Neurointestinal diseases result from dysregulated interactions between the nervous system and the gastrointestinal (GI) tract, leading to conditions such as Hirschsprung’s disease and irritable bowel syndrome. These disorders affect many people, significantly diminishing their quality of life and overall health. Central to GI motility are the interstitial cells of Cajal (ICC), which play a key role in muscle contractions and neuromuscular transmission. This review highlights the role of ICC in neurointestinal diseases, revealing their association with various GI ailments. Understanding the functions of the ICC could lead to innovative perspectives on the modulation of GI motility and introduce new therapeutic paradigms. These insights have the potential to enhance efforts to combat neurointestinal diseases and may lead to interventions that could alleviate or even reverse these conditions. Neurointestinal diseases comprise a range of medical conditions that result from the interplay and malfunctioning of the nervous system and the GI system . These dThese clinical issues are prevalent, with a high incidence rate, significantly impacting patients’ quality of life, physical well-being, and mental health. The manifestation and severity of the symptoms vary depending on the specific type and extent of the disease. The recent coronavirus disease 2019 (COVID-19) pandemic has exacerbated the severity of GI motility disorders in affected patients. This increase is likely attributed to the mental stressors that impact the GI system through the brain–gut axis, thereby highlighting the complex interplay between various diseases and the indirect mechanisms by which they can affect patients . PresentThe intricate regulation of GI motility involves various components, including the smooth muscle cells responsible for mechanical work; the enteric neurons that establish crucial reflexes as well as control accommodation and the sphincter’s functions; the ICC responsible for generating and propagating the electrical slow-wave activity underlying smooth muscle contractions, and mediating nitrergic and cholinergic neuromuscular neurotransmission; and other regulatory interstitial cells and muscularis macrophages (MMs), a specialized type of immune cell found in the muscular layer of the GI tract ,5.The ENS forms a complex network of neurons embedded within the gut wall, orchestrating GI motility through the meticulous coordination of muscle contractions, secretions, and blood flow. ICC, strategically located along the nerve terminals, serve as crucial intermediaries between the autonomic nervous system and the smooth muscle cells, thereby streamlining the transmission of the signals required for regulating muscle contraction. Enteric neurons, upon releasing neurotransmitters such as acetylcholine, incite the ICC to generate electrical slow-wave oscillations, the precursors to muscle contractions . Nitric Notably, the dysfunction of the ICC has been linked to various GI disorders, such as delayed stomach emptying, functional bowel disorders, and motility-related conditions ,9. FurthAs individuals age, numerous changes occur in the nervous and GI tract, which can have an impact on the normal functioning of the digestive system ,11. Eldeklotho mice, a progeria model) [klotho mice [Kipp271) downregulate the proliferation and self-renewal of ICC-SC by interfering with entry into the cell cycle [klotho mice [Evidence indicates that the ICC reduce with age in the stomachs of humans and experimental animals. A study in humans has shown a decrease of approximately 13% in gastric ICC per decade . Similara model) ,18. The a model) ,18,19. Ttho mice . The decll cycle . Recentlklotho mice, despite a decrease in enteric neurons [Unlike the case of those in the stomach, it is still unclear whether intestinal ICC decrease with age. For example, only a slight decline in ICC has been observed in the lower GI tract of  neurons . Similar neurons . FurtherIn summary, the decline in ICC with age is identified as a primary driver of these dysfunctions, particularly in the stomach, and is linked to changes in cell signaling pathways. While interventions targeting the ERK signaling pathway and the proliferation of ICC-SC, such as IGF1, may be valuable in mitigating age-related GI dysfunctions, the role of the ICC in the intestines remains unclear and warrants further investigation.Gastroparesis is a medical condition that disrupts the normal muscular movement in the stomach, resulting in delayed emptying of its contents into the small intestine . It is aIn 2000, Dr. Ordog was the first to discover that the ICC were damaged in streptozotocin-induced diabetic mice, and the reduction in ICC was associated with delayed gastric emptying in these mice . Followidb/dbLepr) mice, which serve as a mouse model of Type 2 diabetes [The primary cause of the decline in ICC in diabetes was found to be reduced insulin and IGF1 signaling, rather than hyperglycemia ,27. The diabetes . These fdiabetes . A recendiabetes . This inAnother potentially targetable cell type in diabetic gastroparesis is the MMs . The polThe reduction in insulin and IGF1 signaling, leading to a decline in the ICC and subsequent myopathy, has been identified as a key contributor to diabetic gastroparesis, distinct from the effects of hyperglycemia. This suggests that ICC and MMs, which both undergo changes in diabetes that adversely affect gastric motility, represent promising therapeutic targets for diabetic gastroparesis. Further research is needed to fully understand these relationships and develop targeted therapies that address the root causes of gastroparesis, rather than just managing its symptoms.IBS is a neurogastrointestinal disorder characterized by abdominal pain, abnormal bowel activity, and changes in the stools’ composition and evacuation from the rectum . The dis3 receptors) within the tissue of the intestinal mucosa, suggests that the ICC may actually increase under the conditions of IBS. The variations in the levels of 5-HT across different IBS subtypes, specifically an increase in IBS–diarrhea and a decrease in IBS–constipation, suggest a complex and nuanced relationship between 5-HT and the ICC. This intricate connection is further emphasized by the observed augmentation of the activity of ICC in response to 5-HT [The association between IBS and the ICC can be attributed to several factors. These include the presence of 5-hydroxytryptamine  receptors on the ICC, an inverse relationship between the ICC and inflammation, and a potential link between the ICC and the visceral hypersensitivity often observed in IBS . Contrar to 5-HT ,57. The  to 5-HT ,59. This to 5-HT . This fiThe relationship between IBS and ICC may be analogous to the findings in a study on neuronal loss induced by infectious inflammation. It would be intriguing to investigate whether the presence of MMs could similarly reduce the loss of ICC. Colonic inflammation has been demonstrated to activate neuronal signaling complexes, leading to cell death in myenteric neurons ,62. It wICC may actually increase under some IBS conditions due to elevated levels of 5-HT and its receptors, revealing potential connections among disrupted serotonin reuptake, the activity of ICC, and IBS. Further research and experiments evaluating the significance of ICC in experimental IBS subjects are needed to fully understand the underlying mechanisms and develop targeted therapies for IBS.Esophageal achalasia is an motility disorder of the esophagus characterized by a lack of peristalsis and often a failure of the lower esophageal sphincter to relax. This leads to obstruction of the passage of food and difficulty in swallowing both food and liquids. Common symptoms include dysphagia, noncardiac chest pain, and regurgitation with a pathophysiological tendency towards autoimmune responses . The risExisting evidence has demonstrated the significance of ICC in nitrergic neurotransmission within the fundus ,74 and oThere is a consistent pattern of reduced ICC in achalasia. Often, achalasia patients show elevated levels of mast cells and M1 macrophages in the lower esophagus, which aligns significantly with the observed loss of ICC and neuronal loss ,81. GiveDespite the limited role of the ICC in nitrergic neurotransmission in the esophagus, the consistent pattern of reduced ICC in achalasia patients, along with elevated levels of mast cells and M1 macrophages, suggests that the ICC remain an important avenue of investigation in esophageal achalasia. Furthermore, there is evidence suggesting a genetic interplay between achalasia and immune mechanisms, but the exact etiology remains unclear, and thus immunosuppressive treatments should be explored.Hirschsprung’s disease is characterized by the absence of the ENS in the rectum of neonates. The absence can span a segment or encompass the entire colon. The disease has a prevalence of 1 in 5000 live births, with a heightened incidence in Asians . Males aGenetic counseling aimed at detecting these genetic anomalies can potentially assist families in understanding their risk, thereby reducing infant mortality.Infant mortality in Hirschsprung’s disease is often tied to the onset of enterocolitis. The underlying etiology might involve a blend of distal obstruction, immature intestinal barriers, and consequent immune reactions . The linGiven the close interaction of the ICC with the enteric nerves , the preWhile there is currently no approved treatment for Hirschsprung’s disease that directly targets the ICC, experimental approaches, such as stem cell transplantation, gene therapy, and tissue regeneration, take the development and regeneration of the ICC into account, as they are pivotal for the normal functioning of the intestine. Any successful future treatment will likely need to address not only the absence of enteric neurons but also the abnormalities in the network of ICC.PD is a well-known neurodegenerative disorder characterized by the loss of dopaminergic cells in the substantia nigra (SN) pars compacta and pars cranialis, along with the accumulation of Lewy bodies, composed of abnormal aggregates of alpha-synuclein .Risk factors associated with PD include male gender, advanced age, and specific environmental factors such as exposure to certain pesticides and residing in rural areas . In induThe accumulation of alpha-synuclein deposits in the GI tract has been associated with a damaged neural network and impaired gastric motility . The pioA comprehensive examination of the early diagnostic markers, the accumulation of alpha-synuclein, the impacts of neurotoxins on ICC, the distribution and functionality of ICC, conflicting autopsy reports, neurohumoral signaling, therapeutic targets, impacts of medication, and alterations in the microbial composition and dysbiosis is imperative for individuals with PD. Elucidating the mechanistic alterations of the ICC in PD patients is crucial for gaining a deeper understanding of the origins of GI symptoms in this neurodegenerative disease.Multiple sclerosis (MS) is an autoimmune and neurodegenerative disease that causes inflammatory damage within the CNS. MS affects both the white matter’s tracts and the cortical and deep gray matter, causing acute and chronic disruption that result in neurologic symptoms and motor disabilities in patients with MS . A diagnA recent study investigated morphological alterations in the ICC and in mice with experimental autoimmune encephalomyelitis (EAE), an animal model for MS. The expression of anoctamin 1  was decreased in EAE mice. Notably, these