Endometriosis is strongly associated with infertility. Several mechanisms have been reported in an attempt to elucidate the pathophysiological effects that lead to reduced fertility in women with endometriosis. However, the mechanisms by which endometriosis affects fertility have not been fully elucidated. Ferroptosis is a novel form of nonapoptotic cell death that is characterized by iron-dependent lipid peroxidation membrane damage. In past reports, elevated iron levels in ectopic lesions, peritoneal fluid and follicular fluid have been reported in patients with endometriosis. The high-iron environment is closely associated with ferroptosis, which appears to exhibit a double-edged effect on endometriosis. Ferroptosis can cause damage to ovarian granulosa cells, oocytes, and embryos, leading to endometriosis-related infertility. This article summarizes the main pathways and regulatory mechanisms of ferroptosis and explores the possible mechanisms of the formation of an iron-overloaded environment in endometriotic ectopic lesions, peritoneal fluid and follicular fluid. Finally, we reviewed recent studies on the main and potential mechanisms of ferroptosis in endometriosis and endometriosis-related infertility. There is a high iron level in both peritoneal and follicular fluid in patients with endometriosis.A high-iron environment may be key to triggering ferroptosis.Ferroptosis may have a double-edged effect on the development of endometriosis.Ferroptosis impairs the function of oocytes and granulosa cells in patients with endometriosis.How does endometriosis tolerate the high levels of iron in the peritoneal fluid?Could ferroptosis inducers be the next potential treatment for endometriosis?How do iron overload and ferroptosis affect endometriosis-related infertility?How can ferroptosis be balanced to treat endometriosis and endometriosis-related infertility?Endometriosis refers to an oestrogen-dependent inflammatory disease characterized by the seeding and growth of endometrial tissue outside the uterine cavity . These eFerroptosis is a novel form of regulated cell death that is distinct from accidental cell death; it can be mediated by different molecular signalling pathways , 11. SpeWe propose the notion that a threshold exists for the occurrence of ferroptosis in ectopic endometrial tissue in endometriosis. Once beyond the threshold, iron overload and oxidative damage can lead to ferroptotic cell death. Multiple oxidative and antioxidant systems can be activated simultaneously and operate in parallel to adjust this threshold, which is implicated in the metabolic reprogramming of the affected cells . On the Dixon et al. first defined ferroptosis as a distinct iron-dependent form of non-apoptotic cell death in 2012 . FerroptGPX4 is a key factor in the antioxidant system that is regulated by multiple molecular mechanisms. In most cells, cysteine is obtained through the system xc- antiporter, which exchanges extracellular cystine with intracellular glutamate . HoweverBased on its unique functions, GPX4 is considered a powerful antagonist of ferroptosis and plays a crucial role in regulating ferroptosis. As a key antioxidant system enzyme, GPX4 can catalyse the reduction in lipid peroxides in complex cellular membrane environments . It can 2+) production [Throughout the antioxidant system, the regulation of multiple inhibitors and ferroptosis inducers has been implicated. Inhibition of the GCL by buthionine sulfoximine (BSO) induces ferroptosis alone or enhances the sensitivity of cells to ferroptosis induced by other agents . The actoduction .Reactive oxygen species (ROS) are a byproduct of aerobic metabolism that are mainly derived from mitochondrial metabolism and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) on the cell membrane, and excessive ROS or the inappropriate location of ROS can damage cells . ROS proNotably, the voltage-dependent anion channel (VDAC) in the mitochondrial outer membrane, also known as the mitochondrial pore, acts as a gatekeeper for the entry and exit of mitochondrial metabolites and is a convergence point for its binding to various ligands and proteins to mediate various cell survival and cell death signals . Erastin2+ and ferric (Fe3+), which are mainly present intracellularly and extracellularly, respectively. The interconversion between Fe2+ and Fe3+ can either donate or accept electrons. This is a process that provides the premise for redox reactions and may affect the sensitivity of cells to ferroptosis. Interestingly, only iron, and not other metals, such as zinc, that also cause ROS generation via the Fenton reaction [3+ can bind to transferrin (TF) in serum and is subsequently taken up by the TF receptor 1 (TfR1), which is encoded by TFRC on the cell membrane [3+ taken up into the cell is reduced to Fe2+ by STEAP3 metalloreductase in the endosome and is then released into the labile iron pool of the cytoplasm by divalent metal transporter 1 (DMT1) [2+ participates in various cellular metabolic and biochemical reactions and maintains cellular homoeostasis. The NFS1 cysteine desulfurase can promote iron–sulfur cluster biosynthesis. This results in increased Fe2+ availability to inhibit erastin-induced ferroptosis in lung tumour cells and attenuates dihydroartemisinin-induced ferroptosis in leukaemia cells [Iron is an indispensable metal for the body and is essential for maintaining biological homoeostasis. Iron oxidation has two states, Fereaction , can indmembrane . Similarmembrane . Proteinmembrane . Subsequ1 (DMT1) . Fe2+ paia cells , 56. Theia cells , 58. Theia cells . This pria cells . Moreoveia cells .2+ from intracellular to extracellular spaces [2+ is subsequently oxidized to Fe3+ by the ferroxidase ceruloplasmin (CP) [Ferroportin1 (FPN1), the only identified mammalian nonhaem iron exporter, can transport Fer spaces , and Fe2min (CP) . Erastinmin (CP) . Knockdomin (CP) . Moreovemin (CP) .2+ and Fe3+ in the CYP450 haem fraction and is identified as the alternative source of ROS that induces ferroptosis-related lipid peroxidation [Lipids are not only important components of cell membranes but also precursors of various molecules that play important biological roles. However, the excessive accumulation of lipids has potentially toxic effects on individual cells, as well as on the whole body. Previous studies suggest that the peroxidation of polyunsaturated fatty acids in phospholipids by lipoxygenases (ALOX) is particularly important for ferroptosis , 66. Aftxidation . Lipid dxidation .Under normal physiological conditions, iron plays an important role in metabolic processes. However, whenever the transporter is mutated or deleted, it will disrupt the iron balance and lead to excessive accumulation, triggering cellular oxidative damage and death , 73. SimIn short, ferroptosis is an iron-dependent lipid peroxidation form of regulated cell death. Iron metabolism and lipid generation, storage, and degradation are all closely associated with ferroptosis. Excessive free iron levels and dysregulated lipid metabolism in cells trigger ferroptosis, but the oxidative and antioxidant systems are also involved in the regulation and maintenance of cellular processes. In addition, ferroptosis is regulated by many other factors. The complex mechanisms involved need to be elucidated further to help us better modulate the degree of ferroptosis caused by drugs or gene regulation for the treatment of diseases.Endometriosis can be divided into three phenotypes due to the diverse of underlying aetiologies: superficial peritoneal endometriosis, ovarian endometriosis, and deep infiltrating endometriosis . StudiesRetrograde menstruation and ectopic endometrial bleeding lesions can transport menstrual endometrial tissue and red blood cells to the peritoneal cavity. Some of these tissues and cells will be phagocytized, absorbed, and degraded by peritoneal macrophages and stored in the form of haemosiderin. Additionally, ferritin and haemoglobin are released into the peritoneal fluid . The haeEndometriosis is a chronic inflammatory disease that is closely related to inflammation and the immune response. As a regulated form of cell death, ferroptosis can activate different downstream pathways and complex molecular effector mechanisms, leading to cell lysis in different forms and resulting in morphological changes and immune responses .As the main substrate of lipid peroxidation released from PL in the cell membrane, AA is a precursor of proinflammatory mediators that can be metabolized by cyclooxygenases (COX), ALOX, and CYP450 monooxygenases to synthesize biologically active inflammatory mediators, such as prostaglandins (PGs) and leukotrienes . InteresSimilar to nonsilent immune forms of regulated necrosis, ferroptotic cell death can release damage-associated molecular patterns (DAMPs) that promote the development of multiple inflammatory diseases and trigger the innate immune system. These DAMPs can drive tissue inflammation and inflammation crosstalk with ferroptosis. This further promotes an autoamplification loop that exaggerates inflammation and cell death and leads to a more severe degree of cell death and a range of inflammation-related responses , 96. ForEndometriosis is also an oestrogen-dependent gynaecological disease in which excessive oestrogen signalling transduction and altered oestrogen signalling pathways play an important role in its pathogenesis, resulting in oestrogen dominance and progesterone resistance , 98. OesThe imbalance of iron metabolism plays an important role in the pathogenesis of endometriosis, and studies have confirmed that iron overload exists in the peritoneal fluid of patients with endometriosis , 102. Th2+ in ectopic ESCs generates ROS via the Fenton reaction, which contributes to the migration abilities of MMPs via the ROS-NF-κB pathway in ectopic endometrial cells [However, the role of ferroptosis in endometriosis appears to be bidirectional. On the one hand, ferroptosis inducers can promote ferroptosis in ectopic endometrial stromal cells, and thus, these inducers may become potential drugs for the treatment of endometriosis. On the other hand, ferroptotic endometrial stromal cells can release inflammatory cytokines and activate downstream regulatory pathways to promote proliferation and angiogenesis in surrounding tissues. Iron overload in ectopic endometrial stromal tissues from patients with ovarian endometriosis-induced ferroptosis, which promoted fibrosis and tissue adhesions, and the process was associated with endometrial stromal cell subpopulations . In a real