Overview: Post traumatic stress disorder (PTSD) has emerged as a severely debilitating psychiatric disorder associated with critical illness. Little progress has been made in the treatment of post-intensive care unit (ICU) PTSD. Aim: To synthesize neurobiological evidence on the pathophysiology of PTSD and the brain areas involved, and to highlight the potential of music to treat post-ICU PTSD. Methods: Critical narrative review to elucidate an evidence-based neurobiological framework to inform the study of music interventions for PTSD post-ICU. Literature searches were performed in PubMed and CINAHL. The Scale for the Assessment of Narrative Review Articles (SANRA) guided reporting. Results: A dysfunctional HPA axis feedback loop, an increased amygdalic response, hippocampal atrophy, and a hypoactive prefrontal cortex contribute to PTSD symptoms. Playing or listening to music can stimulate neurogenesis and neuroplasticity, enhance brain recovery, and normalize stress response. Additionally, evidence supports effectiveness of music to improve coping and emotional regulation, decrease dissociation symptoms, reduce depression and anxiety levels, and overall reduce severity of PTSD symptoms. Conclusions: Despite the lack of music interventions for ICU survivors, music has the potential to help people suffering from PTSD by decreasing amygdala activity, improving hippocampal and prefrontal brain function, and balancing the HPA-axis. Ongoing advancements in Intensive Care Unit (ICU) technology and evidence-based practice have significantly reduced ICU mortality. However, the intense stress and adverse emotions experienced during hospitalization in an ICU have long term effects on survivors’ physiological and psychological well-being ,2,3. PosPTSD is characterized by symptoms including: intrusive memories, hyper-arousal, avoidance of trauma-related stimuli, and negative alterations in mood or cognition that develop following exposure to traumatic life events. According to the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition 2013) criteria for diagnosis, PTSD can be diagnosed if an individual is exposed to actual or threatened serious injury or death. Events such as critical illness, ICU admission and related ICU treatments, such as awareness during intubation, can meet the first criteria for PTSD . The add013 criteThe combination of life-threatening illness or injury, along with the impact of potentially traumatic experiences in the ICU can contribute to the development of PTSD ,17,18. PThis review aimed to summarize neurobiological evidence on the pathophysiology of PTSD and the areas of the brain involved, as well as some of the effects of music on PTSD and ICU survivors to highlight potential mechanisms and effects of music on individuals suffering from post-ICU PTSD. Delineating an evidence-based theoretical framework of the effects of music for rehabilitation after critical illness can inform interventions that improve survivors’ psychological well-being and health outcomes.We used a critical narrative review methodology as this was deemed most appropriate for the delineation of a theoretical framework on music effects on PTSD post-ICU. As there is a lack of guidelines for narrative reviews, we followed methodological recommendations by Ferrari . We searInclusion criteria included: systematic syntheses of evidence, primary research studies in humans regardless of methodology, studies that addressed the pathophysiology and neurobiology of PTSD, and studies that addressed the physiological effects of music on brain function. Studies that were not based on research evidence, that included non-human participants, and were not reported in English were excluded. Due to the scarcity of literature on the topic, we did not include any chronological criteria. We did not employ a formal approach to quality appraisal. We extracted and synthesized results of PTSD-related alterations on specific brain structures, and the impacts and mechanisms of music effects on these brain structures, as well as evidence on the effects of music on related neuropsychiatric entities. The Scale for the Assessment of Narrative Review Articles (SANRA) guided reporting .Our search strategy yielded 363 articles addressing the neurobiology of PTSD, 841 articles addressing the effects of music on PTSD and 61 articles on the neurobiological effects of music therapy in the brain.To summarize evidence on how the brain is affected by PTSD, it is essential to examine the key structures of the brain that are associated with how memories are stored, and how stimuli are associated with emotion. These key structures include: the prefrontal cortex (PFC), the amygdalae, and the hippocampus. Alterations in these areas of the brain are observed across various studies assessing PTSD ,28. SincThe HPA axis involves a complex set of interactions among the hypothalamus, the pituitary gland, and the adrenal gland that determines the level of circulating cortisol. Stress triggers an HPA and sympathetic nervous system (SNS) response. Upon perception of a stressful stimulus, norepinephrine and indirect limbic inputs from the hippocampus, prefrontal cortex, and amygdala stimulate neurons in the paraventricular nucleus (PVN) of the hypothalamus that contain a corticotropin releasing factor (CRF), leading to the activation of the HPA axis and the release of adrenocorticotropic hormone (ACTH) into the systemic circulation. ACTH then binds to melanocortin 2 receptors in the zona fasciculata of the adrenal cortex and stimulates the release of glucocorticoids . Activation of the HPA axis is modulated by pituitary adenylate cyclase-activating polypeptide (PACAP), which appears to mediate the production of CRH. PACAP is also involved in the modulation of the sympathetic nervous system (SNS) response .The SNS contributes to the flight or fight response by signaling the adrenal medulla to release catecholamines (epinephrine and norepinephrine) and enkephalins. Cortisol, catecholamines and enkephalins together stimulate a series of effects such as enhancing glucose availability, regulating the immune system and brain function, and impacting electrolyte balance to manage stressors . SimultaCortisol acts as the primary molecule to enable the stress response, as well as prevent ongoing HPA axis activity. The function of the HPA axis is controlled by two factors: (a) the effectiveness and (b) number of glucocorticoid receptors in the pituitary and hypothalamus ,33, whicThe amygdalae are a subcortical collection of nuclei situated in the anterior temporal lobe of each hemisphere, projecting to the brainstem and hypothalamic regions. The amygdalae play a critical role in emotional processing and generation of fear responses. In particular, amygdalae are associated with the execution of the physical, autonomic, and musculoskeletal components of the emotional response. Moreover, they have connections with other emotional centers in the brain. The amygdalae process the stressful events resulting in the release of cortisol through HPA-axis activation. In the case of an aberrant HPA axis feedback cycle, the continuous cortisol release enhances the amygdala’s ability to communicate within and with other brain structures ,38. ThisThe hyperactive amygdalae shift the brain’s processing mode from the thoughtful prefrontal cortex pathway to its own rapid, emotional, and reactive pathway ,41. ThusThe hippocampus is an extension of the cerebral cortex situated deep within the temporal lobe. The hippocampus plays a crucial role in the consolidation of information from short-term memory to long-term memory. It is also involved in the neuroendocrine regulation of stress hormones. Alterations in the structure and function of the hippocampus are observed in several neurological and psychiatric disorders ,42. BoccTraumatic stressors have also been shown to alter hippocampal dendritic morphology and inhibit neurogenesis in the hippocampus ,44,45,46Altogether, these changes can result in generalizing the fear from the traumatic event to learned-fear in situations that are not related to the traumatic event, with hypervigilance and avoidance behaviors. Thus, the person with PTSD has a difficult time distinguishing between safe and unsafe stimuli and re-experiences a physiological and emotional toll similar to the traumatic event. This results in hypervigilance , exaggerPFC is vitally involved in executive functions, such as concentration, organization, judgement, reasoning, problem solving, decision making, creativity, emotional regulation, and abstract thinking. Chronic exposure to stress impairs prefrontal cortex functioning, which leads to aberrant stress responses and maladaptive coping. Decreased volumes of the frontal cortex are associated with significant hypoactivation of the PFC in individuals with PTSD ,58. TherMusic therapy is a systematic process of intervention wherein the therapist helps the client to promote health, using musical experiences, and the relationships that develop through them as dynamic forces of change . Music nActive music therapy engages patients in some form of music-making, such as vocalizing, singing, playing instruments, song writing or composing, and conducting . ReceptiVarious music and sound interventions have been used to improve health outcomes in a broad spectrum of psychological and neurological disorders ,71,72,73A meta-ethnography of 46 qualitative studies found that participatory music engagement, music actively made by the participant, including singing, and not limited by musical genre such as classical or jazz, improved well-being by facilitating self-development, providing respite from problems, and fostering social connections . There iThe effect of music and sound interventions has also been explored in ICU patients . VariousDespite this gap in evidence, music appears to be a promising adjunct in the treatment of PTSD . EvidencEmpirical evidence suggests that music therapy may reduce prominent symptoms of post-traumatic stress, including emotionally dysregulating intrusions, avoidance, negative alterations in mood, and arousal. A study by Zergani & Naderi (2016) demonstrated beneficial effects of Iranian traditional music on quality of life and anxiety symptoms among hospitalized veterans with PTSD . A doublMusic guided relaxation has also shown a positive impact in reducing depression, PTSD and increasing sleep quality in veterans . In a naMusical stimuli stimulate neural networks associated with various functional domains, such as movement, cognition, communication, emotion, and social responses . StudiesPTSD is characterized by hypervigilance associated with altered connectivity between the amygdalae and the hippocampus . CommuniAttentive listening to or playing music can stimulate neurogenesis and neuroplasticity in the brain ,106,113 Evidence suggests that active vs. passive music therapy may have differential effects on patient engagement and receptivity. According to fMRI and PET scan studies, active music participation engages more parts of the brain than just listening to music . In a quHowever, music selection needs careful consideration. Music that the participant does not enjoy may result in a stress rather than a relaxation response. Moreover, music can trigger strong memories, which influence the affective response to music and can, therefore, modulate the therapeutic effects of music . In the Basic psychoacoustic properties of music, such as pitch (high or low tone of sounds), rate (fast or slow speed of sounds), loudness (loud or soft intensity of sounds), mode (major or minor key), timbre, and rhythm have been shown to be important factors in the perception and induction of positive as well as negative emotional states. The music therapy research supports music containing a slower tempo, low pitch, containing primarily string composition, regular rhythmic patterns, no extreme changes in dynamics, and no lyrics are associated with relaxation, joy, or peace . The temAs the HPA axis and the production of cortisol play a significant role in PTSD, music can be purposefully used to help regulate the stress response in PTSD. The effects of music on neurobiological aspects of PTSD are summarized in PTSD is part of the post-ICU syndrome and impairs the quality of life and functionality of increasing numbers of ICU survivors and their families worldwide. To date, minimal progress has been made in the management of PTSD post-ICU. An impaired HPA axis feedback circle, an exaggerated amygdalic response, hippocampal atrophy and a hypoactive prefrontal cortex accentuate PTSD symptoms, preventing the healthy regulation of the fear response. Music can stimulate the hippocampus and amygdalae that are negatively impacted by stress. Music can also prompt neurogenesis and neuroplasticity within these brain structures and allow the brain to heal. In addition, music can stimulate communication between the amygdalae and PFC/hippocampus, which is vital in the regulation of stress responses. As a result, music can reduce the unnecessary stimulation of the amygdala, increase the effectiveness of both the hippocampus and prefrontal cortex, and balance the HPA-axis. Clinical evidence supports that relaxation music can help improve coping and psychological adaptation after discharge from the ICU. In addition, both sound and music interventions can decrease dissociation symptoms, reduce depression and anxiety levels, and overall reduce the severity of PTSD symptoms. Thus, music could be a cost-effective, easy to access intervention to purposefully address PTSD after an ICU experience and improve the quality of life of both the ICU survivors and their families.Future studies need to consider those neurobiological effects in planning and testing music interventions for PTSD in survivors of severe illness, such as critical illness. Moreover, elucidating the neurobiological effects of specific types of music, taking into account the intensity of music interventions  and specific patient populations will be important in maximizing the impact of targeted music interventions for post-ICU survivors. Insights into the therapeutic potential of music by determining which types of music  are best suited to stimulate specific limbic brain structures can lead to a more systematic use of music in the therapy of PTSD.


