Acupuncture therapy, as a characteristic of Chinese medical therapy, has a long history and remarkable effect in the treatment of gynecological diseases, and so far, it has formed a complete treatment system, but its efficacy and mechanism of action remain unclear. Functional magnetic resonance imaging, a visual technique, provides an objective basis for the study of acupuncture in the treatment of gynecological diseases. This paper summarizes the current status of acupuncture in the treatment of gynecological diseases and summarizes the progress of functional magnetic resonance imaging research related to acupuncture in the treatment of gynecological diseases in the past 10 years, mainly including the common types of gynecological diseases in acupuncture clinics, and the commonly used acupuncture points. This study is expected to provide literature support for subsequent research on the central mechanisms of acupuncture in the treatment of gynecological diseases. Therefore, more and more acupuncture therapies are being performed in gynecological diseases, but the introduction of imaging techniques is essential in order to clarify the main mechanisms by which they exert their efficacy. In recent years, the commonly used imaging techniques include ultrasound, computed tomography imaging, emission computed tomography imaging, magnetic resonance imaging (MRI), and X-ray, but they are not widely used due to their inherent limitations.,9 With the development of neuroimaging technology, the emergence of functional MRI (fMRI) has provided a more effective means of studying the mechanisms of acupuncture in the treatment of gynecological diseases. fMRI not only provides real-time imaging of the brain but also has the advantage of noninvasive, high-quality imaging with high spatial resolution compared to other techniques.Gynecological diseases, with a large variety and complex mechanisms and a wide age range span, seriously affect people’s quality of life and contribute to the financial burden of society.This technological approach, which can already be investigated in several fields, is easily reproducible and therefore has made some progress and great potential in the field of gynecology. The author investigated the mechanism of acupuncture for gynecological diseases based on the fMRI technique, using the China National Knowledge Infrastructure and PubMed databases as the main databases and combining the keywords: acupuncture, pain, neuroimaging, and selected gynecological disease research directions, and included relevant original studies from 2012 to 2022, for the last 10 years, excluding animal experiments, conference papers, case reports, and protocol studies. The detailed types of gynecological diseases treated by acupuncture and the acupoints taken for the treatment of gynecological diseases are reviewed below for future research.,12 which can be traced back as far as the 1990s. It works as a blood oxygen level-dependent fMRI technique by monitoring changes in blood oxygen concentration in active brain regions to reflect functional connections between different brain regions. It can effectively combine the 3 factors of function, imaging, and anatomical morphology, with the advantages of high operability, high safety, good stability, and many analysis methods. As an important technological method for evaluating brain function, fMRI has been widely used and studied, and researchers have classified fMRI into resting-state fMRI and task-state fMRI according to different acquisition states. In addition, common analysis methods for fMRI include functional integration analysis as well as functional separation analysis. Therefore, fMRI techniques have higher applicability for studying the mechanisms of acupuncture in the treatment of gynecological diseases.fMRI is an important technique for measuring acupuncture-induced brain activity, local-and-distant acupoints method, and physiological mechanisms were studied. It is believed that the precuneus brain function connection is the main pathological factor of menstrual headache and it is also closely related to the regulation of distal acupoints, while the frontal lobe-limbic region is also the main site for acupuncture to regulate menstrual migraine patients. Women with premenstrual syndrome have greater amygdala volumes. Gaoxiong Duan et al studied premenstrual syndrome and abnormal neural activity and found that acupuncture treatment could regulate neural activity in premenstrual syndrome patients, and showed a functional connection between the amygdala and some brain regions.,24 Furthermore, many scholars have conducted in-depth studies on primary dysmenorrhea, respectively from the perspective of acupoints and sham acupoints, true or sham acupuncture therapy, brain function connection network,–30 disease and health, and heat-sensitive state. They found abnormalities in brain structure and function in patients with primary dysmenorrhea compared to healthy controls, The clinical symptoms performed by patients with primary dysmenorrhea are related to the frequency of abnormal brain function activity, and the nature of their pain is the hyperconnectivity of the primary somatosensory area (S1)/primary motor area around the cerebral aqueduct, the ventral lateral prefrontal lobe, and the posterior cingulate when primary dysmenorrhea patients are in menstruation, among others, and the change in cerebral blood volume is the mechanism that can verify the efficacy of acupuncture.,36 Premature uterine dysfunction can lead to a variety of menstrual disorders. Using resting-state fMRI, Tingting Zhao et al compared the functional connectivity of brain regions in patients with premature ovarian dysfunction with that of healthy subjects and explored the central mechanism of acupuncture in the treatment of premature uterine dysfunction, suggesting that the mechanism may be related to the regulation of functional connectivity between the hypothalamus and multiple brain regions. A Swedish research team found that acupuncture therapy is quite an efficacy intervention for reducing serum anti-Mullerian hormone levels. Karin Meissner et al also combined moxibustion with psychotherapy to evaluate the degree of pain relief in patients with endometriosis with this therapy. Interestingly, they found that moxibustion with psychotherapy reduced global pain and pelvic pain. Researchers have shown that even self-administered acupressure could have a good effect on fatigued breast cancer survivors. Details of fMRI in acupuncture therapies for gynecological diseases could be found in Table Menstrual headache is a specific type of migraine, and some scholars have studied the functional brain connectivity of patients based on resting-state fMRI techniques,ry area S/primary ry area S/primary The concept of holistic and evidence-based practice has always been the 2 most important basic features of the theoretical system of Traditional Chinese medicine, and evidence-based practice is used throughout every disease, every evidence type, and the beginning and end of every symptom. Based on these principles, we summarize the basic points and main points commonly used in gynecological diseases.,42 As an important point in the treatment of gynecological diseases, Tai Chong acupoint has been widely used in acupuncture clinics, and some domestic and foreign research groups have used fMRI techniques to explore the brain function mechanism of acupuncture at Tai Chong acupoint and found that acupuncture and moxibustion at Tai Chong acupoint can activate specific brain areas, and the activated brain areas are closely related to their main functions.–46 According to traditional Chinese medicine theory, the Sanyinjiao acupoint is the intersection of the 3 meridians, namely, the Liver Meridian, the Spleen Meridian, and the Kidney Meridian, which can tonify the blood and benefit the qi, transport the heart and kidneys, and is used for a variety of gynecological disorders,,48 and is often applied in cases related to liver stagnation. Some researchers have found that acupuncture stimulation of the Sanyinjiao in healthy subjects alone resulted in 2 opposite effects of activation and inhibition of specific brain regions, objectively confirming the bidirectional regulatory effects of acupuncture. In addition, the Taixi point, the original acupoint of the kidney meridian, has the function of regulating the punch and nourishing the kidney to nourish the marrow and is often used in the gynecological classification of the kidney deficiency type. A group of researchers found that acupuncture at the Taixi point enhanced brain network links between the hippocampus and caudate nucleus, and the prefrontal cortex and hippocampus. In the clinical application of acupuncture, not only can single acupoints improve specific symptoms, but also can be used to systematically regulate the disease state of the human body.,53In Tradition Chinese gynecology, the uterus point is often used as an extra-menstrual point to treat menstrual disorders, infertility, uterine prolapse, etc. Therefore, in recent years, many research groups have investigated the mechanism of the acupuncture and moxibustion of the uterus point through fMRI techniques and concluded that stimulation of the uterus point induces functional activity in brain regions such as the precuneus, cerebellum, postcentral gyrus, talar sulcus, and lingual gyrus, whose neural activity is closely related to reproductive hormone levels.–56 Based on the fMRI studies, we found the mechanism of treating some diseases by acupuncture therapies and the functional specificity of acupoints. Therefore, these results will help guide stimulation protocols directed at the brain network in the future.Acupuncture treatment of gynecological diseases is diverse, and the brain areas activated or inhibited are not identical among different groups of subjects in different disease states. Acupuncture can modulate the pathological state of the body, and the brain functional connectivity based on the fMRI technique varies among different types of gynecological diseases, different age groups, and different traditional Chinese medicine evidence groups.Although animal models can enable the study of intrinsic genetic conditions, extrinsic environmental factors, pathogenesis, and even treatment options without human or in vitro experiments, no animal model can completely replicate a complex human disease because of the fundamental genetic relationship between animals and humans, and each animal model has its own shortcomings. In addition, although fMRI technology can be traced back to 1990, it has only been widely used and systematically tested in recent years, so studies in the last decade are used as the main reference. Furthermore, gynecological diseases are so diverse and cover such a wide range that many types of diseases have not been studied under fMRI techniques, which is most likely related to the operability of their trials. Therefore, in the future, if we want to carry out the application of functional MRI technology in acupuncture for gynecological diseases in a comprehensive and multi-level manner, we should investigate the shortcomings and fill in the gaps, strictly standardize the test steps and details, and effectively combine the visualization technology from the clinical perspective of acupuncture to better serve the patients.In the course of our study, we found that primary dysmenorrhea and menstrual headache among gynecological diseases were studied more frequently, and these diseases were studied in detail, with objective and reasonable control groups, which may be related to the hot research on the analgesic mechanism of acupuncture in recent years. In addition, we set the interventions as “acupuncture” and “moxibustion,” but when we summed up and classified the literature, we found that acupuncture is more common than moxibustion as the main intervention, which may be related to the high operability of acupuncture and the high acceptance of patients. Common gynecological conditions usually occur with painful symptoms. Acupuncture analgesia has a good clinical outcome. And the pain relief effect of acupuncture is primarily due to the activation of the nociceptive regulatory system and the limbic system related to nociceptive cognition in the brain which leads to some corresponding effect changes. In addition, fMRI is an imaging method that could study brain function in vivo, with high temporal and spatial resolution, and has made remarkable achievements in recent years in exploring the mechanism of acupuncture therapies, so fMRI has great feasibility in observing acupuncture therapies for gynecological diseases.Conceptualization: Renming Liu.Data curation: Min He, Qianhui Yu.Formal analysis: Mengmeng Sun, Jiazhen Cao.Funding acquisition: Min He, Mengmeng Sun, Tie Li.Investigation: Mengmeng Sun, Qianhui Yu.Methodology: Lin Wang, Jiazhen Cao, Qianhui Yu.Project administration: Tie Li.Resources: Renming Liu, Jiazhen Cao.Validation: Min He, Fuchun Wang.Visualization: Min He, Tie Li.Writing – original draft: Renming Liu.Writing – review & editing: Min He, Tie Li.