cells . The oveal cells , 111.Iron overload and ferroptosis do occur in endometriotic lesions, and the use of ferroptosis inducers may be a potential treatment for endometriosis. However, a series of downstream inflammatory pathways activated after ferroptosis cannot be ignored, and these pathways further promote angiogenesis and focal fibrosis Fig. . TherefoG12D released from autophagy-dependent ferroptotic cancer cell death can limit the antitumour effects of macrophages by activating STAT3-mediated AGER-dependent M2 macrophage polarization [Ferroptosis releases DAMPs and lipid oxidation products, which affect nonleukocytes and cause inflammatory cell death. However, it also mediates immune cell death that leads to losses of immune function, such as macrophage function. Macrophages phagocytose aged erythrocytes and process iron from erythrocytes to participate in iron metabolism. Excessive erythrophagocytosis leads to iron overload in macrophages and induces iron-dependent ferroptosis. Iron overload in bone marrow-derived macrophages can upregulate SLC7A11 expression via the ROS-NRF2-antioxidant response element (ARE) axis to reduce cellular sensitivity to ferroptosis . In contrization . Similarrization . Thus, f2+ through TfRC and DMT1, the major source of iron for macrophages is through the disposal of haem-derived iron. Although macrophages have a remarkable ability to tolerate iron overload [Macrophages play an indispensable role in the chronic inflammatory disease mechanism of endometriosis. Previous studies have shown that macrophages allow the growth of ectopic endometrial tissue, promote angiogenesis, and recruit nerve fibres to contribute to chronic pain . In the overload , the antoverload . Activatoverload . Therefooverload . Therefooverload . In summThe iron-overloaded environment induced by retrograde menstruation is suspected to be an important factor in inducing the continued proliferation of ectopic endometrial tissue. In addition, ferroptosis promoted by an iron-overloaded environment appears to be detrimental to oocytes or embryos and is also closely related to endometriosis-related infertility. Peritoneal fluid and follicular fluid are the external microenvironments for oocyte maturation and blastocyst formation, and these abnormal microenvironments affected by iron overload may lead to impaired reproductive function.In recent years, studies on the role and mechanism of iron overload and ferroptosis in endometriosis-related infertility have been reported successively Table .Table 1SIron overload in peritoneal fluid can affect embryonic development by leading to embryo toxicity and ferroptosis. Chen et al. showed that the pelvic iron-overloaded environment in patients with endometriosis impaired early embryonic development and caused embryo toxicity by triggering GPX4 downregulation-dependent ferroptosis in preimplantation mouse embryos. This leads to endometriosis-related infertility and adverse pregnancy outcomes . During The total iron levels and ferritin and TfR1 expression levels in endometrioma-proximal follicles are higher than those in endometrioma-distal follicles and healthy ovarian follicles. Moreover, the oocyte retrieval rates in endometrioma-proximal and -distal follicles are lower than those in healthy ovarian follicles ; this ilIn recent research, Li et al. studied specific proteins at different concentrations in the follicular fluid of patients with advanced endometriosis and found that the transferrin concentration of the three analogues of cDNA FLJ53691, cDNA FLJ54111, and TRF variant Fragment in the follicular fluid decreased. The iron ion concentration of these analogues increased. The environment of transferrin deficiency and iron overload could increase the level of ROS and lead to oxidative stress. Thus, the in vitro maturation rate of mouse oocytes could significantly decrease, which might be one of the causes of endometriosis-related infertility . Ni et a2+ in the cytoplasm and decreases in the polar body (PB) expulsion rate and blastocyst formation rate. Thus, exogenous ferroptosis inducer-induced ferroptosis inhibits oocyte meiosis by increasing oxidative stress, inducing mitochondrial dysfunction, triggering autophagy splitting process and affecting oocyte quality [Furthermore, after in vitro ferroptosis inducer ferric ammonium citrate (FAC) intervention, mammalian oocytes experienced increases in ROS and autophagy-related protein LC3 and mitochondrial dysfunction. Additionally, there was significant accumulation of Fe quality . Convers quality .In summary, these findings suggest that iron overload and its induced ferroptosis in peritoneal fluid and follicular fluid in patients with endometriosis play an important role in the progression of endometriosis-related infertility Fig. . TherefoIn recent years, researchers have gradually appreciated and revealed the potential role of ferroptosis in endometriosis. These findings highlight the ability of ectopic endometrial tissue to resist iron overload-induced ferroptosis and promote ectopic lesion growth by mediating local cellular ferroptosis in peritoneal fluid in patients with endometriosis. However, oocytes from patients with endometriosis-related infertility are threatened by iron overload, and the development and maturation of oocytes are affected and prone to trigger cellular ferroptosis. This is possibly due to the immature antioxidant system and membrane repair mechanisms of the oocyte. Furthermore, although iron accumulation and lipid peroxidation are unique intermediate events in the onset of ferroptosis, they are not the ultimate executors. Lipid peroxidation can also occur in other cell death types, which depend on different ultimate effectors. Key regulators of ferroptosis can also regulate other types of cell death. For example, GPX4, a key factor in the antioxidant system, also inhibits apoptosis and necroptosis to protect cells from various insults , 130. Th


In this minireview, we summarize the current findings on the relationship between stress and cancer, focusing on the role of inflammation in stress-induced neuroendocrine-immune crosstalk. We also discuss the underlying mechanisms and their potential for cancer treatment and prevention.Stress is an integral part of life. While acute responses to stress are generally regarded as beneficial in dealing with immediate threats, chronic exposure to threatening stimuli exerts deleterious effects and can be either a contributing or an aggravating factor for many chronic diseases including cancer. Chronic psychological stress has been identified as a significant factor contributing to the development and progression of cancer, but the mechanisms that link chronic stress to cancer remain incompletely understood. Psychological stressors initiate multiple physiological responses that result in the activation of the hypothalamic-pituitary-adrenal (HPA) axis, sympathetic nervous system, and the subsequent changes in immune function. Chronic stress exposure disrupts the homeostatic communication between the neuroendocrine and immune systems, shifting immune signaling toward a proinflammatory state. Stress-induced chronic low-grade inflammation and a decline in immune surveillance are both implicated in cancer development and progression. Conversely, tumor-induced inflammatory cytokines, apart from driving a tumor-supportive inflammatory microenvironment, can also exert their biological actions distantly  Hence, ecretion . This HPecretion . New datecretion . This stecretion . In addiecretion .de novo immune activation, thus significantly enhancing the speed and efficacy of the immune response. Functional implications of stress-induced immune cells redistribution are reflected in significantly enhanced immune responses within target tissues which are enriched with leukocytes during stress. It is important to note that leukocytes exhibit distinct sensitivities and redistribution kinetics in response to each stress hormone, depending on the type of cell and its functional characteristics  by adrenergic signaling , signal transducer and activator of transcription 3 (STAT3), and mammalian target of the rapamycin (mTOR). These pathways orchestrate the production of proinflammatory cytokines, which in turn regulate their activation /CCR2 pathway  should be considered. Better understanding how cancer alters stress responsivity may provide novel insights into mechanisms contributing tumor immune evasion and therapy resistance, as well as to point towards the susceptibility/risk biomarkers predicting worse clinical outcomes in cancer patients. Furthermore, multi-omics analysis of peripheral blood cells may enable the identification of distinct cytokine signatures as potential biomarkers assessing the risk for stress-related cancer development and/or progression.Chronic stress and cancer are mutually interconnected conditions that can affect each other


Editorial on the Research TopicComputational methods for pain pharmacologyAs we venture into the year 2024, it becomes clear that we stand in front of a profound technological revolution. Recent developments in the field of data science and artificial intelligence have now made them apparent parts of our daily life. Advanced technologies are not only reshaping our daily experiences but also revolutionizing how we approach intricate challenges like pain management. The complexity of pain perception, the diversity of underlying mechanisms, and the necessity for tailored pharmacological interventions have fueled a growing interest in employing computational methods to enhance our understanding and treatment of pain.Holmes et al., have used different machine learning (ML) classifiers to differentiate pediatric and young adult subjects with post-traumatic headache (PTH) from healthy controls. Authors used data from different self- or caregiver-report questionnaires that reflect concussion symptoms, mental health, pain experience of the participants, as well as brain imaging data including volume measures of cortical and sub-cortical structures. Abovementioned data allowed researchers to predict PTH diagnosis with 85% accuracy, but more interestingly, they were able to establish the score in Child and Parent Fear of Pain Questionnaire to be the most important predictor of PTH, followed by changes in volumes of several brain areas, implicating their role in the neurobiological mechanism involved in the PTH development. These results highlight how much insight, one can get from the data by using computational tools, such as feature selection algorithms. Similarly, Lai