize that adaptive innate immunity related to the intestinal epithelium and the modulation of the inflammatory response could be essential in managing systemic and local inflammation. Finally, most musculoskeletal injuries are disabling, mainly because the neural pain related to the inflammatory processes impairs movement. Furthermore, it is essential to consider that the microbiota and intestinal permeability are complex and influenced by many factors; therefore, it is difficult to determine the influence of a single bacterium or group of bacteria on these processes.7.Based on the evidence from the studies included in this review, many factors could be highlighted in the accentuation of intestinal permeability see :1) Heat stress related to exercise increased core temperatures (hyperthermia> 39ºC), damaging the epithelial cells due to a more outstanding contribution of blood flow to the cutaneous vascular network 2) Stress due to splanchnic ischemia (cellular hypoxia) generates more significant redistribution of blood flow to the active muscles and peripheral organs (heart and lungs), not reestablishing perfusion until the end of physical activity. The degree of damage produced in the mucosa (surface or deeper layers) depends on the severity of the ischemia and its duration  [190]3) Oxidative stress (tissue damage) production by the action of intestinal cytotoxic agents . Regular exercise is associated with an acute increase of oxidative stress and a positive long-term effect on the gut anti-inflammatory response 4) Exercise in altitude or hypoxic conditions has been reported that increase gut permeability and intestinal ischemia more than the same activity performed in normoxia. Moreover, in altitude conditions, the systemic conditions achieved from the environmental conditions increase fluid loss, metabolic stress, and the activation of the sympathetic neural system 5) For example, chronic high-intensity exercise in cyclist competition of three weeks or ultra-endurance running events may increase gut stress due to intestinal ischemia, changes in the intestinal pH, dehydration, hyperthermia, and systemic inflammation Based on current evidence, promoting a healthy GM can directly improve gut health and intestinal permeability. The better modulation of immune response in the gut reduces systemic and local chronic inflammation, indirectly benefiting musculoskeletal homeostasis. Moreover, has been suggested that interventions on GM may effectively prevent the transition from acute to chronic musculoskeletal pain Easy practices to improve GM diversity and intestinal permeability have relation with the nutrition and daily routines. Among others, they should promote a high microbiota diversity through the intake of prebiotics 8.In conclusion, emerging evidence suggests that GM and intestinal permeability may play an essential role in the adaptive innate immunity of the gut, the modulation of systemic and local inflammation, neural sensitivity to pain, and the degeneration of musculoskeletal and joint structures related to sports injuries. Furthermore, the literature suggests that gut microbiota-related gut leaky alterations may decrease the ability to recover and/or repair musculoskeletal tissues after acute damage, inflammation, and injury. Besides, it seems systemic endotoxemia promotes low-grade inflammation that reduces the adaptive capacities in tissues and the immune system, as in aging.Therefore, athletes must consider maintaining a healthy microbiota and adequate intestinal permeability to reduce the risk of suffering more musculoskeletal injuries related to inflammation and pain. In general population, musculoskeletal non-traumatic injuries specially associated with degenerative processes as osteoarthritis, osteoporosis, tendinopaties or muscular sarcopenia are also related to systemic low-grade of inflammation. To prevent the transition to acute to chronic pain effective interventions based in modulate immunomodulation could be further explored in the follow years.To this purpose, practical recommendations can be stated, such as eating a diet rich in prebiotics, consuming probiotics, avoiding excessive consumption of processed and sugary foods, maintaining an active lifestyle and healthy, managing stress levels, incorporating rest and recovery periods into training regimens, sleeping sufficiently, and avoid overuse of antibiotics, ultra-processed foods including sport supplements and NSAIDs.It is important to note that the relationship between gut microbiota, intestinal permeability, and musculoskeletal injuries is complex and still not fully understood. Therefore, further research is needed to determine the mechanisms and specific bacteria underlying this relationship and to develop effective strategies for preventing, managing, and recovering from sports injuries in athletes and general population. In addition, future studies should consider other potential factors that may affect the relationship between gut microbiota, intestinal permeability, and musculoskeletal injuries, such as physiopatological condition, age, gender, and type of activities or sport. Moreover, the relationship between systemic inflammation and hypothalamic sensitivity to pain may have a relation to intestinal endotoxemia and the alteration of nociceptive tolerance and threshold.In conclusion, the modulation of pain and musculoskeletal injuries could have a new field of treatments based on the intervention with GM and intestinal permeability. In such cases, the analysis of the GM both for athletes as also in general populations, is everyday more the present to improve the individual measurement of the gut health. Even more, the symbiotic relationship between the GM and the host is key to maintaining gut and systemic health. The modulation of inflammatory and immune processes after local stress is very important to regulate acute responses related to musculoskeletal homeostasis. Therefore, reduce possibilities to achieve chronical musculoskeletal states of inflammation, degeneration and pain. According to the specific literature in the topic, local and systemic inflammation is related to the leaky gut syndrome, immune system over-activation, and pain sensitivity.The authors declare they have not used Artificial Intelligence (AI) tools in the creation of this article.