Rheumatoid Arthritis is a universal disease that severely affects the normal function of human joints and the quality of life. Millions of people around the world are diagnosed with rheumatoid arthritis every year, carrying a substantial burden for both the individual and society. Hydrogel is a polymer material with good mechanical properties and biocompatibility, which shows great potential in the treatment of rheumatoid arthritis. With the progress of tissue engineering and biomedical material technology in recent years, more and more studies focus on the application of hydrogels in rheumatoid arthritis. We reviewed the progress of hydrogels applied in rheumatoid arthritis in recent years. Also, the needed comprehensive performance and current applications of therapeutic hydrogels based on the complex pathophysiological characteristics of rheumatoid arthritis are also concluded. Additionally, we proposed the challenges and difficulties in the application of hydrogels in rheumatoid arthritis and put forward some prospects for the future research.  Rheumatoid arthritis is an autoimmune disease that is characterized by persistent synovitis, systemic inflammation and autoantibodies (such as citrullinated peptide and rheumatoid factor) . The incThe goal of diverse treatment strategies for rheumatoid arthritis is to relieve patients’ pain and inflammation, protect the normal joint function of patients, and prevent further progression of rheumatoid arthritis and joint damage . CurrentLiposomes are microsopic phospholipid bubbles whose core is encapsulated in a lipid bilayer. They can be applied as the drug carriers due to this special structure. Also, liposomes can be absorbed by the reticuloendothelial system (RES) cells in synovial tissue of rheumatoid arthritis patients . HoweverThey are generally classified into natural, semi-synthetic and synthetic polymers according to their source, which have a promising application prospects in tissue engineering regeneration and repair . Researcin situ formed chitosan ionic network, which showed predominant mechanical properties . There are several studies showing that MTX consistently improves the functional status by 50–80% compared to baseline . In clinin situ. Pan et al.  in preparing hydrogels. Additionally, AuNPs showed the positive outcomes in treating rheumatoid arthritis (DFDFDY were used by (DFDFDY hydrogels showed good performance in reducing joint inflammation via effectively controlling the proliferation and migration of rheumatoid arthritis synoviocytes as well as proinflammatory M1 macrophage polarization. In the experiments of adjuvant induced arthritis (AIA) mice, this hydrogel significantly relieved joint swelling and fever. Therefore, the MTX-GDFDFDY hydrogels show promising application prospects as a novel drug delivery system in the treatment of rheumatoid arthritis.The gelation of hydrogels in biological environments must be accelerated and their comprehensive biological properties must be improved. Nutan et al.  reportedrthritis . The res used by  to creat used by . Then, Min-vivo residence time is of great importance. Seo et al.  has been considered as one of the most suitable biomaterials with comprehensive properties for all kinds of biomedical applications, which has the ability to alleviate cellular inflammatory reaction and heal the diseased tissue, and the good biocompatibility (low toxicity and immunogenicity). However, intra-articular injected HA disappears quickly at the site of injection due to the endogenous degradation of the hyaluronidase . Therefoo et al.  developeAgostini et al.  proposed3O4 and CS-polyolefin into a DN hydrogel with excellent mechanical properties, and it was loaded with transforming growth factor β1 (TGF-β1) and MTX. Hence the hydrogel can serve as an excellent carrier to continuously release TGF-β1 and MTX to supply sustained local thermochemotherapy, improve inflammatory symptoms, and slow the progression of joint erosions. In addition, some in vivo experiments indicated that the composite hydrogel can synergistically inhibit inflammation and promote regeneration of articular cartilage. Also, this hydrogel shows excellent mechanical properties and the ability to load and release drugs. The results show this kind of composite hydrogel combining thermo-chemotherapy and tissue engineering provides an insight on the therapeutic hydrogel with multiple mechanisms.in vitro experiments showed that decreased cytotoxic effect and the uptake of MTX by NPs were enhanced. Thus, the novel drug delivery with bi-modal mechanisms shows a potential in the treatment of rheumatoid arthritis.Lutetium177 (177Lu), a theragnostic radionuclide, could launch β radionuclides to reduce the inflammation of chemical membrane tissue when injected into intraarticular. Therefore, the targeted transport of radiotherapy agents and DMARDs to the expected area in the joint can achieve the synergistic effects of two different mechanisms. Trujillo-Nolasco et al.  combinedIn addition to the injectable hydrogels, MTX is also delivered to the target area through the transdermal way. To enhance the efficacy of MTX, Tekko et al.  developeIn general, MTX is the main drug for the clinical treatment of rheumatoid arthritis. The objective of injectable or transdermal hydrogels is to make MTX continuously released in joints to maximize the therapeutic effect and reduce the adverse effects of drugs on other organs or systems. Therefore, in addition to some necessary properties, this kind of hydrogel needs to be continuously enhanced to improve the encapsulation rate of MTX, and enable it to form a stable drug concentration in the joint to meet the needs of treatment.in situ injected hyaluronic acid hydrogels. This HA hydrogel was cross-linked by PEG (Thiol) 2 (HS-PEG-SH). Drug release experiments showed that it can release IGUR in PBS from the composite for a sustained period (up to 72h). Collagen-induced arthritis (CIA) rats were treated with the NanoIGUR-loaded hydrogel for the evaluation of its properties. The results showed that compared with oral administration, the dosage of NanoIGUR-loaded hydrogel was reduced while achieve the same efficacy. Thus, this kind of hydrogel shows a promising application prospect in the delivery of specific DMARDs because of its excellent mechanical properties and the ability of releasing drugs in a stable way.Iguratimod (IGUR), a novel DMARD, shows great potential in the treatment of rheumatoid arthritis via inhibiting the production of cytokine and promoting bone formation and its anti-inflammatory effect . HoweverDuring the inflammatory reaction of rheumatoid arthritis, membrane phospholipids are released into the body with the destruction of the cell membrane, and are converted into arachidonic acid under the function of enzymes. Arachidonic acid produces prostaglandins (PG), prostacyclin and thromboxane 2 under the function of cyclooxygenase (COX). Among them, PG has high biological activity, involving in many physiological and pathological processes, such as fever, pain, inflammation, thrombosis, anaphylaxis and so on. NSAIDs play an anti-inflammatory and analgesic role by interfering with arachidonic acid metabolism. Therefore, it is widely used in the treatment of rheumatoid arthritis. However, its non-specific mechanism of action often brings many side effects, such as gastrointestinal reactions, kidney damage and so on. Therefore, improving targeting is the key to improve the application of NSAIDs in rheumatoid arthritis.Chen et al.  transforIbuprofen (IB), one kind of NSAIDs, is widely applied in the treatment of rheumatoid arthritis to relieve moderate to severe pain. However, the oral administration and intravenous injection often bring many adverse effects. Therefore, designing a novel drug delivery system is of urgent importance. Skin is the largest organ and has been used as an avenue for the transdermal drug delivery systems (TDDS). Compared with oral administration and intravenous injection, TDDS has better targeting and reduced adverse reactions. Meanwhile, invasive preparations of NSAIDs are not friendly to patients. Therefore, transdermal drug delivery has become the delivery method of many NSAIDs. Khan et al.  designedIn vitro skin permeability evaluation of ACE showed its ability to break through skin barrier through NLC-mediated ACE delivery, increasing the permeation of ACE in expected areas. In conclusion, combined with the great ability to overcome the skin barrier and relese the drug in a sustain way, this hydrogel shows a great potential to be an excellent nanoscale lipid carrier for the local application of therapeutic drugs for rheumatoid arthritis.Aceclofenac (ACE) is a kind of cyclooxygenase-2 inhibitor, which has been widely applied in the treatment of rheumatoid arthritis due to its effective anti-inflammatory and analgesic functions. However, traditional oral administration often causes many adverse effects, hindering the application of ACE in rheumatoid arthritis. To improve the efficiency of ACE delivery, Garg et al.  designedGlucocorticoids also play an important role in the treatment of rheumatoid arthritis. Short term glucocorticoid therapy can improve the synovitis of joints. Although the long-term use of glucocorticoids can decrease some symptoms such as joint damage, it will cause many serious side effects such as infection and osteoporosis. We usually apply