Pelvic organ prolapse (POP) is a multifactorial connective tissue disorder caused by damage to the supportive structures of the pelvic floor, leading to the descent of pelvic organs in the vagina. In women with POP, fibroblast function is disturbed or altered, which causes impaired collagen metabolism that affects the mechanical properties of the tissue. Ideal surgical repair, either native tissue repair or POP surgery using an implant, aims to create a functional pelvic floor that is load-bearing, activating fibroblasts to regulate collagen metabolism without creating fibrotic tissue. Fibroblast function plays a crucial role in the pathophysiology of POP by directly affecting the connective tissue quality. On the other hand, fibroblasts determine the success of the POP treatment, as the fibroblast-to-(myo)fibroblast transition is the key event during wound healing and tissue repair. In this review, we aim to resolve the question of “cause and result” for the fibroblasts in the development and treatment of POP. This review may contribute to preventing the development and progress of anatomical abnormalities involved in POP and to optimizing surgical outcomes. Pelvic organ prolapse (POP) is a multifactorial condition caused by damage to the supportive structures of the pelvic floor , which r® [®  undergo rapid in vivo degradation, and the load-bearing capacity of the remodeled tissue is insufficient [Surgical repair using the patients’ own pelvic support tissues, such as perivesical fascia, known as native tissue repair (NTR) , is used®  and Surgfficient ,25. Syntfficient ,26. Animfficient .Either in NTR or POP surgery with an implant, wound healing and tissue regeneration are highly needed for a successful surgical outcome, which is functional and mechanically self-sufficient pelvic tissue. This can mainly be achieved by a mild and well-orchestrated host response by triggering collagen metabolism without creating fibrotic tissue . The forFibroblasts, having a crucial role in the connective tissue quality such as decreased fibroblast quantity and quality, may contribute to the pathophysiology of POP. On the other hand, fibroblast activity and fibroblast-to-(myo)fibroblast transition play an important role during the healing process and tissue remodeling after POP surgery, and therefore have a significant effect on surgical outcome. (Myo)fibroblast activity can repair the damaged tissue, or in the case of excessive activity, may lead to pathologic fibrotic tissue causing contraction, implant deformation, and may contribute to the pain . The objPelvic organ prolapse is a multifactorial disease caused by a defect in the connective tissue or pelvic floor musculature, or a combination of the two, which results in the loss of the support provided by pelvic fascia and skeletal muscles ,31. DysfThe risk factors for POP are vaginal delivery, pregnancy, or other conditions resulting in increased abdominal pressure, such as obesity, chronic coughing, heavy lifting, constipation, and so on. Vaginal delivery is the strongest risk factor for the development of POP as the forces during delivery are significantly higher than the pelvic floor muscles can withstand . Aging iNative tissue repair (NTR) by using patients’ fascia is the first option in surgery to correct POP. Due to the higher recurrence rates of NTR, synthetic implants have been introduced to restore pelvic floor function by improving the integrity of existing compromised tissue, which caused POP by inducing a favorable host response. In both surgical treatments, the final goal is to create a mechanically self-sufficient and functional tissue.The connective tissue of the vaginal wall remodels to adapt to the changes in the biomechanical environment through the extracellular matrix (ECM) metabolism. The remodeling process depends on the quality and quantity of the cellular components of the connective tissue. Before we theoretically explain the changes and remodeling of the connective tissue, we should briefly mention the structure and layers of the vaginal wall in which these changes occur. The vaginal wall is composed of four layers: non-keratinized stratified squamous epithelium, lamina propria of connective tissue, smooth muscle with bundles of circular and longitudinal fibers, and adventitia, which consists of blood vessels, lymphatic ducts, and nerves . The pelChanges in the ECM and collagen metabolism, such as the decreased amount of collagen, increased collagen break-down, or altered ECM remodeling and/or expression of structural proteins resulting from gen-mutations or decreased estrogen levels, may all increase the risk on POP. Another hypothesis is that POP disturbs the repair of injured supportive tissues due to mechanical stress ,34,42. TFibroblasts play a key role in collagen metabolism and ECM turnover. There are several changes in the quality and quantity of connective tissue in patients with POP. Either with genetic factors or acquired defects due to mechanical stress, the functionality of fibroblasts differs in prolapsed tissue, which subsequently results in changes in the collagen content in POP. Collagen, as the main component, accounts for up to 80% of the connective tissue. There are 28 types of collagen and the most representative ones on the pelvic floor are collagen type I and III, which are the determinants of tissue strength ,45. CollThe collagen metabolism and ECM turnover are controlled by the synthesis or degradation of ECM components, which is important for maintaining tissue integrity. Degradation depends on the activity of the matrix metalloproteinases (MMP). MMPs are a group of proteolytic enzymes that degrade all ECM proteins. Mainly MMP-2  and/or MAnother important component of the connective tissue in the pelvic floor is elastin, which allows the tissue to stretch and has passive recoil capabilities  . The proSeveral factors are affecting the fibroblasts’ activity. The influence of stretch on the fibroblasts, whether as a cause or an effect, should not be overlooked in prolapse. Mechanical stretch disturbs the activity of the fibroblasts by influencing their capacity to synthesize ECM components and maintain their cytoskeleton architecture . Many stAs we discussed, POP might result from a disturbed healing process after trauma. The disease itself affects the stiffness and composition of the ECM. The changes in connective tissue during the development of POP resemble scar tissue by being stiffer and having increased amounts of collagen type III relative to collagen type I protein. Therefore, vaginal fibroblasts might recognize the resulting POP-ECMs after an injury as scar tissues that need to be remodeled. In the case of treatment, during the vaginal wall reconstruction by NTR with autologous fascia graft or implantation of a scaffold, the vaginal microenvironment and the ECM stiffness change. Either the NTR procedure or the presence of a stiffer implant than the POP tissue triggers the wound healing process and promotes fibroblast–myofibroblast differentiation. Understanding the mechanisms of tissue repair and the involvement of fibroblast–(myo)fibroblast transition in the healing process can provide a rational basis for disease modeling and innovative solutions in vaginal reconstruction for POP.Damaged pelvic floor tissues can only recover themselves by wound healing and regeneration by fulfilling two urgent tasks: (1) establishing tissue hemostasis, fighting inflammation, and discarding debris, which is carried out by immune and inflammatory cells, and (2) providing mechanical tissue coherence by forming a scar, which is the task of fibroblasts and so-called myofibroblasts . In normThroughout the wound healing process, (myo)fibroblasts are embedded in the ECM, in which they secrete at the injury site, and a complex and interactive dialogue exists between (myo)fibroblasts and their microenvironment which leads to cell differentiation, proliferation, ECM remodeling, and, in the case of “normal” wound healing, also to apoptosis ,68. FibrDifferentiation and transition of fibroblasts to (myo)fibroblasts occurs in a two-step process, including (1) the formation of proto-myofibroblasts and (2) the development of myofibroblasts . First, The second step in the fibroblast–myofibroblast transition takes place due to the increased mechanical stress in the ECM as a result of the remodeling activity of proto-myofibroblasts, which leads to differentiation of these cells to “myofibroblasts” ,71. The In addition, myofibroblasts have cell-to-matrix (fibronexus) junctions which allow them to make strong attachments, contract and remodel the ECM, and thus transduce the mechanical forces in the tissue . As a haProlapsed connective tissue resembles the characteristics of scar or granulation tissue by being stiffer ,74 and hThe cytoskeletal system and intercellular or cell-to-matrix junctions are not only responsible for cell shape but also for the transduction of mechanical signals between cells and contraction of the tissue. Meyer et al. investigated the contraction role of the vaginal myofibroblast in patients with POP. They compared the contractile forces of the myofibroblasts from young primiparae women who had given birth several years ago prior to POP surgery with older women undergoing POP surgery. According to a myofibroblast-mediated collagen gel contraction assay, vaginal myofibroblasts of young women showed better contraction forces (more rapidly and stronger) than young women with severe uterovaginal prolapse. When they compared the contractile forces of myofibroblasts in young primiparous women with the presence or absence of some degree of uterovaginal prolapse, they found that the genital myofibroblasts of women with uterovaginal prolapse reveal a poor contraction . TherefoMany different biomaterials have been shown to activate macrophages, which in turn contribute to the generation of myofibroblasts by producing TGF-β1 . Even thDegradable materials can provide an advantage in terms of reducing clinical complications in the long term . A graduAnother way to trigger fibroblast proliferation and differentiation to myofibroblasts is by adding growth factors to the vaginal microenvironment. Epidermal growth factor (EGF) and basic fibroblasts growth factor (FGF) , or conn(Myo)fibroblast activity and ECM remodeling are designed to regenerate functional tissue, which is, as explained before, a highly regulated process. When the job of (myo)fibroblasts is complete, they should be eliminated from granulation tissue. The granulation tissue with its dense content of (myo)fibroblasts creates the ECM, and apoptosis should result in decreased proteases, therefore forming a hypocellular scar . HoweverThe changes in mechanical forces and signaling through integrins and TGFβ-1 are also playing a critical role in fibrosis ,100. StiIntroducing a biomaterial to damaged tissue, such as POP, in this case, can trigger the normal healing process and result in mechanically stronger tissue due to optimal connective