Central nervous system (CNS) has a limited regenerative capability, which makes it difficult to repair after injury. Damage of axons from CNS, as in spinal cord injury, traumatic brain injury, stroke and optic neuropathies, leads to permanent functional deficits, due to axonal disconnection. Multiple factors, including the decline of intrinsic growth capacity, the inhibitory extrinsic environment, and neuronal vulnerability after lesion, contribute to regenerative failure in the adult injured CNS. However, the concept that axons from CNS neurons are not able to regenerate after an injury was challenged after the demonstration that those axons can grow into peripheral nerve grafts , a context with higher potential for regeneration, in order to gain insights on the potential mechanisms within CNS. Moreover, in this article it was also included a comprehensive review of promising new therapeutic targets in eliciting CNS axonal regeneration.Upon a CNS injury, the formation of a glial scar is the key event that creates a non-permissive environment for axonal regeneration. Thus, Hemati-Gourabi et al. dissected the dual role of glial scar in the pathological process of spinal cord injury. In this context, the authors described the controversial role of the glial scar over time and explored the underlying mechanisms of its diverse and dynamic nature, with a focus on the disparity, variation, and interactions of scar-forming astrocytes. In this article it was reviewed the neuroprotective effect driven by astrocytic scar in the early phase of acute focal injury and the positive role of astrocytes in axon regeneration and axon sprouting in the mature mammalian CNS. The potential mechanisms underlying axon growth-supportive effects of astrocytes were reviewed in detail, and include the production of neurotrophic factors, remodeling of the extracellular matrix, clearance of myelin debris, and provision of bioenergetic support for axon growth.As the astrocytes are one cellular component of the scar tissue, being activated after axonal injury and proliferating to form an astrocytic scar border commonly associated with inhibition of axon regeneration, Fu et al. explored in their comprehensive review the impressive progress in the biological, engineering and rehabilitation strategies for repairing the injured spinal cord. The authors focused on the use of Schwann cells transplantation to promote spinal cord injury repair, that has shown encouraging results in animal models by enhancement of axon regeneration, remyelination of newborn or sparing axons, regulation of the inflammatory response, and maintenance of the survival of damaged tissue, that leads to functional recovery. Some of these Schwann cells transplantation therapies have been subject to phase I clinical trials, which have confirmed their safety and feasibility for the treatment of spinal cord injury, however little functional improvement was observed. Despite the immense knowledge gained through the years, there is currently no approved treatment for clinical use in spinal cord injury patients. The authors also discuss the challenges in translating Schwann cells transplantation into clinical practice, and argued the complex pathophysiologic mechanisms of spinal cord injury and the marked differences between the animal and human spinal cord as the main barriers for this translation.Lear and Moore focused their review paper on the advantages and disadvantages of the use of human neuronal model systems to study axon regeneration with the goal of bridging basic science studies into clinical trials. Tremendous progress has been made in identifying intrinsic and extrinsic regulators of CNS axon regeneration in rodents, however it is not known yet if these are conserved in human CNS neurons. This makes it extremely important to understand if CNS axon growth and regeneration ability also occurs in a context of human model systems. The authors described that the advent of human pluripotent stem cell (hPSC) technology, which includes both human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs), and direct reprogramming technologies, allow to study axon growth and regeneration in human disease and therapeutic models. Thus, the use of human systems to study CNS axon growth and regeneration may accelerate and increase the success of the transition of preclinical studies to clinical trials.In this way, AS: Writing – review & editing. IA: Writing – review & editing. MA-B: Writing – review & editing. RB: Writing – original draft, Writing – review & editing.


This paper presents recent advances in the theory of multicomponent crystal growth from gas or solution, focusing on the most common step-flow mechanisms: Burton-Cabrera-Frank, Chernov, and Gilmer-Ghez-Cabrera. Analytical expressions for the spiral crystal growth rate are presented, taking into account the properties of all species involved in the growth process. The paper also outlines theoretical approaches to consider these mechanisms in multicomponent systems, providing a foundation for future developments and exploration of previously unexplored effects. Some special cases are discussed, including the formation of nanoislands of pure components on the surface and their self-organization, the impact of applied mechanical stress on the growth rate, and the mechanisms of its influence on growth kinetics. The growth due to chemical reactions on the surface is also considered. Possible future directions for developing the theory are outlined. A brief overview of numerical approaches and software codes that are useful in theoretical studies of crystal growth is also given. In the past century, the field of crystal growth has emerged as a distinct and important branch of materials science, driven by the increasing demand for crystals in various technological applications such as electronics, optics, semiconductors, and more. While silicon formed the basis of modern electronics in the 20th century, high-tech industries are gradually transitioning towards more complex crystalline materials that can facilitate the creation of devices with superior characteristics. These materials include widebandgap semiconductors such as gallium and aluminum nitrides , which are widely used in optoelectronics , perovskNote that there are various regimes of crystal growth, such as step-flow/spiral, nucleation, dendritic, and rough growth refer to , and theThis perspective aims to discuss our recent developments in the theory of crystal growth in multicomponent systems via step-flow/spiral mechanisms, specifically focusing on the BCF , ChernovThe problem of multicomponent spiral growth was formulated in  based onThe Burton-Cabrera-Frank (BCF) model is commonly used to describe step-flow and spiral crystal growth from vapor. In the multicomponent version of this model , all come review ; and 4) −3 to 10−5 cm, which is much smaller than the typical size of the growing crystal. As a result, some macro-diffusional fields may arise during growth, which must be considered to correctly describe the crystal growth over the entire surface.The Chernov model  is commoThe Gilmer-Ghez-Cabrera model  is a sigith component will occur during the BCF growth mode in a train of advancing steps.In , the autThe growth of crystals in the presence of chemical reactions is common in modern synthesis techniques. For example, the metal-organic chemical vapor deposition (MOCVD) process used for GaN crystal growth typically involves surface chemistry . In Red, the autstal see . It was stal see , but if Previous studies have established that mechanical stress may have a significant effect on crystal growth . In Red, it was poration . In  presented in Although the mechanisms considered above are capable of describing numerous growth processes, significant gaps in knowledge and issues must be resolved to fully understand the multicomponent growth process. Further theoretical investigations could focus on several areas, including the impact of surface coverage of different components on mass transport (diffusion) both on the surface and in solution; the use of different adsorption isotherms for components to modify the relationship between surface supersaturation and pressure/concentration; the variation of Schwoebel barriers for each component, potentially affecting the distribution of adatoms; the detailed study of adatom incorporation into kinks, including the statistics of multicomponent kinks; the effect of surface reconstruction on diffusion mechanisms, which may depend on component concentration and growth rate; various morphological instabilities in multicomponent systems; the influence of impurities on incorporation or mass transfer of different components; anisotropic phenomena; the impact of convective flow of components during growth at higher supersaturations, when the step advancement rate cannot be ignored; and many other effects and their combinations.ab initio quantum mechanical (QM) modeling and stable structure prediction (in silico the activation energy of surface diffusion and desorption of atoms of various components (in silico description of macroscopic crystal growth or dissolution, a multiscale approach is often used, involving all the aforementioned techniques (We note that in recent years, significant