glucocorticoids to treat rheumatoid arthritis in two settings. Firstly, applying glucocorticoids in the early progression of rheumatoid arthritis can improve the related symptoms rapidly. The second setting is that intra-articular glucocorticoids are used to alleviate joint related symptoms of rheumatoid arthritis . TherefoAbou-EiNour et al.  designedOliveira et al.  designedTumor Necrosis Factor alpha (TNF-α), an inflammatory cytokine consisting of a trimeric protein, plays an integral role in inducing the synovitis of rheumatoid arthritis and joint destruction, resulting in joint swelling, pain and other symptoms . TherefoInfliximab (IFX), a new monoclonal antibody drug, is the first biological-response modifiers approved for the treatment of rheumatoid arthritis. However, the long-term application of infliximab could bring many adverse effects, such as serious infections and malignancy . Therefo“Sanwujiaowan”, an important Chinese herb formula, shows potential in the treatment of rheumatoid arthritis. However, most of the raw materials used to make “Sanwujiaowan” contain strong toxicity, hindering the wide application in clinical practice. Xiao et al.  construcin-vivo imaging of inflamed can be achieved through this hydrogel. After the intra-articular injection of hydrogel, the HA chain degrades. Under the near-infrared resonance (NIR) irradiation of AuNPs, the inflammatory area generates heat locally; the NPs could release TP and deliver heat and drugs to the joints at the same time. The results of CIA mice also showed improved therapeutic results. Therefore, the targeted photothermal-chemo therapy with improved efficacy and decreased side effects related to dosage provides a potential useful system for the targeted therapy of rheumatoid arthritis. Ren et al. , a kind of DMARDs extracted from traditional Chinese Medicine, plays a significant role in anti-inflammatory and cartilage protection via inhibiting the release of pro-inflammatory cytokines and the expression of adhesion molecules, metalloproteinases. However, the poor water solubility and severe systemic toxicity hinder its clinical applications . Hence, n et al.  combinedn et al. . The 2-cn et al.  developeConsidering the uncertainty of rheumatoid arthritis pathogenesis and the difficulty of treatment, combination therapies have been increasingly applied in recent years to address the problems of side effects and poor therapeutic outcomes associated with the use of single drugs. Many studies show that the combination of agents and cells could exert synergistic effects on the efficiency of improving gene transfection and increasing the anti-inflammatory effect of agents. At the same time, the appropriate combination of drugs with different mechanisms could show a synergistic effect and reduce the amount of agents needed to reduce possible side effects.in situ into gel after the injection into articular cavity of CIA rats, releasing drugs stably for a long time (more than 72 h). In conclusion, the symptoms of joint swelling, expression of inflammatory cytokines in joint fluid and bone erosion significantly improved by the D-NGel. This new delivery system with the ability to deliver two kinds of drugs provides inspiration for the synergistic therapy. They also (Indomethacin (IND), a kind of NASID, can rapidly relieve joint swelling and pain via interfering with the metabolism of arachidonic acid. However, it could not delay the progression of rheumatoid arthritis intrinsically; MTX cannot immediately relieve pain and inflammation, but it fundamentally delays the progress of rheumatoid arthritis. Combining the two drugs in the treatment could well improve the symptoms and control the progression of disease. However, the co-administration of MTX and the IND also increase the toxicity of MTX by increasing the concentration of MTX in serum . Therefohey also  designedThe application of mesenchymal stem cells (MSCs) in rheumatoid arthritis mainly focused on immunomodulatory and tissue-repair properties. MSCs could prevent the happen of joint injury through the characteristics of anti-inflammatory and immunosuppressive. Meanwhile, the protective effects of MSCs against excessive osteoclast-mediated bone resorption are likely regulated through suppressing the inflammatory cytokines. However, the application of MSCs in clinical researches is restricted to patients who have severe rheumatoid arthritis refractory to standard therapies. If the MSCs could be given at the beginning stage of the treatment of rheumatoid arthritis, this therapy maybe more effective by “resetting” the immune system .\Adipose-derived mesenchymal stem cells (ADSCs) are the promising cells applied in the regenerative medicine among all kinds of pluripotent stem cells, because ADSCs could be easily obtained from healthy donors through the minimal invasive approaches. In addition, because this kind of cell transplantation is considered to be auto transplantation and without ethical problems, so they seems really promising in clinical applications . HoweverNitric oxide (NO) plays an important role in human body. But excessive production of NO can lead to rheumatoid arthritis. So it is of great importance to scavenge the excessive NO for the treatment of rheumatoid arthritis . Kim et So far, the properties of hydrogel materials for the treatment of rheumatoid arthritis are continuously improved. The complex physiological environment in the articular cavity of rheumatoid arthritis also puts forward higher requirements for the applied hydrogels, which require a variety of properties to achieve the better treatment of rheumatoid arthritis. These properties include good biocompatibility, strong mechanical strength, good drug or cell loading capacity, controlled and sustained drug release capacity. Therefore, it is an urgent problem that needs to be solved at present to achieve better comprehensive properties of hydrogels through the fusion of different materials. Artificial intelligence can assist us in simulating the fusion of different materials and reducing the times of experiments. Finally, we may find composite hydrogel materials with enhanced comprehensive properties suitable for the treatment of rheumatoid arthritis.The development and treatment of rheumatoid arthritis is highly complicated, bringing about significant trouble to the treatment of rheumatoid arthritis patients. This main reason is the persistent inflammatory environment in rheumatoid arthritis joints. Persistent inflammation leads to significant angiogenesis and cell proliferation, changes in the expression of cell-surface adhesion molecules, proteases, protease inhibitors and many cytokines, and continuous destruction of bone tissue until the patient loses their joint function. However, at present, most hydrogels for the treatment of rheumatoid arthritis only deliver one type of drugs, which may be limited by the properties of hydrogels, resulting in poor treatment effect compared with the application of multiple drugs. Therefore, future studies should focus on improving the comprehensive properties of drug loaded hydrogels to co-deliver therapeutic agents with different mechanisms for synergistic treatment, so as to achieve better therapeutic effect.We look back on the research progress of composite hydrogels applied in rheumatoid arthritis in the recent years. They perform a marked effect mainly through delivering different therapeutic drugs into the joint. Different hydrogels have their own characteristics. Thus, we put forward some suggestions for the following research: 1) Drug loaded NPs combined with hydrogels have shown good therapeutic effects in the treatment of rheumatoid arthritis, so we can pay more attention to this kind of hydrogels in future studies. 2) Using therapeutic drugs and polymer materials to directly synthetize hydrogels is also a promising way in the treatment of rheumatoid arthritis. Additionally, some traditional Chinese medicine preparations such as Triptolide and “Sanwujiaowan” have also shown good therapeutic effects in the treatment of rheumatoid arthritis, which is worthy of in-depth studies. 3) Smart hydrogel has a good application prospect in the future. For example,thermo-sensitive hydrogels are soluble at low temperature, which is conducive to injection, and rapidly solidify at higher temperature. Therefore, thermo-sensitive hydrogels with good biocompatibility are excellent materials for intra-articular injectable hydrogels. When we decide which hydrogel to use, in addition to considering the performance of the hydrogel, we must also pay special attention to the specific situation of rheumatoid arthritis patients and decide which treatment strategy to apply according to the different progress of rheumatoid arthritis.Drug delivery is the main approach to treat rheumatoid arthritis with hydrogels. This method uses hydrogel as the carrier of drugs or cells to suppress inflammation and protect cartilage by loading the agents into hydrogels to function at the lesion site after implantation. Besides, hydrogels can also treat rheumatoid arthritis through other mechanisms, such as removing excessive NO in joints and implanting and promoting the culture of mesenchymal stem cells and so on. This article reviews the application of composite hydrogels for the treatment of rheumatoid arthritis and these hydrogels show broad prospects for the treatment of rheumatoid arthritis.


