Ensuring equitable utilization of healthcare services for those in need is vital to reduce financial risks associated with rising healthcare expenditure in both developed and developing countries. When presenting Sustainable Development Goals, the United Nations clearly link equitable utilization of healthcare services to the health status and overall wellbeing of people. However, socio-economic inequalities in healthcare utilization and out-of-pocket health expenses have increased in countries, creating an intense political pressures on respective governments to have higher budgetary allocations for healthcare. The situation in low-and middle-income countries is even worse as their uneven distribution of healthcare infrastructure has aggravated the situation. This has resulted in degenerated-health outcomes, increased-morbidity and–mortality among deprived-groups in those countries. On this backdrop, examining the issues pertaining to inequality in healthcare utilization and out-of-pocket healthcare expenses is vital from public policy viewpoints. The studies may discuss inequality-related issues faced by countries depending on rich and updated-datasets and novel analytical tools. Accordingly, this special issue publishes six studies of that nature, contributing to the extant literature on the subject.Tian et al. examined the degree of healthcare utilization of migrants in China and how it is influenced by health education. The study argues that health education plays a vital role in enhancing the degree of healthcare utilization among migrants in China, and thereby, health education generates promotional effects with regard to healthcare utilization. The study further finds that counseling is more effective than other methods of health education in this regard. Moreover, the study concludes that the promotional effects of health education on healthcare utilization is favorably moderated by the proximity to medical services: closer to the services, greater the promotional effects. Accordingly, one could expect that health education could play a significant role in mitigating inequality in healthcare utilization by migrants and non-migrants in China.You et al. provide empirical evidence on inequality in consumption-related health education in China during COVID-19. The paper argues that health education could play a significant role in preventing a pandemic like COVID-19, and nonetheless, depending on socio-economic characteristics of individuals, there persists a considerable degree of inequality among different subgroups. The empirical evidence provided in terms of Concentration Index, Horizontal Index, and decomposition analysis show that health education is highly concentrated among the individuals with higher-level of general education, higher income, and more positive consumption preferences. Moreover, the study uncovers that inequality in health education among individuals is also caused by health status, type of residence, and medical insurance ownership. The results imply that the government needs to pay attention on vulnerable people including, the ones with lower-level of education and income and rural living when planning for health educational programs at the recovery stage of COVID-19.Zhang et al. with regard to healthcare utilization by the individuals in economically under-developed regions in Northeast China. The severe inequality in healthcare utilization among people in the aforesaid region is primarily associated with household income, health status, place of living, and health insurance ownership. The results imply policy changes to protect poor people from under-utilization of healthcare services. Moreover, improved-social security systems along with basic health and critical illness insurance would mitigate inequality in healthcare utilization of individuals living in economically backward Chinese regions.The similar nature of analysis is provided by Wang et al. show that rural cancer patients report less-level of healthcare utilization including, screening and treatments compared to their urban counterparts. Thus, the study recommends upgrading rural-sector healthcare infrastructure required for cancer patients.Providing more specific empirical evidence on inequality in healthcare utilization among Chinese cancer patients, Nie et al. develop a model to predict the level of utilization of Family Doctor Contract Services (FDCS). The study finds that individuals' age, gender, household income, educational attainment, insurance status, health condition, smoking and drinking habits, physical activity status, and some supply-side factors can be used to relevant predictions. Overall, the model exhibits moderate performance.Using a cross-sectional dataset from China, Xie et al. analyze the economic burden of neurodevelopmental diseases on Chinese patients with genetic diagnosis. The economic burden is computed by taking direct and indirect medical and non-medical cost associated with relevant healthcare utilization into account. As the insurance coverage is low among these patents, they need to bear a huge economic burden. The study proposes that early diagnosis is crucial in reducing this burden. Moreover, the paper emphasizes role of government in increasing insurance coverage to reduce the vulnerability of patents.The Global South countries were represented in this Topic, present diverse legacy of Inequality in Healthcare Utilization and Household Spending. LMICs countries health systems experience difficult sustainability challenge due to long-term trends . Some ofDespite heavy emphasis on South Asian and ASEAN health systems in this Topic, other world regions might expose dynamic development as well with an impact to global Inequality in Healthcare Utilization and Household Spending . ConveniHeterogeneous Topic contributions could reveal a new knowledge frontier. Global South countries challenges from the perspective of academic health economics . The goaMJ has drafted the manuscript while AP, TV, and AK have expanded it substantially for important intellectual content. All authors have equally contributed to this editorial fulfilling ICMJE criteria for full authorship. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Di (2-ethyl-hexyl) phthalate (DEHP), one of endocrine-disrupting chemicals (EDCs), has widespread concern due to its serious health hazards. Exposure to DEHP in the early stage of life affects fetal metabolic and endocrine function, which even would cause genetic lesions. To date, it is widely believed that the increasing incidence of childhood obesity and diabetes in adolescents is related to the impact of DEHP on glucose and lipid homeostasis in children. However, there remains a knowledge gap to recognize these adverse effects. Thus, in this review, besides the exposure routes and levels of DEHP, we further outline the effects of early-life exposure to DEHP on children and potential mechanisms, focusing on the aspect of metabolic and endocrine homeostasis. Di (2-ethyl-hexyl) phthalate (DEHP), belonging to the family of phthalates, is a plasticizer and solvent in polyvinyl chloride (PVC), which can be used to manufacture various products, such as cosmetics, toys, and medical tubing . ThroughAccording to DOHaD theory, which is based on an epidemiological study about low birth weight and malnutrition , the effThus, in this review, we summarize the effects of early-life exposure to DEHP on endocrine homeostasis in offspring and the potential mechanism, and highlight the common connections existing in the current research, providing some insights for further scientific research and medical precaution.via the digestive tract through food intake is the largest intake route of phthalates , and perfluoroalkyl acids, can contribute to glucose and lipid metabolism in the body . EnvironPerinatal exposure to DEHP may increase the incidence of obesity in offspring and DEHP may be a potential chemical stressor of obesity and obesity-related diseases . A meta-In