findings were consistent with the previous studies that reported a decline in ICC numbers in EAE mice, which was also evident in the bladders of these mice .In summary, there is a need for more comprehensive studies to investigate the unclear association between GI symptoms and the pathology of the ENS in MS patients. Understanding the pathogenesis of MS, including the role of the ICC and ENS, will provide valuable insights into the disease and may lead to the development of new therapeutic strategies.Chronic constipation is a prevalent clinical issue with a high incidence rate, ranking sixth among all major GI indications for ambulatory visits . Slow-trOne significant challenge in managing STC lies in its chronic and complex nature. Treatment responses vary among individuals, and some STC patients may not experience a substantial improvement with the available therapies. In such instances, a multidisciplinary approach involving gastroenterologists, dietitians, and psychologists may be required to provide comprehensive care and optimize the treatment outcomes. Furthermore, further research is needed to gain deeper insights into the underlying causes and develop more effective treatments for STC.The precise etiology of STC remains incompletely understood, but it likely involves factors related to abnormalities in the neural regulation of colonic muscle contractions. Several investigations conducted on individuals with slow-transit constipation have reported a reduced presence of ICC and enteric neurons ,127. HowThere is a pressing need for a more individualized treatment approach for STC patients, comprehensive research to gain deeper insights into the underlying causes of STC, investigations into the exact mechanisms responsible for the decline in ICC and neuronal populations, investigations into the lack of apoptotic damage in the ICC, and the development of more effective treatments for STC. Understanding the pathogenesis of STC, including the role of the ICC, enteric neurons, and inflammatory MM-induced damage, will provide valuable insights into the disease and may lead to the development of new therapeutic strategies.Chronic intestinal pseudo-obstruction (CIPO) is characterized by impaired peristalsis, leading to bowel obstruction in the absence of any discernible mechanical blockade within the intestines. Although uncommon, CIPO frequently presents in children within their first year of life, The lack of effective prokinetic interventions result in a high mortality rate among both pediatric and adult populations, often attributed to subsequent pathophysiologies and autoimmune reactions . These pAnother avenue of investigation has been the connection between CIPO and ICC. Comparative studies between CIPO patients and those with other obstructive bowel disorders revealed an absence of Kit-positive ICC in the former, contrasted with its presence in the latter . HoweverIn summary, there is an urgent requirement for additional research to explore the potential connection between mitochondrial dysfunction and CIPO, to scrutinize the specific role of dysfunction of the ICC in the development of CIPO, to investigate the differences in the development of CIPO across different age groups, and to formulate more potent treatments for CIPO. Decoding the exact etiology of CIPO, encompassing the roles of mitochondrial dysfunction and the ICC, will furnish invaluable insights into the disease and may catalyze the development of novel therapeutic strategies.Inflammatory bowel disease (IBD) is a complex idiopathic disorder characterized by an increasing global prevalence . In the 2-dependent immunosuppression, a molecule previously shown to modulate the functionality of T cells through intricate signaling pathways [Prior research has revealed the therapeutic potential of intraperitoneally administered ICC-SC, which significantly attenuated inflammation in both acute and chronic models of colitis . These bpathways .Furthermore, a recent study by Ferreira-Duarte et al. has shed light on the hypothetical role of ICC in angiotensin II-mediated colonic contractions, specifically in the setting of experimental colitis . AdditioAlthough it is evident that the ICC are vulnerable to damage or depletion across various inflammatory disorders, there is a significant opportunity for further investigations into their mechanistic significance in IBD. Such research could be pivotal in developing innovative, targeted therapies for this increasingly common condition.In this study, we examined the crucial role that the ICC play in the pathophysiology of neurogastrointestinal disorders. Despite substantial advancements in ENS research in recent years, the exploration of the engagement of the ICC in neurogastrointestinal diseases remains nascent, and the comprehension of the underlying mechanisms continues to be constrained.A contemporary investigation disclosed that psychological stress can adversely influence GI function by modulating the activities of the enteric neurons and macrophages . With thThese inquiries bear the potential to shed light on novel therapeutic targets, thereby facilitating the design of interventions that may delay or even reverse the progression of neurogastrointestinal diseases. As we persist in probing these studies, the information gleaned will contribute to a robust foundation for successive breakthroughs in this evolving field .


Complex regional pain syndrome characterized by severe pain and dysfunction seriously affects patients’ quality of life. Exercise therapy is gaining attention because it can effectively relieve pain and improve physical function. Based on the previous studies, this article summarized the effectiveness and underlying mechanisms of exercise interventions for complex regional pain syndrome, and described the gradual multistage exercise program. Exercises suitable for patients with complex regional pain syndrome mainly include graded motor imagery, mirror therapy, progressive stress loading training, and progressive aerobic training. In general, exercise training for patients with complex regional pain syndrome not only alleviates pain but also improves physical function and positive mental status. The underlying mechanisms of exercise interventions for complex regional pain syndrome include the remodeling of abnormal central and peripheral nervous system, the regulation of vasodilation and adrenaline levels, the release of endogenous opioids, and the increased anti-inflammatory cytokines. This article provided a clear explanation and summary of the research on exercise for complex regional pain syndrome. In the future, more high-quality studies with sufficient sample sizes may provide more exercise regimens and better evidence of efficacy. The pat2.For patients with CRPS, starting exercise rehabilitation early provides the best probability of a good outcome and minimizes distress according to the practical guidelines . The guiGraded motor imagery consists of limb laterality recognition, motor imagery, and consecutive mirror therapy, which is designed specifically for patients with longstanding CRPS to shorten the prognostic course of CRPS . Mirror 3.Abnormal remodeling of the central nervous system is common in chronic pain, and CRPS is often secondary to damage of the nervous system, such as stroke . When ne3.1.CRPS pain and punctuate mechanical hyperalgesia can predict the cortical reorganization in the central nervous system . VariousCRPS pain is also related to gray matter hypertrophy in the left amygdala, left posterior hippocampus, and right hypothalamus . The two3.2.CRPS-type 1, known as reflex sympathetic dystrophy, is a sympathetically mediated peripheral pain condition. After the injury occurred, nociceptive fibers in the injured area initiate to express adrenergic receptors. Reduced sympathetic outflow following peripheral nerve injury leads to compensatory up-regulation of local adrenergic receptor sensitivity in the affected limb . This up3.3.Endogenous opioids, such as endorphin and enkephalin, may play a vital role in exercise-induced reduction of CRPS pain . A study3.4.Persistent inflammatory activities in patients with CRPS lead to visible signs, such as edema, severe pain, temperature increase, and hyperalgesia. Pain catastrophizing in patients with CRPS is related to elevated pro-inflammatory cytokine activity in reaction to painful stimuli . Cytokin4.The exercise rehabilitation for patients with CRPS is important and beneficial. As a complementary treatment, exercise including graded motor imagery, progressive stress loading training, and aerobic training can improve patients’ pain and disabilities. This article briefly summarized the effectiveness of different types of exercise on CRPS and indicated the underlying mechanisms of the alleviating effect of exercise on CRPS, including the remodeling of abnormal brain structure and brain function, the reduction in peripheral sensitization, the regulation of vasodilation and adrenaline levels, the release of endogenous opioids, and the increased anti-inflammatory cytokines. Therefore, exercise is a feasible and effective treatment for patients with CRPS to improve pain intensity, physical function, and mental health. In addition, the characteristics of capricious symptom, difficult diagnosis, and refractory of CRPS indicate the need for the matched graded multi-professional care. Some complementary treatments such as medications, transcutaneous electrical nerve stimulation , acupuncX-QW and XS conceived the review. T-SL and RW searched the literature to identify eligible studies and drafted the manuscript and extracted related information. T-SL made the figure and table. All authors contributed to the revision of manuscript, and they have read and approved the final version of the manuscript and the order of presentation of the authors.The study was supported by the Science and Technology Commission of Shanghai Municipality [grant numbers 19080503100 and 21S31902400], the Fok Ying-Tong Education Foundation of China [grant number 161092], the Talent Development Fund of Shanghai Municipal [grant number 2021081], the Shanghai Clinical Research Center for Rehabilitation Medicine [grant number 21MC1930200], and the Shanghai Key Lab of Human Performance (Shanghai University of Sport) [grant number 11DZ2261100], as well as by the Shanghai Frontiers Science Research Base of Exercise and Metabolic Health.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. 