advancements have been made in high-performance modeling methods for multicomponent crystal structures and their growth. Some of these techniques include ediction , moleculediction , kineticediction , phase-fediction , and theediction , among oediction , but allediction . The latmponents , which imponents . Note thmponents , and themponents . MD is amponents , which mmponents . The Monmponents  implemenmponents , which, mponents . To provchniques  from nanchniques , this apchniques , determichniques , and optchniques . These nvice versa, the determination of individual kinetic properties of different components based on the dependence of the growth rate on conditions. We have also discussed the effects and peculiarities inherent to multicomponent systems, including the precipitation of nanoislands, effect of stresses, chemical reactions, and morphological instabilities. These phenomena can have a significant impact on the growth of multicomponent crystals or MOFs, making it crucial to understand their roles and the opportunities they provide for controlling the growth process in such complex systems. We presented approaches for accounting for new effects in theoretical equations, which enable the modification and extension of the theory to include additional factors. Lastly, we discussed some of the available numerical approaches and software packages, which make it possible to deepen knowledge and simplify the theoretical consideration of the crystal growth process.In conclusion, we have summarized several growth mechanisms and effects involved in the growth of multicomponent crystals from vapors or solutions. Our findings demonstrate that growth can be described by the same equations as in the single-component case, with the use of generalized diffusion and incorporation coefficients based on the properties of each component. The results presented herein can be applied to a wide range of complex multicomponent systems, allowing the prediction of the growth rate based on growth conditions or,


Drug evaluation has always been an important area of research in the pharmaceutical industry. However, animal welfare protection and other shortcomings of traditional drug development models pose obstacles and challenges to drug evaluation. Organ-on-a-chip (OoC) technology, which simulates human organs on a chip of the physiological environment and functionality, and with high fidelity reproduction organ-level of physiology or pathophysiology, exhibits great promise for innovating the drug development pipeline. Meanwhile, the advancement in artificial intelligence (AI) provides more improvements for the design and data processing of OoCs. Here, we review the current progress that has been made to generate OoC platforms, and how human single and multi-OoCs have been used in applications, including drug testing, disease modeling, and personalized medicine. Moreover, we discuss issues facing the field, such as large data processing and reproducibility, and point to the integration of OoCs and AI in data analysis and automation, which is of great benefit in future drug evaluation. Finally, we look forward to the opportunities and challenges faced by the coupling of OoCs and AI. In summary, advancements in OoCs development, and future combinations with AI, will eventually break the current state of drug evaluation. Drug discovery and development is one of the most significant translational science activities contributing to human health and well-being. Nevertheless, the discovery and development pipelines are time-consuming and incur massive costs, primarily because of the preclinical validation as well as clinical trials involved in vivo-like models of cell culture because of the dimensional comparisons with biological cells in vitro models which capture cellular and organ-level responses, microfluidic technology is widely used for fast and animal-free risk evaluation of new drugs Microfluidics is the science and technology of manipulating and detecting fluids on a micro-scale  in vivo, offering exciting potential to bridge the gap between in vitro evaluation models and in vivo pathophysiological complexity As a product of microfluidic technology gradually developed, OoCs could faithfully mimic the pathophysiological microenvironment of target organs60 molecules The mechanism of action of drugs is diverse, with various phenotypic effects on cells and organs. Simply recognizing and categorizing these features from the perspective of molecular indicator detection is time-consuming and laborious, which has become a challenge for large-scale molecular library  in vivo. Thus, the predictive value of 2D monoculture models is quite limited.In traditional, 2D cultures cells grow in a culture flask or dish as an adherent monolayer, attached to a plastic surface in vivo-like microenvironments and have received much attention. These models use synthetic or natural cell scaffolds (decellularized) to support cell attachment, growth, and morphogenesis in a 3D environment in vivo state, these models remain lack the multiscale structures and tissue interfaces that are meaningful for organ function. In addition, the lack of controlled and precise application of nutrient supply gradients and chemical cues, results in the poor modeling of an in vivo physiological microenvironment. Importantly, cells are typically not exposed to physical stimuli that are essential for organ development and functioning Efforts to address some limitations of 2D culture models, 3D culture models have been developed, which provide Preclinical animal models are an essential component of the drug discovery and development process. Although animal models have offered a living system to assess the efficacy of drugs on target site and non-target organ toxicity, it captures the physiological complexity with a high degree of fidelity. However, it is not really representative of human physiology, pathological, and genetic characteristics, thus failing to accurately anticipate drug response in humans in vitro microphysiological system (MPS) used for mimicking the human body environment, representing a simplified but realistic model of its organ-level and even organism-level functional counterpart with functionality read-outs matching the intended application  in vitro model, OoCs have been envisioned to replace animal studies. Meanwhile, OoCs may improve the current lack of female individuals in human clinical trials Organ-on-a-chip is an in vivoAs a type of microfluidic device, OoCs are created with microchip-manufacturing methods with a miniaturization feature. Owing to the intrinsic characteristics of microfluidics , OoCs can provide accurate control of biophysical, biochemical, and cellular parameters To date, researchers have developed single-organ-on-a-chip for almost organs in the human body, all of which can be used for drug research. Nevertheless, they lack both a systemic dimension and cross-organ communication After rapid developments in recent years, OoCs that replicate human organ functions are a promising technology for drug evaluation , disease modeling, and personalized medicine, which indicates its potential role in all phases of the drug development Figure . The risThe design guidelines for OoCs are founded on the objective of recapitulating the physiology of the organ system under study. Ideally, the OoCs environment should be created using a minimally functional (simplest feasible) unit of each organ system in vivo, which may contribute to the development of drugs or delivery vehicles , which selectively controls the passage of drugs into the central nervous system (CNS) and prevents it from blood-borne neurotoxic substances as well as maintains homeostasis for optimal brain function s Figure B 23. Morin vivo using collagen and elastin has been developed, which was called the second-generation lung OoCs As the lung fills with air, the respiratory regions cyclically expand and contract to increase the surface area accessible for gas exchange. When the alveoli were considered the smallest functional unit of the lung, cyclic expansion can be simulated by applying mechanical stretch to the gas exchange surface The heart is one of the least regenerative organs in the body in vitro models have already been developed to accurately mimic the complex liver architecture and physiology, and to generalize the human liver's response to drugs in vitro models after screening 122 clinical drugs for liver toxicity in vivo had excellent correlations The liver has a complex microarchitecture with various functions and displays a central role in the synthesis and metabolism of various substances The kidney is a significant organ responsible for metabolism, excretion, and reabsorption, which is a frequent site of toxicity during drug discovery For drug administration, the oral route is the most common. As the first step of ADME , absorption is the vital precondition to play the therapeutic effects of oral drugs in vitro models to reproduce the tumor microenvironment in vivo, as multiple factors in the tumor microenvironment (TME) can be controlled separately and precisely in microfluidic platforms, which is essential to improve anti-cancer drug selection strategies It is still a challenge to predict clinical responses to