et al., used an a priori algorithm to reveal the use patterns of Traditional Chinese Medicine (TCMs) as analgesic drugs in rheumatoid arthritis patients. This study had screened out the potential compatibility combination patterns of drugs for the treatment of rheumatoid arthritis and also set a perfect example of how the use of computational tools can bring better understanding of complex and vague phenomena such as the pharmacology of TCMs and the synergistic effects between various herbs.Two articles in this Research Topic leveraged so-called “big data” to tackle clinically relevant problems. Van der Wal et al., have employed nociception level monitor (NOL) during operation to dose the analgesics. NOL, based on random forest algorithm, constructed pain score from the following parameters: heart rate, heart rate variability amplitude of the finger photoplethysmogram, skin conductance level and their time derivatives. Whenever the patient reached a threshold pain score, they were given an analgesic. This method was compared with standard procedure, where analgesics are dosed based on hemodynamic response. Authors observed that in the NOL-guided group, fewer patients experienced severe pain after operation and less patients required post-operative pain treatment. Thus, application of NOL or other ML based algorithms for dose optimization may significantly reduce risk of opioid overuse.This Research Topic also demonstrates how computational approaches are driving the development of personalized pain management strategies. By integrating patient-specific data, such as genetic profiles, physiological parameters, and pain phenotypes, computational models can assist clinicians in selecting the most suitable medications and dosages, optimizing outcomes, and minimizing adverse effects. Neilan et al., have developed a 3-D computational model of neurons in the central amygdala (CeA) based on the laboratory data. CeA is a heterogenous nucleus including dozens of unique cell types with different functions based on intra-CeA connectivity and localization along the anterior-posterior axis. Generally, neurons expressing protein kinase C-delta (PKCδ) have a pro-nociceptive role in CeA “pain output”, while somatostatin (SST) positive CeA neurons have an anti-nociceptive role. However, there is considerable evidence for expression differences in PKCδ and SST as well as other CeA cell-types based on their location within the nucleus. Nociceptive inputs to these cells differ as well. Authors developed the first computational model of PKCδ and SST neurons in the amygdala, based on cell-type physiology data. Their model simulates the behaviors and interactions of individual PKCδ and SST neurons and is capable of capturing morphological features as well as spatial heterogeneity in the location and connectivity of PKCδ and SST neurons throughout the CeA. One of the advantages of the 3-D model is its ability to target cells in different locations within the CeA to investigate the potential for spatially separate populations to differently impact nociception. The value of computational modeling is its ability to address these questions quickly prior to investment in resource-heavy wet lab experiments. Based on the simulations, authors suggest that manipulation of the anterior vs. posterior CeA causes a disproportional impact on nociceptive output from two populations of CeA neurons, a phenomenon recently demonstrated in mice (Finally, a great proportion of computational work focuses on creating functional models of biological phenomena.  in mice .In conclusion, the research topic “Computational Methods for Pain Pharmacology” underscores the transformative role of computational methods in revolutionizing pain management and research. From unraveling the intricacies of pain neurobiology to accelerating drug discovery and enabling personalized treatments, computational approaches are pushing the boundaries of our understanding and capabilities. As technology continues to evolve and interdisciplinary collaborations flourish, the future holds the promise of more effective, safer, and patient-centric pain relief strategies.


Implantation of mesenchymal stem cells (MSCs) is a potential cell-based modality for cartilage repair. Currently, its clinical use largely surrounds focal cartilage defect repair and intra-articular injections in knee osteoarthritis. The MSCs’ implantation efficacy as a treatment option for osteoarthritis remains contentious. This systematic review aims to evaluate studies that focused on MSCs implantation in patients with knee OA to provide a summary of this treatment option outcomes.A systematic search was performed in PubMed (Medline), Scopus, Cinahl, and the Cochrane Library. Original studies investigating outcomes of MSCs implantations in patients with knee OA were included. Data on clinical outcomes using subjective scores, radiological outcomes, and second-look arthroscopy gradings were extracted.Nine studies were included in this review. In all included studies, clinical outcome scores revealed significantly improved functionality and better postoperative pain scores at 2–3 years follow-up. Improved cartilage volume and quality at the lesion site was observed in five studies that included a postoperative magnetic resonance imaging assessment and studies that performed second-look arthroscopy. No major complications or tumorigenesis occurred. Outcomes were consistent in both single MSCs implantation and concurrent HTO with MSCs implantation in cases with excessive varus deformity.According to the available literature, MSCs implantation in patients with mild to moderate knee osteoarthritis is safe and provides short-term clinical improvement and satisfactory cartilage restoration, either as a standalone procedure or combined with HTO in cases with axial deformity. However, the evidence is limited due to the high heterogeneity among studies and the insufficient number of studies including a control group and mid-term outcomes.IV. Within the scope of knee joint preservation in early osteoarthritis, the hierarchy of the treatment strategy is to first optimize alignment, second achieve joint stability, followed by undergoing meniscus procedures and/or cartilage surgery . High tiMesenchymal stem cell (MSC) implantation as a potential cell-based modality for cartilage repair has had promising outcomes in clinical studies when used in patients with knee OA, either combined with HTO in patients with varus deformity  or as a To fill this literature gap, the present systematic review evaluates studies that focused on MSCs implantation in patients with knee OA providing an up-to-date summary of clinical, radiological, and second-look arthroscopy outcomes. Hypothesis is that MSCs implantation is associated with satisfactory postoperative outcomes but with contentious duration of improvement.This systematic review was performed in accordance to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines .A comprehensive search was systematically conducted in PubMed (Medline), Scopus, CINAHL, and Cochrane Central databases. The following search algorithm was used for all databases:  AND (osteoarthritis OR OA OR degeneration OR gonarthrosis) AND knee. The search was performed by two independent investigators (HR and LC) and was updated just before the final analyses on 3rd March 2023.To be included in this review, the studies must fulfil the following predefined criteria: (i) clinical trials of any level of evidence, reporting outcomes of MSCs implantation in patients with knee OA, and (ii) studies published in English language.The predefined exclusion criteria were: (i) studies on knee OA patients treated with injected MSCs, (ii) studies evaluating focal/isolated chondral lesions and defects, (iii) cadaveric, laboratory or animal studies and (iv) secondary research articles .Two investigators (HR and TT) independently assessed the titles and abstracts of all identified records. The same investigators screened the full texts of all potentially eligible studies independently, according to the defined inclusion criteria. Additionally, references of the included studies were retrieved and manually reviewed to identify further eligible articles, according to the snowball method. Investigators were blinded to each other throughout the study selection and data extraction processes. Any disagreements or discrepancies were resolved by consensus.The methodology of the study was assessed using the list of criteria as recommended by the Cochrane Collaboration and an Oxford Centre for Evidence-Based Medicine (OCEBM) level of evidence (LoE) was assigned to each study. The quality of included studies was evaluated using different scales based on study design: randomised controlled trials or non-randomised clinical studies. Randomised controlled trials were assessed by the modified Jadad scale that is an 8-point scale based on the domains: randomisation blinding, account for lost to follow-ups, eligibility criteria, adverse effects, and statistical analysis . Non-ranTwo authors (HR and OS) independently extracted data from eligible studies using a data extraction form that was predefined according to the protocol. For each study, characteristics of participant , type of cartilage restorative procedure and, if present, type of control procedure, lesion size and location, grade of osteoarthritis, number of applied MSCs, follow-up, clinical and radiological outcomes as well as second-look arthroscopy findings were recorded. Clinical improvement of the patients, which was evaluated using patient reported outcome measures (PROMs), were the primary outcomes of the current study. Radiologic and arthroscopic appearance of the treatment site were secondary outcomes.Mean and standard deviation were calculated for continuous variables while absolute and relative frequencies were reported for categorical variables. Due to heterogeneity of the included studies in relation to study protocols, no data pooling and meta-analysis was performed.The PRISMA flowchart is illustrated in Fig. The mean QoE was 12.8 for non-comparative studies , 29, 30 A total of 1058 knees with knee OA were included in this review. MSCs implantation was performed in 983 knees using either autologous adipose-derived MSCs , 18, 19 The International Knee Documentation Committee subjective score (IKDC)  was usedThree studies evaluated the quality of repaired cartilage with the Magnetic Resonance Observation of Cartilage Repair tissue (MOCART) scoring system , 20, 29 Among the five studies that performed