The occurrence and development of many diseases are highly associated with the aging of the body. Among them, osteoporosis (OP) is a common age-related disease that tends to occur in the elderly population and is highly related to the aging factors in the body. In the process of aging transmission, the senescence-related secretory phenotype (SASP) can convey the information about aging through the paracrine pathway and endocrine mechanism through the extracellular vesicles (EVs) connected to SASP. EVs can be used as a way of conduction to join the connection between micro-environmental aging and age-related illnesses. EVs are double-layer membranous vesicles separated or secreted from the cell membrane, which mainly include microvesicles (MVs) and exosomes. Vesicular bodies secreted by this exocrine form carry a variety of cell-derived related substances . These substances are mainly concentrated in human body fluids, especially can be transported to all parts of the body with the blood circulation system, and participate in the interactions between cells. Osteoporosis is closely associated with aging and aging cells, suggesting EVs were active in this pathological process. In this article, the basic mechanisms of aging cells in the occurrence and progression of osteoporosis through EVs will be discussed, to explore the connection between aging and osteoporosis, thereby providing a new perspective on the occurrence and development as well as prevention and treatment of osteoporosis. The loss of balance in bone remodeling is what defines osteoporosis, which is known as the process of skeletal change and entails the resorption of old and damaged bone mediated by osteoclasts, followed by the deposition of new bone regulated by osteoblast lineage cells. Osteoporosis occurs when bone resorption outweighs bone formation, resulting in the decreased bone mass, destruction of bone microstructure, and increased bone fragility. Fractures occur easily by very minimal trauma, like cough, in patients who are suffering from osteoporosis. It is expected that there will be one osteoporotic fracture in every two fractures in the 2050s .The intercellular communication between but not limit to osteoblasts and osteoclasts plays an essential role in osteoporosis as osteoblasts and osteoclasts primary occupy discrete territories without physical interaction in the steady-state in bone remodeling , and theEVs, a kind of small membrane vesicles 30–100 nm in diameter, are secreted by cells and released into extracellular spaces. EVs are one of the most crucial intercellular communication mediators because they can transmit their cargo, which includes lipids, nucleic acids, and proteins, to nearby or distant cells, changing the physiological activity of recipient cells. EVs are common in serum and other bodily fluids ,6.Osteoporosis is a senile disease highly associated with hyperactive senescent cells. Among the hallmarks of senescence, the senescence-associated secretory phenotype (SASP), in particular, SASP-related EV signal transduction is mainly carried out through paracrine and endocrine ways .In this review, we detail the production of EVs and their role in information transmission from aging cells in the osteoporosis and hope to provide new ways for anti-osteoporosis treatment with aging-related EVs.Osteoporosis, as the most common bone-related diseases in clinic, is demonstrated by the lower bone density, porous bone microstructure, and thinner bone trabeculae than normal ones. Osteoporosis mainly includes primary osteoporosis and secondary osteoporosis. Primary osteoporosis includes postmenopausal osteoporosis, senile osteoporosis, idiopathic osteoporosis, and so on, while the second one refers to the disease of bone loss resulting from the external use of drugs and related diseases.Senile osteoporosis is bone loss that results from aging . It may Bone tissues serve as a repository for vital minerals, including calcium phosphate and various biologically active molecules, such as growth factors. Osteoclasts are mobile on the bone surface and responsible for liberating minerals and other molecules stored within the bone matrix, while osteoblasts/osteocytes are responsible for forming new bone matrix to maintain the bone mass. In the adult skeleton, osteoblasts/osteocytes, which control bone creation, maintain a delicate balance with osteoclasts, which control bone resorption. Osteoporosis occurs because of the long-standing imbalance between bone formation and bone resorption.By now, there is no clear pathogenesis for the occurrence and development of senile osteoporosis. Researchers mainly focus on the functional disorder of osteoblasts and osteoclasts and the intercommunication between different types of cells ,12. AmonIn the generation and development of senile osteoporosis, SASP-related EV signals play a major role in spreading aging through paracrine and endocrine mechanisms . SuccessThe International Society of Extracellular Vesicles (ISEV) believes that two distinct isoforms of EV have been widely confirmed based on the mechanism of EV biological origin: one is from the protoplasm membrane , and the other is from the inner system/polyvesicles (MVB) (exosomes) . MicroveThe generation and release of different types of EVs are also different due to the different intracellular events and this process has been well reviewed . In shorAlthough the content and volume of EVs are different, the uptake of different subsets of EVs and the general principle of intercellular transport may be the same . Once reAging is a nonreversible sophisticated physiological process and exists throughout the whole life. Age-related disorders and cell senescence, a state of sustained hyperactivity in an aging environment, are strongly related . Evidencin vitro [in vivo [Cellular senescence is a stage between life and death that tightly controls cellular survival and demise. Senescence cell elimination is crucial for encouraging tissue healing, controlling organ development, and maintaining body homeostasis ,29. In din vitro . Transge[in vivo ,35.SASP as the sign of senescence, SASP-related EV signal transduction plays a significant part in the transmission of aging. As a suin vivo circulation of EVs [The senescence-associated secretory phenotypes are formed after cell aging, which can affect cell function through the release and n of EVs . After En of EVs . These Sn of EVs . Once thCell senescence plays a key role in the pathogenesis of many age-related illness, including OP, Type 2 diabetes mellitus (T2DM), metabolic syndrome, and possibly other endocrine-related diseases . In oste+EVs in osteoporosis patients than osteopenia patients and healthy individuals, and osteoporosis EVs promoted osteoclastogenesis and inhibited osteogenesis in vitro, suggesting EVs from osteoporosis could regulate bone homeostasis.The dynamic balance between osteoblasts and osteoclasts is the basis for maintaining the homeostasis of bone homogeneity, while EVs are vesicles of endocytosis origin between cells, which can mediate the process of intercellular communication and participate in the balance of osteoblasts and osteoclasts. Exosomes secreted by MSCs from the neonatal umbilical cord (UC) could enhance the regenerative capacity of aging adult bone marrow-derived MSCs in bone formation, wound healing, and angiogenesis . Pepe etMoreover, micro-RNAs could shuttle between cells and tissues through EVs, enabling them to reach distant cells and play a systemic role. EVs with miR-20a incorporated could directly regulate the osteogenic differentiation of bone mesenchymal stem cells (MSCs) , and miRSenescent cells use SASP, which involves EVs, to transmit senescence-related active substances, thus promoting the aging process of cells and organs . In the BMSCs could differentiate into osteoblasts and promote osteogenesis, playing an important role in maintaining bone mass . HoweverAccording to numerous reports, aging-related disorders are intimately related to the senescence of BMSCs, such as osteoporosis. Liu et al.  found thBased on the facts mentioned above, we come to some conclusions about the connection between senescent cells and their secretory EVs in bone remodeling . First oSecondly, the aging signals could be transmitted by SASP involving EVs. The occurrence of aging can promote the secretion of EVs, transfer the aging active factors in the vesicles to the recipient cells, accelerate the aging process, and affect cell function. The exosomes and the ‘active substances’ carried by them can work in the ‘aging-related secretory phenotype’ of aging cells and provide a carrier and way for signal transmission between cells. In addition, the ‘letters’ carried by EVs secreted by various types of cells are different, suggesting EVs from different aging cells had different roles in bone homeostasis.At last, aging is an important factor in vascular endothelial dysfunction. In the intravascular environment, aging may lead to the reduction of intravascular neovascularization, the slowing down of repairing bone damage, and the serious bone loss, and finally osteoporosis occurs.Osteoporosis is characterized by bone mass loss, but the key affecting bone mass remains poorly understood but highly associated with aging. The EVs secreted by senescent cells provide a new idea for the study of the functional changes of BMSCs, osteoblasts, and osteoclasts, and also put forward the information exchange between cells, that is, through cell vesicle transport, which combines the cells of the whole body. The EVs of senescent cells also act as SASP-related active factors and play a key role in aging-related diseases represented by osteoporosis. Therefore, clarifying the relation between senescent cells and their EVs and the way they affect cell function may provide a new treatment strategy for aging diseases such as osteoporosis.