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Subretinal injection is performed in vitreoretinal surgery with two main aims, namely, the subretinal delivery of therapeutic agents and subretinal injection of fluid to induce a controlled and localized macular detachment. The growing interest in this technique is mainly related to its suitability to deliver gene therapy in direct contact with target tissues. However, subretinal injection has been also used for the surgical management of submacular hemorrhage through the subretinal delivery of tissue plasminogen activator, and for the repair of full-thickness macular holes, in particular refractory ones. In the light of the increasing importance of this maneuver in vitreoretinal surgery as well as of the lack of a standardized surgical approach, we conducted a comprehensive overview on the current indications for subretinal injection, surgical technique with the available variations, and the potential complications. Subretinal injection is a delicate surgical maneuver whose application in vitreoretinal surgery is progressively increasing. This is mainly due to the suitability of subretinal injection to deliver a controlled amount of therapeutic agent directly to the retinal pigment epithelium (RPE) cells and photoreceptors. Additional advantages include the need for a reduced concentration of drug and the delivery in an immune-privileged and anatomically closed subretinal space ,2. FurthBased on this, subretinal injections are now the established preferred route of administration of gene therapy for the treatment of inherited retinal diseases (IRDs), where RPE cells and photoreceptors are primarily affected . In termDespite the growing role of subretinal injection in ophthalmic surgery, there is no standardized surgical technique, and different variations are described in the currently available literature . With thInherited retinal diseases (IRDs) comprise a small proportion of all retinal diseases. They are a group of diseases with a multitude of phenotypic expressions, wherein the etiology is a genetic abnormality within the cells of the retina or choroid ,10. SincSubretinal injection is the preferred route of administration of gene therapy as it is superior to the other potential routes, which include delivery into the anterior chamber and vitreous cavity ,9,11.Indeed, the subretinal delivery of a therapeutic agent allows the direct delivery to the targeted disease cells with less overflow into other uninvolved sites, low immunogenicity, good biodistribution control, and the overcoming of limitations of other routes of administration, such as the poor penetration of the viral vector through the internal limiting membrane (ILM) in case of intravitreal injection ,12,13.Each patient should be assessed on an individual basis through a comprehensive assessment including clinical appearance and genotyping, in order to evaluate the suitability for the current available gene therapies.The patient may be pretreated with oral corticosteroids to reduce the immune response to viral vectors, which has been described with retinal gene therapy . The steThe standard technique for subretinal injection of gene therapy involves carrying out three-port 23- or 25-gauge (G) vitrectomy (PPV). After inducing the posterior vitreous detachment (if needed) and completing the core and peripheral vitrectomy along with peripheral retina examination, it should be ensured that the injection site is completely clear of any residual vitreous. This maneuver can be facilitated by the use of diluted triamcinolone acetonide injected intravitreally to the site of interest.The site of gene therapy injection should be selected taking care to avoid areas of advanced retinal atrophy, epiretinal membranes (ERMs), blood vessels, and the papillomacular bundle . If needThere are different ways in which the subretinal injection can then be performed, namely, manually or automatically, and with or without formation of a pre-bleb ,17 AutomCreation of a pre-bleb with balanced salt solution (BSS) prior to the subretinal injection of gene therapy vector has the potential benefit of conserving viral vector . Indeed,A 23- or 25-G cannula with a retractable cannula, with size variable from 38- to 41-G, is then attached to the VFIM syringe ,16,20. TThe injection pressure is then set on the machine, more commonly between 12–18 psi ,16. YounA useful adjunct during the process of subretinal injection can be the microscope-integrated optical coherence tomography (MI-OCT). The MI-OCT reticule can be positioned close to the injection site prior to insertion of the cannula. Once the injection begins, if the cannula is correctly placed, the immediate separation and elevation of the retina from RPE is seen. MI-OCT allows monitoring of successful bleb creation with the “fleur de lis” sign, with the central “stem” made by the subretinal cannula and the petals on either side made by the adjacent retina elevated by the subretinal bleb . MI-OCT If the gene vector is injected after the formation of the pre-bleb, the same retinotomy should be used for the vector injection. Three main complications can be associated with the creation of the pre-bleb and the subsequent gene therapy injection. In particular, a second retinotomy can be created accidentally or the first retinotomy can be widened. leading to an increased risk of reflux of the vector. This can potentially not only reduce the drug in the subretinal space where it is needed, but also increase the risk of immune reaction to the viral capsids escaping into the vitreous cavity. Finally, as mentioned above, the higher subretinal volume can increase the risk of retinal overstretching and, potentially, FTMH formation if the fovea is detached.If, no pre-bleb has been created, the vector itself is used to detach the retina and create the bleb . SometimAfter the drug has been delivered into the subretinal space, a vitreous cavity washout is performed to remove any vector that has refluxed into the vitreous cavity ,16,21. ASome limitations of subretinal injections include physiological surgeon tremor, and instrument drift. A potential future development was investigated by Ladha et al., who showed that robotic-assisted subretinal injection helps reduce the aforementioned surgeon-related factors when performing subretinal injections in artificial retina models . SeveralAn alternative to the traditional subretinal injection technique following vitrectomy is being explored currently using an orbital subretinal delivery system (Gyroscope Therapeutics Orbit SDS™). In this technique, a flexible cannula mounted on a delivery system is introduced into the suprachoroidal space through a scleral incision and progressed towards the posterior pole using MI-OCT, before gently introducing the microneedle into the subretinal space . This suSubmacular hemorrhage is a harmful and sight-threatening complication associated with neovascular age-related macular degeneration and polypoidal choroidal vasculopathy, but, less commonly, it can also be associated with ocular trauma, pathological myopia, or rupture of retinal arterial microaneurysm . The accSeveral therapeutic options, and combinations of them, have been proposed for the management of submacular hemorrhage, including antivascular endothelial growth factor (VEGF) agents, photodynamic therapy, pneumatic displacement using expansile gases, intravitreal injection of tPA, and PPV. PPV in this context allows the performance of different maneuvers, such as subretinal injection of tPA, active drainage of subretinal blood, RPE patch grafting, macular translocation, or removal of the choroidal neovascularization ,33.The rationale of the subretinal injection of tPA relies on the thrombolytic activity of this serine protease which binds the fibrin, forming a complex able to activate the plasminogen to plasmin, and, thus, has the ability to lyse the blood clot. By liquefying the blood, tPA can not only facilitate its drainage/displacement but also reduce the risk of iatrogenic damage to photoreceptors during clot removal as well as the need for large retinotomies and the associated risk of retinal detachment, epiretinal membrane (ERM), and proliferative vitreoretinopathy .The use of subretinal tPA was first described by Peyman et al.  and invoIn addition, several surgical variants have been described and multiple aspects of this surgical technique are still not standardized, such as the site of injection, the dose of tPA, the need to drain the subretinal blood, and the use of intraoperative adjuvants.Different sites have been proposed for the injection, including the superior edge of the SMH ,39 and tThe concentration of tPA used is more commonly 12.5 μg/0.1 mL , but canRecently, the first in-human randomized controlled trial compared surgical outcomes  of robot-assisted versus conventional manual subretinal injection of tPA for SMH . This piThe subretinal injection of BSS to induce a macular detachment has been proposed as surgical option for the primary or, more commonly, secondary repair of FTMH . The mecSubretinal injection of BSS for FTMH repair is usually facilitated through standard 23- or 25-G PPV . After PSubretinal injection can be associated with different intraoperative and postoperative complications; however, the exact rates of these complications have not been established due to the paucity of patients treated and of studies analyzing long-term outcomes.Subretinal injection can cause iatrogenic RPE damage/irregularities due to direct mechanical trauma, both from the instrumentation and the flow rate of the therapeutic agent/BSS ,20,21,55Another severe complication that may occur is the formation of FTMH, usually as a result of overstretching of the fovea during the injection ,21,25,55Finally, as the subretinal injection is performed in the context of PPV, additional generic complications can be associated with the whole procedure, such as iatrogenic retinal tears, cataract formation, alterations of intraocular pressure, retinal detachment, endophthalmitis, bleeding, and vision loss .There are a number of potential complications that are specifically associated with subretinal gene therapy injection. One of the main complications specific of subretinal gene therapy is the reflux of viral vector and the potential subsequent intraocular inflammation ,14,15. IRecently, the development of progressive perifoveal chorioretinal atrophy, not related to the site of injection, has been described as a postoperative complication of the subretinal injection of voretigene neparvovec-rzyl; however, no predisposing or intraoperative factors have been so far associated with this complication . AtrophiSubretinal injection is now an established technique for drug delivery into the subretinal space, in particular due to the progressive evolution of gene therapy as well as, more recently, cell therapy. Indeed, ongoing trials are evaluating the therapeutic potential of therapies based on the delivery into the subretinal space of embryonal stem cells (hESCs) and human-induced pluripotent stem cells (hiPSCs) in eyes affected by age-related macular degeneration and Stargardt disease ,62. The