second-look arthroscopy, three observed an improvement to the cartilage status according to the ICRS grading system , 30, 36 The most important finding of this systematic review is that in all included studies clinical outcome scores revealed significantly improved functionality and better postoperative pain scores in patients with knee OA who underwent MSCs implantation at 2–3 years follow-up. Improved cartilage volume and quality at postoperative MRI and second-look arthroscopy was consistently observed. No major complications or tumorigenesis occurred. Outcomes were consistent in both single MSCs implantation and concurrent HTO with MSCs implantation in cases with excessive varus deformity.6 cells). To add to the ambiguity, the estimation of MSCs dosage may vary as some studies included the entire mononuclear cell count in dosage calculation, involving heterogenous population of cells such as platelet-rich plasma (PRP), autologous conditioned serum (ACS) apart from MSCs. Nonetheless, the current study suggests that clinical outcomes after MSCs’ implantation are significantly influenced by MSCs’ counts [There is no current consensus on the MSCs optimal therapeutic dose to be implanted for cartilage regeneration as demonstrated by the range of MSCs concentrations used among eligible studies in the present systematic review  is important because the incidence of primary TKA is increasing among younger age patients. There is evidence that the risk of revision TKA and dissatisfaction increases as the age of the patient decreases . While tAmong the included studies, all methods have shown benefit in clinical outcomes despite the heterogeneity in lesion location, number of cells, grading of OA and follow-up periods. There are reports of cartilage status improvement in the affected compartment after HTO without any concomitant cartilage procedures . HoweverThe present study revealed that radiological outcomes based on MRI and second-look arthroscopy correlate with clinical outcomes. However, plain radiographic outcomes were not significantly correlated with clinical outcomes , 20. A pThe findings of this study must be interpreted in light of its limitations. Firstly, heterogeneity in terms of MSCs source and primary outcomes reported in the studies may have affected the analysis and data interpretation. Secondly, several included studies in this review were from South Korea, and from the same principal investigator which adds to bias , 18–20. MSCs have been suggested for treatment of knee OA since their differentiation into chondrocytes can lead to cartilage repair. Next, homing characteristics of MSCs make them ideal seed cells for gradual OA treatment , 4, 33. According to the available literature, MSCs’ implantation in patients with mild to moderate knee osteoarthritis is safe and provides short-term clinical improvement and satisfactory cartilage restoration, either as a standalone procedure or combined with HTO in cases with axial deformity. However, the evidence is limited due to the high heterogeneity among studies and the insufficient number of studies including a control group and mid-term outcomes.


Antimicrobial peptides (AMPs) are components of natural immunity against invading pathogens. They are polymers that fold into a variety of three-dimensional structures, enabling their function, with an underlying sequence that is best represented in a non-flat space. The structural data of AMPs exhibits non-Euclidean characteristics, which means that certain properties, e.g., differential manifolds, common system of coordinates, vector space structure, or translation-equivariance, along with basic operations like convolution, in non-Euclidean space are not distinctly established. Geometric deep learning (GDL) refers to a category of machine learning methods that utilize deep neural models to process and analyze data in non-Euclidean settings, such as graphs and manifolds. This emerging field seeks to expand the use of structured models to these domains. This review provides a detailed summary of the latest developments in designing and predicting AMPs utilizing GDL techniques and also discusses both current research gaps and future directions in the field. Bacterial resistance to antibiotics is causing a rise in mortality due to what were once treatable infections. Novel strategies to counter such infections are needed. AMPs have been recognized as promising substitutes for traditional therapies . These bin vitro experiments required for collecting such parameters are usually laborious, expensive, and time-consuming  . The CNNTo improve the representation of the three-dimensional structure and physicochemical properties of amino acids, AMPs can be modeled as graphs that are based on either their structural data or manifolds describing their geometric shapes. Considering the small size of AMPs compared to proteins, the burden of having a graph with a large number of nodes representing the data size reduces the challenge for machine learning processing.Distinctive geometric deep learning methods for graphs have been proposed thus far for general applications , such as spectral-based graph convolutional networks: spectral convolutional neural networks (SCNN) are based on the application of the Fourier transform to graphs ; smooth Spatial-based graph convolutional networks, such as graph neural networks (GNN), have also been proposed. Until they reach a state of convergence, they repeatedly adjust and improve the hidden representation of nodes . GraphSaAMPs-Net, as presented by Explainable artificial intelligence (XAI) has emerged as a remarkable tool to enhance the accuracy and understanding of machine learning approaches as applied to drug design . XAI aimGDL has achieved promising accuracy levels for predicting AMPs; additional methods not yet applied in this area, such as GAE, GGN, MoNet, GNN, SCNN, etc., promise to further improve performance. Future work should focus on furthering our understanding of how machine learning models are able to predict molecular function. XAI methods have been applied to drug design and protein-ligand interactions with some success but not yet to AMP design. Although several limitations still need to be overcome, GDL methods hold great promise for antimicrobial peptide prediction and design.The GDL techniques application in the AMP domain will result in better AMP structure modeling and further functional relation understanding due to its non-Euclidean nature. Furthermore, more accurate AMP prediction and rational design of new targeted specific molecules. Ultimately, the manifold AMP representation can create a new corpus of peptide language that can be used for large language models and improve the drug design process.


Chronic stress exposure represents a prominent risk factor for the development of neuropsychiatric disorders, including depression, anxiety, substance use disorders, and post-traumatic stress disorder (PTSD), significatively affecting the well-being and health of millions of individuals worldwide . Together, this work suggests D-serine signaling and hippocampal neurogenesis have a key role in promoting contextual fear memory by promoting reconsolidation.Abnormal persistence and reactivation of stressful or fearful experiences are a key characteristic of PTSD. The work by Ruan et al. brought insights into the phenotypic heterogeneity of AHRL and tinnitus, and the contribution of chronic non-audiogenic and chronic audiogenic stressors to such heterogeneity. They elegantly reviewed literature regarding the chronic effects of stress exposure on limbic brain structures and on those systems closely related to auditory processing, and how such effects could lead to different frailty phenotypes and aggravate AHRL and/or tinnitus.Epidemiological studies suggest a relationship among age-related hearing loss (AHRL), tinnitus, and psychiatric diseases related to stress exposure , amygdaloid complex, and hippocampus of adult male mice 48 h after termination of repeated stress exposure. Results showed that chronic social defeat induced social avoidance, increased anxiety-like behaviors, and impaired short-term memory. Although social defeat did not induce a clear depressive-like phenotype, it led to increased deterioration of coat state and weight gain. Moreover, social defeat increased ΔFosB expression in glutamatergic neurons in BNST and amygdala, increased ΔFosB immunoreactivity in the ventral hippocampus, and reduced ΔFosB labeling in the dorsal hippocampus. The authors discuss the potential relationships between the behavioral outcomes and the immunoreactivity patterns observed, suggesting that differential activity may underlie behavior.Favoretto et al. expand on this idea of cell-type differences as they review how different cell types in the brain contribute to stress susceptibility. Beginning with non-neuronal cells, they discuss how astrocytes and microglia respond to stress, and how functional changes in these two cell populations are related to stress outcomes. They then explore relationships between stress-induced changes in neuron function and behavioral outcomes focusing on a specific collection of neuronal subtypes. This discussion also highlights key studies that have experimentally manipulated these cell types to establish causal relationships between neuronal activity and behavior. This focused, yet thorough, review of the literature provides important insight into the cellular and molecular diversity that underlies responses to stress, which is an important consideration for understanding the pathophysiology of stress-related disorders and discoveries of next-generation treatments.The work presented in this Research Topic highlights the multifaceted effects of stress from molecules to behavior. Unraveling the complexities of stress and its effects on the brain will be important for understanding the neurobiological basis of stress responses with key insight into the pathophysiology underlying stress-based psychiatric disorders. Advances in understanding the involvement of precise neural substrates on stress-related outcomes may unravel specific cellular and molecular targets for the development of next-level therapies for neuropsychiatric disorders. The editors hope you enjoy this Research Topic and that it will be useful and insightful to your research.GM-S: Writing—original draft, Writing—review and editing. CF: Writing—original draft, Writing—review and editing. MP: Writing—original draft, Writing—review and editing. TL: Writing—original draft, Writing—review and editing.