Agricultural green development is increasingly being discussed in sustainable development. This paper constructs agricultural green development from four dimensions: resource savings, environmental protection, ecological conservation, and quality industrialization. We apply the entropy-weighted Technique for Order Preference by Similarity to an Ideal Solution (TOPSIS) method to measure agricultural green development and employ a panel dataset of provinces in China from 2011–2019. Then, the dynamic spatial Durbin model is adopted to estimate the spatial effect of digital inclusive finance on agricultural green development. The main findings are as follows: (1) digital inclusive finance effectively promotes agricultural green development, and the promotional effect shows temporary and spatial spillover; (2) regional heterogeneity exists in the spatial effect in the short and long term; and (3) education, digital infrastructure, and traditional finance are important factors influencing this spatial effect of digital inclusive finance on agricultural green development. With the improvement of living standards, the Chinese have paid more attention to food safety and environmental protection [Agricultural green development is an important concept within the 2030 Sustainable Development Goals proposed by the United Nations . 2019 daotection , so the otection . TherefoAccording to the 49th Statistical Report on China’s Internet Development, 284 million rural residents have access to the Internet in 2021. Digital inclusive finance, which through digital technologies provides accessible and affordable financial services and products for Chinese farmers cannot be completely covered by traditional finance , but canFurthermore, Li et al.  found thThis paper estimates the level of agricultural green development in 31 Chinese provinces by employing the entropy-weighted TOPSIS method. Base on this, the dynamic spatial Durbin model is used to explore the effect of digital inclusive finance on agricultural green development. Then, this paper chooses education, digital infrastructure, and rural traditional finance as moderating variables to discuss the effect in depth. The marginal contribution of this article includes two main aspects. First, to the best of our knowledge, no study has focused on the effect of digital inclusive finance on agricultural green development. This paper extends the existing literature by discussing the spatial impact. Second, this article explores the moderating effect of education, digital infrastructure, and rural traditional finance when the spatial effect of digital inclusive finance on agricultural green development is studied.The remainder of the paper is organized as follows: To empirically analyze the effect of digital inclusive finance on agricultural green development, we must first clarify what agricultural green development is and how it is measured. The present understanding of agricultural green development is divided into two stages. The first stage constitutes the greening of the agricultural production mode, which emphasizes the reduction of pesticides, fertilizers, and plastic-films . The secThe current understanding of agricultural green development has different forms of measurement. Xu et al. , construUnder the premise of determining how to measure agricultural green development in China, existing studies have analyzed its level and characteristics. For example, Zhang and Chen  found thThe World Bank and the G20 have vigorously promoted the development of inclusive finance in developing countries since 2010. With the population of the Internet and mobile devices, China seized the opportunity to promote the integrated development of inclusive finance and digital technology and pioneered the concept of digital inclusive finance. The 2016 G20 summit in Hangzhou, China took digital inclusive finance as the important topic, and put green finance into the agenda for the first time. According to the actual situation of China’s digital inclusive finance development, Peking University released the digital inclusive finance index from 2011 to 2020, providing the statistical data for scholars’ research.China’s digital inclusive finance has achieved rapid development, establishing itself as a cutting-edge world leader in this space . Meanwhigad) is the core variable in this paper. Based on a review of relevant literature in green agriculture, eco-agriculture, and organic agriculture [res), environmental protection (env), ecological conservation (eco), and quality industrialization (qua), as shown in Agricultural green development , which is specifically characterized by the total digital inclusive finance index at the provincial level in the Digital Inclusive Finance Index System of Peking University.The second core variable in this paper is digital inclusive finance (fai) reflects the strength of state subsidies to agriculture and is measured by the share of expenditures on agriculture, forestry, and water affairs in local general public budget expenditures; (2) government investment in environmental management (gep) reflects the government’s investment in energy conservation and environmental protection and is expressed as the proportion of local general public budget expenditure on energy conservation and environmental protection; (3) the agricultural price index (api) reflects the price fluctuation of agricultural products and is expressed as the producer price index of agricultural products, of which the data for Tibet is missing and is replaced by its total regional production index [eor) reflects the economic activity of the region and is defined as the proportion of total regional imports and exports to GDP; (5) the natural disaster incidence rate (ndr) reflects the natural production conditions of the region, and it is expressed as the proportion of the affected area to the total sown area of crops.Base on the main conclusion of the related literature ,36, the on index ; (4) ecoedu), digital infrastructure (inf) and traditional finance (rtf) as the moderating variables. First, the level of education is expressed by the proportion of people with a college degree or above in the population aged 6 and above. Second, the digital infrastructure level is measured by the proportion of rural Internet access users. Third, the development level of rural traditions is expressed by the ratio of the year-end loan balance to the year-end deposit balance of rural credit cooperatives.Referring to Guo et al. , we seleDue to the incomplete data for Hong Kong, Macao, and Taiwan, the observed samples are limited to 31 provinces in China from 2011 to 2019. The sources of digital inclusive finance data from the Peking University Digital Inclusive Financial Index (2011–2020). The original data of agricultural green development can be seen in The entropy-weight TOPSIS method is used to measure and evaluate agricultural green development in this paper. First, the data are dimensionless processed by the deviation method, then the index weight is determined by the entropy-weight method, and finally the relative level of agricultural green development in each province is calculated by the TOPSIS method. The steps of TOPSIS method are as follows:Step 1: build a weighting matrix Step 2: determine the positive ideal solutions Step 3: calculate the distance measures for the positive ideal solutions Step 4: calculate the relative closeness to ideal solutions Here, The descriptive statistics of variables are shown in According to the first geographical law of Tobler , every pMeanwhile, this paper uses the method of changing the spatial weight to test the robustness, and it uses the actual GDP of each province in the sample period to construct the economic distance matrix line In Equation (6), This paper uses the Moran index to test the spatial correlation of variables, and the calculation formula is shown in Formula (7):In order to measure the spatial effect of digital inclusive finance on agricultural green development and take the continuity and spatial correlation of agricultural green development into account, the dynamic spatial Durbin model is chosen as the econometric model, and the expression is shown in Equation (8): is a constant term, , e et al. , the spaFrom the setting process of spatial metrology model, we can see that dynamic spatial Durbin model can not only obtains short- and long-term spatial effects, but also investigates the lag term of variables. The spatial weight matrix Considering the regional heterogeneity, we further divide the sample into three subsamples, the eastern, middle, and western regions of China, to compare the heterogenous influence and spatial effect of digital inclusive finance on agricultural green development. According to the standards of the National Bureau of Statistics, the eastern region includes Beijing, Tianjin, Hebei, Liaoning, Shanghai, Jiangsu, Zhejiang, Fujian, Shandong, Guangdong, and Hainan; the middle region includes Shanxi, Jilin, Heilongjiang, Anhui, Jiangxi, Henan, Hubei, and Hunan; the western region includes the inner Mongolia Autonomous Region, the Guangxi Zhuang Autonomous Region, Chongqing, Sichuan, Guizhou, Yunnan, the Tibet Autonomous Region, Shaanxi, Gansu, Qinghai, the Ningxia Hui Autonomous Region, and the Xinjiang Uygur Autonomous Region.Next, we build the moderating effect model to explore the heterogeneous effect of digital inclusive finance on regional agricultural green development in which the differences in the level of higher education, digital infrastructure, and rural traditional finance influence.edu, inf or rtf) are assigned, when Before conducting the regression analysis in this paper, the Levin, Lin and Chu (2002) Panel Unit Root Test (LLC) and Im, Pesaran and Shin (2002) Panel Unit Root Test (IPS) tests are used to determine the