animal experiments involving metabolomics evaluation, the weight of offspring significantly increased after exposure to DEHP during pregnancy in mice, and the performance of the male offspring at low doses of DEHP is more obvious . MeanwhiExposure to DEHP during pregnancy is associated with shortening of the pregnancy cycle, suggesting that exposure to DEHP during pregnancy can significantly increase the risk of preterm birth . It is rvia autophagy in the fetal ovary in a mouse model (DEHP not only directly affect the exposed population but also affect the offspring of the exposed population. The DOHaD theory proposes that there is a critical period of growth and development early in life, which is an important stage of fetal gene coding and expression. If environmental factors interfere with gene expression during this period, then the growth trajectory of life can be changed . DEHP hase model . Moreovese model . Previouse model . Early-lse model . Maternase model . Exposurse model . In addise model . An overExisting research suggests there is a strong correlation between maternal exposure to DEHP and childhood obesity, in accord with the results observed in animal experiments. However, the exposure dose of DEHP s in each study was not identical, and the exposure dose of DEHP in animal experiments differs from the human exposure dose. Compared with rodents, primates are less sensitive to DEHP and this has been attributed to differences in the absorption, distribution, metabolism, and excretion of DEHP between these mammals . Consequ


To investigate a novel combined microinvasive trans-submandibular and nasendoscopy surgical approach for nasopharyngeal carcinoma involving the parapharyngeal space.Seven patients diagnosed with nasopharyngeal carcinoma involving the parapharyngeal space between May 2018 and April 2021, two males and five females, aged 37–63 years.Six of the 7 patients underwent submental flap preparation and dissection of the lymph nodes in the upper neck and parapharyngeal space on the lesion side. The nasopharynx lesions and tumor margins were dissected under nasal endoscopy. The medial boundary of internal carotid artery separated by open cervical approach was used as the lateral boundary of the tumor to realize en bloc resection of the tumor.The patients were preoperatively diagnosed with T2~3N0M0 nasopharyngeal carcinoma, including mucoepidermoid carcinoma (n=2), papillary adenocarcinoma (n=1), and nonkeratinizing squamous cell carcinoma (n=4). The tumors were removed completely, and patients achieved primary healing of the incision. No recurrence and no serious complications were recorded during the 13–48 month follow-up.Complete resection of the tumor was obtained in the 7 patients without recurrence and serious complications during the follow-up. The findings of this cohort study suggest that, patients with recurrent nasopharyngeal carcinoma after radiotherapy and radiotherapy-insensitive types of nasopharyngeal carcinoma, the combined microinvasive trans-submandibular and nasendoscopy surgical approach may be considered as an surgical options. The results of this study provide an additional option for surgical treatment of NPC in the clinic. Surgery has become the treatment of choice for recurring nasopharyngeal adenocarcinoma (NPC) after radiotherapy, and some special tumor types insensitive to radiotherapy, such as adenoid cystic carcinoma, mucoepidermoid carcinoma, and nasopharyngeal adenocarcinoma . HoweverVarious approaches, including infratemporal, transcervico-mandibulo-palatal, transpalatal, transmaxillary, transcervical, maxillary swing, facial translocation, and degloving, have been developed to dissect tumors radically . HoweverWe attempted a novel tumor resection surgical procedure that enables safe and thorough dissection of the PPS, including the internal carotid artery segment, and performed nasopharyngeal wound repair using a cervical-parotid approach. The procedure includes the following steps: a) create a submental flap; b) dissect the internal carotid artery through a cervical-parotid approach to the PPS; c) dissect the lateral border of the tumor; d) dissect the nasopharynx by an endoscopic approach. The complete resection of the tumor is achieved by a combination of an “inside and outside” approach. The presented method is convenient and excellent in protecting the internal carotid artery while completely removing the tumor and performing nasopharyngeal wound repair.This study aimed to analyze the advantages and limitations of a combined trans-submandibular and endoscopic surgical approach to the PPS by reporting the outcomes of a series of patients with recurrent or radiotherapy-insensitive NPC.This retrospective study included seven patients , aged 51.57 ± 7.52  years, diagnosed with NPC at the Department of Otolaryngology-Head and Neck Surgery of Beijing Tongren Hospital, affiliated with Capital Medical University, Beijing, between May 2018 and April 2021. Surgical resection was recommended by comprehensive multidisciplinary discussion in all cases. The clinical research ethics committee of Beijing Tongren Hospital approved this study. The characteristics of our study population are shown in Six of the seven patients were treated with a submental island flap for reconstruction, and lymph nodes in the upper neck and PPS on the lesion side were dissected. The vascular sheath of the PPS at the base of the skull was dissected superiorly through a cervical-parotid approach and medially from the PPS to the nasopharynx. The tumor was resected using a combination of internal and external approaches. The nasopharynx lesions and tumor margins were dissected under nasal endoscopy. The medial boundary of internal carotid artery separated by open cervical approach was used as the lateral boundary of the tumor to realize en bloc resection of the tumor.The specific surgical procedure was as follows: A transverse incision was made at 1 cm from the lower border of the mandible. The marginal manibular branch of the facial nerve was protected during the dissection, the starting point of the submental artery was detected, and a submental perforator flap was made by dissection toward the midline of the neck.The digastric muscle was cut at the middle bond when making the submental flap, the anterior belly of the digastric muscle and part of the mylohyoid muscle were cut together with the submandibular gland flipped outward to form the vascular pedicle structure of the submental flap. The stylohyoid muscle and the posterior belly of the digastric muscle were dissected poster laterally. Take care to protect the hypoglossal nerve. The carotid sheath was dissected upward along the internal jugular vein, the internal carotid artery was dissected all the way from the anterior to the medial aspect of the carotid sheath, until near the rupture hole. During dissection, the stylohyoid and stylopharyngeal muscles are cut, the medial pterygoid muscles are exposed first, and the glossopharyngeal nerve is dissected superiorly and protected, at which point the stylohyoid process can be fully exposed, and a yellow PPS above the stylohyoid process is visible containing fat and lymphoid tissue. The fat and lymphoid tissues in the PPS were excised and the lower border of the lateral pterygoid muscle was bare. The medial pterygoid muscles, lateral pterygoid muscle were dissected with a bipolar or a harmonic scalpel, and tumors that protruded into the PPS were located superiorly medial to the internal carotid artery and lateral to the pharyngeal superior constrictor muscle. The perpendicular plate and pterygoid bone were grinded under nasal endoscopy. Removed the sphenoid sinus ostium and sphenoid septum, dissected the contralateral safety boundary of the tumor in the nasopharynx, dissected the tumor from the surface of the longus capitis muscle, beneath the sphenoid bone, and removed the tumor from the oral or PPS. After resection of the tumor, a natural passage through which the