The brain is built with hemispheric asymmetries in structure and function to enable fast neuronal processing. In neuroimaging studies, several mental disorders have been associated with altered or attenuated hemispheric asymmetries. However, the exact mechanism linking asymmetries and disorders is not known. Here, studies in animal models of mental disorders render important insights into the etiology and neuronal alterations associated with both disorders and atypical asymmetry. In this review, the current literature of animal studies in rats and mice focusing on anxiety and fear, anhedonia and despair, addiction or substance misuse, neurodegenerative disorders as well as stress exposure, and atypical hemispheric asymmetries is summarized. Results indicate overall increased right-hemispheric neuronal activity and a left-sided behavioral bias associated with symptoms of anxiety, fear, anhedonia, behavioral despair as well as stress exposure. Addiction behavior is associated with right-sided bias and transgenic models of Alzheimer’s disease indicate an asymmetrical accumulation of fibrillar plaques. Most studies focused on changes in the bilateral amygdala and frontal cortex. Across studies, two crucial factors influencing atypical asymmetries arose independently of the disorder modeled: sex and developmental age. In conclusion, animal models of mental disorders demonstrate atypical hemispheric asymmetries similar to findings in patients. Particularly, increased left-sided behavior and greater right-hemispheric activity were found across models applying stress-based paradigms. However, sex- and age-dependent effects on atypical hemispheric asymmetries are present that require further investigation. Animal models enable the analysis of hemispheric changes on the molecular level which may be most effective to detect early alterations. Hemispheric asymmetries, that is, differences between the left and the right hemisphere are present on the structural, functional, and molecular level   to induce stress and anxiety in the rats. Both exposures resulted in a greater dopamine release in the right basolateral amygdala and infralimbic cortex in males. However, females showed greater dopamine release in the left hemisphere  in the second session while right-biased rats did not differ between sessions  to get the food reward. Then, the animals were tested in the forced swim test and the Morris water maze. Results show that rats with a left-sided paw preference demonstrated more behavioral despair but also had better reference memory than right-pawed rats while spatial learning performances did not differ between groups  activity, that is essential in inflammatory processes and associated with oxidative stress, was shown in the left hemisphere of frontal and parietal cortices compared to age-matched controls. Older Nogo-A-deficient rats demonstrated a bilateral decrease in the expression of the NMDA receptor subunit NR1 and increased expression of the NMDA receptor subunit NR2B in the right hemisphere. At both ages, changes in interactions within the investigated pathway were observed in the experimental groups. The authors conclude that young Nogo-A-deficient rats experience accelerated aging and abnormal frontoparietal cortical interactions similar to findings in humans  where mice from a C57BL/6 genetic background harbor PS1(M146V), APP(Swe), and tau(P301L) transgenes, were socially isolated and compared to non-transgenic mice as well as non-isolated transgenic mice (controls). Mice from this transgenic line progressively develop plaques and tangles as well as synaptic dysfunction all of which is present in Alzheimer’s disease  via cross-sectional PET scans and observed that over 30% of the experimental animals had strong asymmetric fibrillar plaque distribution but no hemispheric predominance across models was found. In terms of microglia activation, asymmetric amyloid-β accumulation was positively correlated with ipsilateral TSPO expression  expression, pregnant Sprague Dawley rats were subjected to unpredictable variable stressors two to three times daily during the last week of gestation. The offspring was group-housed until adulthood. Then the expression of subunits of nAChR was analyzed using autoradiography. Studying the distribution of nAChR expression is an interesting target as nAChR are involved in fast synaptic transmission and in cognitive processes such as learning and memory  at gestational day 15 to induce a maternal immune reaction. Adolescent and adult offspring were then analyzed for turning behavior examined in the open-field test. In adolescents, maternal exposure resulted in a rightward turning bias compared to controls whereas, in adults, maternal immune activation led to an absence of turning bias that may be associated with reduced asymmetry. The authors furthermore analyzed dopamine D2 receptor expression in the prefrontal cortex and found bilateral reduced expression after stress in adolescence Arte) with a genetical B6C3H background was studied. In a previous study including this mouse model it was shown that lithium treatment prevented stress-induced increased glutamine synthetase activity in the hippocampus (Mundorf et al. One study investigated the effects of chronic stress exposure in adult mice on turning behavior (Mundorf et al. Summing up, studies highlight that exposure during early periods as well as in adulthood leads to behavioral left-sided preference or attenuated asymmetry behavior similar to findings in patients. On the neuronal level, prenatal stress, and exposure in adulthood results in increased right-sided activity. Interestingly, treating the animals with psychiatric drugs seems to reverse stress-induced asymmetric alterations.The results of animal studies modeling symptoms of mental disorders suggest an association between psychopathological symptoms and an altered side preference along with atypically asymmetric increased neuronal activity. In detail, increased anxiety and anhedonic behavior are linked to increased right-hemispheric neuronal activity and a left-sided behavioral bias is associated with increased behavioral despair. Similarly, stress exposure leads to atypical left-side preferences in behavior as well as increased right-sided neuronal activity. In contrast, addiction behavior as a result of substance exposure is associated with increased consumption in right-bias animals and a greater decrease in neurotransmitter levels in the right hemisphere. Transgenic mice models of Alzheimer’s disease indicate an asymmetrical accumulation of fibrillar plaque burden as well as an asymmetrical atrophy predominantly associated with the right hemisphere. Models of Parkinson’s disease apply unilateral lesion to the right hemisphere. Across studies, two crucial factors influencing atypical asymmetries arose independently of disorder modeled: sex and developmental age with partially opposing effects found in females and males as well as in adolescents versus adults (Sullivan et al. Human and animal studies have repeatedly shown that stress exposure results in stronger right-hemispheric activation that is connected to increased leftward behavioral asymmetry (Czéh et al. Interestingly, early exposure resulted in similar alterations as exposure in adults with adolescence and early adulthood marking a time of great neuronal change Galván , 2017 thAnother interesting finding is the predictive value of left-lateralized behavior for behavioral despair in animals. In particular, as studies on human handedness do not find an increased ratio of left- or mixed-handedness in patients with depression (Packheiser et al. Besides the direction of lateralization, e.g., the preferred side, analyzing the strength of lateralization may render important insights. Especially given that, for some behaviors such as paw preference, meta-analytical integration demonstrated that rodents show strong individual lateralization but no population-wide side preference (Manns et al. Lastly, the two studies on chronic stress exposure in adulthood reveal an interesting finding on the effects of psychopharmacological treatment on hemispheric asymmetries: treatment with the antidepressants fluoxetine and ketamine seems to abolish stress-induced atypical asymmetries whereas lithium, a mood stabilizer, increased general asymmetry behavior independent of side (Czéh et al. The study of hemispheric and behavioral asymmetries currently holds some limitations. First, it is difficult to objectively assess and score lateralized behavior as most behaviors are still being assessed manually. Here, new computational methods are needed that allow for an objective and comparable scoring of behaviors. Second, most of the included studies only focused on regions of interest or one specific behavior. This is understandable as whole-brain analyses, and several behavioral tests are quite expensive and laborious. However, the current studies are biased towards changes in other brain regions or might miss behavioral asymmetries. Third, studies often do not distinguish between sub-regions when analyzing neuronal changes. But nuclei-specific lateralization is already known, at least for some regions such as the amygdala (Ocklenburg et al. In conclusion, animal models of mental disorders demonstrate atypical hemispheric asymmetries similar to findings in patients. Particularly, increased left-sided behavior and greater right-hemispheric activity was found across models applying a stress-based paradigm. However, sex- and age-dependent effects on atypical hemispheric asymmetries are present that require further investigation. Animal models enable to analyze hemispheric changes on the molecular level which may be most effective to detect early alterations.