tissue remodeling. However, the mechanical load of the intra-abdominal forces on the vagina and surrounding tissues, together with the unpaired implant properties and altered fibroblast function, can induce fibrosis. We already mentioned that the fibroblasts in prolapsed tissues are exposed to altered ECM and therefore, they may display abnormal phenotypes, including decreased proliferation, and altered patterns of cytokine release, as well as abnormal MMP and TIMP activity  or apoptOld-generation PP meshes had a very high density (weight per surface), which implies that they were stiff and had incompatible mechanical properties with the vaginal wall. Therefore, they resulted in a disturbed host response, fibrosis, and finally exposure ,112. PP ECM-mimicking scaffolds can also create a more optimized host response as they mimic the tissue architecture which regulates the vaginal microenvironment. Electro-spun implants for example can create an ECM-like topography that can provide larger surface areas, enabling protein adsorption and cellular binding sites. PLCL, with its biocompatibility and elastic modulus matching to vaginal native tissue, has been used in pelvic floor tissue engineering. PLCL blended with fibrinogen resulted in a less fibrotic response by calming down the aggressive foreign body reaction as compared to PP mesh . HoweverReleasing mechanical stress or reducing stiffness can prevent fibrosis and reduce α-SMA expression and myofibroblast contraction ,122. In In this review, we explained the role of fibroblasts and fibroblast–(myo)fibroblast transition in POP, which is a connective tissue disorder. Changes in the pelvic connective tissue can “cause” development of POP and/or at the same time, these changes can occur as a “result” of POP. Risk factors for POP, such as vaginal delivery, aging, weight, coughing, and genetic predisposition, lead to changes in the collagen metabolism by affecting the fibroblast function ,9,34. InHowever, some points should be mentioned before making firm conclusions. Making comparisons between studies and drawing concrete conclusions are challenging due to the variation among patients, limited samples sizes, differences in the biopsy sites, or heterogeneity in methods such as protein quantification and histological examinations. In addition, the process of human tissue procurement, which is cross-sectional by necessity, might interfere with the changes observed in the biopsy, such as increased collagen III. Even after recognition of these limitations, the role of fibroblasts on connective tissue quality and tissue regeneration, and thereby on the development or treatment of POP, is undeniable. Changes in the collagen metabolism and altered ECM remodeling are a result of altered fibroblasts/(myo)fibroblast behavior due to exposure to mainly mechanical loading, and due to estrogen deprivation or genetic mutations ,42. AlteFuture research should focus on regulating (myo)fibroblastic transition and its activity to improve healing. Future studies should be performed under mechanical loading in which fibroblasts from POP and non-POP patients respond differently in terms of collagen metabolism. These studies also provide insight to develop implants with appropriate mechanical properties, in which fibroblasts can contribute tissue regeneration by differentiation into (myo)fibroblasts and by the formation of the appropriate connective tissue. In addition, the activity of (myo)fibroblasts can be regulated by changing the mechanical stress in the environment. Inhibition of the profibrotic cytokines such as TGF-β1 may interfere with the multitude of cells contributing to tissue repair rather than avoiding fibrosis. One potential approach is manipulating (myo)fibroblasts’ mechano-perception via cell-to-matrix and cell-to-cell adhesions to minimize the internal stress, which triggers the apoptosis of (myo)fibroblasts . In conclusion, even though we still have a way to go, current advances in understanding the role of fibroblasts in wound healing, fibrosis, and pathophysiology of POP may lead to the prevention of POP and improved surgical outcomes.


Pediatric abdominal surgery is constantly evolving, alongside the advent of new surgical technologies. A combined use of new tools and traditional surgical approaches can be useful in the management of complex cases, allowing less invasive procedures and sometimes even avoiding multiple interventions. This combination of techniques has implications even from the anesthetic point of view, especially in post-operative pain control. Thereby, tertiary level centres, including highly-specialized professionals and advanced equipment, can maximize the effectiveness of treatments to improve the final outcomes. Our paper aims to present some possible combinations of techniques recently used at our institution to provide a one-session, minimally invasive treatment within different areas of abdominal surgery. Pediatric abdominal surgery is constantly evolving. The introduction of new surgical techniques and new therapeutic approaches is playing a key role in the treatment of complex cases, especially when traditional surgery alone would not be able to provide the finest outcome. The advent of surgical technologies that can be combined with traditional techniques allow us to achieve higher survival rates and a better quality of life.Moreover, a growing interest in national and international multidisciplinary networks combining experts from different specialties is helping to define more complete therapeutic approaches.As a result, an ever-increasing combination of technologies and approaches is resulting in new therapeutic strategies, allowing surgeons to reach the best outcome possible.Despite many techniques being well-known and daily-used in the adult population, they are rarely performed in the pediatric population and require careful patient selection. Examples involve robotic-assisted surgery, brachytherapy, MicroWave ablation and fluorescence image-guided surgery.® Xi system obtained the Food and Drug Administration’s approval in July 2000, and since then has gained popularity within different surgical specialties. In the adult population, it is a daily used technology, especially for urologic and gynecologic interventions, and is increasingly also being used for abdominal surgery. The pediatric population greatly differs in terms of size, physiology and pathology, resulting in obstacles for robotic-assisted surgery. At present, the main limitations refer to the dimensions of trocars and surgical instruments that are not compatible with the size of infants and small children, and the cost-effectiveness of the procedures due to the intrinsic epidemiology of the pediatric diseases [Referring to robotic surgery, the Da Vincidiseases . DespiteOn the other side, brachytherapy and MicroWave ablation are still scarcely used in the pediatric oncologic field, requiring not only a proper patient selection but also sophisticated equipment and the presence of a sub-specialty multidisciplinary team.Finally, there is near-infrared fluorescence, a fairly new technique for a fluorescence image-guided surgery .Considering that the number of pediatric patients requiring such treatments is quite low, it is difficult to standardize them; in this vision, we report some surgical strategies we applied at our center to treat difficult cases in which the combination of different techniques improved the outcome.In the last three decades, the number of pediatric endoscopic procedures has increased alongside the therapeutic options possible with this technique and the development of pediatric-adapted instruments . BesidesOver the last ten years, our center has adopted the mini-invasive technique as the preferred approach for neurologically-impaired children . From 2008 to 2018, a total of 127 patients underwent a gastrostomy fashioning; 91% of them underwent a Gauderer–Ponsky pull-technique percutaneous endoscopic gastrostomy , while tThe mean time for gastrostomy fashioning was 23 min. When combined with Nissen fundoplication, the mean operative time was 180 min. The mean postoperative length of stay was five days, mainly due to progressive implementation of enteral nutrition. Short-term minor complications  were observed in 30% of the patients, while short-term major complications  were detected in 9% of the patients .® Xi System and decided to insert Nissen fundoplication, with or without gastrostomy fashioning, in the procedures list for robotic-assisted surgery training. The decision relapsed on this procedure due to the comparable results with the laparoscopic fundoplication reported in literature [In 2018, we started a robotic surgery program with the Da Vinciterature ,13. FurtThis combined laparo-endoscopic approach comes with different advantages. The robotic system permits better dexterity of movements thanks to its seven degrees of freedom for instruments ; also, tA combined use of robotic surgery and endoscopy leads to advantages even from the point of view of anesthesia. From one side, the mean operative time to perform a PEG is shorter compared to both laparoscopic and open gastrostomy ; on the Additionally, the use of mini-invasive surgical techniques might determine an easier management of post-operative pain . In thisA combined use of endoscopy and traditional abdominal surgery is not generally needed apart from the above-mentioned indication. The main limitation to this combined approach is the need for a highly-trained pediatric endoscopist ,20, a prThe first case was an eight year old boy with short bowel syndrome due to total colonic agangliosis and home parenteral nutrition support. The patient referred a monthly history of increased hematic losses from the distal ileostomy and recurrent anemia. An exploratory laparotomy and ostomy re-do were planned. Intraoperatively, an ileoscopy was performed, which allowed the identification of the ulcerated area. Thereby it was possible to minimize the bowel resection to the affected area and preserve the healthy tissue. Moreover, endoscopy was used to redirect the already on-site JPEG. In line with recent literature reports, endoscopy resulted in an effective diagnostic and therapeutic tool in the treatment of anastomotic ulcers .Another case was an eleven year old girl admitted for a trichobezoar; the mass occupied from the distal third of the esophagus to the proximal third of the duodenum. Endoscopic foreign body removal is widely used and presents a high success rate. However, foreign body dimension, location and impaction time have been described as risk factors predicting conversion to open surgery.  