After 30 years of development, laparoscopic inguinal hernia repair (LIHR) has become the main method for treating adult inguinal hernia. LIHR is more standardized, the approach of single-port laparoscopic hernioplasty, the advantages of robotic inguinal hernioplasty, the application of new patches and the selection of surgical methods for different populations have become the focus and difficulty of current research. This article summarized the research progress of LIHR in recent years. Different keywords and phrases including inguinal hernia, LIHR, transabdominal laparoscopic preperitoneal hernia repair, and total extraperitoneal hernia repair were used to search the PubMed, China National Knowledge Infrastructure, and Web of Science databases for related original and review articles that serve the aim of this article well, which was to perform a nonsystematic review of the development, progress, and current status of LIHR. The occurrence and development of inguinal hernia are closely related to congenital factors, such as patent processus vaginalis and dysplasia of the groin, acquired factors, such as anatomical abnormalities caused by advanced age, stunted growth, and malnutrition, and other factors, such as abdominal wall muscle weakness or increased abdominal pressure, which can in turn be caused by multiple factors.,3 The prevalence of inguinal hernia increases with age.,5 According to data from 2017, the cumulative prevalence of inguinal hernia in men aged 25 to 34 years was 5%; 35 to 44 years, 10%; 45 to 54 years, 18%; 55 to 64 years, 24%; 65 to 74 years, 31%; and 75 years and above, 45%. The incidence of inguinal hernia is 8 times higher in men than in women, and 90% of patients undergo inguinal hernia repair. Currently, inguinal hernia in adults can only be cured by surgical treatment methods. Surgical approaches have evolved from different open tissue repair techniques to the use of patches and eventually the widespread use of minimally invasive techniques. Laparoscopic inguinal hernia repair (LIHR) has evolved over the past 30 years and has reached a basic level of maturity in terms of procedure and technique. LIHR has the advantages of minimal invasiveness, favorable aesthetics, mild postoperative pain, and fast recovery. The recurrence rate is not significantly different from that of traditional tension-free repair, and the incidence of postoperative complications is lower than that of traditional tension-free repair. This manuscript summarizes the development, progress and current status of LIHR.Inguinal hernia is a common clinical condition, and it is estimated that more than 20 million inguinal hernia surgeries are performed worldwide each year. In 1991, Fitzgibbons reported the direct use of mesh to cover and repair the hernia ring opening and surrounding tissues via the abdominal cavity. This method, called intraperitoneal onlay mesh (IPOM) repair, yields good early results, but carries the risk of serious postoperative complications, such as intestinal obstruction, intestinal perforation and abdominal erosion; at the same time, the mesh patch is prone to displacement, leading to a high hernia recurrence rate. In 1990, Schultz reported a method consisting of hernial sac tamponade with mesh repair, which still shows a recurrence rate of 25%. However, this method mainly involves cutting the peritoneum and placing the patch directly in front of the peritoneum, which reduces the occurrence of abdominal intestinal adhesion. This method was improved through continuous research with biomechanical and anatomical analysis, leading to increases in the area of the hernia mesh, removal of the hernia mesh filling, and eventually the development of transabdominal laparoscopic preperitoneal (TAPP) hernia repair.,12 McKernan was the first to report a completely extraperitoneal laparoscopic repair method, called total extraperitoneal (TEP) hernia repair.In the context of the rapid development of modern medicine, various surgical modalities for the treatment of inguinal hernia through laparoscopic techniques have arisen. In 1982, Professor Ralph Ger first proposed the theory of LIHR, which became popular in late 1990 and was gradually phased out due to the lack of abdominal wall defect repair and the high rate of postoperative recurrence.,15 To date, all major guidelines and hospitals around the world have clearly noted that IPOM repair is not recommended as a treatment for primary inguinal hernias. The IPOM procedure is now mainly indicated for the treatment of incisional hernias. Among those with inguinal hernias, IPOM repair is limited to those who have experienced recurrence many times, especially those who have undergone patch implantation in the preperitoneal space.–19 The technical aspects of IPOM repair have been improved, resulting in methods such as transabdominal partial preperitoneal repair.–22 The design concept is perfect, but the execution is limited by technical bottlenecks related to materials.IPOM repair is the earliest reported LIHR method. Because the patch is placed over the hernial defect and fixed at that location under laparoscopy without peritoneal separation, the postoperative pain is obvious, the patch may easily shift, and the recurrence rate is high. The operation steps generally include the following: A supraumbilical or subumbilical viewing hole into the abdominal cavity is created to explore the abdominal cavity and inguinal region and determine the type and stage of the hernia. Approximately 4 cm above the hernia ring, the peritoneum is incised in an arc from the medial umbilical ligament to the anterior superior iliac spine, and the medial pubic bladder gap (Retzius gap) and the lateral iliac fossa gap (Bogros’ gap) are incised, allowing lateral exposure to the iliopubic bundle, anterosuperior exposure up to the iliac spine, medial exposure exceeding the pubic symphysis, and inferomedial exposure exceeding the pectineal ligament by 2 cm. The hernial sac, spermatic cord, and vas deferens are identified and mobilized, and the hernial sac is transected or completely dissected. A patch is positioned to cover the entire area of weakness in the anteroinferior abdominal wall and fixed in place. Finally, the peritoneum is closed. The TAPP procedure is performed directly in the abdominal cavity, with a wide surgical field allowing easy identification of anatomical structures , upper abdominal surgery, and surgier with a transverse lower abdominal incision or a paramedian incision, while the TAPP method is preferred in cases requiring a median lower abdominal incision and in patients with a history of bladder surgery.–42 TEP repair is preferred for straight hernias, bilateral hernias, and hernias with a short history.,44 TEP repair is preferred in elderly patients when they are suitable for both TEP and TAPP repair.,46At present, the common views on the selection of TAPP or TEP repair are as follows: TAPP repair is preferred for patients with a long onset history, large hernial sac, incarcerated hernia, recurrent hernia, and history of sclerotherapy injection and for female patients. Single-port LIHR can be performed in 2 ways. One is the placement of a multichannel trocar through a single hole; the other is the placement of multiple functionally independent trocars through the umbilicus. The single-port TAPP procedure is similar to the conventional TAPP procedure. Single-port TEP repair has progressed more rapidly, and many novel ideas have been proposed, including the posterior sheath approach, lateral approach, and Arcuate approach. The posterior approach to the posterior sheath establishes an operating space at the umbilical border and enters the posterior layer of the posterior sheath  methods and the benefit of allowing minimally invasive surgical access in very challenging situations. As with laparoscopic surgery, both robotic total extraperitoneal (rTEP) and robotic transabdominal preperitoneal (rTAPP) repair are feasible; however, because of technical factors, rTAPP repair is performed much more frequently than rTEP repair.,60 Compared with traditional laparoscopic approaches, robotic approaches have similar early clinical outcomes in terms of postoperative pain, quality of life, mobility, cosmesis, wound-related morbidity and complications. However, robotic approaches are more costly and require longer operations.,62 Robotic inguinal hernia repair is currently performed at only a few hospitals, where it is available classification, as well as a multitude of risk factors. It has also been shown that the incidence of postoperative complications increases with age from the age of 80 years. Therefore, age > 65 years does not constitute a risk factor for LIHR. In elderly individuals, TAPP repair carries an increased risk of postoperative and general complications and is associated with a longer operation and hospital stay.The rapid development of medical technology and increased understanding of the anatomy of the inguinal region have promoted the emergence and improvement of various surgical treatments for inguinal hernia. In addition, as minimally invasive methods are becoming more common, TAPP and TEP surgical methods become more standardized, the choice of single-port laparoscopic hernioplasty approach, the advantages of robotic inguinal hernioplasty and the application of new patches will become the focus of future laparoscopic Inguinal hernia research. In addition, for patients of different ages and sexes, the choice of LIHR and anesthesia will become more personalized. Laparoscopic Inguinal hernia repair is becoming more and more mature and perfect, providing a better choice for surgical treatment of Inguinal hernia. Therefore, the development prospect of inguinal hernia surgery is very optimistic. I believe LIHR will have a better future.Writing – original draft: Li shuai xu, Qian Li, Ye Wang, Jiawei Wang, Chengwei Wu, Song Wang, Tingting Cao.Writing – review & editing: Li Xu, Xiaoxu Huang, Yabin Xia.


Respectful maternity care (RMC) - a fundamental human right for all women - prioritizes autonomy and rights of pregnant and birthing women throughout the entire childbirth journey. Despite increasing acknowledgment of the importance of RMC for optimal maternal and new-born outcomes, women often experience disrespectful and abusive practices during pregnancy and childbirth. This Editorial points to the need for development of international guidelines for the implementation of RMC programs globally. Respectful maternity care (RMC) is a fundamental human right for all women. RMC is defined as care that maintains dignity, privacy, and confidentiality of pregnant and birthing women, ensures freedom from harm and mistreatment, and enables informed choice and continuous support during labor and birth , 2. RMC RMC should be a primary goal for all healthcare providers, but women often experience disrespectful and abusive practices during pregnancy and childbirth across global contexts, especially in low and middle-income countries –6. WhileStudies have demonstrated links between disrespectful and abusive care and adverse maternal and infant health outcomes such as postpartum haemorrhage, physical injuries to the mother or new-born, and psychological consequences such as post-traumatic stress, suicidal ideation, and feelings of helplessness , 7–9. ItAccumulated evidence has supported the development of international guidelines for the implementation of respectful maternity care programs , 12. TheDespite increasing acknowledgment of the importance of RMC for optimal maternal and new-born outcomes, there is limited evidence on the uptake of RMC, particularly in low-resource settings. This knowledge gap is driven by the failure of routine health information systems and facility assessments to capture data on RMC practices . HoweverThus, several challenges to the application of RMC remain. One primary challenge is a lack of evidence-based health care provider training and resources on RMC, which leads to poor awareness and knowledge of RMC standards and practices as well as negative attitudes and poor adherence . There iIt is vital to prevent disrespect and abuse in maternity care to ensure the well-being of pregnant and birthing women and their babies. Respecting women’s right to freedom from harm, providing compassionate care, and fostering a supportive environment are essential for positive birth experiences and healthy outcomes , 2. Ther