Timely detection and monitoring of acute brain injury in children is essential to mitigate causes of injury and prevent secondary insults. Increasing survival in critically ill children has emphasized the importance of neuroprotective management strategies for long-term quality of life. In emergent and critical care settings, traditional neuroimaging modalities, such as computed tomography and magnetic resonance imaging (MRI), remain frontline diagnostic techniques to detect acute brain injury. Although detection of structural and anatomical abnormalities remains crucial, advanced MRI sequences assessing functional alterations in cerebral physiology provide unique diagnostic utility. Head ultrasound has emerged as a portable neuroimaging modality for point-of-care diagnosis via assessments of anatomical and perfusion abnormalities. Application of electroencephalography and near-infrared spectroscopy provides the opportunity for real-time detection and goal-directed management of neurological abnormalities at the bedside. In this review, we describe recent technological advancements in these neurodiagnostic modalities and elaborate on their current and potential utility in the detection and management of acute brain injury. Over the last decade, management-based improvements in survival of pediatric critical care patients have led to a shift in focus beyond survival to neuroprotection and quality of life. Primary neurologic diagnoses requiring critical care intervention occur in 26.9 per 100,000 US children per year , accountIn the event of suspected moderate or severe closed head injury in children, noncontrast head computed tomography (CT) is widely accepted as the frontline diagnostic modality to determine the presence of life-threatening intracranial injuries and skull fractures –8. The dDue to these limitations and evidence of the elevated cancer burden in children associated with ionizing radiation exposure , 16, theIn this review, we provide a technical summary of both existing and emerging MRI, HUS, EEG, and NIRS techniques and elaborate on their current and potential indications in the detection and management of acute brain injury in pediatric populations Table .Table 1NIn the emergent and critical care setting, rapid MRI sequences with reduced duration on the order of seconds for individual sequences and < 30-min total scan time , 31 has Arterial spin labeling (ASL) enables noninvasive imaging of cerebral blood flow (CBF) on a voxel-by-voxel basis by detecting the arrival of magnetically tagged water molecules in blood , 37. TheThe ability to noninvasively localize and quantify perfusion alterations provides critical physiologic information that may be used to detect acute neurological insults or monitor efficacy of therapeutic treatment. ASL has seen increasing routine adoption in adult patients with suspicion of stroke  and withWhen ASL is combined with a diffusion-weighted imaging (DWI) acquisition, a mismatch showing high diffusivity on DWI with low blood flow on ASL may help identify at-risk hypoperfused regions prior to infarct , 46. ASLDiffusion tensor imaging (DTI) is an advanced computational derivative of DWI that permits characterization of white matter structure and function . CommonlDTI sensitivity to microstructural abnormalities and disruptions of white matter fiber tracts has shown significant correlation with functional status, even in the absence of apparent abnormalities on conventional T1 and T2 structural imaging. In neonates with HIE, severity of DTI abnormalities, present in white matter, basal ganglia, posterior limb of the internal capsule, and watershed areas, was correlated with seizure severity . SignifiChallenges remain in improving the accuracy of tract reconstruction. DTI reconstruction based on increased directional density (250 + directions), termed high-definition fiber tractography, is capable of resolving complex fiber crossings using diffusion spectrum imaging and has demonstrated increased fidelity and robustness of tract reconstruction , 68. Spe1H) in water, MRS utilizes the magnetic field signal of hydrogen protons on these other molecular species to quantify alterations in metabolism, neuronal cell death, and demyelination.Magnetic resonance spectroscopy (MRS) provides noninvasive concentration profiling of several significant metabolites, including small molecular weight amino acids, carbohydrates, fatty acids, and lipids, to aid in the detection and treatment of brain tumors, infection of the central nervous system, mild TBI, HIE, and other subclinical acute insults Table  69–73].–73.69–73MRS yields critical diagnostic information in neonates with perinatal asphyxia in which N-acetylaspartate (NAA) concentration, the lactate (Lac)/NAA ratio, and the Lac/choline ratio have been correlated with poor outcome –78. ReceIn TBI, NAA level has been demonstrated as a measure of neuronal and axonal integrity, with reduction in the NAA level following TBI , 82. An Contrast-enhanced MRI techniques provide high-resolution anatomical and structural information to improve diagnostic discrimination of intracranial vascular malformations, vasculitis, and brain tumors in children , 89. Int“Black-blood” T1-weighted vessel wall imaging (VW-MRI) permits contrast-enhanced visualization of periarterial vessel wall structure in the anterior circulation –102 and HUS is an important neuroimaging modality in the pediatric neurocritical care setting due to its portability, safety, and ability to capture real-time bedside images. In neonates and infants, the open fontanelles serve as a natural acoustic window. In children with closed fontanelles, the thin squamous portion of the temporal bone can be used as the acoustic window. Despite the availability of advanced neuroimaging techniques, HUS, due to its unique advantages, remains a pillar of brain imaging in pediatric neurocritical care.Ultrasound frequency waves in the MHz range are generated and transmitted into tissue by a piezoelectric transducer; the echoes reflected from the tissues are also detected by the transducer. The echoes contain spatial and contrast information, which generates electrical signals and can be quantified and extrapolated into images of internal tissues and organs. Conventional HUS techniques used include grayscale, B-mode HUS, and transcranial Doppler (TCD).Selective filtering of returning echoes allows the visualization of information beyond that of conventional grayscale ultrasound. In this regard, Doppler ultrasound assesses frequency changes of returning echoes and can determine whether there is movement of tissue toward or away from the transducer. The technique allows assessment of blood flow through macrovessels and interferences about tissue health , 115. SpMicrovascular imaging (MVI) is an advanced Doppler technique that permits visualization of slow flow in cerebral microvessels Fig. . In MVI,There is emerging evidence that MVI may be used to detect cerebral microvessels in the brain, thereby attaining information on normal neurodevelopment and functional alterations related to a variety of brain pathologies . InitialContrast-enhanced ultrasound (CEUS) is a technique that uses the intravenous injection of an ultrasound contrast agent called microbubbles for assessment of tissue perfusion Fig. . These cAlthough the use of CEUS in the brain is relatively new, there is great potential for quantitative and qualitative evaluation of many neurological pathologies and evaluation of cerebral perfusion for diagnostic and prognostic use. Given the inherent challenges of detecting symmetric and/or diffuse pattern injury as can be seen in hypoxic–ischemic injury, Hwang et al. assessed the feasibility of quantitative detection by evaluating the ratio of basal ganglia to cortex perfusion . In stroA recent article by Zhang et al. has shown that cerebral microvascular flow as assessed using microbubbles can provide robust measures of intracranial pressure (ICP) and brain ischemia in hydrocephalus . In thisElastography is an advanced ultrasound technique that allows for the noninvasive assessment of brain tissue stiffness , 131. BrBrain elastography has been applied predominantly in infants due to open acoustic fontanelles. Age- and region-dependent differences in brain elasticity have been shown –136. AppEEG, initially developed in the 1920s , has traDuring an EEG recording, an array of electrodes is placed on the scalp (using a conductive paste and/or glue) in standardized locations (10–20 system of electrode placement); the number of electrodes used may vary by patient age and head circumference, with a sparser array used in neonates . The eleThere is increasing interest in the application of mathematical transformations to raw EEG, termed quantitative EEG (QEEG), to enhance the efficiency of EEG interpretation, to allow for real-time bedside interpretation, and to identify subtle changes in brain activity that may not be evident on conventional intermittent review of raw waveforms by an electroencephalographer. The basis of QEEG analysis is transformation of raw time-domain (TD) EEG waveforms into a frequency-domain (FD) distribution using the fast Fourier transform (FFT); the FFT may be used to assess the relative contributions of various frequency bands of electrical brain activity to overall power (spectrograms) . AmplituSeizures typically manifest on FFT spectrograms as abrupt increases in power (“flames”) and rhythmicity ; QEEG ha2), physiologically analogous to regional tissue oxygen saturation and the tissue oxygenation index, is the most widespread optical technique [2 assesses the balance of arterial oxygen delivery and tissue consumption and has repeatedly shown potential utility for rapid detection of cerebral hypoxia and ischemia. Compared to other modalities highlighted in this review, clinical NIRS devices are typically more portable and rapidly applied and do not require a clinical specialist. Ease of use has promoted increasing application in emergent and critical care settings [Optical neuromonitoring using near-infrared (NIR) light provides the unique ability for continuous noninvasive quantification of cerebral hemodynamic and metabolic risk factors for acute brain injury at the bedside , 161. NIechnique . StO2 assettings , 162–180settings , 181–1842. Current clinical pediatric NIRS devices use continuous-wave (CW) NIR light-emitting diode light sources, which enable compact, disposable patient interfaces but only permit signal contrast in detected light amplitude; population-based scattering assumptions are required to estimate absorption [2 accuracy using increased spectral and temporal information.Within tissue, NIR photons are either scattered or absorbed; scattering events are roughly 100 times more likely than absorption events. This relative “transparency” of tissue permits photons, emitted from a light source on the surface of the skin, to travel to, and back from, the brain , 185. Thsorption . AdvanceIn broadband or hyperspectral DOS, a CW white light source paired with a spectrometer light detector measures amplitude changes at hundreds of NIR wavelengths –189. Thi2 based on these absolute values compared to CW NIRS. Total hemoglobin concentration provides an additional diagnostic measure of cerebral blood volume (CBV) [FD and TD DOS techniques provide the ability to quantify absolute values of tissue scattering and absorption properties –195. In me (CBV) .In contrast to broadband DOS, specialized optoelectronics are typically required for each measurement wavelength, which increases the