submental flap can be pulled upward into the nasopharynx to repair the wound in the denuded internal carotid artery, medial cavernous sinus, and posterior nasopharyngeal wall is created. Unless no cervical lymph nodes remained, we routinely dissected lymph nodes of Levels IB, II, and Va. In cased of metastases, we handled them following the neck lymph node dissection principles. We carefully protected the glossopharyngeal, hypoglossal, accessory, and vagal nerves. We made sure not to mistaken the superior sympathetic ganglion on the deep surface of the internal carotid artery for a lymph node and perform lymphadenectomy. After adequate wound irrigation, the premade submental flap was moved over the PPS to the nasopharynx to repair the defects and cover the wounds. Subsequently, a nasopharyngeal iodoform yarn strip was packed and placed, and a negative pressure drainage tube was placed in the PPS. Finally, the neck incision was closed routinely. The cervical PPS drainage tube was removed 2–3 days after the operation. The iodoform yarn stripe was removed from the nasal cavity 7–8 days postoperatively, followed by daily nasal irrigation. The patient visited the outpatient clinic 1–2 weeks postoperatively for review and nasal clearance. Patients requiring radiotherapy after the surgery started treatment 4–5 weeks postoperatively. Nasal feeding was usually maintained for 5–7 days.We followed the multidisciplinary comprehensive therapy (MDT) pattern and chose a rational use of radiotherapy, chemotherapy, immunotherapy, or other means for recurrent and radiotherapy-insensitive NPC postoperatively. We aimed to develop an individualized comprehensive treatment strategy when possible to improve efficacy while ensuring the patient’s survival and quality of life.The study included seven patients treated by the combined trans-submandibular PPS and endoscopic surgical approach. No major surgical complications occurred. Minor complications observed included facial sweating and pain in lifting the right hand, diplopia, xerostomia, and nasal blockage with choking on eating, each in one patient Table 1.Among the seven patients, four had nonkeratinizing, undifferentiated recurrent NPC after radiotherapy, two were with mucoepidermoid carcinoma of the nasopharynx , one was with nonkeratinizing papillary adenocarcinoma. Two patients with recurrent NPC were confirmed to have cervical lymph node metastases, one with bilateral metastases  and the other with unilateral metastases . Rapid intraoperative tumor margins pathologic results were negative in all patients.The mean follow-up time was 31 months. None of the patients died from the disease during follow-up, and no recurrences were observed. While the patients had slight paresis of the facial nerve mandibular ramus postoperatively, all recovered completely within three months.Postoperatively, there was only a short period of small crusting in the nasopharynx incision that had disappeared within 2–3 months. The patients had good nasal ventilation and no significant decrease in nasal function.Nasopharyngeal carcinoma is a global disease, but it shows marked geographical differences, with a high incidence of approximately 25–50/100,000 in China and Southeast Asian countries , and undAlthough intensity-modulated radiotherapy has significantly decreased the NPC local recurrence rate, 10–15% of patients still experience recurrence . The MDTBecause of their deep location and numerous surrounding vital structures in the nasopharynx, it is extremely difficult to completely remove tumors from this region while protecting the surrounding vital tissues. The traditional open surgical approaches, such as transhiatal resection through a nasolabial incision, transhiatal resection via a maxillofacial approach, and maxillary swing resection via a lateral cervical approach, are aggressive and effective treatments for recurrent NPC, with 5-year overall survival rates of 30–60% . HoweverWith the development of nasal endoscopy-related surgical instruments and techniques in recent years, transnasal endoscopic surgery for recurrent NPC has gradually become a widely recognized safe and effective treatment modality –13. HoweThe above indicates that despite its advantages, endoscopic surgery alone has some limitations in treating recurrent and radiotherapy-insensitive NPCs. To address these issues, we designed a surgical strategy that combines nasendoscopy and a submandibular approach to resect NPCs that involve the PPS. Freeing the inferior pole of the parotid gland or dissecting the marginal manibular branch of the facial nerve to the carotid trunk during surgery can fully expose the PPS structure at the skull base and facilitate full dissection of the internal carotid artery PPS segment. Besides, this surgical approach facilitates the creation of a submental island perforator flap for nasopharynx wound repair and avoids life-threatening massive necrotic bleeding and denudation of the internal carotid artery. We uneventfully revealed and protected the glossopharyngeal, accessory, vagal, and hypoglossal nerves in the PPS and dissected the fat inside the carotid sheath and lymph nodes in all seven patients. Given the access to the PPS, it was easy to divert the submental perforator flap superiorly to the nasopharynx and perform surgical wound revision after tumor resection. All seven patients achieved primary healing of the incision and nasopharynx. While the patients had slight paresis of the facial nerve mandibular ramus postoperatively, all recovered completely within three months. The scar of the neck incision in the submandibular region is essentially invisible when the patient is in frontal view, achieving high patient cosmetic outcome satisfaction. The nasopharynx was repaired with a submental flap, leaving no exposed wounds. Postoperatively, there was only a short period of small crusting in the nasopharynx incision that had disappeared within 2–3 months. The patients had good nasal ventilation and no significant decrease in nasal function.Our designed surgical approach has the following advantages: a) the surgery relies little on instruments and does not need the hybrid operating rooms or navigation equipment. It is relatively easy to dissect the internal carotid artery upward to the parapharyngeal segment through the neck. The surgical manipulations are performed under direct vision, and it is easy to locate the internal carotid artery using ultrasonographic Doppler. b) The submental flap protects the exposed internal carotid artery and nasopharynx wound after dissection and reduces the risk of patient death from massive hemorrhage due to internal carotid artery rupture. The submental flap had less local inflammatory exudation and scabbing and faster postoperative recovery than with temporalis flap repair. c) The retropharyngeal lymph nodes are the most common target NPC metastases . StudiesEn bloc resection of the tumor was obtained in the 7 patients without recurrence and serious complications during the follow-up. The findings of this cohort study suggest that, patients with rNPC and radiotherapy-insensitive types of nasopharyngeal carcinoma, the combined microinvasive trans-submandibular and nasendoscopy surgical approach may be considered as an surgical options. The results of this study provide an additional option for surgical treatment of NPC in the clinic. Although the sample size in our study was small, all patients achieved good treatment outcomes and had no serious complications, providing a reference basis for future clinical applications of the procedure.The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding authors.The studies involving human participants were reviewed and approved by clinical research ethics committee of Beijing Tongren Hospital. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.JF had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Concept and design, JF, YZ, and QZ. Acquisition, analysis, or interpretation of data, LZ, CW, JC, ML, XS, and YY. Drafting of the manuscript, JF and YZ. Critical revision of the manuscript for important intellectual content, all authors. Statistical analysis, JZ, QS, and YZ. Administrative, technical, or material support, JC, LF, SH, LZ, and RW. Supervision, HM, LH, and CW. All authors contributed to the article and approved the submitted version.This work was supported by the Key R&D Program of China (No. 2020YFB1312805), Capital Health Research and Development of Special Fund (No.2022-1-2051), Priming Scientific Research Foundation for the Junior Researcher in Beijing Tongren Hospital, Capital Medical University (2021-YJJ-ZZL-018), National Natural Science Foundation of China , Beijing Municipal Administration of Hospitals Incubating Program(PX2021008), Beijing Hospitals Authority Youth Programme (QML20200205).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Brain function is dependent on the ability of neural circuits to remodel synaptic connections in response to internal and external stimuli. Historically, brain plasticity studies focused on excitatory synapses, with inhibitory connections considered largely stable. However, there is growing evidence that inhibitory synapses undergo short- and long-term forms of plasticity through a variety of pre- and postsynaptic mechanisms. Activity-dependent regulation of inhibitory transmission by Hebbian mechanisms has been well documented. On the other hand, homeostatic plasticity of inhibitory synapses has been demonstrated under physiological, pathological, pharmacological, and drug abuse conditions. These diverse forms of inhibitory synaptic plasticity represent an important source of neuronal network reorganization, and their crosstalk with excitatory synaptic plasticity maintains the brain's overall excitatory/inhibitory balance. Despite this growing experimental evidence of inhibitory synapse plasticity, several key issues remain.Fish and Joffe and Speigel and Hemmings review the functional diversity of the main classes of cortical and hippocampal interneurons: parvalbumin INs, somatostatin INs, 5HT3a serotonin receptor INs, calretinin/vasoactive intestinal peptide INs and neurogliaform/ivy cells. These articles describe neurophysiological properties, sites of synaptic connections, and expression of molecular targets in these GABAergic cells. They also discuss the different IN plasticity mechanisms induced by anesthetics and alcohol. Garcia DuBar et al. examined the synaptic connectivity of INs within the pontine circuit that coordinates arousal and voiding behaviors associated with micturition. The authors demonstrate that only somatostatin INs contribute to behavioral modulation, supporting the heterogeneity of GABAergic cell populations and indicating that they participate in specific brain circuitry. Finally, by investigating the biophysical and pharmacological properties of the δ-containing subtype of the GABAA receptor, Shu et al. highlight the importance of different GABAA receptor subtypes in inhibitory plasticity. Given the wide variety of INs, the intricacy of their microcircuits, and the importance of GABAA receptor subtypes, more studies are needed to fully elucidate the mechanisms of inhibitory plasticity during development and in adulthood.In this collection, two papers by Melkumyan and Silberman which examines the opposing effects of chronic alcohol on glutamatergic and GABAergic neurotransmission in the central amygdala. These authors introduce new players (astrocytes and microglia) and molecules (TNFα and IL-1β) and conclude that further studies are needed to determine the contribution of all these cell types, receptors and neuromodulators to the balance of excitation/inhibition neurotransmission. Similarly, the articles by Chapman et al. and Tipton and Russek review the interplay of plasticity between excitatory and inhibitory synapses. They describe how the induction of inhibitory LTP causes excitatory LTD and reduces excitatory neurotransmission. Conversely, they explain that stimulation-induced excitatory LTP dampens proximal inhibitory synapses (LTD). Thus, convergence of glutamatergic and GABAergic signaling mechanisms may allow for coordinated receptor plasticity and balancing of excitation/inhibition. They also identify calcium as a master regulator of synaptic crosstalk, and describe the importance of posttranslational modifications of the receptors and scaffolding proteins to coordinate the interplay of glutamatergic and GABAergic synapses. Since the homeostatic balance between excitation and inhibition is important for brain functioning, future studies should explore the imbalance of inhibitory and excitatory synaptic plasticity during disease.The importance of this topic is highlighted in the review by Speigel and Hemmings explain that anesthetics cause temporary cognitive dysfunction in adults and long-term effects in neo- and pre-natal babies due to disruptions in IN plasticity and development. Neonatal propofol exposure causes parvalbumin and somatostatin IN hypoactivity and vasoactive intestinal peptide IN hyperactivity, suggesting differential cellular effects. Similar to anesthetics, varied sensitivity to acute and chronic alcohol exposure has also been observed, as discussed by two reviews in the collection. Melkumyan and Silberman focus on alcohol's effects on distinct sub-regions of the central amygdala. The authors analyze the role of neuroinflammatory cells, the endocannabinoid system and different neuropeptides and neuromodulators, in the modulation of GABAergic and glutamatergic transmission by alcohol. The article by Fish and Joffe examines inhibitory microcircuits of the pre-frontal cortex as potential targets for the treatment of alcohol use disorder. Notably, both of these papers highlight the important of sex differences in alcohol's regulation of inhibitory synaptic plasticity and advocate for greater identification of sex-specific mechanisms that can be targeted for therapeutic drug development.Homeostatic disruption due to pharmacologically active compounds or drugs of abuse can induce plastic changes in inhibitory neurotransmission, as can long-term pathology. These alterations are associated with diverse neuropsychiatric and neurological disorders. Several papers in this collection address these issues in the context of therapeutic drug discovery. Mackenzie-Gray Scott et al. studied the correlation between hippocampal parvalbumin IN-generated gamma rhythmicity and amyloid beta plaques in a mouse model of Alzheimer's disease. The authors found no relation between gamma oscillations and plaque formation suggesting that hippocampal network activity is resilient. In contrast to Alzheimer's disease, the onset of epilepsy can occur during childhood or as an adult. Regardless of its genetic or acquired basis, inhibitory plasticity and shifts in the excitation/inhibition balance contribute to its pathophysiology, as reviewed by Tipton and Russek. The authors outline the plasticity mechanisms that control GABAA receptor function, modulation of inhibitory synapse formation and elimination, and the vulnerability of selective IN classes to seizures. Tipton and Russek highlight the importance of using single cell studies to identify selective IN vulnerability and develop more specific therapeutic approaches. They also propose identifying factors that make these cells resilient to the disease in order to promote survival of susceptible IN populations.Altered inhibitory synaptic plasticity has been associated with the cognitive decline that accompanies normal aging and in Alzheimer's disease. This Research Topic outlines recent progress and future directions in the field of inhibitory synaptic plasticity. We hope this collection will encourage further studies to elucidate the mechanisms of inhibitory transmission regulation, thus contributing to the development of new therapeutic interventions for neuropsychiatric and neurological disorders.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.