Aging is a non-modifiable risk factor for stroke and the global burden of stroke is continuing to increase due to the aging society. Muscle dysfunction, common sequela of stroke, has long been of research interests. Therefore, how to accurately assess muscle function is particularly important. Electrical impedance myography (EIM) has proven to be feasible to assess muscle impairment in patients with stroke in terms of micro structures, such as muscle membrane integrity, extracellular and intracellular fluids. However, EIM alone is not sufficient to assess muscle function comprehensively given the complex contributors to paretic muscle after an insult. This article discusses the potential to combine EIM and other common quantitative methods as ways to improve the assessment of muscle function in stroke survivors. Clinically, these combined assessments provide not only a distinct advantage for greater accuracy of muscle assessment through cross-validation, but also the physiological explanation on muscle dysfunction at the micro level. Different combinations of assessments are discussed with insights for different purposes. The assessments of morphological, mechanical and contractile properties combined with EIM are focused since changes in muscle structures, tone and strength directly reflect the muscle function of stroke survivors. With advances in computational technology, finite element model and machine learning model that incorporate multi-modal evaluation parameters to enable the establishment of predictive or diagnostic model will be the next step forward to assess muscle function for individual with stroke. Population aging is an urgent global issue, accompanied with a substantial burden for age-related diseases. It was reported that about 1,000 among every hundred thousand people aged 70 years or older suffer stroke in the world . As one Electrical impedance myography (EIM), a non-invasive evaluation instrument, aims at quantifying the intrinsic passive electrical properties of muscle . AlteratGiven that the factors leading to muscle dysfunction are uncertain and the sensitivity of techniques varies at different pathological features of muscle, there is a need for combined assessments of muscle function in clinical settings. Apart from muscle properties itself, its dysfunction tends to initially derive from the denervation of muscle after stroke  and follOver the past decades, quantitative assessment of muscle function gained popularity due to their precision and objectivity. These assessment methods evaluate various aspects influencing muscle function, including morphological, mechanical and contractile properties. Here, we discuss the potential utility for combined assessments of EIM with other quantitative techniques and provide the insights and challenges for evaluating muscle function in patients with stroke . The maiThe loss of muscle function is typically accompanied with changes of muscle morphology after stroke . Common Faced with above limitations, increasing number of researchers turned their sights on EIM to search for alternative verifiable biomarkers of muscle status. There is evidence that the application of EIM can estimate well for the muscle cross-sectional area , myofibeIn addition to accuracy, combined assessments could improve the understanding of mechanisms of muscle dysfunction. Parameters from EIM, including resistance, reactance and phase angle, are reported to be closely associated with muscle’s components, extra- and intra-cellular fluids, tissue interfaces and the integrity of cell membrane . EIM datThe combination with other assessment methods would advance the application of EIM. As the electrical impedance data is susceptible to subcutaneous fat tissue, our team investigate the effect of subcutaneous fat on EIM with ultrasound assistance and found appropriate electrode configuration to reduce the impact . Sung etDystonia is a common muscle dysfunction for stroke patients, characterized by reduced or increased muscle tension . These dMyotonometry was proposed as a way to quantify individual muscle mechanical properties including stiffness, elasticity, and muscle tone . The priSpastic hypertonia stems from the neural and non-neural factors is frequently observed in stroke survivors . ConventMotor function deficits, those caused by muscle weakness, can only be observed during voluntary muscle contraction. Thus, understanding of muscle contractile property  is of great interest . Active Actually, the generation of force is inseparable from active muscle contraction, depending on the number and size of active motor units, as well as the rate and timing of their discharge . In the Standards for EIM parameters in clinical applications are still lacking, especially when the comparison of data across individuals is considered. As this technique is sensitive to muscle morphological, electrical properties and the electrode configuration , it is tAs the data of muscle assessment becomes increasingly diverse, how to identify and integrate valuable information are attracting more and more attention. Multimodal learning has grown rapidly with the continuous progress of multimodal information input and algorithm . DrawingOverall, the application of combined assessments based on EIM with quantitative techniques is a promising direction to assess muscle function in stroke patients. In view of different purposes, distinct combinations are selected to evaluate specific aspect of muscle function. Combining different techniques could improve the accuracy and comprehensiveness of muscle assessment, and also advance the understanding of physiological mechanism that underpins muscle dysfunction.Despite the potential of combined assessments in clinical application, several challenges remain at both the mechanistic and clinical levels.At the mechanistic level, there were lacks of robustness in identifying the relationship between EIM and standard parameters of other assessments, thereby hindering the application of EIM in clinical settings. Establishing this relationship requires a deeper understanding of the biophysical mechanisms of EIM, which requires further investigation. Secondly, most studies cannot provide a causal interpretation, and the sequence of alterations in variables remains unclear. To address this issue, more longitudinal studies with longer period of follow-ups are required. Thirdly, research efforts in the field of muscle function assessment have been uneven, with the combination of EIM and mechanical property assessment receiving less attention and requiring further exploration see . FurtherLL and ZG: conceptualization. ZG, WL, RW, and LL: methodology. ZG and WL: writing – original draft preparation. WL, RW, and LL: writing – review and editing. All authors contributed to the article and approved the submitted version.


To further improve the operational performance of a phononic crystal air-coupled ultrasonic transducer while reducing the number of simulations, an intelligent optimization design strategy is proposed by combining finite element simulation analysis and artificial intelligence (AI) methods. In the proposed strategy, the structural design parameters of 1–3 piezoelectric composites and acoustic impedance gradient matching layer are sampled using the optimal Latin hypercube sampling (OLHS) method. Moreover, the COMSOL software is utilized to calculate the performance parameters of the transducer. Based on the simulation data, a radial basis function neural network (RBFNN) model is trained to establish the relationship between the design parameters and the performance parameters. The accuracy of the approximation model is verified through linear regression plots and statistical methods. Finally, the NSGA-II algorithm is used to determine the design parameters of the transducer. After optimization, the band gap widths of the piezoelectric composites and acoustic impedance gradient matching layer are increased by 16 kHz and 13.5 kHz, respectively. Additionally, the −6 dB bandwidth of the transducer is expanded by 11.5%. The simulation results and experimental results are consistent with the design objectives, which confirms the effectiveness of the design strategy. This work provides a feasible strategy for the design of high-performance air-coupled ultrasonic transducers, which is of great significance for the development of non-destructive testing technology. Due to its high precision, high resolution, safety, and non-destructive, air-coupled ultrasonic detection technology has been widely used in industrial inspections ,2,3,4. TIn recent years, efforts have been made to enhance the performance of ultrasonic transducers in two aspects. On one hand, researchers have focused on suppressing lateral vibrations by employing various methods, such as adding decoupling materials to polymers ,6,8, usiArtificial intelligence (AI) has been widely used to solve complex engineering modeling and optimization problems due to its unique advantages ,20,21. RIn this paper, an optimization design strategy for a phononic crystal air-coupled ultrasonic transducer is proposed based on AI methods, which further improves the working performance of a phononic crystal air-coupled transducer while reducing the number of simulations. Firstly, the optimal Latin hypercube sampling (OLHS) method is used to sample the design parameters of the 1–3 piezoelectric composites, including the thickness and radius of the piezoelectric columns, as well as the thickness and period of the acoustic impedance gradient matching layer. Then, the COMSOL software is employed to calculate performance parameters such as the upper and lower limits of the bandgaps in the piezoelectric composite, the upper and lower limits of the bandgaps in the acoustic impedance gradient matching layer, the operating frequency and the −6 dB operational bandwidth of the ultrasonic transducer. Based on the simulation data, a RBFNN model is trained to describe the relationship between the design parameters and performance parameters. The accuracy of the approximate model is validated through error analysis using linear regression plots and statistical methods. Subsequently, the NSGA-II optimization algorithm is utilized to obtain the optimal design parameters. Finally, the optimized transducer is subjected to simulation and experimental validation, confirming the effectiveness of the proposed optimization design strategy.The hexagonal lattice arrangement of piezoelectric columns can better suppress lateral vibrations in 1–3 piezoelectric composites, resulting in improved performance . Therefoε represents the thickness of the acoustic impedance gradient matching layer, and the acoustic impedance of the matching layer changes with the variation of the parameter t (0 ≤ t ≤ ε) in the thickness direction, and In order to effectively suppress lateral vibrations of the transducer while achieving good acoustic impedance matching, Ji et al.  designedBased on simulation data, an optimization design strategy for the piezoelectric layer and acoustic impedance gradient matching layer of phononic crystal air-coupled ultrasonic transducer is proposed. The design parameters of the transducer include the thickness of the 1–3 piezoelectric composites, the radius of the piezoelectric column, the thickness, and the period of the acoustic impedance gradient matching layer. The performance parameters include the upper and lower limits of the bandgap of the 1–3 piezoelectric composites, the upper and lower limits of the bandgap of the acoustic impedance gradient matching layer, the operating frequency, and −6 dB bandwidth of the ultrasonic transducer. In the optimization design strategy, the OLHS method is first used to sample the data. Then, RBFNN is employed to model the nonlinear relationship between the design parameters and performance parameters. Error analysis is conducted to validate the reliability of the obtained approximation model. Finally, the NSGA-II genetic algorithm is utilized to determine the optimal design parameters.Structural optimization of phononic crystal air-coupled ultrasound transducer is achieved through numerical optimization methods. To begin with, it