A first Finally, there is the case of a nine month old boy admitted for hematemesis. Thoraco-abdominal x-ray revealed a safety pin in the epi-mesogastric region, without signs of pneumoperitoneum or pneumomediastinum. An esophagogastroduodenoscopy first and, subsequently, an exploratory laparoscopy were performed, but no foreign body was found. Lastly, the triangulation obtained with the use of laparoscopic and endoscopic instruments, under fluoroscopic guide, allowed localization of the safety pin at the splenic flexure . LaparosThese examples highlight how the combination of different techniques might help in solving situations otherwise requiring very invasive procedures.The “rendezvous” procedure  is a oneThis technique foresees a simultaneous laparoscopic cholecystectomy, ERCP and endoscopic Oddi’s sphincterotomy.A peculiarity of this procedure is that it does not require the opening of the common bile duct and a postoperative ERCP.The main benefits involve a shorter length of stay, the requirement of a single anesthesia and a lower rate of post-ERCP pancreatitis; moreover, in the case of endoscopic stone extraction failure, surgical exploration can be carried out during the same intervention .Etiology of post-ERCP pancreatitis, reported with an incidence between 1 and 14% , seems tIn addition to pancreatitis, perioperative complications involve bleeding and perforation; a lower incidence of these complication has been described when compared with the two-step procedure .A further advantage of this combined approach is that the ERCP might prove easier to perform, as the surgeon can help the endoscopist by performing an anterograde cholangiography and eventually place a guidewire through the papilla . This maStudies in the adult population defined the rendezvous as an effective procedure for cholecysto-choledocolitiasis, with a common bile duct clearance of 95–100% .To date, we have performed a laparoendoscopic rendezvous (LERV) in three patients affected by symptomatic cholecysto-choledocolitiasis. In all cases, magnetic resonance cholangiopancreatography highlighted the presence of gallstones in the gallbladder and the biliary tree, associated with a dilated common bile duct. The LERV procedure was indicated and performed as described by La Barba et al. . After sIn our experience, the LERV procedure provides a safe option to treat cholecysto-choledocolitiasis, avoiding multiple interventions and minimizing the length of hospitalization.Robotic surgery in pediatric cases largely varies in terms of indications and anatomical targets. This peculiar feature requires the pediatric surgeons to be familiar with most of the instrumentation available for this surgery. Image enhanced surgery has been advocated as the future route to safe dissection. Unfortunately, this technology is far from the routine application . Other t® Xi, are integrated with the fluorescence imaging [Referring to abdominal surgery, its main applications involve: recognition of vascular and extrahepatic biliary anatomy, assessment of bowel perfusion before anastomosis and identification of lymphatic draining . Moreove imaging .We recently applied this technology as a supplemental tool for a safe dissection in cases of pancreatic benign masses . The NIRF application allowed us to properly define the cystic walls  and was We also benefited from NIRF application in a case of combined splenectomy and cholecystectomy for hereditary spherocytosis. In this case, thanks to indocyanine biliary excretion, we were able to identify both vascular anatomy and the cystic duct. After injecting the dye, we were first able to define the splenic vessels and perform a safe robot-assisted splenectomy; once splenectomy was finalised, we used the dye excretion to better identify the cystic duct and perform a more precise dissection for cholecystectomy.® Xi processor, which allows the visualization of scan images live in the visor during tissue manipulation. The use of real time intraoperative ultrasound has been reported as a useful tool to supply the lack of tactile feedback inherent to laparoscopic or robotic-assisted surgery [A further combination of image-guidance is the application of intraoperative ultrasonography; this is eased by the DaVinci surgery . In adul surgery . Its maiIntraoperative ultrasonography has been applied in our practice for kidney and liver tumors. In a hepatic hamartoma case, we started to isolate the lesion, and by the use of intraoperative ultrasound we were able to better define the edges for an appropriate segmentectomy, preserving hepatic tissue and at the same time performing a radical exeresis of the lesion. Also, in a kidney angiolipoma case we used intraoperative ultrasonography to free the healthy tissue from the disease, maintaining a good renal parenchyma .Nowadays, the surgical approach to locally invasive tumors in children should rely on avoiding mutilating interventions. The combination of different strategies, including neoadjuvant chemotherapy, surgery and radiotherapy, is crucial for the treatment of these diseases, especially genitourinary rhabdomyosarcoma, that present extended local invasiveness at diagnosis .To achieve local control in these cases, radiotherapy is as effective as surgery but might increase the risk of local and systemic adverse events through the irradiation of the perineal region . RecentlFor this reason, the introduction of brachytherapy might change the course of the treatment of genitourinary rhabdomyosarcoma. This new strategy consists of a conservative surgery for the removal of tumor residuals after neoadjuvant chemotherapy and in the placement of trans-perineal tubes during the same surgical intervention. In addition to that, bilateral oophoropexy might be considered in order to preserve ovarian function. The administration of radiotherapy through trans-perineal wires can start after a few days .However, this innovative approach is still presenting several issues regarding patient selection, the different medical figures with multidisciplinary skills required for management, such as oncologists, surgeons, anesthesiologists and radiotherapists, and long-term effects on bladder function . MoreoveDespite the recent introduction, published case-series described a five-year survival rate higher than 90% after this innovative local treatment that combines surgery and brachytherapy . FinallyThree patients recently underwent the combined local treatment for genitourinary rhabdomyosarcoma at our institution. All of them underwent conservative surgery followed by brachytherapy and adjuvant chemotherapy; in all three cases the position of tubes was defined together by the surgeon and the radiotherapy oncologist based on the study of the preoperative imaging and the intraoperative appearance of the residuals. For these reasons, four, five and six tubes were placed in the three patients, respectively, in order to give the best opportunity for volume irradiation. After multidisciplinary discussion, an epidural catheter was intra-operatively placed in two patients to ensure proper pain control and increase the tolerance to the devices; the catheter was left in place for 72 h and a combination of chirocaine and fentanyl was continuously infused. Postoperatively, epidural analgesia was associated with multi-agent intravenous medication, mostly acetaminophen at fixed hours, non-steroidal anti-inflammatory drugs and opioid derivates as a rescue option. In the third patient, postoperative pain was controlled with a continuous infusion of morphine at 0.2–0.3 mg/kg/h; vital sign checks and focused neurological exams were regularly performed. All patients remained hospitalized for a couple of weeks, during which two daily brachytherapy sessions were performed. Each brachytherapy session required a sedation, and thus parenteral nutrition support was provided to ensure correct fasting before each anesthesia. Brachytherapy was followed by adjuvant chemotherapy in all cases. None of them presented significant post-voiding after four weeks and the epicystostomic catheter was removed. Our recent experience underlines how the association of surgery and brachytherapy allows the treatment to be tailored to the patient’s and the tumor’s characteristics.MicroWave Ablation (MWA) is a minimally invasive technique for the treatment of small neoplastic lesions, especially of the liver, kidney, bone and lung.A needle-like device connected to a generator creates an electromagnetic field that delivers heat-energy directly in the target area, causing tissue necrosis .Compared to radiofrequency ablation, MWA requires less time to determine tissue heating while reaching of the target temperature more quickly; a shorter procedure time is particularly important in children as it reduces the anesthesia time and the need for anesthetics administration .Hepatic lesions are the main target of MWA in the pediatric population, and they can be accessed through different approaches: percutaneous, laparoscopic and endoscopic. Few studies comparing the effectiveness of the different approaches are available, preferring the laparoscopic one when treating lesions next to high-risk areas or subcapsular tumors .An ultrasound guidance is needed during the whole procedure, either percutaneous or laparoscopic-assisted.A complete lesion necrosis, corresponding to surgical excision, requires a 5 mm enlarged ablation beyond the lesion’s margins; residual liver volume is one of the main predictive factors for the development of severe hepatic dysfunction after the procedure.Possible complications of this technique involve fever, skin burn, abdominal pain, hepatic dysfunction, pleural effusion and intraperitoneal hemorrhage .We recently used this approach to treat a case of liver recurrence of pancreatoblastoma, unresponsive to thermoablation and chemotherapy. Metastatic lesions were defined through laparoscopy and lesion-targeted ultrasound-guided MWA was performed. Complete ultrasound-guided MWA of the main recurrence and two additional subcapsular lesions was assessed. Laparoscopy allowed the exclusion of any extra-hepatic recurrence. During follow-up, the patient developed further retroperitoneal recurrence of disease, but there was no evidence of liver metastatic recurrence after more than twelve months . LiteratThe development of new therapeutic approaches and the spread of these techniques in the pediatric field has assumed ever greater significance in the last years.At the same time, a multidisciplinary team approach allows a complete therapeutic plan to be set up, especially for complex patients.Combining techniques belonging to the same or to different sub-specialties might help in diminishing the invasiveness of a surgical procedure and, simultaneously, increase the chances of a good outcome, sometimes even avoiding multiple interventions. Advantages of these therapeutic approaches are remarkable, even from the anesthesia point of view. Patients treated with a one-session surgery require a single anesthesia and, because of the mini-invasiveness of the procedure, an easier management of the post-operative pain.The availability of advanced equipment and highly-specialized healthcare professionals in a tertiary level centre enables the implementation of increasingly effective therapeutic processes that spread alongside the evolution of medical care.