complexity and sampling time for multispectral measurements . Due to 2/s) is derived from temporal and spatial characterization of rapid intensity fluctuations (termed “speckles”) resulting from the constructive and destructive interference of the scattering of coherent NIR light by moving red blood cells [Diffuse correlation spectroscopy (DCS) and laser speckle contrast flowmetry are emerging optical neuromonitoring techniques that permit continuous noninvasive quantification of cerebral perfusion and remain robust in low-flow states. A cerebral blood flow index (BFI) (cmod cells , 203–205od cells . DCS meaod cells , 209–214od cells –218.Several state-of-the-art diffuse optical neuromonitoring devices have implemented combined DCS and advanced DOS techniques for investigational use in pediatric settings , 219–229Longitudinal neurometabolic optical monitoring has elucidated risk factors for hypoxic–ischemic brain injury in several pediatric contexts, including during birth transition in healthy and high-risk neonates , 234–240Broadband DOS quantification of CCO and water provides unique diagnostic utility and oxygen metabolism insights beyond the vascular compartment to intracellular mitochondria . TemperaNovel optical methods have recently demonstrated promising evidence of noninvasive ICP assessment , 251–254A source of uncertainty in this initial optical approach is the necessity for arterial blood pressure pulsatility measurements, which were estimated by systolic and diastolic cuff measurements. Application of advanced machine learning models may enable ICP prediction based on standalone DCS BFI or FD DOS measurements of trends in oxyhemoglobin, deoxyhemoglobin, and total hemoglobin concentrations , 256. Th2 as surrogates of CBF [Noninvasive optical assessment of cerebral autoregulation via quantification of cerebrovascular pressure reactivity has emerged as a valuable diagnostic of acute brain injury vulnerability in children , 257–259s of CBF –262. An s of CBF , 257. Ths of CBF , 263–268s of CBF , 269.2 neuromonitoring has been tempered by limitations in accuracy. Emerging advanced DOS and DCS techniques provide improved quantitative accuracy and novel physiologic information for injury detection. For both ultrasound and optical techniques, neurocritical care applications have largely been limited to neonates and infants; improving depth sensitivity is critical to characterizing focal deep-brain pathologies in older pediatric populations. Ongoing standardization of these emerging techniques will improve reproducibility and aid in necessary multicenter studies to establish high-quality evidence of clinical impact on neurodevelopmental outcomes.Advancements in noninvasive quantification of cerebral physiology provide novel insights for improved detection and management of acute brain injury in children. Emerging MRI techniques uniquely afford whole-brain spatial characterization of cerebral perfusion, metabolism, and structural abnormalities for detection and quantification of injury. This is particularly critical for localized injuries due to trauma, stroke, or neoplasms. Timing of MRI following injury and dynamic changes in MR signals with age remain a challenge for interpretation and generalizability. HUS imaging has become another essential neurodiagnostic modality due to its accessibility, safety, and portability. The emergence of advanced ultrasound techniques, such as MVI, CEUS, and elastography, expand the quantitative and functional evaluation of many neurological pathologies. Continued optimization of acquisition parameters for efficacy and safety is underway. cEEG is critical for detection of dynamic background changes and seizures in critically ill children and neonates. QEEG is an evolving technology permitting real-time optimization of care in critically ill children. Optical neurometabolic monitoring of the brain is an emerging multiparameter modality that provides unique advantages in this respect but has limited utility in the detection of focal deep-brain injury where light is unable to penetrate. Use of cerebral NIRS for continuous StO


A pillar of systems neuroscience has been the study of neural oscillations. Research into these oscillations spans brain areas, species, and disciplines, giving us common ground for discussing typically disparate fields of neuroscience. In this review, we aim to strengthen the dialog between sensory systems research and learning and memory systems research by examining a 15–40 Hz oscillation known as the beta rhythm. Starting with foundational observations based largely in olfactory systems neuroscience, we review evidence suggesting beta-based activity may extend across sensory systems generally, as well as into the hippocampus and areas well known for coordinating decisions and memory-guided behaviors. After evaluating this work, we propose a framework wherein the hippocampal beta oscillation and its diverse coupling with other brain areas can support both sensory learning and memory-guided decision-making. Using this framework, we also propose circuitries that may support these processes, and experiments to test our hypothesis. When researchers studying olfaction started recording from the hippocampus in the 1990s and 2000s they found that hippocampal activity could oscillate coherently with activity in early olfactory regions. The rhythmic coupling between these structures was strongest in the 15–40 Hz frequency band–the frequency of a classic olfactory system oscillation known as the beta rhythm. Prior work had indicated that beta rhythms occurred in other early sensory systems, such as the visual and auditory systems, and work since then has reaffirmed the existence of hippocampal beta in contexts that seemingly have nothing to do with active olfaction.At the core of systems neuroscience is the promise of illuminating relationships between typically distinct sub-disciplines. Thus the goal of this review is to examine and relate the literature describing beta rhythms in sensory systems to beta rhythms in hippocampal processing. After briefly summarizing historical reports of beta, both in early sensory regions and the hippocampus, we will discuss new evidence suggesting cross-regional interactions between the hippocampus and a number of areas at beta frequencies. Based on these results, we will suggest that hippocampal beta is a distinctive rhythm that may have dual roles in sensory- and memory-guided behaviors.Since this review will focus on sensory-cortical and hippocampal beta, as well as hippocampal beta coupling with other brain regions, we will not be reviewing all aspects of the beta rhythm. Instead, for reviews on beta rhythms in (primate) cortical information processing, we refer the reader to Before exploring the early work on beta, we should note that beta is not always defined in the same way, and its definition has changed over time. Fortunately, sensory systems work has been relatively consistent with its definition of beta as an often brief, 15–40 Hz rhythm. In contrast, early hippocampal research often separated rhythms into regular slow activity (often recognized as theta) and fast rhythms, which we would now call gamma, without consistent reference to their frequency content . To mainReports of beta rhythms in mammalian sensory systems extend at least as far back as the 1940s, when Explicit observations of a hippocampal beta rhythm in early research were scarce, but there were several notable exceptions. First, Boudreau showed hippocampal auto- and cross- spectral peaks in the 15–20 Hz range of awake cats . CompariA series of papers in the 1990s helped bridge the gap between sensory systems and hippocampal work by studying hippocampal and olfactory bulb processing in tandem. Hippocampal dentate gyrus recordings showed that 15–40 Hz “fast waves” were triggered when rats were coaxed to sniff toluene, xylene, or several predator-mimicking odors . Though Following up on these results, Building on olfactory-hippocampal beta coupling and early sensory systems work, one recent study demonstrated beta-based hippocampal interactions with non-olfactory sensory areas. To clarify how rhythmic activity was patterned across sensory cortices, Though it’s not yet clear how beta between the hippocampus and sensory cortices becomes coordinated, one possible candidate is through interactions with the basal forebrain . The basRecent work has provided more details on how hippocampal beta relates to learning and memory. Using a task that combined sensory-guided behavior with sequence-memory, Interested in characterizing the relationship between hippocampal cell classes and LFP dynamics with respect to behavior, While most research on hippocampal beta has come from studies using olfactory stimuli, Showing that beta oscillations could link the hippocampus and non-sensory areas, Although the hippocampus and medial prefrontal cortex (mPFC) are classically known for their theta oscillatory coupling , recent In another study using the previously mentioned olfactory sequence-memory task, Taken together, these results show that coordinated beta-rhythmic activity can exist between the hippocampus and areas not traditionally considered sensory processing regions, such as the mPFC and ventral striatum. Beta coupling between the hippocampus and mPFC seems to be linked to successful memory-based decision-making , beta-rhWhat remains unclear is whether beta-based interactions between the hippocampus and sensory areas have the same characteristics as beta-based interactions between the hippocampus and “non-sensory” areas . The olfper se do not drive the interaction, but the flexible contingency re-learning or attentional shift required to update behavior does.Resolving this ambiguity will require more studies that record concurrently from the hippocampus and sensory areas during active sensation, as has been done in the olfactory system. Analogous tests of the visual system could be done using tasks that change which visual cues are associated with reward. Presumably, visual cortex and hippocampus would show beta during cue presentations, but coherence between areas would only significantly increase while learning cue-reward associations or after they change. The test could be made even stronger using a task that switched reward contingencies between different modalities of sensory cue . If beta coherence between the hippocampus and sensory structures switched based on rewarded sensory modality, it would support the idea that beta coherence enables sensory-driven, cue-reward association. Additionally, if the cross-regional coherence increases were specific to transition periods, it would suggest that learned sensory cues We also have reason to believe that hippocampal beta coupling with non-sensory areas has relevance for task performance, learning, and memory . The tasWe hypothesize that one role for hippocampal-based beta is to coherently oscillate with sensory areas and promote cue-reward associations, while another is to coherently oscillate with decision-making and action selection areas, enabling successful memory-guided behavior. Continued study of neural coordination within and across sensory and memory systems could reveal new insights into the nature and significance of beta-based activity across disparate brain structures .JM, KK, and SM contributed to the conceptualization of the review. JM wrote the initial drafts of the document, proposed the model, and made the associated figure. All authors contributed to manuscript revision, read, and approved the submitted version.