is necessary to establish the functional relationship between the output responses and the structural parameters. However, in phononic crystal theory, particularly in solid/solid phononic crystal, elastic waves undergo complex reflection, transmission, and scattering phenomena at the interfaces of different materials. These various effects are coupled together, making the mechanism of bandgap formation more intricate. Currently, there is no precise theory available to accurately describe the relationship between structural parameters and bandgap frequencies. Furthermore, the highly complex nonlinear mapping relationship between the structural parameters and performance parameters of the transducer cannot be obtained through theoretical calculations alone. Therefore, in the structural optimization design, we employ an approximate model to establish the relationship between the input sample data and the output responses.1, X2, X3, and X4 in the experimental design. The initial values and ranges of these parameters are shown in up1), the lower limits of the bandgap of 1–3 piezoelectric composites (BGdown1), the upper of the bandgap of the acoustic impedance gradient matching layer (BGup2), the lower limits of the bandgap of the acoustic impedance gradient matching layer (BGdown2), the center frequency of the transducer (CF) and the −6 dB bandwidth of the transducer (BW), are considered as the output responses of RBFNN model.In this paper, the RBFNN model is chosen as the approximate model in the optimization of phononic crystal air-coupled ultrasonic transducer. The RBFNN typically consists of an input layer, a hidden layer, and an output layer, as shown in The OLHS method ,33 is emThe interpolation function of the radial basis function can be expressed as follows:lgorithm ,35.X represents the n-dimensional input variables, i-th basis function, i-th basis function, dmax is the maximum distance between selected center points, and M is the number of nodes in the hidden layer.It has been demonstrated that a linear combination of Gaussians can approximate any continuous functions with arbitrarily high accuracy. Moreover, neurons with the Gaussian RBF present a very selective response with high activation for patterns close to the radial unit center and tiny activation for the distant pattern. This property reduces the calculated amount and improves the learning rate of the neural network. Therefore, we choose the Gaussian function as the basic function:W represents the optimal weight matrix between the hidden layer and the output layer of the RBFNN, which is trained by the Gradient descent algorithm [According to Equations (2) and (3), the approximate model expression of the neural network can be obtained as follows:lgorithm ,35.To assess the accuracy of the approximate model, a linear regression plot is used to compare the predicted values from the RBFNN with the corresponding finite element simulation values. Cross-validation is performed with 50 sample points, and the results are shown in NRMSE), normalized maximum absolute error (NMAE), and reliability indicators –(8) are shown in Based on the linear regression plots and the related accuracy evaluation metrics, it can be concluded that the approximate model obtained using RBFNN can accurately predict the nonlinear relationship between the performance parameters and structural parameters of the phononic crystal air-coupled ultrasonic transducer. Therefore, this model can be used as a substitute for COMSOL simulation results in subsequent optimization designs.Due to the large number of optimization variables and objectives, the optimization design problem of the phononic crystal air-coupled ultrasonic transducer can be formulated as a constrained multi-objective optimization problem. The NSGA algorithm exhibits strong search capability for optimal solutions in multi-objective optimization problems and demonstrates good robustness. NSGA-II algorithm, an improved version of NSGA, introduces a crowding distance comparison operator and incorporates an elitist strategy, which expands the sampling space and reduces the computational complexity of non-dominated sorting. As a result, NSGA-II has replaced NSGA as the mainstream algorithm for multi-objective optimization. NSGA-II algorithm is based on the Pareto solution set for solving multi-objective optimization problems, and its main process is illustrated in desCF represents the desired center frequency of the transducer, CFmax represents the maximum calculated center frequency of the transducer, and CFmin represents the minimum calculated center frequency of the transducer.In this paper, the objective of the optimization design is to obtain a phononic crystal air-coupled wideband transducer with a center frequency; Based on the obtained optimization model, iterative calculations are performed using the NSGA-II algorithm. The parameter settings for the algorithm are shown in Based on the optimized design parameters, the impedance-phase curve of the transducer  is simulBW), which can be defined using the following equations:From the time and frequency domain analysis of the echo signal, it can be calculated that the BW of the optimized transducer is about 107.8%, which represents an improvement of 11.5% compared to the pre-optimized. Therefore, the proposed optimization design strategy for the phononic crystal air-coupled ultrasound transducer is effective and feasible.To further verify the effectiveness of the optimization design strategy, a transducer sample  is fabriFirst, the fabricated transducer was subjected to impedance testing using the HIOKI-IM3570 Precision Impedance Analyzer to determine its resonant frequency. Due to variations in the driving frequency of the transducers, there are corresponding differences in the internal currents generated. When the driving frequency matches the mechanical resonant frequency of the transducer, the internal current reaches a peak. Therefore, the actual resonant frequency of the transducer can be obtained through impedance measurements. During the test, the impedance analyzer was used to sweep the connected transducer samples, resulting in impedance-phase curves for each corresponding frequency. The test results are shown in pp. The test result (After determining the resonant frequency of the transducer sample, pulse-echo analysis was performed to test its operational performance. A pulse-echo test platform  was asset result  shows thThe obtained results from intelligent optimization, finite element simulation, and experimental testing demonstrate consistency. However, it is observed that the measured resonant frequency of the transducer is slightly lower compared to the simulated value. The main reason for the discrepancy is that during the experiment, impedance testing was conducted on the transducer, while in the simulation, only the impedance analysis of the piezoelectric composite material was conducted, neglecting the effects of the backing layer and matching layer. The backing layer primarily serves to absorb acoustic waves emitted by the piezoelectric composite material toward the backside, thereby reducing reflection. However, in the experiment, it is not possible to completely absorb the acoustic waves, which may lead to a slight deviation in the resonant frequency. The backing layer and excessive epoxy resin in bonding the parts increase the mass and stiffness of the transducer, which can also lead to a lower resonant frequency. Furthermore, the thickness of the fabricated piezoelectric material might be larger than the designed thickness due to limitations in processing precision, which could also contribute to this phenomenon. Despite the variation, the experimentally measured resonant frequency still falls within the bandgap frequency range of the piezoelectric composite material and the acoustic impedance gradient-matched layer. The suppression effect on transverse vibration is not significantly weakened. Therefore, the impact of this deviation on the overall performance of the air-coupled ultrasonic transducer is minimal.The consistency between the finite element simulation and experimental results confirms the improved performance of the optimized transducer, validating the effectiveness of the proposed optimization design strategy for phononic crystal air-coupled ultrasound transducer based on RBFNN and NSGA-II algorithm. However, during the optimization process, we only consider the influence of four factors: the thickness and piezoelectric column radius of 1–3 piezoelectric composite, as well as the thickness and period of the acoustic impedance gradient matched layer, while neglecting the impact of other factors. For example, the backing layer, which primarily serves for sound absorption and damping, prevents acoustic waves from reflecting back to the piezoelectric composite material. The material, structure, and thickness of the backing layer determine the effectiveness of backward sound wave suppression, further affecting the bandwidth of the ultrasonic transducer. Additionally, the relative position of the resonant frequency of the transducer within the bandgap of the piezoelectric composite material and the acoustic impedance gradient matched layer was found to influence the suppression effect of transverse vibration. Moreover, when the filling ratio of the piezoelectric composite is fixed, changes in the lattice constant can alter the bandgap width and position, consequently affecting the suppression effect of transverse vibration. Therefore, the lattice constant of the piezoelectric composite is another potential influencing factor. Certainly, considering more influencing factors will bring forth new potential challenges. Firstly, it increases the complexity of the optimization problem, and the complexity and workload of training the RBFNN model and implementing the NSGA-II algorithm will significantly escalate. Additionally, during the optimization process, certain trade-offs or compromises may be required. For instance, in pursuit of placing the resonant frequency in the middle of the bandgap, it might be necessary to sacrifice a portion of the bandgap width.In this study, based on the RBFNN model and NSGA-II algorithm, an optimization design strategy for the piezoelectric layer and impedance gradient matching layer of phononic crystal air-coupled ultrasound transducer is proposed to further improve its performance. Firstly, by combining the OLHS method with simulation data obtained from COMSOL software, a RBFNN model is trained to describe the nonlinear relationship between the design parameters and performance parameters of the transducer. The accuracy of the approximate model is verified through error analysis using linear regression plots and statistical methods. Then, the optimal design parameters of the transducer are determined based on the RBFNN model and NSGA-II algorithm. Furthermore, the effectiveness of the proposed optimization design strategy is verified through simulations and experiments. After optimization, the resonant frequency of the transducer falls within the bandgap range of both the piezoelectric composite material and the acoustic impedance gradient matching layer. Additionally, the bandgap width of the piezoelectric composite material and the acoustic impedance gradient matching layer is increased by 16 kHz and 13.5 kHz, respectively, and the −6 dB bandwidth of the transducer is improved by 11.5%. The optimized phononic crystal air-coupled ultrasound transducer holds great potential for applications in non-destructive testing.