stationarity of variables. The results show that all variables pass the LLC tests at the significance level of 1%, while the variables pass the IPS tests at least at the 5% significance level. All the variables are stable, as shown in The global Moran’s I, an important indicator to judge the spatial correlation of variables , is perfTo further investigate the spatial dependence of specific regions, we use the local Moran’s I to analyze the spatial relationship between each region and adjacent areas. The results are shown in As shown in Column 1, digital inclusive finance effectively promotes agricultural green development, with the promotion effect being a temporary and spatial spillover. In terms of the direct effect of digital inclusive finance on agricultural green development, the estimated coefficient in the short term is 0.189 while its long-term direct effect is positive but insignificant, suggesting that digital inclusive finance can promote agricultural green development; however, its positive effect is only temporary. One possible reason for this is that a large injection of digital inclusive finance will leverage rapid agricultural green development in the short term. However, as the conflict between the government’s goal of supporting agriculture and market institutions’ profit intensifies, the goal of digital inclusive finance in rural areas may not be achieved . Thus, tIn terms of indirect effects, the coefficients in the short-term and long-term effects are positive and pass the 1% significance test in the short term, but not in the long term. This suggests that there is a positive spatial spillover of digital inclusive finance on agricultural green development in the short term, effectively demonstrating the green behavior of agricultural production in neighboring provinces. However, the long-term indirect effect is not significant. One possible reason for this that the spatial spillover effect of digital inclusive finance has to be realized through technological innovations such as the Internet . The spiIn addition, both the time-lagged term and the space-lagged term of agricultural green development are positively significant at the 1% level, indicating superimposed and spatial spillover effects.Second, the short-term positive effect of digital inclusive finance on agricultural green development existing in the eastern, middle, and western regions of China also experiences spatial spillover. Specifically, the short-term positive effect is most obvious in the middle, where spatial spillover also performs better. The reasons are as follows. The development level of digital inclusive finance in the middle region is on a higher level than the other regions. As the main agricultural producing areas, the middle faces the greatest pressure of resource conservation and environmental constraints . Thus, dThird, the role of digital inclusive finance in supporting agricultural green development in the western region is limited in the long run. Due to the level of digital inclusive finance development as well as technological development and innovation, digital inclusive finance cannot play a larger leveraging role in promoting agricultural green development in the western region . HoweverColumns 1 to 3 of First, digital inclusive finance can provide basic financial services for groups with low education levels and enhance its role in promoting agricultural green development, but its spatial spillover effect on agricultural green development is not affected by education. Specifically, the short- and long-term direct effects are significantly positive, and the long-term direct effect is greater than the short-term direct effect. This shows that the positive effect of digital inclusive finance on agricultural green development is greater in provinces with lower education levels, and this phenomenon grows more obvious with time. Meanwhile, the short- and long-term indirect effects are not significant, indicating that education does not affect the spatial spillover effect.Second, digital inclusive finance has greater support and spatial spillover effect on agricultural green development in provinces with low levels of digital infrastructure. The estimation coefficients of short- and long-term direct effects are 0.006 and 0.020, respectively, both at the 5% significant level. The long-term direct effect is greater than the short-term direct effect, which indicates that the provinces with lower digital infrastructure levels have stronger support for agricultural green development. This phenomenon is more obvious with the passage of time. The reasons for this are as follows. At the initial stage, the digital inclusive finance mostly depended on offline promotion, and its supporting role was not greatly limited by the level of digital infrastructure . With thThird, the low level in traditional finance can restrain the short-term effect of digital inclusive finance on agricultural green development. In the long term, the emergence of late-developing advantages will enhance the effect. The short-term direct effect is significantly negative, while the long-term direct effect is positive but insignificant. This phenomenon indicates that the short-term positive effect of digital inclusive finance on agricultural green development is more obvious in provinces with higher levels of traditional finance; however, this advantage of such provinces will be gradually lost in the long term, for the following potential reasons. The role of digital inclusive finance relies on traditional finance in the early stages of development . MeanwhiThe robustness test results are shown in Columns 1 to 4 in This paper selects 14 indicators to construct agricultural green development from four dimensions of resource savings, environmental protection, ecological conservation, and quality industrialization using provincial panel data from 2011 to 2019. Then, agricultural green development is estimated using the entropy-weighted TOPSIS method. By using the dynamic spatial Durbin model, we empirically analyze the effect of digital inclusive finance on agricultural green development. Finally, we choose education, digital infrastructure, and traditional finance as moderating variables to explore this effect.The dynamic SDM results show that digital inclusive finance has a positive effect on agricultural green development, and the short-term effect is more significant than the long-term effect, suggesting that the promotion of digital inclusive finance could be an effective measure for ensuring agricultural modernization. Furthermore, digital inclusive finance has regional heterogeneous effects on agricultural green development. Specifically, in the short term, the direct and indirect effects of digital inclusive finance on agricultural green development are more pronounced in the middle region, while in the long term, both effects on agricultural green development are only effective in the eastern region.We find that digital inclusive finance also exhibits heterogeneity in agricultural green development in provinces with different socio-economic characteristics, such as education, digital infrastructure, and traditional finance. Higher levels of the above three indicators tend to result in greater and more significant effects on the level of digital inclusive finance.Due to the impact of COVID-19, the research data collection period is limited. At the same time, this research is based on China’s national conditions, and other developing countries or developed countries can be selected for future research.According to the conclusions, the following policy implications should be put forward:(1) Promoting the overall development of digital inclusive finance. Digital inclusive finance can effectively promote agricultural green development and has regional heterogeneity. Therefore, the government should provide legal and financial support to financial institutions, ensuring the quantity and level of financial supply in rural areas, and pay attention to digital technology innovation.(2) Focusing on the sustainability of the development of digital inclusive finance. The east should give better play to the spillover effect and support the development of the middle and western regions. The middle should accelerate the transformation of agricultural industrialization and carbon reduction. Due to the restriction of natural resources and different industrial forms, the west should actively use digital technology to guide financial resources to flow to agricultural technology innovation activities.(3) Improving the financial literacy and skills of rural people. Digital finance education and training is an important way to improve the financial literacy and skills of rural people. The improvement of financial literacy is conducive to farmers’ mastering financial knowledge. It is suggested to provide diversified and multi-channel financial education and training for rural areas.(4) Strengthening rural digital financial infrastructure. Digital inclusive finance is limited by digital financial infrastructure. Therefore, the government should vigorously promote the construction of rural digital financial infrastructure, formulate corresponding preferential policies in combination with the development of regional characteristics, encourage financial institutions to take root in rural development, and further release the positive role of digital inclusive finance.(5) Promoting the innovative combination of traditional finance and digital technology to develop digital inclusive finance. Such measures can build financial and agricultural service platforms through innovating financial instruments, and provide financial support for farmers’ activities, such as agricultural carbon reduction production, living and production pollution prevention, and ecological protection.