Background: Lipid-based nutrient supplements (LNS) are effective for treating childhood wasting and for preventing stunting, wasting, and anemia, but large-scale production and programmatic use are a barrier. Locally-developed and produced LNS may be more affordable and reduce logistical procurement and importation hurdles, while promoting private sector engagement and partnership.Methods: In northwestern Bangladesh, we conducted a community-based trial of complementary food supplementation to test its efficacy to reduce childhood stunting. Two locally-developed, small-quantity LNS  were designed, developed first at small scale in the ‘kitchen’ laboratory under controlled conditions, followed by taking them to a local food manufacturer for larger production for the study. We describe here the partnership, required expertise and capacity, experiences, and lessons learned that made this uniquely complex undertaking possibleResults: Key steps in the journey included addressing the dynamics of clear communication between partners, executing on carefully assigned tasks and roles, correcting course when needed, and maintaining timeliness and roadmaps. Knowledge of food science and technology was key in solving many food-production challenges that were encountered in taking the laboratory recipe to the factory. Factory production was established and had to meet quality and hygiene criteria set for young children.Conclusions: We provide documentation of this experience as a model to describe the various steps and considerations and what is entailed in local LNS production. We highlight the importance of a well-conceived collaboration with clear roles that created a ‘win-win’ situation for all partners for achieving common goals, establishing improved technology at the factory, and building new capacity to produce such products for children in a low resource setting. Key words: micronutrient, lipid-based nutrient supplements, maternal and child, malnutrition, multiagency collaboration Globally, in addition to counseling for infant and young child feeding practices, provision of nutritious foods for young children during the complementary feeding period from 6 months of age through the end of breastfeeding has long been part of nutrition and food aid programs. Currently, among the complementary foods (CFs) that exist, the United Nations World Food Programme (WFP) distributes them in the form of enhanced fortified blended foods such as SuperCereal Plus which requires cooking or other ready-to-eat lipid-based nutrient supplements (LNS) in settings where children face a high risk of chronic and acute malnutrition due to natural disasters, conflict, or seasonal or chronic hunger.The global burden of childhood stunting at 149 million worldwide is associated with a myriad of risk factors, including inadequate quality of complementary foods starting at 6 months of age and may increase the likelihood of severe outcomes including mortality. Lipid-based nutrient supplements (LNS) are CFs designed to prevent wasting, micronutrient deficiencies, and stunting through regular consumption of small quantities provided in 20 to 50 g servings. In a recent Cochrane review of 17 randomized controlled trials (RCTs) that included 23,200 children and a meta-analysis of individual participant data from 14 studies with more than 37,000 children, supplementation with fortified small-quantity  LNS as complementary food supplements showed significant reduction in child stunting, wasting and anemia as well resulted in a 27% reduction in child mortality. In the recent Lancet nutrition series, these evidence-based interventions are recognized for impacting the global burden of undernutrition. Lipid-based nutrient supplements also support improved linear growth better than fortified food blends in some settings and with some formulations. Internationally distributed SQ-LNS products such as Nutributter and LNS-Medium Quantity  such as Plumpy’doz  are ready-to-eat peanut-based formulations that are available for use as complementary food supplements but may likely be more expensive than locally manufactured products, although not many settings have local production capacity of such products. Additionally, local wariness of imported nutritional products and of population habituation to complementary foods that are not locally available, and low acceptability of peanut-based LNS are challenges to sustaining wide distribution of globally-available LNS products. Further, even with successful local production to date, using internationally developed recipes, some populations may not prefer the products because in some settings, such as Cambodia and Vietnam, peanut-based LNS was not well accepted. To address this, some local programs, including Pakistan’s program, use more preferred local chickpea-based LNS formulations, such as Wawamum. In Bangladesh, social enterprises have recently started commercial production of economical LNS such as Hashi Khushi for children (Frontier Nutrition).Interest in special nutritious foods specifically designed for complementary feeding has largely emerged with the development of special high-energy and nutrient-dense therapeutic foods for the local management of severe acute malnutrition. The emergence of those novel products and the gradual shift in global food assistance toward settings of protracted disasters have also sparked interest in refining traditional food aid products to better meet the needs of the complementary feeding period. From 2012–2014 we conducted a community-based RCT, implemented at the JiVitA Project site in rural northwestern Bangladesh, involving over 5300 children who received different types of complementary food supplements, including two locally designed and produced rice-lentil and chickpea based LNS along with one fortified blended food, and one ready-to-eat LNS. The study evaluated the impact of supplementation on improving growth and reducing stunting, wasting, and improving micronutrient status if consumed daily by children from 6 to 18 months of life.Interest is mounting in developing and distributing alternative, locally or regionally developed and produced LNS through governmental, non-governmental, or commercial channels independent of food assistance programs, especially where undernutrition is highly prevalent. In support of this goal, designing more cost-efficient and efficacious solutions to enhance the quality and accessibility of these products in low-resource settings is paramount. Further, there is a need to develop LNS tailored to the special demands of the complementary feeding periodThe novel aspect of this study entailed design, development, and production of 2 local LNS products, prior to testing them in the RCT. In order to accomplish this work, 1.5 years prior to the RCT, a group of organizations developed a strategic partnership . The groThis paper presents the journey of the development and production of two local LNS products through partnership with a local food manufacturing company, key challenges faced and overcome, lessons learnt, and the central role the collaboration played in project success. This partnership design and experience serves as a model for achieving a similar goal in another setting.We describe the experience and work that led to the successful design, production, and supplementation of children with two LNS produced using local ingredients and manufacturer. Information for this paper was gathered from experiences documented in meeting minutes, study protocols and standard operating procedure manuals, regular reports and communication between the partners, and site visits to the production plant. Additionally, at the completion of the field trial, all colleagues were interviewed by soliciting written responses through a standard survey for their opinions and experiences. The study received ethical approval from the Ethical Review Committee (ERC) at icddr,b, Bangladesh and the Institutional Review Board (IRB) of the Johns Hopkins Bloomberg School of Public Health, MD, USA on August 3, 2011 (reference no. 00003703).In order to develop, produce, and test a locally-produced LNS, a range of expertise and routine and transparent communication among the partners with established roles and agreed upon responsibilities was required. The group recognized that convening multiple partners from numerous locations on a regular basis was a critical step towards establishing effective communication and a forum to resolve issues, both of which were invaluable for supporting the overall project objectives. Additionally, the partners felt that developing a co-owned collaborative framework was important for launching and maintaining the effort.  