Together with socio-cultural components, the family environment and early parent–child interactions play a role in the development of eating disorders. The aim of this study was to explore the nature of early parent–daughter relationships in a sample of 49 female inpatients with an eating disorder. To acquire a detailed image description of the childhood experiences of the patient, we used diagnostic imagery, a schema therapy-derived experiential technique. This procedure allows exploring specific contents within the childhood memory , bypassing rational control, commonly active during direct verbal questioning. Additionally, patients completed self-report measures to assess for eating disorder severity, general psychopathology, and individual and parental schemas pervasiveness. Finally, we explored possible differences in the diagnostic imagery content and self-report measures in two subgroups of patients with anorexia nervosa and bulimia nervosa. The results showed that the most frequently reported unmet needs within the childhood memories of patients were those of safety/protection, care/nurturance, and emotional expression, referred specifically to the maternal figure. Overall, mothers were described as more abandoning, but at the same time particularly enmeshed in the relationship with their daughters. Conversely, patients perceived their fathers as more emotionally inhibited and neglecting. Imagery-based techniques might represent a powerful tool to explore the nature of early life experiences in eating disorders, allowing a more detailed case conceptualization and addressing intervention on early-life vulnerability aspects in disorder treatment. The nature of the association between parenting difficulties and eating disorder psychopathology is unclear, and the findings of the studies are still inconclusive. Literature exploring the connection between eating disorders and early parent–child relations includes studies based on the attachment theory and the parental bonding construct  to explore the content of negative childhood episodes  in a sample of inpatients with eating disorders, through diagnostic imagery exercises; (ii) to investigate whether specific unmet core needs reported in the memory were associated with the individual and parental schemas of patients, as assessed through schema therapy-related self-report measures; and (iii) to explore the differences between anorexia nervosa and bulimia nervosa in individual and parental maladaptive schemas and the content of the childhood memories.Forty-nine patients  with eating disorders participated in the study. All were above 18 years of age and were consecutively admitted to the eating disorder inpatient unit of the Villa Garda Hospital of Northern Italy. The patients were referred from all over Italy by general practitioners or by eating disorder specialists of outpatients. Thirty-three patients were diagnosed with anorexia nervosa , and 16 patients were diagnosed with bulimia nervosa . DSM-5 diagnosis was performed by an expert in eating disorders (RDG) using the Eating Disorder Examination (EDE) interview   was derived by dividing the weight (in kilograms)/height squared (in meters).The Eating Disorders Examination 17.OD .Two certified schema therapists (BB and CN) who did not know the patients collected the diagnostic imagery interviews between May 2018 and September 2020. Imagery interviews took place within the first 5 weeks of hospitalization of individuals. The experiential exercise started with women closing their eyes and imaging themselves in a safe place. Then, they were asked to leave the situation and enter a positive and safe situation (the “safe place imagery” exercise), such as being at a peaceful beach, or any other personal safe place. Later, the therapist asked the patient to wipe the image away and to recall a childhood memory where she had experienced a negative emotion with one or both parents. The therapists, then, asked the patient to describe the selected event in detail, speaking in the present tense and in the first person. Particular attention was paid to experienced emotions and associated bodily sensations. When the emotion was clear and intense enough, the patient was asked to express the needs associated with the childhood situation . In the final phase, the woman was asked to return to the safe place, and when a positive emotional state was re-established, the imagery exercise was concluded. In a final debriefing phase, the therapist and the patient together discussed the content of the childhood memory, to detect whether there could be any link with symptoms of actual eating disorders. Patients were instructed to speak out loudly about their experience within the imagery exercise in order to record the interview for later decoding. Each interview took place in one single session and lasted between 15 and 30 min. A complete description of the imagery exercise , who were blind to the aim of the study, separately classified the imagery exercises of patients, after training and initial supervision (held by BB). Judges classified the content of the episode according to a grid with specific categories  and categorical (contents of the memory) variables. Partial correlations, controlling for BMI and BSI depression subscale score, to assess for the association between self-reported parental and individual schemas, and psychopathology measures were run. Moreover, the chi-square test was used to explore the most frequently reported emotions and unmet core needs within the childhood memory and the caregiver involved in the episode. Finally, partial correlations, controlling for BMI and BSI depression subscale score, between unmet core needs within the memory, and parental and individual schemas were analyzed. As well, linear regression analysis was run to assess the extent to which unmet core needs in the past (IV) were associated with the current self-reported parental (DV) and individual schemas (DV).U-test and chi-square test, respectively. To avoid type I errors, the p-value for comparison tests was set at 0.05/18 = 0.003. Logistic regression was performed to test the extent to which emotions (IV) and unmet core needs (IV) of childhood memory were associated with the belongingness of participants to the specific group of ED .Differences between patients with anorexia nervosa and bulimia nervosa in the self-report measures  and the content of the imagery exercises  were explored through Mann-Whitney Demographical information, severity of the eating disorder, and general psychopathology levels are reported in SD = 3.11, range from 3 to 14) years, whereas the caregivers involved in the memory were the mother , the father , and both parents together , with two (4%) patients reporting significant others to be involved. The most frequently reported emotions within the memory included (participants reported a maximum of three emotions within the episode), in order, sadness equally as often as fear/anxiety , anger , shame equally as often as guilt , surprise , emptiness and humiliation , and self-disgust . The unmet core needs within the episode (in a range of 1–3 needs per episode) included safety and protection ; care, nurturance, and safe attachment ; emotional expression , attention , reassurance , empathy and acceptance , limit setting , and play . Due to the low number of cases in some categories, we will analyze only those classes including more than 10 cases. The negative emotions and unmet needs reported in the memory referred to contents such as physical or emotional abuse , abandonment , and inhibition of the feelings of patient .According to the information collected through the imagery exercises, we analyzed the content of the past memories examining specific categories. The mean age of patients within the childhood episode was approximately 9.3  and negatively correlated with feelings of sadness . Likewise, the need for care, nurturance, and attachment was inversely correlated with the emotions of sadness  and shame , whereas the unmet core need for attention was positively associated with feelings of sadness . When considering the associations between unmet core needs within the early memory and actual schemas, significant correlations were observed between the need for safety and protection, and emotional deprivation  and failure  schemas of patients, and maternal  and paternal  emotional deprivation and paternal emotional inhibit_on  schemas of patients. The need for care,-nurturance, and attachment correlated with paternal pessimism/negativism  and dependency  schemas; whereas the need for emotional expression correlated with paternal  emotional deprivation schema.Partial correlations  between emotions and unmet core needs within the memory, and core needs and parental and individual schemas were analyzed. The lack of safety and protection need was positively associated with emotions of fear and anxiety  = 9.56, p = 0.003, β = 0.41, p < 0.005] and emotional deprivation schema of patients . The need for care, nurturance, and attachment was significantly associated with maternal vulnerability to harm and illness . While entering personal schemas as a dependent variable, this unmet core need within the childhood memory was significantly associated with mistrust/abuse , inadequacy/shame , and failure  schemas. The need for emotional expression was significantly associated with maternal emotional deprivation  and with paternal schemas  of emotional deprivation , punishment , and search for approval and admiration . Finally, the need for attention was significantly associated with paternal schemas  of enmeshment/undeveloped self  and emotional deprivation .Multiple linear regression analyses were run to assess the extent to which unmet core needs (IV) in the past memory were significantly associated with current self-reported parental (DV) and individual schemas (DV). The need for safety and protection was significantly associated with maternal  and not with the diagnosis of anorexia nervosa.No significant differences were observed between the two eating disorder groups of patients when examining childhood age within the memory, caregiver, emotions, and unmet core need reported in the imagery exercises. We ran a logistic regression analysis to detect whether specific core needs within the childhood memory would be associated with the belongingness to the eating disorders diagnosis. The overall logistic regression model . Further, in a later phase of treatment, these early memories could be addressed through Imagery Rescripting technique, allowing such needs to be fulfilled through imagination. Future studies should assess whether specific individual or parental schemas, as considered by the schema therapy approach, could somehow predict treatment outcomes. If this were the case, imagery assessment might become a useful clinical tool to assess eating disorders psychopathology, to develop a case conceptualization, or to inform directions for treatment.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Università Guglielmo Marconi—Roma. The patients/participants provided their written informed consent to participate in this study.BB and FM contributed equally to the conception and design of the study. BB and CN conducted the diagnostic imagery interviews and organized the database. RD conducted all the assessments. BB and SC performed the statistical analysis. BB wrote the first draft of the manuscript. All authors contributed to manuscript revision, read, and approved the submitted version.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.