During national health emergencies such as the COVID-19 pandemic, a robust primary care system plays a crucial role in triaging, educating patients and testing. Notwithstanding, the primary care system worldwide has been underprepared for the pandemic, largely because it had been weakened by chronic underinvestment and workforce shortages. In turn, the primary care system experienced massive setbacks from the pandemic, with significant reductions in visit volume as patients stopped seeking in-person care, important organizational challenges with more phone consultations and many countries adopted digital-first strategies, remote monitoring and telehealth platforms to enable healthcare provision without physical interactions [Due to the reduction in face-to-face consultations, an unprecedented decrease in community antibiotic consumption has been observed in many countries between 2019 and 2020  found thDespite lowering the threshold to prescribe antibiotics for respiratory infections during the first wave of the COVID-19 pandemic, the lack of face-to-face consultations, mainly during the first wave of the pandemic, resulted in a lower net antibiotic prescribing in primary care. In a Dutch study, Boeijen et al.  found thA French study compared the prescribing rates of antibiotics in 2019 and 2020 among primary care doctors, pediatricians and dentists . In compBarbieri et al.  observedFinally, with the use of a large Catalonian primary care database which included all the suspected and confirmed COVID-19 infections during the first four months of the pandemic, a composite severity endpoint, comprising pneumonia, hospital admission and death due to COVID-19, was found to be more frequent among individuals who has previously consumed antibiotics compared to those who did not. This correlation was stronger for high antibiotic exposure, exposure to the highest priority critically important antimicrobials and recent exposure, after potential confounders were adjusted by logistic regression . This siThis Special Issue collects multidisciplinary research papers focusing on how antibiotic prescribing has changed due to the COVID-19 pandemic. The different contributions collected in this issue constitute valuable knowledge for primary care doctors and researchers working in the field of the rational use of antibiotics during a pandemic. All these research articles highlight the safety of withholding antibiotic therapy for common infections in primary care. As we have witnessed with COVID-19, everyone is responsible for implementing and developing actions to control or stop the spread of disease, but it is equally important to change dangerous practices through the appropriate and prudent use of antibacterial agents . The COV


Carpal tunnel syndrome (CTS) is an upper extremity median nerve entrapment disorder that is rare in children and adolescents. Anatomical variations of the wrist, such as anomalous muscles, persistent median artery (PMA), and bifid median nerves (BMN), are rare etiology of CTS. Coexistence of all three variants combined with CTS in adolescents has been rarely reported. Case description: A 16-year-old right-hand dominant male presented to our clinic with several years of bilateral thenar muscle atrophy and weakness but no paresthesia or pain in his both hands. Ultrasonography showed that the right median nerve become significantly thinner, and the left median nerve was split into two branches by PMA. Magnetic resonance imaging (MRI) revealed that anomalous muscles in the bilateral wrist extending to the carpal tunnel, causing compression of the median nerve. Considering the possibility of CTS clinically, the patient underwent bilateral open carpal tunnel release without resection of anomalous muscles and PMA. The patient has no discomfort after 2 years. This suggests that anatomical variations of the carpal tunnel may contribute to CTS, which can be confirmed by preoperative ultrasonography and MRI, and the possibility of carpal tunnel anatomical variations should be considered when CTS occurs in adolescents. Open carpal tunnel release is an effective treatment for juvenile CTS without the need to resect abnormal muscle and PMA during the operation. Carpal tunnel syndrome (CTS), the most common upper extremity nerve entrapment disease and mostly occur in adult women, is characterized by paresthesia and numbness in the area innervated by the distal median nerve, usually accompanied by atrophy and weakness of the thenar muscle. Compression of the median nerve at the wrist is the etiology of CTS, and the space-occupying lesions and anatomical variations of the wrist are the potential causes of CTS.CTS in children and adolescents is rare and mostly secondary to various hereditary diseases, such as lysosomal storage disease, including mucopolysaccharidoses(MPS) and mucolipidoses (ML) . FurtherWe report a rare case of bilateral CTS in an adolescent, which presents anomalous muscle in the bilateral carpal tunnel, and coexistence of PMA and BMNs in the left carpal tunnel. Knowledge about the anatomic variations of carpal tunnel is necessary to avoid any iatrogenic injuries.−/5 (MRC)  . Phalen'/5 (MRC) . As showin situ. Routine dressing changes were performed after surgery, and active and passive movements of wrist joints and fingers were performed early to reduce hand edema and local adhesion. The surgical incision healed well and no complications were found.The possibility of CTS was considered clinically, and bilateral open carpal tunnel release was performed on the patient. Operative exploration was shown in −/5 (MRC).Regular follow-up was performed post-operative and the last follow-up period was two years after the operation, with no complaints of discomfort. Physical examination showed that bilateral thenar muscles still atrophied, but the atrophy was not further aggravated compared with two years ago . The strCTS is the most common clinical upper extremity nerve entrapment disease, which is characterized by paresthesia and motor dysfunction of the median nerve innervation due to the entrapment of the median nerve when passing through the carpal tunnel. Common causes of CTS are menopause, diabetes, hypothyroidism, obesity, arthritis, and pregnancy , and othAlthough rare in clinical practice, anatomical variations in the carpal tunnel, such as anomalous muscles, PMA, and BMN, may all contribute to the occurrence of CTS. Muscle variations in the carpal tunnel are mostly discovered accidentally during surgery, and some are unexpectedly detected during autopsy. The prevalence of anomalous muscles in CTS is about 1.3% to 2.9% , while tSeveral authors reported that they found abnormally lumbrical muscles, which origin extended proximally across the carpal tunnel, during open carpal tunnel release, and they suggest that aberrant lumbrical muscles contribute to the development of CTS , 18. AddPMA and BMN are also common anatomical variations in the wrist, with BMN often coexisting with PMA , and BMNPMA was found in 1.2% to 2.6% of patients during carpal tunnel release surgery, and as high as 8.6% to 23%% at autopsy –29. SincIn our case, abnormal muscles were present in the bilateral carpal tunnel, and the aberrant muscles were confirmed to be derived from the first lumbrical muscle. The origin of the lumbrical muscle was higher than the normal position, which reduced the volume of the carpal tunnel and caused the median nerve entrapment. However, this patient had no typical paresthesias but had marked thenar muscle atrophy, which we believed was caused by entrapment of the recurrent thenar branch of the median nerve. Interestingly, in addition to the abnormal muscles, the PMA was found in the left carpal tunnel, which divided the median nerve into two branches and caused compression of the median nerve, however, the patient's left hand had milder symptoms than the right. We did not remove the abnormal muscles and PMA during the operation, which may lead to the recurrence of carpal tunnel syndrome in the future, requiring further observation and follow-up.CTS is very rare in children and adolescents. Differential diagnosis should pay attention to lysosomal storage disease, wrist trauma, carpal tunnel space-occupying lesions, etc., which are more common in children and adolescents with CTS , 32. In Congenital thenar hypoplasia, also called Cavanagh's syndrome, is a developmental rather than an acquired thenar deformity, which presents with unilateral or bilateral marked flattening and weakness of the thenar eminence, and without paresthesia, pain, numbness of median nerve innervation area . Hand raHirayama disease (HD), also known as juvenile muscular atrophy of the distal upper extremity, is a rare benign self-limited lower motor neuron disease, mainly involving the hand and forearm, with progressive exacerbation of muscle weakness and muscular atrophy, and MRI of the cervical spine can reveal characteristic imaging changes . The patCurrently, there is no consensus on the management of CTS caused by anatomical abnormalities in the carpal tunnel. For abnormal muscles, some scholars  suggesteAnatomical variations in the carpal tunnel can lead to reduced carpal tunnel volume and contribute to CTS. When CTS occurs in adolescents, the possibility of anatomical variations in the carpal tunnel should be considered, which can be confirmed by preoperative ultrasonography and MRI and can help prevent iatrogenic injury. Open carpal tunnel release is an effective method for the treatment of CTS in adolescents, and it is not necessary to remove the abnormal muscle and PMA during the operation.