anticancer drugs in cancer treatment At present, tumor OoCs also include colorectal  in vitro, which contains a capillary network for the first time that allows operating within physiological pressure gradients and interstitial flow ranges, showed an application in drug discovery The vasculature is important for providing adequate gas, transporting nutrients, removing waste, and offering a selective barrier for drugs introduced through the circulatory system TM, EpiSkinTM, and SkinEthicTM) and full-thickness skin models have been used for many applications, such as pharmacological The skin acts as the largest organ in the human body and severs as the main barrier to the environment, which is critical for evaluating the cutaneous effects of drugs and modeling transdermal drug absorption + cells, which can generalize myeloerythroid toxicity following exposure to chemotherapeutic agents The bone is one of the active organs which is undergoing a carefully choreographed remodeling process throughout the life course in vitro by a retina OoC platform, which was integrated with over seven different hiPSC-derived essential retinal cell types. Importantly, the model recapitulated the retinopathic side effects of the antibiotic gentamicin and the anti-malaria drug chloroquine, exhibiting the potential of facilitating drug development Human donor retinal explants offer a fully functional model, but due to inter-donor variability, limited availability, and poor cultivability, it is not suitable for drug development and testing Nowadays, muscle OoCs have been employed in mechanistic research to better comprehend the human skeletal muscles and assess the effects and toxicity of drugs Fat tissue, as a major energy reserve, will contribute to obesity due to the imbalance between energy intake and expenditure, and its associated comorbidities present a looming challenge to healthcare delivery throughout the world in vivo role of vascular perfusion and allows control of the culture environment to reproduce some aspects of homeostasis in vitro tools for assessing drug toxicity and PK/PD As the development of single OoCs matures, when these single organs are fully functionally characterized , they can be combined to create the proposed multi-organ-on-a-chip (often referred to as body-on-a-chip or human-on-a-chip). Connecting a single OoCs to another by microfluidics simulates the in vitro, especially during combinational therapies In most cases, many drugs fail in phase III clinical trials or have serious side effects after marketing in-vitro-to-in-vivo translation of PK and PD parameters via fluidically coupled OoCs  of drug candidates. On the other hand, PD researches investigate the effects of the drug on target organs or tissues, such as a correlation between drug dose and pharmacological or toxicological response s Figure E 177. Ins Figure B 180. Res Figure H 182. In+ T cells in vitro model was lacking for researchers to elucidate potential microbiota-neurodegeneration mechanisms. The European Research Council has funded a project called 'MINERVA' (ID 724734), which seeks to build the first multi-OoC device for microbiome-gut-brain engineering to assess the effect of intestinal microflora on neurodegeneration The dearth of clinically applicable models is a challenge for many human diseases, especially those complex diseases that involve multiorgan interactions. As a systematic multi-organ metabolic disease, Type 2 diabetes mellitus (T2DM) is characterized by the dynamic interplay of various organs  in vitro platforms have been developed for drug development screening, there are few that exist for clinical deployment to benefit unique patients. This is an unmet clinical need because patient responses to drugs are frequently unpredictable due to genetic and microenvironmental heterogeneities Although variousOoC technology and deep learning are frontier fields in biomedical engineering and AI, respectively, and represent an ideal combination of experimental and analytical throughput in vitro models , while machine learning can be used to speed up data analysis In the past few years, AI has supplied significant advantages in many areas of healthcare in research and clinical settings, such as disease diagnosis, precision medicine, and drug discovery and development. Notably, opportunities for applying AI arise at all stages of drug discovery and development, including clinical trials ML is a common technical means to achieve AI, and DL is a type of ML algorithm. Of note, DL is the most representative research field in AI With the development of OoCs, especially utilizing higher-throughput, highly parallelized microfluidic systems, generating unprecedented quantities of data; however, the large amount of data generated has far exceeded researchers' capacity to process it efficiently, creating a bottleneck in the analysis To date, the most common data output structure for OoCs is fluorescence microscopic images in vitro-in silico approach to achieve real-time prediction of tumor evolution  platform quantified the microenvironment of brain metastatic tumors (breast cancer) by using confocal tomography and machine learning  to identify intrinsic phenotypic differences in tumor cells capable of metastasizing through the model CellHunter is a DL-based cell tracking analysis algorithm. As reported, CellHunter has been successfully applied to reveal the interactions between human peripheral blood mononuclear cells (PBMCs) and tumor cells in OoCs and showed that only cells from 'wild type' donors  establish sustained interactions with chemotherapy-treated cancer cells Angiogenesis has been reported to be associated with more than 70 diseases. Lately, a study has utilized DL-based image processing algorithms to analyze and quantify angiogenesis on a chip. This method allows the assessment of angiogenesis using up to 16 angiogenesis-related metrics and the extraction of 3D indicators from 2D images. In this work, the model successfully showed changes in response to biochemical gradients and can be applied to drug development in situ sensing of microenvironment biophysical and biochemical parameters -based deep Q network can utilize image feedback to assist in retaining stable flow conditions for prolonged periods by automatically adjusting flow conditions to mitigate the inconsistent system performance exhibited in microfluidic platforms during extended experiments Figure B 248, whs Figure D 181, whIn conclusion, even though only a few OoC studies have incorporated AI, we believe that these existing studies are sufficient to indicate exciting prospects for synergy between OoCs and AI in future drug evaluation Figure -9. NeverOoCs using human cell sources  could possibly eliminate the effects of cross-species differences introduced by utilizing animal models for clinical drug studies. A major obstacle of OoCs is the limited lifespan of cells in the device, and such limitation is exacerbated when not using immortalized cell lines in vitro disease models, an important aspect of which is rare disease models, and OoCs could fill the gaps where animal models do not work or even do not exist. To date, only about 400 of over 7,000 identified rare diseases have active research programs due to the absence of animal models for others, resulting in significant hindrances to the development of new drugs in the field in vitro and in vivo models or clinical samples, as OoCs enable long-term and real-time monitoring of changes in physiological processes. Through further analysis of these data by ML/DL in real-time, it is possible to analyze the progression at the molecular level of such diseases, and eventually discover the specific mechanisms by which the diseases occur OoCs have been extensively used to build a variety of Perhaps more importantly, OoCs can be used first time in emergencies for disease mechanism research and drug repurposing, discovery, and toxicity evaluation. For instance, during the COVID-19 global pandemic, several OoC platforms have been successfully used AI itself is a rapidly developing discipline, and deep learning networks and automated machine learning have promoted the development of generative AI. AI has shown unprecedented creativity, based on OoCs' own needs and new creative needs, the development of OoCs will be greatly accelerated.in vivo simulations in response to clinically relevant drug exposures, as well as OoC platforms capable of quantitatively predicting human pharmacokinetic parameters, were manufactured almost by PDMS (Table in vitro tissue/organ models and testing devices for drug screening Firstly, AI can address the bottleneck issue in the development of OoCs hardware. PDMS is one of the most popular materials for fabricating microfluidic devices. However, there is a common concern that OoCs made out of PDMS are unable to be utilized efficiently for drug research because of drug absorption MS Table . Despitein vivo, relying on appropriate scaling rules and methods, and the fluid volume and dynamics in chips should be adjusted in accordance with specific human organs in vitro organ models Despite this, OoCs remain facing various challenges that must get past in order to promote their physiological relevance and facilitate their translation into the clinic. For example, introducing