The efficacy of selenium administration to treat severe sepsis or septic shock remains controversial. We conduct a systematic review and meta-analysis to explore the impact of selenium administration on severe sepsis or septic shock.We search PubMed, EMbase, Web of science, EBSCO, and Cochrane library databases through May 2020 for randomized controlled trials (RCTs) assessing the effect of selenium administration on severe sepsis or septic shock. Meta-analysis is performed using the random-effect model.Five RCTs involving 1482 patients are included in the meta-analysis. Overall, compared with control group in septic patients, selenium administration is not associated with reduced 28-day mortality , but results in substantially decreased all-cause mortality  and length of hospital stay .Selenium administration results in notable decrease in all-cause mortality and length of hospital stay, but shows no substantial influence on the 28-day mortality, length of ICU stay, duration of vasopressor therapy, the incidence of acute renal failure, adverse events, and serious adverse events for septic patients. Sepsis and septic shock remain a major health care problem, and the incidence of severe sepsis has increased by 1.5 % ever yearInflammatory cytokines and oxidative stress released during sepsis are high in septic patients, and their concentrations have some association with severity and evolution of organ dysfunctionsThe use of selenium has not been well established in septic patients. Recently, several studies on the topic have been published, and the results have been conflictingEthical approval and patient consent are not required because this is a systematic review and meta-analysis of previously published studies. The systematic review and meta-analysis are conducted and reported in adherence to PRISMA Two investigators have independently searched the following databases (inception to May 2020): PubMed, EMbase, Web of science, EBSCO, and Cochrane library databases. The electronic search strategy is conducted using the following keywords: s/span>elenite or selenium, and sepsis or septic. We also check the reference lists of the screened full-text studies to identify other potentially eligible trials.The inclusive selection criteria are as follows: (i) population: patients diagnosed with severe sepsis, septic shock; (ii) intervention: selenium administration; (iii) comparison: placebo; (iv) study design: RCT.We have extracted the following information: author, number of patients, age, body mass index, Acute Physiologic and Chronic Health Evaluation II (APACHE II) scores etc. The data have been extracted independently by two investigators, and discrepancies are resolved by consensus. We also contact the corresponding author to obtain the data when necessary. No simplifications and assumptions are made. The primary outcomes are 28-day mortality and all-cause mortality. Secondary outcomes include length of ICU stay, length of hospital stay, duration of vasopressor therapy, the incidence of acute renal failure, dverse events, and serious adverse events.We used the risk of bias tool to assess the quality of individual studies in accordance with the Cochrane Handbook for Systematic Reviews of InterventionsWe estimate the mean difference (MD) with 95% confidence interval (CI) for continuous outcomes  and the RR with 95% CIs for dichotomous outcomes . A random-effects model is used regardless of heterogeneity. Heterogeneity is reported using the I2 statistic, and I2 > 50% indicate significant heterogeneityA detailed flowchart of the search and selection results is shown in The baseline characteristics of the five eligible RCTs in the meta-analysis are summarized in Among the five studies included here, four studies report the 28-day mortalityRisk of bias analysis  showed tThese two outcome data are analyzed with the random-effects model, and the pooled estimate of the four included RCTs suggested that compared to control group in septic patients, selenium administration shows no substantial influence on the 28-day mortality , with low heterogeneity among the studies  .In contrast, selenium administration is found to significantly reduce all-cause mortality  after pooling the results of three included RCTs, with low heterogeneity among the studies  .Low heterogeneity is observed among the included studies for the 28-day mortality and all-cause mortality. Thus, we do not perform sensitivity analysis by omitting one study in each turn to detect the source of heterogeneity.Compared to control group in septic patients, selenium administration has no remarkable impact on length of ICU stay  stay, duration of vasopressor therapy, and the incidence of acute renal failure in septic patients.An overwhelming inflammation occurs in the initial phase of sepsis, during which migration of the neutrophils into the inflamed tissue releases free radicals that result in capillary congestion due to the damage of the endothelium and epithelium tissue, and respiratory failure due to leukocyte and macrophage infiltration into the site of inflammation of the respiratory systemSome multiple-center trials confirm the efficacy of high-dose sodium selenite supplementation in patients with severe sepsis and septic shock to reduce of 28-day mortality Patients are resuscitated with selenium initially, and end up with fewer recurrent pneumonia and sepsis, but they are weaned quicker due to cardioprotective properties of selenium against reperfusion and reoxygenation. Thus, selenium may increase sepsis-related cardiomyopathy and other complications The signaling pathways in inflammation and oxidative stress in vivo are quite complex during the sepsis, and there is always a cross talk between inflammation, oxidative stress and coagulation This meta-analysis has several potential limitations that should be taken into account. Firstly, our analysis is based on only five RCTs and three of them have a relatively small sample size (n<100). Overestimation of the treatment effect is more likely in smaller trials compared with larger samples. Next, the methods and duration of selenium administration are different in included RCTs, and may have an influence on the pooling results. Finally, some unpublished and missing data may lead bias to the pooled effect.Selenium administration may have the important ability to reduce mortality and length of hospital stay in patients with sepsis or septic shock, and selenium should be recommended to be administrated in clinical work with caution.


The glymphatic system is a fluid-transport system that accesses all regions of the brain. It facilitates the exchange of cerebrospinal fluid and interstitial fluid and clears waste from the metabolically active brain. Astrocytic endfeet and their dense expression of the aquaporin-4 water channels promote fluid exchange between the perivascular spaces and the neuropil. Cerebrospinal and interstitial fluids are together transported back to the vascular compartment by meningeal and cervical lymphatic vessels. Multiple lines of work show that neurological diseases in general impair glymphatic fluid transport. Insofar as the glymphatic system plays a pseudo-lymphatic role in the central nervous system, it is poised to play a role in neuroinflammation. In this review, we discuss how the association of the glymphatic system with the meningeal lymphatic vessel calls for a renewal of established concepts on the CNS as an immune-privileged site. We also discuss potential approaches to target the glymphatic system to combat neuroinflammation. The blood–brain barrier (BBB) is a critical component of the central nervous system (CNS) that dampens environmental perturbations in interstitial ionic and chemical concentrations, and thereby supports the stability of synaptic transmission. Long-distance neural networks require a protected environment with limited fluctuations of the concentrations of interstitial ions, neurotransmitters, essential metabolic intermediates, and toxic xenobiotics. The BBB also restricts the entry to the brain of peripheral inflammatory mediators and pathogens that might negatively impact neuronal activity. In the eye, the blood–retina barrier (BRB) similarly protects the environment of the neuroretina. The CNS lacks a parenchymal lymphatic vessel system that supports fluid homeostasis and provides a path for immune surveillance in the peripheral organs. The lack of lymphatic vessels in the retina and brain presented a conceptual challenge in understanding how fluid homeostasis and the export of waste products are obtained within the confines of the CNS . With thThe heterogenic nature and function of astrocytes in neurological diseases has been studied excessively at molecular and cellular levels. Many excellent reviews exist on this topic ,13,14. TOnly a few years after the initial description of the brain glymphatic system, the research groups of Kipnis and Alitalo independently discovered a lymphatic vessel network in the cerebral meninges. The meningeal lymphatic system serves traditional functions such as immune-cell trafficking and clearance of macromolecules from the brain ,16. The We have come to understand that the neuroimmune interface of the glymphatic/lymphatic system allows immune surveillance of the CNS . Yet, thThe first compartment, the glymphatic influx, occurs in the subarachnoid space, where CSF enters by bulk flow into the periarterial spaces surrounding the arteries that penetrate deep into the brain parenchyma [The second compartment, the exchange of CSF and ISF, occurs in the interstitial space of the brain parenchyma. Here, the movement of CSF into the parenchyma is facilitated by the aquaporin-4 (AQP4) water channels abundantly expressed on astrocytic endfeet lining the peri-arterial spaces [In peripheral tissues, leaky capillaries in peripheral tissues allow a constant influx of a plasma ultrafiltrate. Inflowing fluid support distribution and energy metabolites, as well as signaling molecules. Within the tissue, the plasma ultrafiltrate mixes with interstitial fluid (ISF), while excess fluid is transported away by the lymphatic system . Thus, lrenchyma . The secl spaces ,22. Thesl spaces . Aquaporl spaces . In the l spaces ,26,27,28The third compartment, the glymphatic efflux, consists of drainage of interstitial fluid into the perivenous space, from which neurotoxic and metabolic wastes from the ISF either re-enter the CSF or are transported directly out along meningeal and cervical lymphatic vessels, and along cranial and spinal nerves  , meningiThe reactive astrogliosis resulting from an inflammatory insult ,75 likelCSF hypersecretion in response to local injury will likely enhance clearance of antigens  and thereby support a rapid immune response. At the same time, acute inflammation is also linked to an opening of the BBB and subsequent infiltration of immune cells into the CNS parenchyma . Classicdecrease in glymphatic flow [AQP4 knock-out mice demonstrate reduced glymphatic fluid transport, possibly explaining why experimental models of meningitis and multiple sclerosis; i.e., the experimental autoimmune encephalomyelitis model, exhibit less-severe symptoms ,83. It itic flow . Similartic flow ,70,85. Itic flow ,88,89,90In addition to altered AQP4 polarization, infiltrating immune cells are known to accumulate in the perivascular spaces during inflammation, and may then physically block perivascular flow and influx of CSF ,91,92. IPeripheral inflammation refers to any activation of the innate or adaptive immune system outside of the CNS . An initA recent study elucidated how the glymphatic system reacts to a peripheral inflammatory challenge . In thatIn As described in Early studies that led to the conceptualization of the CNS as an “immunologically privileged site” involved implanting a tissue graft without provoking a subsequent immunological response and graft rejection ,134. GraHence, recent and ongoing studies extend and renew the classic definition of CNS immune privilege by introducing the concept of dynamic and close communication between the CNS and periphery, driven by fluid efflux along the glymphatic and meningeal lymphatic vessels, to present antigens at distal sites.Drainage of fluid and antigens from the CNS via the glymphatic system and the meningeal lymphatic vessels prompts a redefinition of the CNS as an immunologically privileged site ,154,155.The meningeal lymphatic vessels carry peripheral immune cells, cytokines, and CNS-derived antigens out of the cranium via, for example, peri-sinus locations to the foramina at the base of the skull ,155,158.The glymphatic and meningeal systems thereby act as a drainage route for CSF and simultaneously contribute to the immune surveillance of the CNS. Considering recent findings for an immune-regulating role of the meningeal lymphatics, the emergence of CSF spaces for immune surveillance of the CNS and