Plant growth-promoting bacteria (PGPB) are endowed with several attributes that can be beneficial for host plants. They opened myriad doors toward green technology approach to reduce the use of chemical inputs, improve soil fertility, and promote plants’ health. However, many of these PGPB harbor antibiotic resistance genes (ARGs). Less attention has been given to multi-resistant bacterial bioinoculants which may transfer their ARGs to native soil microbial communities and other environmental reservoirs including animals, waters, and humans. Therefore, large-scale inoculation of crops by ARGs-harboring bacteria could worsen the evolution and dissemination of antibiotic resistance and aggravate the negative impacts on such ecosystem and ultimately public health. Their introduction into the soil could serve as ARGs invasion which may inter into the food chain. In this review, we underscore the antibiotic resistance of plant-associated bacteria, criticize the lack of consideration for this phenomenon in the screening and application processes, and provide some recommendations as well as a regulation framework relating to the development of bacteria-based biofertilizers to aid maximizing their value and applications in crop improvement while reducing the risks of ARGs invasion. In the last few years, there has been growing interest in using microbial-based products as bioinoculants or/and substances. However, their use is facing many challenges from the lab to the field . Plant gper annum  have similar routes into the bacterial cell. In this case, when a resistance response is triggered, cell defense is effective against both metal and antibiotic contaminants. Under such contamination, selective pressures are likely to persist longer than pharmaceutical compounds because of the non-degradability of metals in the environment .Furthermore, the presence of polycyclic aromatic hydrocarbons (PAHs) also induces shifts in the indigenous bacterial communities by increasing hydrocarbon-degrading bacteria . InteresSoil microbial communities were found to harbor cassettes of ARGs serving as a reservoir of genes potentially exchangeable with human bacterial pathogens . Additiovia mobile genetic elements so-called the mobilome (via transformation (integration of DNA in the environment), conjugation (sharing of plasmids between bacteria species), and transduction  compared to the sequences of their closest proteins at the amino acid level . Noteworectively .tetA, sul1, blaOXA2, blaCTX-M, and qnrS has been shown by tetM, tetO, and tetW, was significantly greater in manure-treated soils ] and MGEs [IS26 (MGEs) and IS6100 (MGEs)] were noticed following biofertilizer application. However, the overall relative abundance of ARGs was no significant at the applied dose but the authors suggested that biofertilizers application should be evaluated over time as resistance transfer is time dependent (Serratia plymuthica MBSA-MJ1 namely chloramphenicol acetyltransferase (cat) gene providing resistance to chloramphenicol and six copies of the efflux pump responsible for tetracycline resistance , bicyclomycin (bcr), polymyxin (arnABCD), and β-lactam multi-drug resistance . In some soils, plasmids harbor bac gene conferring resistance to bacitracin in Bacilli strains. This gene is acquired by HGT and is mandatory for their survival in most soils  harbored by biofertilizer and soil samples using high-throughput quantitative polymerization chain reaction (HT-qPCR). Fluctuation in specific ARGs , are haetection . In a stetection .Many diagnostic methods are being used to detect ARGs from different environments. In this section, we provide an outline of some current and emerging tools for diagnostics and fast detection of ARGs ; Table 2The conventional methods relying on molecular-based technologies provide fast and sensitive detection of ARGs and have extended the availability of huge ARGs targets in various databases . In the PCR is the most used method for the detection of ARGs . RecentlIn vitro diagnostic products based on PCR and isothermal nucleic acid amplification technology (NAAT) are commercialized , simultaneous detection of ARGs among achieved . Recentlproposed .In this section, some of the most promising non-conventional methods for ARGs detection are described. They include sequencing, matrix-assisted laser desorption/ionization, time-of-flight mass spectrometry (MALDI-TOF MS), and Fourier transform infrared (FTIR). spectroscopy.Numerous methods, tools, and databases have been reported in recent years for the detection of ARGs from WGS and WMS data . These eMycobacterium tuberculosis. Reliable and robust detection of resistance-associated mutations in M. tuberculosis isolates was achieved with very high specificity  as well as their position and structure  can also be employed for the detection of ARGs . MALDI-Tnano-QCM) biosensor  is a microfluidic technology made of a physical nanogram-sensitive device with a piezoelectric sensor. QCM facilitates the real-time, rapid, on-site detection of antibiotic resistant bacteria . This apiosensor . QCM is iosensor .tetC, tetG, tetW, and tetX) and sulfonamides (sulI and sulII) in soil and plant tissues  geAs the biofertilizers market still lags behind synthetic fertilizers, greater attention should be played to regulatory aspects to share responsibilities in overcoming the challenges and offering high-quality products. Among the major constraints, antibiotic resistance across agroecosystems is urgent to combat with a target on prevention and remediation prospects. Commercialization should also require strict reference systems to demonstrate their effectiveness and potential associated risks. In developing countries, the spread of this public health scourge is due to (i) the lack of surveillance of resistance occurrence, (ii) the poor quality of utilized antibiotics, (iii) the clinical and agricultural excessive/misuse, and (iv) the improper and easy disposal of antibiotics and pharmaceutical wastes. However, these factors differ from developing to developed countries. Overall, there is still a need to improve and update the regulatory aspects for antibiotic use especially in agriculture . In the in silico taxonomic profiling, it is mandatory to compare the potential strains physiologically and morphologically with closely related ones for phylogenetic delineation , chemotaxonomic , and molecular aspects . Bacteria falling in BSL-1 class are more likely to be null of biosafety risk. This implies further experiments such as formulation and testing. However, strains falling in the BLS-2 class of higher are more likely to be risky with potential negative impact. In this case, pathogenesis investigation and characterization at the strain level should be carried out. When it is a pathogenic species, it should be excluded from downstream experiments unless alternatively used, under confinement conditions in the laboratory, to optimize the production of metabolites and compounds of interests .To promote the acceptance of biofertilizers by the users, the quality of a bioinoculant must refer not only to the specification of the strain, efficacy, and preservation etc. but also to its antibiotic resistance profile and potential pathogenesis for human. This information can be reflected in the labelling requirements .Controlling biofertilizers is essential to ensure their compliance with standards, product safety, and efficacy. Poor quality products can be expected when the regulatory setup is not well established, leading to poor performance in the field or potential health risks to users. The lack of effective regulation of biofertilizers in most countries is one of the major factors to their low availability and adoption. Afterwards, periodic monitoring of commercialized biofertilizers is important to ensure product quality and safely throughout the marketing chain .To mitigate the risks posed by the continued emergence of antibiotic resistance, behavioral changes and practical strategies should be considered by all the stakeholders. In agriculture, the trend of PGPB, which is claimed to be sustainable and environmentally friendly, could be a significant threat and cause large-scale dissemination of multi-drug resistant bacteria and/or ARGs in different environments including human beings. The future development of more effective bacteria-based biofertilizers should consider environmental issues as there is enough evidence supporting the hypothesis that antibiotic-resistant biofertilizers could contribute substantially to the global antibiotic resistance crisis. Additionally, understanding the underpinning mechanisms is necessary to develop effective approaches in the battle against the spread of antibiotic resistance. Ultimately, to tackle this issue at its source, better formulated strategies are needed based on agricultural, environmental, and public health aspects.The need for knowledge of the antibiotic resistome in plant agricultural systems and especially those in which biofertilizers are applied is critically important because we need to understand whether their application to the soil has the potential to select ARGs that could impact human health. As this has the potential to impact human health, and current implications for the use in agriculture, commercial biofertilizers should be well characterized with respect to their ability to transfer ARGs to other microorganisms. Detecting organisms harboring ARGs and their identification is important for risk assessments with co-inhabiting antibiotic-resistant communities. If ARGs of importance in clinical medicine are identified in the resistome of bioinoculants and/or inoculated plants, it is critical to determine whether their frequency and/or bacterial host range changes based on strain exposure. Finally, more in depth studies should address the genetic behavior, the bacterial diversity, and the activity of PGPB harboring ARGs with regards to indigenous communities.IM and NF reviewed the literature and wrote the original draft of the manuscript. MH reviewed and corrected the manuscript. MS revised the manuscript. IM, MH and MS designed and conceived the work. All authors contributed to the article and approved the submitted version.This work was supported by funding from the OCP Group  and Mohammed VI Polytechnic University , which are greatly acknowledged.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.