more cell subtypes, metabolites, and microbiomes, as well as biochemical and biophysical gradients Secondly, AI will increase the detection throughput of OoCs. Typically, OoC devices are low-throughput, which limits their applicability in the early phases of drug discovery Finally, AI further promotes the convenience of OoCs data processing. At present, the iterative development speed of AI is astonishing. A simpler, more open, and more user-friendly AI-based algorithm platform will be developed, making image and big data analysis for OoCs dynamic processes simpler. Recently, especially with the emergence of open AI, it will also be applied in the scientific field. The design of OoCs and the extraction of more biological-related features will be completed by AI. Imagine the future, where people will become emitters of commands, AI-controlled automated OoCs production and analysis platforms will present the data we need, and drug evaluation will become an easy task at that time.We can foresee that AI will further help us invent new OoCs products in the design, production, and control of OoCs, as well as data processing, to expand the application of OoCs. While OoCs' potential is exciting, the technology is still in its early stage Last but not the least, while OoCs have advanced significantly in the academic environment, and a few OoC platforms have even been successfully converted into commercial products, numerous challenges prevent its complete deployment in an industrial setting, and OoCs are still marginalized in the pharmaceutical industry in vitro model, showing encouraging performances in a variety of drug evaluation platforms. Nevertheless, the current OoCs still must face many challenges that take it from academia to industry. Continuing development with AI, it is undeniable that OoCs will likely dramatically change drug development, disease modeling, and personalized medicine.In summary, organ-on-a-chip successfully replicates the critical physiological functions and environment of the human organs, as a state-of-the-art


Despite significant improvement in prognosis, myocardial infarction (MI) remains a major cause of morbidity and mortality around the globe. MI is a life-threatening cardiovascular condition that requires prompt diagnosis and appropriate treatment. The primary objective of this research is to identify instances of anterior and inferior myocardial infarction by utilizing data obtained from Ultra-wideband radar technology in a hospital for patients of anterior and inferior MI. The collected data is preprocessed to extract spectral features. A novel feature engineering approach is designed to fuse temporal features and class prediction probability features derived from the spectral feature dataset. Several well-known machine learning models are implemented and fine-tuned to obtain optimal performance in the detection of anterior and inferior MI. The results demonstrate that integration of the fused feature set with machine learning models results in a notable improvement in both the accuracy and precision of MI detection. Notably, random forest (RF) and k-nearest neighbor showed superb performance with an accuracy of 98.8%. For demonstrating the capacity of models to generalize, K-fold cross-validation is carried out, wherein RF exhibits a mean accuracy of 99.1%. Furthermore, the examination of computational complexity indicates a low computational complexity, thereby indicating computational efficiency. Despite recent developments in the prognosis of diseases, cardiovascular disease (CVD) is a major cause of morbidity and mortality around the globe . The WorMyocardial infarction (MI) is among five manifestations of coronary heart disease (CHD), which include angina pectoris (both stable and unstable), MI, heart failure, and sudden death . Acute MThe monitoring of electrocardiograms (ECGs) and timely detection of abnormalities play a crucial role in reducing mortality rates associated with MI. Single-lead portable ECG monitors are becoming increasingly popular due to their affordable price, effectiveness, and user-friendly interface . ECG datThis study proposes a non-contact methodology to effectively tackle the challenges and facilitate accurate categorization of anterior and inferior MI. Anterior MI is characterized by myocardial damage that occurs in the front (anterior) region of the heart, specifically affecting the anterior wall of the left ventricle , as showStudies ,21 reporRecent technological advancements offer promising possibilities for the effective detection of anterior and inferior MI. Ultra-wideband (UWB) is a frequently utilized technology in the monitoring of vital signs ,25,26,27This study evaluates the feasibility and efficacy of UWB-based data for inferior and anterior MI detection. Data were collected in a hospital setting from individuals diagnosed with anterior and inferior MI using UWB radar under the supervision of a resident cardiologist. The use of UWB radar in clinical settings provides a practical and real-world perspective to the study.The study presents an innovative method for feature fusion, which integrates temporal and class prediction probability features obtained from the spectral feature dataset. The integration of these characteristics seeks to enhance the efficacy of ML models.Signal processing techniques were employed to perform preprocessing and enhance the raw UWB data. Afterward, feature extraction techniques were utilized to extract relevant spectral features. For experiments, different ML models were deployed, including random forest (RF), the k-nearest classifier , Gaussian Naive Bayes (GNB), support vector machine (SVM), and long short-term memory (LSTM).Performance of the approach is analyzed, using parameters like accuracy, F1 score, etc. In addition, k-fold cross-validation is also performed to check the robustness of the approach. Performance concerning computational complexity is also employed.Despite the advantages offered by the UWB radar, its efficacy for detecting MI needs to be evaluated. Evidently, the question is: can UWB radar, in conjunction with machine learning (ML) techniques, accurately differentiate between anterior and inferior MI using the contraction magnitude and their specific positions on the heart? The primary objective of this study is to examine the feasibility of utilizing UWB radar in conjunction with ML algorithms for accurately distinguishing between anterior MI and inferior MI. This research endeavors to make a valuable addition to the field of medical diagnostics by improving the diagnostic capabilities and making the following contributionsThe rest of the article is organized as follows. MI is a prevalent cause of mortality and morbidity around the globe. The early detection of MI is of utmost importance in the effective management and screening of patients. Unfortunately, the initial diagnosis of patients experiencing chest pain often leads to inappropriate admissions, leading to instances where patients without MI receive treatment, whereas those with MI may be overlooked. The utilization of physical examination, precise ECG findings, evaluation of cardiac troponins, and careful consideration of the patient’s medical history are all crucial factors in the timely identification of MI. AI has revolutionized medical fields by enhancing diagnostic accuracy through image analysis and data-driven disease prediction ,36,37,38The study  developeAnother study  presentsThe authors described a unique approach for detecting MI from 12 to lead ECGs . This meThe study  used 12-Utilizing ECG data from the PhysioBank database, the study  implemenThe study  investigThe above-discussed research works indicate that high-accuracy results can be obtained using ECG data. The conventional implantation of ECG electrodes necessitates the use of conductive gel and may result in skin discomfort and potential health risks. Similarly, in the prevalence of epidemics, a non-contact technology is desired to monitor patients remotely. In order to address these concerns, a novel approach utilizing UWB signals is proposed to distinguish between inferior and anterior wall MI without physical contact. This approach aims to provide a practical solution for remote monitoring in rural settings where conventional ECG placement may pose challenges or be inaccessible.This section introduces a novel research methodology for the detection of patients with inferior and anterior wall MI utilizing UWB radar. A UWB radar-based signal dataset relevant to these MI conditions was first gathered in the step-by-step approach, shown in The data collection process involved the participation of patients diagnosed with inferior wall MI and anterior wall MI at Sheikh Zayed Medical College and Hospital (SZMC and H), Rahim Yar Khan, Pakistan. The data collection was carried out under the supervision of a resident cardiologist. The ethical approval statement was obtained from the ethics committee of the Khwaja Fareed University of Engineering and Information Technology (KFUEIT), in accordance with the criteria outlined in the Helsinki declaration. Consent was obtained from each participant for this study and participants signed a consent form. In order to streamline the process of gathering data, a demonstration