The use of lingual spurs has been described as one efficient option, withgreat stability of results, but with scarce information of toleration foruse in the mixed and permanent dentition phases. The purpose of this study was to assess the impact of lingual spurs on theoral health-related quality of life of children and/or adolescents duringanterior open bite treatment. The review was recorded in the PROSPERO database. Eight electronic databasesand partial gray literature were searched, without restrictions until march2022. A manual search was also performed in the references of the includedarticles. Studies assessing the impact of lingual spurs on the oralhealth-related quality of life were included. Risk of bias was assessedusing JBI or ROBINS-I tool, according to the study design. The level ofevidence was assessed through GRADE. Five studies met the eligibility criteria. Two non-randomized clinical trialshad a serious risk of bias. Of the case-series studies, two had a low riskof bias and the other, a moderate risk of bias. The certainty of theevidence was classified as very low for all the evaluated results. Ingeneral, the studies reported an initial negative impact with the use oflingual spurs, however this was transitory in nature. A quantitativeanalysis was not performed due to the great heterogeneity between thestudies. Current evidence, although limited, suggests that lingual spurs have aninitial transient negative impact during interceptive treatment. Additionalwell-conducted randomized clinical trials are needed. Grey literature was consulted throughOpenGrey and Google Scholar. A hand search was conducted by reading thereferences of the included articles, for eventual additional relevant studies.No restriction on language or date of publication was applied. The search wascontinued until March 15th, 2022.The databases were independently searched by two reviews (LBM and SMMR).Disagreements were settled by discussion and consensus and, when necessary, athird author’s opinion (SCCJ) was consulted. The search strategy was developedthrough a combination of Mesh, entry terms and keywords related to the PICOstrategy using Boolean operators (Appendix 1).After the searches, the results were imported to a reference manager software. Duplicate studieswere excluded by automatic and manual assessment. The selection process wasperformed in two phases. In the first phase, the title and abstract that did notfollow the established eligibility criteria were excluded. In the second phase,the articles remaining from phase I were assessed by reading the full-text. Inaddition, the reference list of the selected studies were also evaluated toretrieve new articles that followed the eligibility criteria.Data collected from each article included: authors, year of publication, country,study design, participants, age, follow-up, statistical analysis, methods ofevaluation and results . For the case-series, the risk of bias was performed following the Joanna BriggsInstitute (JBI) Critical Appraisal Checklist tool.The ROBINS-I tool Risk of Bias in Non-Randomized Studies of Interventions)The included articles were given a narrative score related to the outcomeassessed in this review  according to the GRADE tool .The results are provided in a narrative synthesis of the included studies thatcomprised study type, sample size, age of population, intervention group,comparison group and outcome.-The electronic search revealed a total of 1,007 citations: 195 from PubMed, 198from SCOPUS, 47 from Web of Science, 4 from Cochrane, 132 from LILACS, 422 fromGoogle Scholar, 6 from Clinical Trials, and 3 from OpenGrey. After removingduplicates, 685 studies remained. One study was added for screening after a handsearch, resulting in 686 articles for review. After reading the titles andabstracts, 20 articles were evaluated in full, and 15 were excluded. The reasonsfor exclusion are show in -,---The characteristics of the included studies are described in -,,,The methods used to evaluate the impact of lingual spurs on the oralhealth-related quality of life of children and/or adolescents during anterioropen bite treatment were questionnaires,In relation to lingual spur types, two studies bonded lingual spurs to thepalatal and lingual surfaces of the maxillary and mandibular incisors,,The use of lingual spurs in early treatment for anterior open bite has someinitial negative impacts on the oral health-related quality of life, the averageopen bite treatment duration was between 3 to 12 months. In the studies, therewas the application of the questionnaire duringThere was a questionnaire application during treatment with 4 objective questionsfor speech, feeding, tongue pain and discomfort, and use of spurs. The spurswere well-tolerated after 7 days during the functions of chewing andfeeding.,,Oral symptoms reported were pain in teeth, bad breath, mouth sores and foodcaught between teeth,-Speech and chewing problems were the most common functional complicationsdeveloped during lingual spur therapy;One study concluded that treatment with spurs does not seem to be related to thedevelopment of other parafunctional habits, such as nail biting, bodyscratching, nibbling hair or clothes and snapping fingers. Nevertheless,patients became more restless, bored and they cried more easily.A meta-analysis was not considered in this systematic review due to themethodological heterogeneity. The included studies used different design ofappliances and methods to evaluate oral health-related quality of life.,Regarding the case-series studies, two resulted in a low risk of bias In addition, there is heterogeneity between the studied groups, which cangenerate greater variability.,Regarding the non-randomized clinical studies,Blinding was not considered a determining factor for the analysis of risk of biasin relation to the research topic. The adaptation and assessment of lingualspurs requires visual clinical monitoring, which does not allow the blinding ofparticipants and operators. The risk of bias assessments for all includedstudies are shown in --,,The level of certainty of outcomes evaluated in this systematic review wereclassified as “very low”-,-,,Among the five studies included in this review, all described that the physicaland psychological negative reactions found during the lingual spur treatmentwere of a transitory nature. There was a tendency for these reactions todecrease throughout treatment and were tolerated by patients, with a range of7,The impact of lingual spurs on children’s oral health-related quality of life mayhave been influenced by some factors, such as different perceptions betweengenders. One study observed that this sensation was more tolerated bygirls.-,Oral speech and chewing functions, previously impaired by the presence of an openbite, were evaluated in the five studies.The effects on chewing due to the use of spurs were also transitory, according tothe authors. However, the adaptation period was slightly longer, about 30days,Other negative impacts that were reported were that children became more upset,irritated and cried more easily, ranging from 1 to 30 days, ceasing in 1 to 3weeks.,About the impact of patient losses during follow-up on the result, it is knownthat it is important to consider all individuals included in the sample and notjust those who completed the entire follow-up period. However, studies suggestthat the impact of the loss depends on the number of individuals who abandon orare excluded.Regarding the positive impacts, studies suggest the advantage of spurs, as it isa fixed device, which does not depend on the patient’s collaboration, it isquick to install, can be used in both the upper and lower arches at a lowcost.Understanding the importance of this subject for further clinical clarification,a randomized clinical trial was found in progress, while searching the databasesof clinical trial records. However, to date, the study has not been published orany results have been reported.-,The case-series-The variation in the methods of assessing oral health-related quality of life mayhave been a confusing factor for the results found in the studies included inthis review, given that there was no homogeneity in the choice of thequestionnaires used.,Still, the lack of data on dropouts could have some influence on the result ofthe impact of the perception of spurs related to quality of life,Of the five studies, only oneThe lack of standardization and other important methodological limitations of thestudies included in this review show the need for future standardized clinicalstudies regarding methodology and error analysis. In addition, further studieswith longer follow-up periods are needed. Therefore, a RCT evaluating the impactof lingual spurs on oral health-related quality of life is mandatory.Current evidence points out that the anterior open bite treatment with lingual spurscauses negative impacts on the oral health-related quality of life, morespecifically discomfort in speech and chewing, but these impacts seem to betransitory by nature. These results should be evaluated with caution, based on thelow level of certainty, suggesting the need for new well-designed studies.


The differing global trends in alcohol consumption and policy measures implemented during the COVID-19 pandemic warrant a closer look at the actions taken by civil society organisations (CSOs) and community-led efforts to describe how they may influence and accelerate action for change in alcohol control measures. This paper analyses actions undertaken by CSOs at the national and local levels to safeguard communities and improve alcohol control policies during the COVID-19 pandemic in six African countries.A cross-sectional survey was distributed via email to CSOs involved in alcohol prevention, outreach and policy development in Kenya, Lesotho, Namibia, South Africa, Tanzania and Zimbabwe. Individuals (n = 19) working at CSOs responded to the questionnaire from February to March 2022. Questions related to the role of CSOs during the pandemic are analysed and synthesised in this paper. 19 CSOs respondents representing the six countries were included in the study.Action areas led by CSOs during the COVID-19 pandemic included: (i) direct lobbying advocacy, (ii) conducting public awareness media campaigns and (iii) legal and regulatory interventions linked to the pandemic.Given the size of the challenges governments faced during the COVID-19 pandemic, the role of CSOs, during the ongoing pandemic and beyond, has become even more relevant to strengthen advocacy and public health interventions for alcohol control in Southern Africa. For this, CSOs should have a “seat at the table” when public health policies are designed, discussed and enforced. The COVID-19 pandemic highlighted the extent to which alcohol consumption is closely intertwined with the mitigation efforts implemented to curb global transmissions during pandemic events. This includes measures such as stay-at-home directives that shifted consumption from on-premises to at-home, as well as closures of bars, pubs, and restaurants that increased off-premise sales through e-commerce and retail shops, among others , 3. ReseAlcohol consumption is a risk factor for developing non-communicable and communicable diseases, premature mortality, injury and domestic violence, all of which have severe economic and societal costs . AlcoholThe fear of COVID-19 infection, uncertainties about the future, isolation, loneliness and social disruptions have significantly influenced global mental health . LonelinThe challenges associated with alcohol consumption and the COVID-19 pandemic are enduring and warrant crosscutting, evidence-based solutions. Policies regulating the production, supply and purchasing of alcoholic beverages are effective and proven strategies for reducing alcohol consumption and COVID-19 transmission. However, in the wake of the COVID-19 pandemic, governments have sparsely taken up these possible interventions . The LanA cross-sectional survey was distributed via email to CSOs involved in alcohol prevention, outreach and policy development in Kenya, Lesotho, Namibia, South Africa, Tanzania and Zimbabwe. Individuals working at non-governmental organizations and community-based organizations responded to the questionnaire from February to March 2022.The Southern African Alcohol Policy Alliance (SAAPA) distributed the self-completion 23-open ended question survey to its members and, in turn, distributed it to their contacts via email. Respondents did not receive any compensation.Three sets of open-ended questions were asked in the questionnaire. The first set related to the regulatory changes to alcohol from January 2020 to July 2021 (17 questions). The second set was related to industry interference and corporate social responsibility (3 questions). Finally, a third set related to the role of CSOs during the pandemic (3 questions). The responses to the third set of questions are reflected in this paper. Specifically, these questions referred to the role played by CSOs in alcohol control during the COVID-19 pandemic.Overall, the response rate was 100% but not all 19 enquired CSOs responded to all three questions related to the role of CSOs during the pandemic. The interviewees disclosed no circumstances that could represent a potential conflict of interest concerning the