their role in peripheral CNS antigen recognition presents a novel perspective . That laWith the discovery of the glymphatic and meningeal lymphatic system, it is now clear that antigens are drained from the CNS in a manner remarkably similar to antigen clearance in the lymphatic system. However, the lymphatic system in the periphery drains solutes and waste nonselectively, such that all antigens can reach the lymph nodes. On the other hand, CNS resident and perivascular immune cells are positioned to phagocytose and degrade proteins excreted by or drained from the brain parenchyma. Thus, there is limited immune trafficking and surveillance, which grants the CNS parenchyma a specialized and partially privileged immune status. At least 400–600 mL of CSF leaves the brain daily ,165,166,Compared to other body fluids , the CSF has a lower abundance of immune cells. Crossing of the BBB by immune cells in the absence of neuroinflammation is restricted to a few activated T cells in rodents ,142. IndAs described in fluid drainage and immune surveillance during physiological and homeostatic conditions is presented on the left side (white). Lymphatic vessels and lymph nodes (green), choroid plexus (purple), and brain fluid transport . During phase I, acute inflammation (light grey), the upregulation of MHC molecules, and an increased production of inflammatory cytokines induces hypersecretion of CSF and activation of glial cells, resulting in an increased shunting of CSF out of CNS via the meningeal and cervical lymphatic vessels. Phase II of acute inflammation, edema formation (dark grey) sharply reduces glymphatic transport due to a combination of factors, including immune cell accumulation in the perivascular spaces and edema. The choroid plexus hypersecretion of CSF results is an increase of shunting of CSF out of CNS. The inserts and the time schema show gliosis with loss of AQP4 polarized expression in the vascular endfeet of astrocytes and a reduction in perivascular CSF influx. Phase III, edema elimination (light grey), is linked to decreased CSF secretion in conjunction with a more polarized expression of AQP4 in the endfeet, supporting edema resolution and a gradual return towards normal conditions, albeit seldom with complete return of homeostasis.The top panel shows changes in CSF production over the time course of inflammation. The insets on the left of the coronal view of the human brain depict the macroscopic changes in fluid dynamics of perivenous spaces and meningeal lymphatic vessels (drainage pathway). The time graph below depicts changes in CSF production, perivenous fluid flow, edema formation, and AQP4 mislocalization over time. The schema in the bottom part of the figure illustrates the change of pro-inflammatory cytokine secretion, accumulation of immune cells, and gliosis over the time course of acute inflammation. The steady-state of The pivotal role of the astrocytic water channel AQP4 for the function of the glymphatic system demonstrates the crucial role of astrocytes, not only on a local scale by interaction with other CNS resident cells, but in in a broader role by maintenance of CNS fluid homeostasis. With the discovery of the glymphatic ,3,4,5 anThere is little doubt that glymphatic fluid transport is suppressed in acute and chronic neuroinflammatory conditions ,70,115. Neuroinflammatory and neurodegenerative diseases impose an enormous and ever-growing economic burden, now causing millions of deaths every year worldwide ,177,178.Conversely, slowing brain drainage might also be used therapeutically in certain circumstances. Impeding solute clearance could potentially slow the removal of therapeutic agents like anti-cancer drugs, immunotherapy, and immune modulators. In this regard, one should be mindful that glymphatic clearance peaks at night, such that the circadian clock should be taken into consideration when administering intrathecally delivered medications . It coulWe do not yet have an adequate understanding of the mechanisms whereby CSF hypersecretion affects the glymphatic system. However, in other conditions, glymphatic flow has been shown to function independently of CSF production , suggest


A tumor microenvironment (TME) is composed of various cell types and extracellular components. It contains tumor cells and is nourished by a network of blood vessels. The TME not only plays a significant role in the occurrence, development, and metastasis of tumors but also has a far-reaching impact on the effect of therapeutics. Continuous interaction between tumor cells and the environment, which is mediated by their environment, may lead to drug resistance. In this review, we focus on the key cellular components of the TME and the potential strategies to improve the effectiveness of drug therapy by changing their related factors. Tumor microenvironment (TME) refers to the cellular environment in which tumor cells and cancer stem cells (CSCs) exist. It can directly promote angiogenesis, invasion, metastasis, and chronic inflammation, and help maintain the stemness of the tumor . DiffereIn the TME, cancer-associated fibroblasts (CAFs) can promote and maintain the stem cell-like properties of liver cancer cells through the IL-6/STAT3/Notch signaling pathway . In contCancer-associated fibroblasts are the most common type of host cells in the TME. It is now generally accepted that CAFs are a heterogeneous population with distinct functions which can serve as positive and negative regulators of tumor progression . Under tMost activated CAFs originate from resident fibroblasts, which can recruit and activate many growth factors and cytokines, such as transforming growth factor β, fibroblast growth factor-2, and platelet-derived growth factor (PDGF). It has been found that these growth factors and cytokines are abundant in TME . CAFs cain vivo growth of the Wnt-deficient pancreatic ductal adenocarcinoma (PDAC) organoid mode. CAFs are also an important source of growth factors and cytokines , which can stimulate the growth of tumor cells in vitro and lead to therapeutic drug resistance . VDR is the main genomic inhibitor that is activated by PSCs. In addition, treatment with the VDR ligand calcipotriol induced matrix remodeling, which can inhibit tumor-related inflammation and fibrosis, and also improves the transport of gemcitabine to the tumor area, thus reversing chemotherapy resistance in the pancreatic ductal adenocarcinoma model . Due to Furthermore, the CXCL12/CXCR4 axis activates multiple signaling pathways to promote tumor cell proliferation, invasion, distant metastasis, and inhibit apoptosis. Therefore, the screening of antagonists targeting the CXCL12/CXCR4 signaling pathway is a promising target for tumor therapy. in vitro  are a heterogeneous population composed of bone marrow progenitor cells and immature bone marrow cells (IMCs) . Under nMyelogenous suppressor cells produce high levels of inhibitory molecules, such as Arg1, reactive oxygen species (ROS), inducible nitric oxide synthase (iNOS), and prostaglandin E2 (PGE2), to directly inhibit the anti-tumor immune response induced by effector T cells . MDSCs cThe key roles played by MDSCs in the TME show that it is necessary to target them effectively by blocking or deleting them. Although they play a key role in tumor progression, there are no FDA-approved drugs or treatments that directly target MDSCs. At present, clinical trials are underway to target the activities of iNOS Arg1 and STAT3, metabolism through CD36, transport through CXCR2, and other mechanisms for different types of cancer . The antin vivo. In patients and animal models, the failure of anti-angiogenic therapy based on inhibition of the VEGF pathway is often concomitant with an increase in the number of MDSCs or TAMs infiltrating tumor tissues , vardenafil and tadalafil and bardoxolone methyl, can directly block the immunosuppressive activity of MDSCs and restore T cell response . Recent  tissues . Along tRecent studies have shown that the accumulation of MDSCs in tumors limits the effect of anti-programmed death 1 (PD1) in the treatment of rhabdomyosarcoma checkpoint blockage. Inhibition of MDSC metastasis with an anti-CXCR2 antibody can enhance the efficacy of anti-PD1 . In a tuMost of the treatments are focused on a certain aspect of the TME. Although some of these therapeutic responses have produced positive results, a more effective way is to promote inflammatory innate immune cells, such as CD8+ T cells, and to alter many aspects of TME through a strong inflammatory response. Breakthrough drug resistance remains a major clinical challenge. The response of tumor cells to treatment depends not only on the regulation of the TME but also on the aberration of its genome. Targeted therapy cannot focus on the complete depletion of all inherent cells in the TME, as this may cause severe complications in the patient. The solution must be a complex combination, with focus on developing multidrug management that targets both tumor cells and TME to overcome resistance and improve prognosis as much as possible.DC, XN, JL, YH, ZC, BC, JL, and JG: wrote the review article prepared and assembled the figure and table. QD, JA, LL, and QW: critically organized and revised the manuscript by incorporating significant reports. All authors contributed to the article and approved the submitted version.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.


Objective: To compare the efficacy of various listed Chinese patent medicines combined with letrozole in the treatment of ovulation disorders using network meta-analysis (NMA). Methods: We conducted a systematic literature search in PubMed, Cochrane Central Register of Controlled Trials, Embase, Chinese Biomedical Literature, China National Knowledge Infrastructure, Wanfang, and VIP Information databases up to June 2020. Randomized controlled trials reporting Chinese patent medicine combined with letrozole for ovulation disorders were included. The Stata 13 and WinBUGS1.43 software were used for data analysis. Results: A total of 24 randomized controlled trials were included, involving 2,318 patients. The results showed that when compared with patients using only letrozole, the ovulation rate was higher in patients using letrozole combined with Kuntai capsules, Fuke Zaizao capsules, Fufang Xuanju capsules, or Dingkun Dan, and Fufan Xuanju capsules showed the greatest improvement; the pregnancy rate was higher in patients using letrozole combined with Kuntai capsules, Fuke Zaizao capsules, or Dingkun Dan; and the endometrial thickness on the day of follicular maturity was greater in patients using letrozole combined with Kuntai capsules, Fuke Zaizao capsules, Fufang Xuanju capsules, Bailing capsules, or Dingkun Dan. In terms of the sequencing of NMA results, Fufang Xuanju capsules combined with letrozole gave the best results in improving the ovulation rate and increasing the endometrial thickness, while Dingkun Dan combined with letrozole achieved the best results for improving the pregnancy rate. Conclusion: Letrozole combined with Chinese patent medicine is more effective than letrozole alone in the treatment of ovulation disorders. Fufang Xuanju capsules is good at improving the ovulation rate and increasing the endometrial thickness. Dingkun Dan is good at improving the pregnancy rate. The appropriate choice of treatment should be made according to the actual clinical situation. This study is registered with the International Prospective Register of Systematic Reviews (CRD42020200603). Ovulation disorders are a common cause of infertility or difficulty in achieving pregnancy in women of childbearing age. In infertile women, approximately 25–30% of patients have ovulatory dysfunction.   The indMany clinical studies have proven that a combination of Chinese patent medicine and letrozole in the treatment of ovulation disorders is more effective than using letrozole alone, and the combination of these drugs can increase the ovulation and pregnancy rates of patients and improve endometrial receptivity. Some of these studies have included meta-analyses of the combined treatment of some Chinese patent medicines and letrozole. However, there are currently few studies that have compared the efficacy of different Chinese patent medicines, making it difficult to evaluate the efficacy of various Chinese patent medicines when combined with letrozole in the treatment of ovulation disorders. Network meta-analysis (NMA) can summarize the existing evidence through direct comparisons, provide useful information through indirect comparisons, and rank the effects of various interventions to provide insights into the advantages and disadvantages of these interventions.Therefore, this study uses the NMA method to systematically evaluate the efficacy of various Chinese patent medicines when combined with letrozole in the treatment of ovulatory disorders to provide evidence for clinical treatment.This research followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses for the Network Meta-Analysis checklist.  