was carried out for the cardiologists. Subsequently, the suggestions by the cardiologists were incorporated, and a configuration, as illustrated in The radar system employed a monostatic arrangement, wherein distinct transmit and receive antennas were positioned in close proximity. The device adhered to the regulations set by the Federal Communications Commission (FCC) for emitting radio waves within the frequency range of 3.1 GHz to 5.3 GHz. The emitted waves were centered at 4.3 GHz and have a bandwidth of 2.2 GHz.For MI data collection at the hospital, a total of 926 participants were selected in consultation with the cardiologists. The participants included 655 males and 271 females. The age of the participants varied between 40 years and 70 years. Among these individuals, 479 had anterior MI, and 447 had inferior MI, which was diagnosed by the cardiologists. The MI patients were diagnosed by the cardiologists through the interpretation of the electrocardiogram (ECG) recording, which involved recognizing ST-elevations that were indicative of anterior and inferior MIs. Complete details of the dataset are given in During data collection, the participants were instructed to take a comfortable position on the bed. Subsequently, the radar device was affixed to a frame positioned approximately 50 cm above their chests, as depicted in Total scan distance in centimeters = 950 cmTotal columns = 1440Distance each column covers = 950/1440 = 0.659 cm The 3 min radar scan was presented in the form of a matrix, wherein each column corresponded to a vector representing the radar return signal in the fast time domain. Similarly, each row of the dataset corresponded to a vector representing the radar return signal in the slow time domain corresponding to a fast time. The radar scan of three min was divided into segments of the 1 min scan. The radar’s indoor scan range was a distance of 9.5 m, yielding a total of 1440 columns, wherein each column corresponded to a distinct distance from the radar. The measurement of the distance represented by a single column was derived by:The radar scan results in this study were presented in a matrix format, where each column represented a radar return signal vector that spanned 0.659 cm from the radar. Based on the proximity of the subject’s chest to the radar, which was estimated to be approximately 50 cm, a specific column range of 70 to 100 (19.1 cm) was chosen to effectively represent the area surrounding the heart. The range under consideration was presumed to encompass a region where the signals originating from the heart were anticipated to be detectable. It provided vital information for the analysis of MI affecting the anterior wall and inferior wall. The data underwent a two-pulse canceller procedure, as outlined in Equation  analysis. The FFT was utilized to analyze the cardiac signal and discern the distinct frequency components. This enabled the identification of significant frequency components that were associated with the activity of the heart. The phase component of each heart cycle was also acquired through the utilization of FFT analysis. Phase information was a valuable tool for examining the temporal characteristics of the heart’s functioning, as it offered insights into the timing and synchronization of different frequency components within the cardiac signal. Subsequently, the features that were extracted were averaged across all identified physiological rhythmic windows, thereby offering a comprehensive depiction of the cardiac signals from the radar scan. Furthermore, in order to guarantee results that were both meaningful and comparable, the features underwent additional normalization to address any potential discrepancies in signal magnitudes. The amplitude, frequency, and phase of each physiological rhythmic window were used to derive a set of key attributes that included energy entropy (EE), spectral entropy (STE), zero-crossing rate (ZCR), root mean square (RMS), centroid frequency (SCF), kurtosis (SK), skewness (SKNS), roll-off (SR), decrease (SD), flatness (SFLT), contrast (SC), flux (SF), spread (SSP), and slope (SSL).The extraction of these features from a signal had great significance, as it enabled the acquisition of useful insights into the distinctive characteristics that were inherent to the signal. The details of these features are given in A novel feature engineering approach is proposed that combines features to detect patients with anterior and inferior conditions, using signals from a UWB radar. This approach is a key component of the proposed approach. A novel feature set was generated by combining the features of temporal prediction probability and class prediction probability by LSTM and RF, respectively. The incorporation of this comprehensive set of features enabled us to attain exceptional efficacy in identifying patients with anterior and inferior conditions.The healthcare and medical industry has undergone significant transformation as a result of the implementation of artificial intelligence (AI) techniques. These techniques have introduced a wide range of applications that have the capacity to revolutionize patient care, diagnostics, and treatment. ML algorithms, including neural networks, have exhibited notable achievements in the field of medical image analysis. These algorithms have proven to be effective in accurately identifying and categorizing diseases based on different types of medical scans such as X-rays, magnetic resonance images (MRIs), and computed tomography (CT) scans. This study investigated the utilization of ML models in the detection of patients with anterior and inferior MI conditions, using a dataset of signals obtained from a UWB radar. In order to attain accurate and effective outcomes, a variety of ML algorithms were utilized, including RF, KNC, LR, GNB, SVM, and LSTM.The accurate and efficient performance of ML models is heavily influenced by the configuration of hyperparameters. The main focus of this study was to examine the most effective configurations of hyperparameters in order to improve the efficacy of models in identifying anterior and inferior patients. The objective was to enhance the accuracy, sensitivity, and specificity through careful adjustment of these hyperparameters. The utilization of ML methods for identifying anterior and inferior patients yielded encouraging outcomes, as evaluated through essential performance metrics, such as accuracy, precision, recall, and F1 score. The accuracy metric evaluated the general accuracy of the AI-based detection system, whereas the precision and recall metrics offered insights into the system’s ability to correctly classify anterior and inferior patients while minimizing the occurrence of false positives and false negatives, respectively. The F1 score, which considered the balance between precision and recall, provided additional evidence of the efficacy of the model in achieving a balanced and robust detection performance. The analysis of label distribution offered valuable insights into a dataset’s composition and the distribution of patients categorized as anterior and inferior. Ensuring a well-balanced dataset, which included a relatively equal representation of both classes, was crucial in mitigating class bias. This practice contributed to enhanced accuracy and reliability of a model’s outcomes. The label distribution of the dataset is depicted in This study employed a preprocessed dataset derived from UWB radar signals to evaluate the efficacy of various models. The analysis demonstrated that the utilization of the employed models with original features yielded suboptimal performance, as shown in The performance analysis of the LSTM neural network technique is presented in This section presents the results obtained through the application of the proposed innovative feature fusion method. The feature sets included both temporal features and class prediction probability features. These feature sets were applied to each of the techniques used in the study. Experimental results are presented in The findings demonstrated a significant improvement in the performance of each model when incorporating the features from the proposed approach. Both the RF and KNC approaches demonstrated exceptional accuracies of 98.8% each. However, the GNB approach attained a comparatively lower accuracy of 87.1%. Based on these findings, it can be inferred that the suggested fused feature methodology demonstrated a high level of effectiveness in attaining exceptional performance results for the identification of anterior and inferior MI patients.The performance evaluation of the utilized methods was carried out in this section by applying k-fold cross-validation. The features were divided into 10 subsets for validation. The findings presented in The computational complexity of each model was measured in terms of execution time, as presented in This research investigated the application of machine learning techniques to UWB radar signal data to identify anterior and inferior patients. Due to the inherent complexities of the dataset, the initial findings with the original features demonstrated difficulties in attaining high accuracy. The size of the dataset posed challenges for deep learning, specifically LSTM. The introduction