During the first partners’ conference call, occurring 13 months before the expected trial launch date, participants clarified roles and communication strategies and established terms of reference to reflect agreed-upon achievable deadlines in light of project funding and in-kind support, ongoing, non-project related activities, and anticipated challenges . During In addition to the communication among partners, it was critical to ensure the Bangladesh government was involved and informed. Thus, partners prioritized presenting the activity to and maintaining routine communication with key public health and nutrition stakeholders and government agencies. Toward this objective, an initial partner task was established focusing on building country-based knowledge about and support for the complementary food supplementation project within the Ministry of Health and Family Welfare (MoHFW), the Bangladesh Institute of Public Health Nutrition (IPHN), and the Bangladesh offices of Alive and Thrive, Nutrition International, UNICEF, and the US Agency for International Development (USAID), among other identified key stakeholders. Additionally, as one of the first actions, the partners introduced the project objectives to the existing Nutrition Working Group, comprised of representatives of the key nutrition partners including UN Agencies, development organizations, civil society, and public sector institutes. This dialogue led to cultivating a venue for answering questions and seeking inputs on the project. A Technical Committee was also formed and led by a leading scientist (TA) and member of a partnering organization, icddr,b, and was composed of child nutrition and health leaders and scientists in the MoHFW, and in academic, medical, and public health fields. This Technical Committee informed and sought guidance from our collaborative project. Recipe development. An important aspect of developing an LNS as a complementary food supplement for rural Bangladeshi children 6–23 mo of age, guided by existing international products, required creating a recipe that incorporated locally-available, culturally recognized and acceptable ingredients. The partners needed to ensure the products were fortified with multiple micronutrients at agreed upon levels sufficient to bridge the requirement gap in this age group while not adversely affecting the organoleptic or shelf-life qualities of the final product. Detailed consultations among nutritionists and food scientists were needed to finalize the target composition of the LNS including the amount of animal source (dairy) protein in the supplement recipe as well as levels of nutrients included in the premix. Further, the partnership leveraged their broader networks of experts, including a food technologist with WFP based in Pakistan (SM) who was supporting the production and distribution of a chickpea-containing LNS. The food technologist participated in developing the Bangladesh LNS version and provided other technical assistance throughout the LNS production activities.Product development. Collaborators affiliated with the icddr,b food processing laboratory played a seminal role in the development of the LNS products. Details about how these products were designed, developed, and finalized are described in detail elsewhere. In brief, the icddr,b food technologists created two recipes – one with a rice and lentil base and another with a chickpea base. The formulations were designed as LNS and thus in addition to the grains, the products contained vegetable oil, and dried skim milk powder was the source of animal protein in addition to the plant proteins found in the grain and cereal grains. Producers could procure the ingredients in bulk locally, at a reasonable price, and at a standard required to maintain a consistently high quality LNS. Once the new formulations were defined and the nutrient composition of the final products measured, the partners determined the desired micronutrient composition of the LNS which would be met by adding a premix to the formulation. The food technologists on the team participated actively in the composition discussions to provide guidance on ensuring the levels and ratios of certain vitamin and minerals and their influence on product stability and organoleptic properties, while the nutritionists ensured fulfilling daily requirement gaps based on a diet of breastmilk and complementary foods. To specify the micronutrient composition, the following aspects were considered: desired portion sizes of the LNS and daily recommended micronutrient intake consumed through one serving by children; the ratio of minerals (such as iron and zinc) to preserve bioavailability; levels of nutrients that could influence organoleptic properties of the product; shelf-life of the product; accounting for micronutrient amounts intrinsic in the LNS ingredients, etc. Once finalized, DSM supported the production and provision of the appropriate micronutrient premix. The chemical form of the micronutrients was chosen considering their application in the specific food matrix, including bioavailability, stability, and organoleptic properties.The consensus among the partners was that a daily portion of the LNS should provide energy levels found in SQ-LNS  to fill the energy gap in home-based traditional diet. However, because this food would be distributed to a population consuming a diet low in micronutrient content and variety, they devised the premix to provide 75 to 100%, on average, of vitamin and mineral requirements. For a year-long supplementation starting at 6 mo of age, provided by the JiVitA-based RCT, the partners agreed that the LNS would provide children 6–11 mo of age 125 kcals per day through a single sachet of SQ-LNS and children 12–17 mo with 250 kcals per day through two sachets.. Concurrent with the acceptability trial, the icddr,b team executed a shelf-life study to determine, among other characteristics, safety , water activity, and oil separation tendencies of the products.Once the food processing lab at icddr,b finalized the recipes, they shared samples with the partners. We then proceeded to conduct an acceptability trial of the two products among the target group of young children in the rural Gaibandha district where the RCT was to be conducted. The results of this study showed high level of acceptability for both productsSelecting a food manufacturer. Partners had to select a local food manufacturing company interested in and capable of producing the foods in the quantities required for the RCT. This production had to adhere to strict, established food product hygiene standards and requirements for children under 2 years of age.The other success factor for this phase of the project was creating clearly defined tasks and responsibilities for each partner in the manufacturing process. More specifically, a detailed LNS production plan map with a timeline of tasks and individual or groups named responsible for completing tasks guided the effort. Clear reporting from each individual in regular meetings resulted in establishing a good understanding of whether the plan was being executed as anticipated and for course corrections decided collectively.WFP, a global expert in procurement, logistics, transportation, and storage, played an important role in selecting a suitable and interested manufacturer, leveraging existing collaborations for their fortified biscuit programs. The partners formed a Task Force from the collaborating organizations who developed a shortlist of potential food manufacturers based on their available product range as well as having access to the required equipment, facilities, and quality assurance methods for LNS production.The selected food manufacturer would have to assume a variety of responsibilities for the study, which required production of a total of 12–15 metric tons each of the two products including creating a separate production line that met the factory specifications for products designed for children less than 2 years old and take this on without knowing if there would be future demand for the product. In addition, before initiating any production, the factory would need to undertake product development efforts to adapt the recipes from the kitchen-based to the manufacturing versions.The partners approached the five listed companies to request meetings with senior teams and visits to production units to assess the companies’ capacity and willingness to produce food products for young children. Notably, none of the companies, nor any in Bangladesh, were engaged in producing food for children under 2 years of age. Two of the three companies were not interested in initiating the activity due to the resources required to achieve and maintain the strict, high standards, especially without promise of future business and associated revenue for such products. Based on the Task Force assessment, Olympic Industries, Dhaka, one of the largest manufacturers and distributors of biscuits in Bangladesh, met the various criteria including an expressed interest to participate. Olympic was also the most open to the collaboration and was willing to make modifications to their production equipment and lines to meet the needs for production of the complementary foods for children.The partners established a memorandum of agreement with Olympic Industries with agreed upon payment of the contractual services, largely coordinated by WFP including early investments to set up a separate production room, dedicating equipment, purchase of clean raw ingredients, among others. Following this, the company initiated setting up a production line assembly, modifying existing machines and their location, sourcing raw consumable and package materials, and developing a hygiene and quality assurance plan. The partners supported and monitored these activities. To