The prot1) Participants: patients with ovulatory disorders  requiring fertility treatment2) Intervention: any kind of Chinese patent medicine combined with letrozole3) Comparison: letrozole alone4) Outcomes: change in ovulation rate, pregnancy rate, and endometrial thickness after the treatment5) Study design: randomized clinical trial (RCT)6) Language: English or Chinese studiesWe used the following inclusion criteria:1) studies not including the required outcomes2) repeated publications3) self-control studies and non-RCTs4) preclinical studies, systematic reviews, case reports, and meta-analyses5) protocols, unpublished studies, or duplicate studies6) studies based on a research design with obvious defects or suspected fraudWe excluded studies based on the following criteria:The Chinese Biomedical Literature, China National Knowledge Infrastructure, Wanfang, Weipu, PubMed, Embase, and Cochrane Central Register of Controlled Trials databases were searched to find RCTs on the use of Chinese patent medicine combined with letrozole in the treatment of ovulatory disorders.Search words included Chinese medicine, patent medicine, herbal medicine, letrozole, Kuntai, Dingkun Dan, Fuke Zaizao, Bailing, Xiaoyao, Fuke Yangying, Fufang Xuanju, etc. The publication dates included were from the creation of each database to June 2020 , incomplete outcome data (attrition bias), selective reporting (reporting bias), and other bias, and they were ranked as high, low, or unclear risk. If there were differences of opinion, they were solved through discussion or with the assistance of a third party.The ovulation and pregnancy rates are dichotomous variables, and the odds ratio (OR) was used to indicate the size of the effect. The endometrial thickness on the day of follicular maturity is a continuous variable, and the mean difference (MD) was used to indicate the quantity of the effect, and the 95% confidence interval (95% CI) of the OR and the MD were calculated. The RevMan 5.3 software was used for bias evaluation and direct pairwise meta-analysis. 2, with I2 < 50% and p > 0.1 indicating no statistical heterogeneity. A fixed-effect model was used for meta-analysis. If statistical heterogeneity was found between the studies, subgroup and other methods were used to find the source of the heterogeneity, and if it could not be found, the random-effect model was used for meta-analysis. .  Two chaiA total of 200 related articles were obtained through the initial examination. After screening layer by layer, 24 RCTs  were finThe subjects of this study were patients with ovulation disorders, all of whom were from studies that involved double-arm clinical trials, and a total of six kinds of Chinese patent medicine preparations were finally included from 15 studies of Kuntai capsules, two studies of Fuke Zaizao capsules, two studies of Fufang Xuanju capsules, 1 study of Fuke Yangying capsules, 1 study of Bailing capsules, and three studies of Dingkun Dan. Of these studies, 12 reported the ovulation rate , 15 reported the pregnancy rate , and 21 reported the endometrial thickness on the day of follicular maturity  after treatment. The basic features of the included studies are shown in α < 0.05), but there was no significant difference in patients using Fuke Yangying capsules combined with letrozole (α > 0.05); the pregnancy rate was higher in patients using letrozole combined with Kuntai capsules, Fuke Zaizao capsules, or Dingkun Dan (α < 0.05), but there was no significant difference in patients using Fuke Yangying capsules combined with letrozole (α > 0.05); and the endometrial thickness on the day of follicular maturity was greater in patients using letrozole combined with Kuntai capsules, Fuke Zaizao capsules, Fufang Xuanju capsules, Bailing capsules, or Dingkun Dan (α < 0.05). The results of the pairwise meta-analysis are shown in The results of the pairwise meta-analysis showed that when compared with patients using only letrozole, the ovulation rate was higher in patients using letrozole combined with Kuntai capsules, Fuke Zaizao capsules, Fufang Xuanju capsules, or Dingkun Dan . Based on the three outcome indicators, the intervention effect of the Fufang Xuanju capsules combined with letrozole was the greatest in terms of increasing the ovulation rate and the endometrial thickness on the day of follicular maturity. In terms of increasing the pregnancy rate, the intervention effect of Dingkun Dan combined with letrozole was the greatest see .In this study, except for the Bailing capsule, which is a single plant extract, the other five Chinese patent medicines are all compound preparations. These five types of Chinese patent medicines mainly contain the following traditional Chinese medicines:rehmanniae radix praeparata (shu di) , paeoniae radix alba (bai shao), asini corii colla (e jiao), poria (fu ling), angelicae sinensis radix (dang gui), cyperi rhizoma (xiang fu), atractylodis macrocephalae rhizoma (bai shu), eucommiae cortex (du zhong), chuanxiong rhizoma (chuan xiong), leonuri herba (yi mu cao), and scutellariae radix (huang qin). See Modern pharmacological studies have found that rehmanniae radix praeparata, paeoniae radix alba, and scutellariae radix have anti-inflammatory, antioxidant, and immune-regulating effects. Poria and atractylodis macrocephalae rhizoma can regulate blood glucose and lipid metabolism. Paeoniae radix alba, asini corii colla, cyperi rhizoma, and leonuri herba have estrogen-like effects, which can improve ovarian function and regulate the contraction activity of the uterine smooth muscle. Angelicae sinensis radix has an anticoagulant and antithrombotic function and can improve the microcirculation of the reproductive system. Polyrhachis vicina roger is the main component of the Fufang Xuanju capsule, and studies have found that it can coordinate the endocrine system in the body, regulate the synthesis of hormones, and boost immunity. It can also effectively regulate blood sugar and blood lipid levels in the body. The Bailing capsule contains fermented cordyceps powder, which has the effect of regulating immunity and the glucose metabolism of the body.The composition of Chinese patent medicine is complex, with many drug targets, and the mechanism of the pharmacological action is not completely clear. At present, the main results of the pharmacological research on the six Chinese patent medicines in the treatment of ovulation disorders are as follows:Bailing capsules can effectively improve glucose metabolism and reduce the degree of insulin resistance in patients, which are important mechanisms in improving ovulation disorders. Fufang Xuanju capsules can stimulate the production of endometrial blood vessels by regulating angiogenic factors, which improves uterine blood circulation, thereby improving the nutritional status of the endometrium. By regulating the nitric oxide levels, it can relieve vascular smooth muscle contractions and improve endometrial blood flow to promote the implantation of the embryo. In addition, the compound Xuanju capsule contains selenium, zinc, and other trace elements, which can effectively regulate the hypothalamic–pituitary–ovarian–uterus axis. The Kuntai capsule can improve ovarian function by upregulating the level of superoxide dismutase and regulating the expression of the B-cell lymphoma 2 (Bcl-2) and Bcl-2-associated X proteins through the oxidative stress pathway  and can The Fuke Zaizao capsule can regulate the level of androgens in patients with polycystic ovary syndrome and inhibit the expression of microRNA (miRNA)-383 and miRNA-320 in follicular granulosa cells, which regulates the expression of downstream target genes and hormone synthesis and produces the corresponding biological effect. The Fuke Yangying capsule can effectively improve ovarian blood circulation, promote the development and maturation of dominant follicles, promote ovulation, improve luteal function, and improve endometrial receptivity to increase pregnancy and embryo survival rates. Dingkun Dan has an estrogen-like effect,  can diluOvulation disorders are the main cause of infertility or difficulty achieving pregnancy in women of childbearing age who require fertility treatment, which seriously affects women’s physical and mental health and family harmony. Ovulation induction is the main treatment for ovulation disorders, and letrozole, a third-generation aromatase inhibitor, is currently commonly used to promote ovulation. When compared with clomiphene, a first-line ovulatory drug, letrozole has been shown to reduce the risk of ovarian hyperstimulation syndrome, increase the endometrial thickness, and improve the cervical mucus score. Although letrozole has many advantages over clomiphene for ovulation induction, numerous clinical studies have found that due to the short half-life of the drug, the effect of letrozole decreases continuously as estrogen levels drop in the later stage of follicular development, resulting in the possibility that the dominant follicles may not be released. Various studies have shown that the success rate of letrozole for ovulation induction is about 70–84%, but the pregnancy rate is only 20–27%. According to the pharmacological effects of the abovementioned Chinese patent medicines, the author believes that Chinese patent medicine can achieve complementary effects with letrozole, such as regulating glucose metabolism, alleviating insulin resistance, improving endometrial blood circulation, promoting endometrial growth, improving endometrial receptivity, regulating hormone levels and the reproductive axis, and improving the conception rate, thus improving the efficacy of letrozole in treating ovulation disorders.In traditional Chinese medicine theory, the kidney dominates reproduction: “… kidney dominates Chong and Ren meridian, Chong meridian is the repository of blood, Ren meridian connects with the uterus and pregnancy.” Therefore, there is a close relationship between fertility and both kidney deficiency and the disharmony of the qi and blood of zang-fu. Tonifying the kidney and filling essence and harmonizing the qi and blood are the main methods to treat infertility. Doctors in Western hospitals and general hospitals in China are more inclined to use Chinese patent medicine to treat ovulation disorders when they are combined with ovulation promoting medicines. The Chinese patent medicines in this study, which tonify the kidney and harmonize the qi and blood, are recognized by the majority of front-line doctors in clinical practice.This study evaluated the efficacy of six Chinese patent medicines combined with letrozole in the treatment of ovulation disorders. The results showed that the combination of Fufang Xuanju capsules and letrozole was more effective than the other intervention measures in improving the ovulation rate and endometrial thickness on the day of follicular maturity, and the combination of Dingkun Dan and letrozole was better than other the intervention measures in improving the pregnancy rate.Chinese patent medicines are widely used on the clinical front line, especially by gynecologists and reproductive doctors in general hospitals. In this study, the maximum number of citations for a single Chinese patent medicine pharmacological study was 115 times, and the maximum number of citations for a single article in the literatures included in the NMA was 38 times  The quality of the included research is low. Some of the literature did not clarify the random method, and all of the literature lacked an appropriate blinding method, so the results of this NMA are likely to be biased to some extent. The potential risks associated with this bias may affect the authenticity and reliability of the results and lead to reduced test performance. 2) The sample size of the included literature is small, and the statistical efficacy may be insufficient. 3) The quality of results from the NMA was not graded in this study. Based on the defects of the existing research, the decision makers should consider the influence of the above factors and consider carefully when applying the research conclusions.Therefore, there is a need for relevant studies in the future to further optimize the design scheme of clinical trials. It is expected that future studies can further guide the rational use of drugs in the clinical setting.Through network meta-analysis, we demonstrated that Letrozole combined with Chinese patent medicine was more effective than letrozole alone in the treatment of ovulation disorders. Fufang Xuanju capsules was good at improving the ovulation rate and increasing the endometrial thickness. Dingkun Dan was good at improving the pregnancy rate. These founding can provide an important reference for clinicians in specific medication.