of a novel feature fusion method that incorporated temporal and prediction probability features, however, marked a significant advancement. This innovative strategy considerably enhanced model performance, with RF and KNC achieving a remarkable 98.8% accuracy. Cross-validation results demonstrated the robustness of these models, particularly RF, whereas computational complexity for real-time applications remained low. The limitations of this work encompassed the relatively modest size of the dataset, thus compromising the generalizability of the findings and, therefore, influencing the performance of the model. The lack of detailed information about the specific features engineered and their clinical relevance also left room for further clarification. Moreover, although the study showcased remarkable precision, the implementation of these models in actual clinical environments presented challenges that went beyond their performances. These challenges included the capacity to understand the models, ensuring compliance with regulations, and taking into account hardware limitations, which were not thoroughly discussed in this study.Myocardial infarction is a critical cardiovascular condition that necessitates timely identification and intervention. However, the diagnosis of myocardial infarction can pose significant challenges due to its potential to exhibit a wide range of clinical manifestations and symptoms. Recently, the combination of UWB radar and ML approaches has shown significant potential to improve the diagnosis of various medical conditions. This study aimed to develop a non-contact approach for the detection of anterior and inferior myocardial infarction using UWB radar data. This study collected data in a real-world setting from confirmed patients of anterior and inferior myocardial infarction. The data were refined using signal processing approaches before feature extraction, for which a novel feature engineering approach was designed. The proposed approach integrated temporal and class prediction probability features derived from RF and LSTM models. The experiments involved using several models, like RF, KNC, LR, GNB, SVM, and LSTM, with originals, as well as features extracted using the proposed approach. The experimental results demonstrated that the incorporation of the fused feature set led to a significant enhancement in both the accuracy and precision of models with RF, obtaining the highest accuracy of 98.8%. Further validation was carried out for RF using k-fold cross-validation, and RF showed a 99.1% accuracy. Although the performance of the RF model was better than other models, it showed high computational complexity.In future work, there are several promising areas to explore in the detection of anterior and inferior myocardial infarction using UWB radar data. An essential factor to consider is the expansion of the dataset by incorporating a broader and more heterogeneous cohort of myocardial infarction patients. It will enhance the generalizability of the proposed approach. The performance and robustness of MI detection can be improved by further refining feature engineering methods and exploring ensemble learning techniques. Moreover, the development of interpretable artificial intelligence models can yield significant insights into the decision-making mechanisms and foster enhanced trust within the medical community.


Lactobacillaceae and Bacillus spp. cells and products on the growth, colonization, and survival of ESKAPEE pathogens. While the diversity of study methods limits evidence analysis, results presented by narrative synthesis demonstrate that several species have the potential as cells or their products or supernatants to displace nosocomial infection-causing organisms in a variety of in vitro and in vivo settings. Our review aims to aid the development of new promising approaches to control pathogen biofilms in medical settings by informing researchers and policymakers about the potential of probiotics to combat nosocomial infections. More targeted studies are needed to assess safety and efficacy of different probiotic formulations, followed by large-scale studies to assess utility in infection control and medical practice.Combatting the rapidly growing threat of antimicrobial resistance and reducing prevalence and transmission of ESKAPEE pathogens in healthcare settings requires innovative strategies, one of which is displacing these pathogens using beneficial microorganisms. Our review comprehensively examines the evidence of probiotic bacteria displacing ESKAPEE pathogens, with a focus on inanimate surfaces. A systematic search was conducted using the PubMed and Web of Science databases on 21 December 2021, and 143 studies were identified examining the effects of  Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumonia, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species, and Escherichia coli). As patients with weakened immune systems and antibiotic-induced dysbiosis are at increased risk of developing these infections, hospitals are particularly vulnerable to the spread of ESKAPEE pathogens ”.“ AND  AND (Lactobacillus, Lacticaseibacillus, Lactiplantibacillus, Limosilactobacillus, Latilactobacillus or Bacillus spp. or their products/supernatants on one or more ESKAPEE pathogens. ESKAPEE pathogens were defined as Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species, and Escherichia coli. Full-text articles were then obtained for all potentially eligible studies and assessed for inclusion based on the predefined inclusion and exclusion criteria. Any discrepancies between the reviewers were resolved through discussion and consensus.For the assessment of search results, results were imported into CITAVI Database. Two reviewers independently screened the titles and abstracts of the identified studies for eligibility. Studies were eligible for inclusion if they examined the effects of Overall, a total of 143 studies were included in the review see . The stuData were extracted from the included studies using a standardized data extraction form. The following data were extracted: examined bacteria, ESKAPEE pathogens they were tested against, environment tested in, type of experiment, and, if applicable, additional relevant information. The extracted data were synthesized and analyzed using a narrative synthesis approach. The results were organized by bacteria and pathogens tested and summarized in a tabular format.Lactobacilli and Bacilli or their products against ESKAPEE pathogens. By synthesizing and analysing the data from the included studies, we aimed to evaluate the potential of these probiotic bacteria as means to combat infections caused by these pathogens.Our review aimed to provide a comprehensive overview of the available evidence on the effects of Lactobacillaceae and Bacillus species are able to suppress the proliferation of ESKAPEE pathogens. However, the experimental conditions under which these studies were conducted do not allow conclusive assessments of the efficacy of the species in protecting hospital surfaces, which could contribute to the development of new promising approaches to prevent or eradicate bacterial biofilms in medical settings. More targeted studies on hospital surfaces and pathogens to be displaced are needed to understand the potential of each species and strain in more detail, along with their respective safety profiles. Once a safe and effective formulation is identified, conducting large-scale studies seems imperative, given the potential they carry in tackling several issues infection control and medical practice in general are currently facing.The evidence collected from the multitude of scientific studies shows that many


Dear Editor,Spiradenocylindroma is an adnexal neoplasm that shows histopathological characteristics of both spiradenoma and cylindroma.A 78-year-old woman with a history of hypertension was appointed to our clinic with the complaint of a nodule on the right forehead present for eight years. A detailed history taken from the patient revealed that the nodule was excised seven years ago but recurred within the last year. Dermatologic examination revealed a pinkish, shiny, telangiectatic nodule on the right forehead . In ordeSpiradenocylindromas are benign cutaneous adnexal neoplasms that are derived from apocrine or eccrine glands, demonstrating histopathological features of both spiradenoma and cylindroma.To our knowledge, our patient is the first spiradenocylindroma case that shows rosette-like structures dermoscopically. By defining dermoscopic features of cylindroma, we want to emphasize the fact that spiradenocylindromas can demonstrate dermoscopic findings such as blue-gray clods and rosette-like structures which may also be detected in other cutaneous neoplasms leading to diagnostic confusion.None declared.Ecem Bostan: Preparation and writing of the manuscript; Data collection, analysis and interpretation; Critical literature review.Etkin Boynuyogun: Data collection; Approval of the final version of the manuscript.Ozay Gokoz: Data collection, analysis and interpretation; Approval of the final version of the manuscript.Ibrahim Vargel: Data collection, analysis and interpretation; Approval of the final version of the manuscript.None declared.