Uterine leiomyomas or uterine fibroids are the most common benign soft tissue tumor in reproductive-aged women. Fumarate hydratase deficient (FH-d) uterine fibroids are a rare subtype that is diagnosed only on pathologic evaluation. FH-d uterine fibroids may be the first indicator of hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome. Therefore, identifying and understanding the clinical implication and diagnosis of FH-d uterine fibroids is critical for early diagnosis of HLRCC. This case series investigates the uncommon yet significant condition of FH-d uterine fibroids. We examined the clinical manifestation, diagnostic imaging, and histopathological characteristics of FH-d uterine fibroids in five cases identified at our institution over the last ten years. All diagnoses were confirmed by pathologic evaluation after surgical treatment. Gynecologists and pathologists play a critical role in the early diagnosis of FH-d uterine fibroids and must recognize the relevant clinical and pathologic findings that raise suspicion about this diagnosis. The detection of these cases is largely dependent on the pathologist’s ability to recognize unique histopathologic features. Once these characteristics are identified, it should prompt a referral to a gynecologist to consider conducting germline genetic testing. The management of FH-d uterine fibroids necessitates a multidisciplinary approach, including proper genetic screening and regular surveillance, especially for renal tumors. FH-d uterine fibroids often manifest similar clinical symptoms and imaging features as typical uterine fibroids, which can make their identification challenging. Therefore, meticulous patient history-taking becomes paramount, particularly noting any personal or family history of potential malignancies. This level of detail can help raise suspicion for conditions like FH-d uterine fibroids and HLRCC syndrome. It emphasizes the need for gynecologists to maintain a high index of suspicion and collaborate closely with pathologists who can confirm the diagnosis through histopathological examination. This collective approach can ensure early recognition and improved management of these cases, potentially preventing serious complications associated with these conditions.1. Awareness of Similar Presentation: FH-d uterine fibroids is crucial to improving patient outcomes and minimizing risk. Gynecologists should be vigilant for any symptoms, such as abnormal or heavy bleeding and pelvic pain, while radiologists must be thorough in identifying any anomalies during imaging. Pathologists play a critical role in diagnosing FH-d uterine fibroids by identifying unique histopathological features, such as atypical cell structures or abnormal growth patterns. Close collaboration between gynecologists and pathologists is essential for formulating a timely and appropriate management plan, which may include surgical intervention or medical management, depending on the individual patient’s circumstances.2. Early Diagnosis and Management: Recognizing the importance of the early diagnosis of FH-d UFs, a multidisciplinary team approach is crucial to provide optimal care. This team may include gynecologists, radiologists, pathologists, and genetic specialists, to ensure comprehensive evaluation, treatment, and follow-up care for affected patients.3. Multidisciplinary Approach: Given the rarity and complexity of FH-d UFs is essential for the development of new diagnostic tools, targeted therapies, and preventive measures. This will contribute to improved patient care and better overall outcomes for individuals suffering from this rare and significant condition.4. Advancements in Research: Continued research into the pathophysiology, molecular mechanisms, and genetic factors of FH-d) UF is a rare subtype of UF characterized by its association with both somatic and germline FH gene mutations. FH-d UF is a unique subset of UFs with distinct clinical implications [Uterine leiomyomas, or uterine fibroids (UFs), are extremely common. Moreover, 20% to 50% of women will develop uterine leiomyomas by 30 years of age, and more than 80% of females may have uterine leiomyomas by 50 years . FumaratFH) is an important enzyme of the tricarboxylic acid cycle, also known as the Krebs cycle. This enzyme is responsible for the conversion of fumarate to malate, which plays a crucial role in cellular energy production [FH gene can lead to fumarate accumulation, which is hypothesized to contribute to tumorigenesis [FH gene located at chromosome 1q42.3-q43 [Fumarate hydratase . This specific missense change, guanine to adenine at nucleotide position 1055, results in an amino acid change from glycine to aspartic acid at codon 352. At the time, there was not enough evidence to know whether this change disrupts protein function; this specific missense variant had not been reported by other laboratories, nor had it been reported in the literature in individuals with FH-related conditions. However, given the family history of renal cancer, the patient was advised to undergo screening for this malignancy. A subsequent abdominal ultrasound and computed tomography (CT) scan revealed a large mass extending from the left kidney . This mutation results in a premature stop codon in exon 2, causing disruption of protein production. A year later, the patient returned with pelvic pain, and a pelvic MRI showed her uterus contained at least 4 fibroids , 2 in the right/fundus and 2 on the left  in the FH gene and subsequently developed renal cell carcinoma. Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a disorder in which affected individuals tend to develop benign smooth muscle tumors (leiomyomas) in the skin and, in females, the uterus. This condition is also associated with an increased risk of renal cancer. In this disorder, growths on the skin (cutaneous leiomyomas) typically develop in the third decade of life. Most of these growths arise from the tiny muscles around the hair follicles that cause “goosebumps” [This case series presents five patients with diverse racial and ethnic backgrounds diagnosed with sebumps” . They apsebumps” .FH-d uterine fibroids associated with HLRCC to appropriately manage affected patients.Approximately 10% to 16% of people with HLRCC develop a type of kidney cancer called renal cell carcinoma , with syFH-d fibroids are the same. While sporadic FH-d fibroids are more common, syndromic FH-d fibroids are rare and often associated with hereditary leiomyomatosis [FH gene if needed. The pathologist should be expected to notice and correctly diagnose these histologic features, then perform stains and alert the gynecologist to pursue genetic testing.It is essential to recognize that not all omatosis . IdentifFH-d UFs were identified. This observation aligns with the broader literature, where the ultrasound features of these rare fibroids have not been well-delineated and may not significantly differ from those of more common forms of UFs. This ambiguity in ultrasound imaging underscores the challenges in identifying FH-d UFs based on imaging alone and emphasizes the importance of maintaining a high index of suspicion for these lesions in patients presenting with certain clinical features or risk factors. Ultimately, the role of imaging in these cases may be more nuanced, potentially contributing to general fibroid detection and monitoring rather than acting as a definitive diagnostic tool for the identification of FH-d UFs.In our series of five cases, no distinct or consistent ultrasound characteristics specific to In addition to the gynecological examination, all patients were thoroughly examined for skin changes, as cutaneous leiomyomas are a characteristic feature of HLRCC. Notably, no skin changes indicative of HLRCC were observed in any of the five patients.Post-hysterectomy, all patients were closely monitored for potential renal malignancy, another association of HLRCC. The follow-up period ranged from 1–3 years post-surgery. It is significant to mention that one patient, who was diagnosed with HLRCC, was found to have renal malignancy one-year post-hysterectomy.FH deficiency characterized by the following histologic features (In all five cases, pathology reports confirmed features of features . Images FH-deficient fibroids from other types of uterine fibroids [Previous studies have highlighted specific histopathological features that distinguish fibroids . Our obsFH-d UF because timely diagnosis enables appropriate cancer surveillance and management for patients and their families. The presence of unusual skin lesions, early onset fibroid disease, numerous and large fibroids, extensive family history of early onset fibroids, and personal or family history of renal cell cancer should raise suspicion for HLRCC [FH deficiency, supported by immunohistochemistry. Gynecologists should educate patients and encourage genetic counseling if this diagnosis is made.Gynecologists are crucial in the early diagnosis of HLRCC by identifying or HLRCC . EmphasiFH variants, at-risk relatives can pursue testing. Proper screening and surveillance should begin once the diagnosis is established, especially for renal tumors [By identifying germline l tumors .FH-d UFs requires a multidisciplinary approach and surveillance. Genetic counseling and testing are crucial, helping to identify germline mutations in the FH gene and enabling informed decision-making for patients and their families.Managing See a summary of HLRCC management in FH-d UFs frequently mirror regular uterine fibroids in terms of clinical symptoms and imaging findings, which can make initial diagnosis challenging. This similarity underscores the vital role that thorough patient history-taking plays in the differential diagnosis process. However, in the case of FH-d UFs, a detailed medical and family history can provide crucial clues to the potential presence of this rare condition. Key indicators could include a history of early-onset or unusually severe uterine fibroids, the presence of cutaneous leiomyomas, or a family history of renal cell carcinoma, all of which could signal an underlying FH gene mutation.In our investigation, we observed that FH-d UFs for early diagnosis of HLRCC and adequate treatment and surveillance. It recommends a holistic, interdisciplinary approach involving genetic counseling and testing to improve patient outcomes and inform decision-making regarding monitoring and treatment strategies. The case series also stresses the need for medical professionals to be more aware of the risks linked to FH-d UFs. It calls for further research to enhance our knowledge of the clinical implications, best management practices, and long-term outcomes for patients with FH-d uterine fibroids.This case series emphasizes the significant role gynecologists play in recognizing the distinctive features of