scope, development or outcome of this work. While some of these CSOs focused their work generally on non-communicable disease risk factors regulation, some work specifically on alcohol control, and a few on specific measures such as road safety.The responses to all the open questions were anonymized and analyzed. Two authors (KA and AMD) summarised and discussed the findings with the research group. The group collectively identified four areas of CSO intervention. The synthesis and analysis across CSOs were carried out using the four areas adopted Annex . DiffereWHO Publications Review Committee oversees and provides clearance for all documents related to public health emergencies, including the COVID-19 pandemic. The decision of the Committee is made at the planning and executive clearance stages to ensure relevance, consistency, methodological validity and compliance with quality standards. The Committee approved the protocol in the context of the broader study [Limitations of the methods include the possible bias in selecting the CSOs interviewed and the validation of the questionnaire. The selection of CSOs may have been limited to a pre-existing network of CSOs. The number of CSOs working in the alcohol prevention field (denominator) is not necessarily known as there is no register to consult and some community-based organizations may work on alcohol only as a risk factor for non-communicable diseases or violence against women and children. Given the low number of CSOs, a group of experts working on advocacy, lobbying and public health designed and reviewed the questionnaire. During its administration, online support was provided to clarify and address specific challenges raised by the interviewed CSOs.Among the 19 respondents, five action areas were led by CSOs during the COVID-19 pandemic: direct lobbying advocacy (in three of the six countries), conducting public awareness media campaigns (in five of the six countries); and legal and regulatory interventions (in South Africa). Other action areas led by CSOs included building capacity through community training (Namibia).The countries and sample sizes are displayed in Table Direct lobbying advocacyCSOs are instrumental in creating momentum and accelerating action. CSOs can play a role in setting priorities for national agendas, increasing public demand for policies, laws and regulations, and ensuring that services reach communities , 16. CSODuring the COVID-19 pandemic, the Southern African Alcohol Policy Alliance -SAAPA- actively engaged in extensive advocacy related to COVID-19 alcohol restrictions. SAAPA is part of a broad alliance of CSOs working on advocacy in the Southern African region. SAAPA supported the bans or restrictions imposed on the sale and consumption of alcohol during the pandemic and advocated for continued restriction beyond the COVID-19 pandemic to avoid losing all ground gained while the restrictions were in place , 18. SAASAAPA and its partners lobbied for additional tighter alcohol restrictions to minimize the risk of the spread of COVID-19. They petitioned the Government to restrict alcohol sales and advertising in South Africa and called for a host of restrictions to be placed on alcohol trade, including a ban on all alcohol advertising, restrictions on alcohol promotions and suspension of liquor licenses for establishments that contravened the Regulations, reduce off-consumptions operating hours, and temporarily impose zero breath and blood concentration levels for drivers . They alb.Public awareness media campaignsIn Kenya, the NCD Alliance Kenya participated and made oral interventions during the Community COVID-19 Sub-committee meetings . AdditioIn July 2020, the NCD Alliance launched the Solidarity Fund on NCDs and COVID-19, totalling US$300000, to support 20 national and regional NCD alliances across all regions . With thnew norm advocating for evidence-based alcohol policies that reduce alcohol availability. They based their advocacy on the decline in alcohol-related harm seen when the sale and consumption of alcohol were restricted in the country in response to the COVID-19 pandemic [new norm and conducted several interviews on radio and television. SAAPA Lesotho was the first SAAPA chapter to advertise in a local newspaper to promote the idea of a new norm. They advocated for policy interventions to limit the amount of purchased alcohol, limit the hours and days of sale, the enforcement of license for trade, the enforcement of requesting identity cards for purchase of alcohol, for increasing the minimum age from 18 to 21, for no bulk buy specials, for increasing the price of alcoholic beverages, for restricting advertising at the point of sale, and for applying a lower blood-alcohol concentration limit while driving. Similar campaigns on the radio and in the local newspaper were carried out by SAAPA Zimbabwe [SAAPA and its partners engaged in an education and awareness campaign through broadcasting, print and social media. SAAPA promoted a campaign tagged pandemic . SAAPA LZimbabwe .On August 2020, the NCD Alliance Kenya urged the government to urgently address the underlying drivers of the NCD pandemic that fueled COVID-19 mortality and asked to prioritize the needs and care of People Living with NCDs by placing them at the centre of the COVID-19 response in Kenya .c.Legal and regulatory interventionsSome CSOs reported building capacity amongst local volunteers through community training by educating them about the the health risks of alcohol use and the consequences of the harmful use of alcohol.With Amandla.mobi, SAAPA South Africa launched a petition against the court challenges launched by alcohol manufacturers like South African Breweries and Vinpro . SAAPA SThe alcohol ban and the public health justification put forward for the ban by the South African government were supported by the South African Medical Research Council (SAMRC) and other academics. They provided evidence of the reduced alcohol-related trauma caseload for the healthcare system to show the effectiveness of the alcohol ban , 27. ThiThese achievements are not without challenges, e.g., lack of resources and recognition. A study of West African CSOs working on alcohol harm prevention found that their work was adversely affected because of the pandemic including due to lack of adequate financial resources, and this may have affected access to services provided by CSOs in some countries .The examples described in this paper illustrate the role CSOs can play in supporting government efforts further and contributing to alcohol control activities by generating evidence, documenting, monitoring and reporting on the implementation of alcohol control policies; advocating and engaging through various government technical working groups  such as For this, governments should create the conditions for CSOs to be empowered and engaged in public health policy development by recognizing the legal status of CSOs, providing resources and ensuring democratic CSO representation on statutory bodies and working groups.This paper sought to synthesize the role of CSOs in six African countries during the COVID-19 pandemic. Three areas were identified (i) direct lobbying advocacy, (ii) public awareness media campaigns and (iii) legal and regulatory interventions. Given the size of the challenges governments faced during the COVID-19 pandemic, the role of CSOs during the ongoing pandemic and beyond has become even more relevant for public health interventions aimed at reducing the harm derived from alcohol consumption in the studied countries. For this, CSOs should have a “seat at the table” when public health policies are designed, discussed and enforced.


Despite the relationship between Autism spectrum disorder (ASD) and personality disorders (PD) still being scarcely understood, recent investigations increased awareness about significant overlaps between some PD and autism spectrum conditions. In this framework, several studies suggested the presence of similarities between BPD and ASD symptoms and traits, based on the recent literature that increasingly reported increased comorbidity rates and significant symptomatologic overlaps between the two conditions. The aim of this review is to describe the available studies about the prevalence of the association between different forms of autism spectrum  and BPD. Despite some controversial results and lack of homogeneity in the methods used for the diagnostic assessment, the reviewed literature highlighted how subjects with BPD reported higher scores on tests evaluating the presence of AT compared to a non-clinical population and hypothesized the presence of unrecognized ASD in some BPD patients or vice versa, while also describing a shared vulnerability towards traumatic events, and a greater risk of suicidality in BPD subjects with high autistic traits. However, the specific measure and nature of this association remain to be explored in more depth. Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder that features behavioral patterns, restricted and repetitive interests and chronic difficulties in social communication and interaction . InteresA central feature of ASD is the presence of an atypical social approach to dialogue reciprocity and a decreased sharing of interests, emotions and sentiments, caused by difficulties in the development of an adequate Theory of mind (ToM) ,8. It shAccording to the Diagnostic and Statistical Manual of Mental Disorders (DSM)  and the Even though the relationship between ASD and PD is still scarcely understood, recent investigations increased awareness about some symptoms’ similarities, which makes differentiating diagnostic evaluation more difficult ,40,41,43As defined by the DSM-5-TR and the ICD-11 , BPD is On the other hand, interestingly, several studies have suggested similarities between BPD and ASD symptoms and traits ,51,52,53Although in the recent literature, an increasing number of studies are analyzing the possible overlaps and correlations between ASD and BPD, to date, the literature in this area is still fairly young, and more has to be understood about the specific features of these correlations, the nature of the symptomatologic overlaps and how they relate to the manifestation of both disorders and the overall psychopathological illness trajectory. To our knowledge, to date the topic has been assessed exclusively by one meta-analysis, but without including subthreshold autistic traits . In thisOne of the first studies aiming to examine the comorbidity between full-blown ASD and BPD came from Rydén et al. , who comOther authors investigated instead the prevalence of BPD among subjects with ASD. In a 2006 study, Anckarsäter et al.  evaluateIn addition to the studies that investigated the comorbidity between full-blown ASD and BPD, other studies focused on evaluating the prevalence and correlations of sub-threshold autistic traits in patients with BPD. In the study by Nanchen et al. , 38 femaIn recent years, several studies have suggested a similarity between BPD and the manifestation of ASD without cognitive impairment ,93. The In particular, females with ASD may show a reduced impairment in social communication and interactions and be more aware of their social difficulties, thus developing higher social anxiety levels and more frequently adopting social camouflaging strategies in order to mask their difficulties ,97,98,99Another interesting focus of some research was the correlation between suicidality, ASD and BPD ,92. It iAnother major link between ASD and BPD is represented by the shared vulnerability towards traumatic events, which can lead to higher rates of stress-related symptoms and altogether worsen the global clinical picture ,117,118.This review should be considered in light of some limitations. First of all, this is a narrative review, so it lacks the systematicity and reproducibility of a systematic one. Secondly, the literature available is still limited and often based on small samples of subjects. Thirdly, the BPD being a disorder mainly represented in females, there could be a possible influence of gender in the symptomatologic manifestation, not yet investigated. Moreover, to this date there is a lack of validated and widespread instruments for the evaluation of BPD traits. Lastly, we recognize the presence of a recent meta-analysis on the topic that, however, did not include subthreshold autistic traits in the evaluation.In conclusion, despite the limited literature available, some interesting correlations between BPD and ASD or autistic traits were highlighted. However, despite much evidence supporting the possible overlap between autism spectrum and BPD, the specific measure and nature of these associations remain to be explored. To date, many aspects of this dimension remain controversial and should be further investigated by longitudinal studies and integrated in light of a dimensional approach to psychopathology. Further studies in the field should focus on evaluating the overlapping features and comorbidity between autism spectrum and BPD in light of a gender-specific approach. Improving knowledge in this field may ultimately lead to an improvement in the available preventive strategies, diagnostic procedures and treatment options for these conditions, as well as to reach a better understanding of gender specific psychopathology.