Head and neck cancers are a significant global health burden, with radiation therapy being a frequently utilized treatment. The aim of this systematic review was to provide a critical appraisal of laboratory studies that assessed the effect of irradiation on the adhesive performance of resin-based biomaterials. The analysis included 23 laboratory studies obtained from five databases, with most studies using human enamel, dentin, or both, and bonding procedures involving the fabrication of direct restorations, standardized specimens, bonding of orthodontic brackets, and luting of endodontic fiber posts. The protocols used for irradiation varied, with most studies exposing specimens made from extracted teeth to irradiation using cabinet irradiators to simulate treatment of head and neck cancer. The findings indicate that irradiation reduces the bond strength of dental adhesives and resin-based composites on flat, ground enamel and dentin specimens, with different adhesives and timing of irradiation having a significant impact on adhesive performance. Irradiation also increased microleakage in most studies. The effect of irradiation on marginal adaptation of direct resin-based composite restorations was inconclusive. This systematic review indicates that irradiation has detrimental effects on the adhesive performance of resin-based biomaterials and highlights the need for further clinical and laboratory studies evaluating the performance of adhesive materials and approaches to improve it. Head and neck cancers pose a significant global health burden, accounting for approximately 5.7% of all cancer-related deaths worldwide ,2. TreatBetween 30% and 40% of patients with head and neck cancer are diagnosed with stage I or II disease, which can often be effectively treated with either surgery alone or definitive radiation therapy alone . Over 60However, despite its efficacy, radiation therapy has significant toxicity with both acute and late side-effects. Acute side-effects of radiation therapy include mucositis, xerostomia, dysphagia, and taste disturbance or loss . Late siRadiation-related caries occur in approximately 29% of patients within 3 months of completing treatment . This suPatients with head and neck cancer who undergo radiation therapy require comprehensive dental care, with special measures needed for caries prevention and control ,15,16,17The adhesive performance of dental biomaterials refers to their ability to bond to tooth structure or other dental materials, creating a strong and durable bond. This performance is a critical factor in the success of many dental treatments, including orthodontic procedures and restoration of teeth with defects caused by caries, tooth wear, or dental injuries ,20. DentThe purpose of this systematic review is to provide a critical appraisal of laboratory studies that assessed the effect of irradiation, performed to simulate head and neck cancer treatment, on the adhesive performance of resin-based biomaterials. By synthesizing the findings of these studies, this review aims to contribute to a better understanding of the impact of radiation therapy on dental biomaterials and to inform clinical decision making for the management of radiation-related dental complications.The protocol for this systematic review was prospectively registered in the International Prospective Register of Systematic Reviews . The systematic review, taking account of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement, addressed the following question using the PICO  framework ), can be a useful tool [The risk-of-bias assessment of the included studies revealed some opportunities for improvement in methodological design and reporting, particularly in the areas of sample randomization, sample size justification and reporting, and blinding of investigators. To assist researchers in designing laboratory studies that assess dental materials and in drafting study reports, the RoBDEMAT checklist, along with reporting guidelines issued by the Equator Network (Irradiation causes a degradation of the interprismatic substance of enamel . There iThe effect of irradiation on dentin appears to be more severe than enamel owing to the higher content of water and organic matter. In dentin, decarboxylation caused by irradiation destroys the electrostatic linkages between the carboxylate and phosphate side-chains of collagen and leads to a decoupling of calcium from collagen side-chains ,50. ThesIn line with the body of published evidence, etch-and-rinse adhesives appear to provide higher bond strengths to both irradiated and control enamel than self-etch adhesives applied without prior phosphoric acid etching ,33,51. IAssessments of microleakage can be used to evaluate the adhesive performance and quality of restorations. Four studies investigated microleakage of restorations placed in irradiated teeth. The majority of these studies reported higher microleakage in irradiated teeth compared with control teeth ,35,48. HConventional fractionation radiation therapy with a total dose level of 60 to 66 Gy is a standard of care in high-risk patients with squamous-cell carcinoma of the head and neck ,5. Most According to the findings of this systematic review, patients with head and neck cancer who are scheduled to undergo radiation treatment should receive dental evaluation and necessary restorative treatments before radiation therapy begins. To minimize radiation exposure of teeth, measures such as lead shielding and stents should be used whenever possible. Given that bond strength of restorations that are placed 6 months after radiation may equal that of unirradiated teeth, restorations placed 6 months or longer after radiation therapy may obtain better adhesive performance compared with restorations placed within half a year of radiation therapy. While it is advantageous to use enamel conditioning with phosphoric acid, there is no consensus on the preferred adhesive strategy for bonding to irradiated dentin. Dental practitioners need to consider the difference in performance of different adhesives and select restorative materials with due care.This systematic review generated several important conclusions that are relevant to both research and clinical patient care.Evidence derived from laboratory studies suggests that irradiation has a detrimental effect on the adhesive performance of resin-based dental biomaterials.The long-term impact of radiation on dental adhesion remains unclear, but it is plausible that the adverse effects may lessen with time between radiation therapy and the restorative procedure. However, current evidence on this is scanty.Significant differences have been observed in the performance of different adhesives on irradiated enamel and dentin. To achieve favorable restorative outcomes, it is, therefore, crucial to choose adhesives with a proven performance record in both laboratory and clinical studies, and to take painstaking care during bonding and buildup procedures.Further research is necessary to gain a comprehensive understanding of the effects of irradiation on teeth with restorations, develop methods to mitigate the adverse effects of irradiation, and explore ways to improve the efficacy of dental restorations.