provide more specialized support, an independent food technologist from Thailand who was an expert in food microbiology and large-scale manufacturing processes especially related to quality control, texture, appearance, and viscosity analyses visited the production site every other week, accompanied by icddr,b and WFP-Bangladesh colleagues, to provide technical inputs during the early phases of the factory production. A main highlight of the project was the successful technology and knowledge transfer from a food processing lab to a local processed food producer for the production of foods for young children requiring markedly high standards. However, one of the challenges faced was that the time required to establish the specialized factory lines was longer than expected.Olympic Industries first undertook a trial production run, which facilitated addressing numerous issues including better defining the roasting duration of the lentils and chickpeas, adjusting the overall moisture content and size of ground particles, adjusting fluidity to change the products’ stickiness, shifting the recovery rate, and improving extrusion. Simultaneously the partners and company leadership refined hygiene protocols and completed microbiological testing on initial product during the trial.LNS packaging. Designing single serving sachet packaging for SQ-LNS (i.e. 25–28 g/sachet) required considering the type of material, product stability, labeling, cost, transportation, and storage. After much discussion, the partners finalized sachet packaging material as triple laminated with low-density polyethylene as a compromise between cost and ability to extend shelf life. As required by Codex Alimentarius, a set of food standards established by the World Health Organization (WHO) and the Food and Agriculture Organization of the United Nations (FAO), the partners included labeling of ingredients on each individual serving sachet. Additionally, they decided on the size of each sachet, the number of sachets per box (labelled with ingredients and storage instructions), and the number of boxes in a shipping box. Importantly, the partners ensured that the sachet marked an ‘easy tear’ location after hearing that other regional programs learned during implementation that community members resorted to using razors when unsure how to open the product, which could introduce contamination.Maintaining quality and hygiene standards. Adhering to Codex Alimentarius requirements was important for LNS designed for young children. Thus, the partners carefully scrutinized manufacturing standards on quality and hygiene and put qualitycontrols in place. The various elements of this component included a) factory line cleaning and hygiene protocols, b) sourcing of affordable but high-quality local ingredients, c) batch-specific microbiological and contaminant testing and approval, and d) shelf-life testing and expiry date labeling.Olympic Industries management instituted strict protocols for their staff to support proper hygiene. Between batch productions, factory staff rigorously and thoroughly cleaned the machinery to remove any contamination that could have built up. One challenge in Bangladesh was to procure ingredients of consistently high quality. Further, it was not possible to trace the purchased product back to a specific region or farm, as a vestige of the complex, multistep supply chain system in rural, agricultural Bangladesh. The small scale of production by family farms in Bangladesh meant that a bulk purchase of 300 kilograms of lentils was likely composed of product from more than 10, if not a multiple of 10, farms. This aspect of the supply chain highlights the challenges producers may face when trying to procure ingredients of consistent quality at scale. To address this challenge, Olympic Industries routinely procured from a wholesale market three hours away from Dhaka. During each market visit, the procurement lead identified the vendor with the highest quality product. Of note, milk powder and the vitamin and mineral premix were sourced outside of Bangladesh.Related to the raw ingredients, one of the first challenges the partners faced was that the first few batches had higher than permissible levels of mold contamination. This resulted in increasing rigor in purchasing quality ingredients and in pre-picking, -sorting, and -sifting lentils and chickpeas. These consistent actions helped reduce the risk of contamination.SGS Laboratory in France for testing and certification. At the time of this activity the icddr,b laboratory followed ISO 17025 but had not concluded global accreditation. This testing and certification process in France was time consuming requiring two or three days for sample shipment to SGS and at least 10 days for analyses and report generation and cost over $1000 per sample. Thus, the lack of availability of a credible local laboratory for contaminant testing increased the cost of and time required for testing and ultimately production at scale. This type of delay regularly challenged the supply pipeline and required a dedicated budget.One of the most persistent challenges the partners faced was achieving and maintaining appropriate microbiological and contaminant standards in the final product. Due to not having local laboratories that could certify the hygiene quality of the products, Olympic Industries and the partners had to ship samples from each lot to theBacillus cereus either unexplainable or possibly resulting from a number of factors ranging from a contaminated batch of ingredients to a protocol breach with staff hygiene practices.Another significant hurdle was not having Codex-specified cut-offs for microbiological levels at the time this project was undertaken. Fortunately, we were able to apply WFP’s established cut-offs. The food technologists discussed each report and determined acceptability of the lot. In the event a batch was classified as contaminated, Olympic burned the whole batch, often about three metric tons worth  and started over again with production and SGS contaminant testing. Contamination was largely due to elevated total plate count, total coliforms, molds, and for wider programmatic use of such products in high burden countries. At scale production and procurement of complementary food supplements will require country and regional manufacturing capacity to meet the demand of wide-scale use. While the study collaborators did not anticipate several challenges faced throughout the process of developing and producing two new, local LNS products for trial purposes, the lessons learned from our experience can help provide a model to replicate and improve production in other low-resource context including partnerships with food manufacturers as well as creating systems for testing the quality and safety of the products . Adding this element would be of great benefit to future researchers undertaking the task of developing and testing specialised nutritious foods in low-resource settings. It would also have been useful to compare and contrast the Bangladesh experience with those similar experiences elsewhere that have been documented, notably in Cambodia (BorgDoes the article adequately reference differing views and opinions?PartlyAre all factual statements correct, and are statements and arguments made adequately supported by citations?YesIs the Open Letter written in accessible language?YesWhere applicable, are recommendations and next steps explained clearly for others to follow?YesIs the rationale for the Open Letter provided in sufficient detail?YesReviewer Expertise:Development of locally produced ready-to-use supplementary foodsI confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. The manuscript describes the route the authors have taken to design, develop and trial a lipid-based nutrient supplement in Bangladesh. The letter details the various aspects of building partnerships with local and international institutions, think-tanks and companies in order to produce more accessible LNS. The manuscript is very well-written and is a great example and inspiration for researchers who aim to develop nutrition interventions in low- and middle-income countries. Although not a ground for revision/rejection, I would appreciate this letter even more if description of the warehousing and storage of the products are also described. How do we maintain the stability and shelf-life of the products during storage? Do we need large temperature-controlled warehouses? Nonetheless, I believe this paper is an important manuscript. As the letter only explains their experiences, there are no methodological, statistical nor technical aspects to be reviewed. I therefore recommend indexing this paper as it is.Does the article adequately reference differing views and opinions?NoAre all factual statements correct, and are statements and arguments made adequately supported by citations?YesIs the Open Letter written in accessible language?YesWhere applicable, are recommendations and next steps explained clearly for others to follow?YesIs the rationale for the Open Letter provided in sufficient detail?YesReviewer Expertise:child malnutrition, food technology, molecular epidemiology, food chemistryI confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.


Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease affecting global public health at present, which can induce cirrhosis and liver cancer in serious cases. However, NAFLD is a multifactorial disease, and there is still a lack of research on its mechanism and therapeutic strategy. With the development of the gut–liver axis theory, the association between the gut–liver axis and the pathogenesis of NAFLD has been gradually disclosed. Polysaccharides, as a kind of natural product, have the advantages of low toxicity, multi-target and multi-pathway action. It has been reported that polysaccharides can affect the gut–liver axis at multiple interrelated levels, such as maintaining the ecological balance of gut microbiota (GM), regulating the metabolites of GM and improving the intestinal barrier function, which thereby plays a protective role in NAFLD. These studies have great scientific significance in understanding NAFLD based on the gut–liver axis and developing safe and effective medical treatments. Herein, we reviewed the recent progress of polysaccharides in improving nonalcoholic fatty liver disease (NAFLD) through the gut–liver axis. Non-alcoholic fatty liver disease, which mainly refers to a clinicopathological syndrome characterized by lipid accumulation and inflammation, is caused by multiple factors , in addition to alcohol and other certain liver damage factors . It includes non-alcoholic fatty liver (NAFL), non-alcoholic steatohepatitis (NASH), related liver cirrhosis and hepatocellular carcinoma . Over thIn recent years, more and more researchers have focused on the study of the gut–liver axis and found that the intestinal mucosal barrier, gut microbiota (GM) and its metabolites are closely related to the pathogenesis of NAFLD . The gutPolysaccharides are biological macromolecules composed of 10 or more monosac-charides linked by glycosidic bonds. Structurally, glycosidic bonds can link different types of monosaccharide molecules in multiple ways and at multiple sites, and finally form polysaccharides with complex and diverse main and branched structures . In addiThe gut–liver axis, consisting of the gut barrier, GM, and liver, is named after the close anatomical and biological function between the gut and liver. From an anatomical point of view, both the intestinal and liver embryos originate from the foregut. They also build a bidirectional interaction through the portal vein and the enterohepatic circulation of bile, where the portal vein can transport intestinal-derived products to the liver, and then the liver secretes bile and antibodies into the gut. In terms of biological functions, the gut and liver together constitute a defense barrier for the body to contact exogenous substances . TherefoThe pathogenesis of NAFLD is complex, and previous studies have focused on de novo lipid synthesis in the liver and oxidative stress responses ,21. WithGM is a diverse ecosystem composed of bacteria, protozoa, archaea, fungi and viruses, which also coexist with the human body in a specific symbiotic relationship . The floGM is a part of the human metabolism and immune system, which is essential for human health. Under normal circumstances, huge amounts of microbiota coexist in a certain proportion, maintain the intestinal microecological homeostasis, and participate in the process of food digestion, bile acid metabolism, and intestinal mucosal immunity . StudiesA variety of specific metabolites may be involved in the interaction of GM with the liver through the gut–liver axis. Among them, LPS, secondary bile acids, SCFAs, and choline metabolites, such as trimethylamine (TMA), and trimethylamine N-oxide (TMAO), were found to be associated with NAFLD . DysbiosUnder normal circumstances, the intestinal flora may conduct material exchange  and signal transduction  with the liver via the intestinal barrier. When the homeostasis of the intestinal flora was disrupted, the composition and proportion of the flora may be changed, and accordingly, the metabolites of the flora may be affected. These events may eventually lead to liver inflammation, insulin resistance, lipid metabolism and glucose metabolism disorders, and further the occurrence and development of NAFLD.(I) The concentration of LPS may increase owing to the increased producing bacteria. LPS stimulation may damage the local mucosa of the intestinal tract, which may cause LPS to pass through the compromised intestinal barrier and enter the liver through the portal vein and finally induce an inflammatory cascade in both the intestine and liver.(II) SCFAs may participate in the regulation of lipid and energy metabolism, insulin sensitivity, and oxidative stress. When the total amount of SCFAs decreased, their positive regulatory function in the liver would be attenuated.(III) Trimethylamine (TMA), a metabolite formed from choline metabolism by gut flora may be transformed to trimethylamine oxide (TMAO) in the liver, which may increase the level of TMAO, reduce the utilization of choline in the liver, and lead to dysregulation of hepatic lipid metabolism and glucose metabolism.(IV) During the bile acid cycle, the bile acids converted from cholesterol in the liver may be metabolized into secondary bile acids by the intestinal flora. When bile acid homeostasis was disrupted, in that the secondary bile acids are reduced, the corresponding FXR and TGR5 signaling in the liver may be weakened, which may in turn adversely affect hepatic lipid and glucose metabolism.O-antigen) [LPS is a complex amphiphilic molecule derived from the cellular wall of Gram-negative bacteria, consisting of a hydrophobic part (lipid A) and a hydrophilic part (carbohydrate core and polysaccharide antigen) . LPS wasantigen) . LPS mayantigen) .Lactobacilli, Bifidobacteria, Clostridium and Bacteroides in the gut could deconjugate BAs, which may not only increase the absorption of bile acids in the gut but also enhance toxicity tolerance to bile acids and their derivatives [Bile acids (BAs) are the main components of bile. Cholesterol could be metabolized to primary bile acids in hepatocytes by cholesterol 7α-hydroxylase (CYP7A1) . The BAsivatives ,42. In aivatives . Conversivatives . Since Bivatives ,45,46. Iivatives . In thisivatives . Studiesivatives . TGR5, aivatives . It was ivatives ,51. In aivatives . It can SCFAs, another kind of important metabolite of GM, are mainly produced in the cecum and proximal colon . SCFAs iUnder normal circumstances, the liver uses choline to produce phosphatidylcholine (lecithin). When the microbial flora proliferates abnormally, the choline in the diet may be consumed excessively, which may reduce the effective utilization of choline by the liver and further induce dyslipidemia, eventually NAFLD. On the other hand, GM may metabolize choline into toxic TMA. Then, TMA may be oxidized by hepatic flavin-containing monooxygenase 3 (FMO3) to TMAO after being transported to the liver . Once thThe intestinal mucosa is a semipermeable membrane barrier with complex functions, which may serve as a line of defense for gut–liver interactions. On the one hand, intestinal mucosa allows nutrients to enter the circulatory system and reach the liver; on the other hand, it can separate the substances in the intestinal lumen and limit the transmission of intestinal microorganisms and endotoxins to the liver. Therefore, intestinal mucosa plays an important role in the homeostasis of the gut–liver axis. Broadly, the intestinal barrier is divided into the biological barrier, mechanical barrier, chemical barrier and immune barrier. Among them, the biological barrier is composed of normal GM, while the chemical barrier is composed of gastric juice, bile, mucus, mucin, mucopolysaccharide, various digestive enzymes, lysozyme, and other chemicals secreted by the gastrointestinal tract . The intThe intestinal mucosal mechanical barrier is mainly composed of mucosal epithelial cells and their intercellular junction complexes, the latter mainly including tight junctions (TJs) and subsequent adhesive junctions. The proteins that constitute TJs include occludin and claudins, which maintain the integrity of the mechanical barrier . TJs are+ T lymphocytes in mesenteric lymph nodes (MLN) play an important role in resisting gut bacteria. Their different cell subtypes serve different functions, and the changes in the proportion of cells of their subtypes are related to NAFLD. For example, T helper cells (Th1 and Th17) derived from naive T cells are involved in the pro-inflammatory response, whereas Th2 and Treg cells have an antagonistic function [+ T lymphocytes in MLN in the progression of NAFLD. They found that Th1/Th2 and Th17/Treg ratios were increased in the intestinal MLN of NAFLD mice. These results suggested the imbalance between pro-inflammatory and anti-inflammatory responses causes intestinal inflammation during the pathogenesis of NAFLD, which may further aggravate intestinal barrier damage and promote the disease process. In addition to changes in CD4+ T lymphocytes and their subtypes in MLN, changes in sIgA produced by B cell differentiation also affected the occurrence and development of NAFLD. IgA is the major immunoglobulin subtype in the gut which may help maintain the stability of the gut homeostasis. IgA secreted into the intestinal lumen (or sIgA) has multiple functions, including controlling the composition of the microbiota and protecting the intestinal epithelium from pathogenic microbiota [In terms of the immune barrier, lymphoid tissue and some immune cells  at the lamina propria of the intestinal mucosa together with the immune molecules  secreted by plasma cells may act as a line of defense to enhance intestinal barrier function. This defense line may exert immune defense against invading antigens  that cross the intestinal mechanical barrier . Studiesfunction ,67. Su ecrobiota . Yang etcrobiota  found thcrobiota ,71. Convcrobiota . These pIn the gut–liver axis, the gut barrier generally maintains structural integrity and permeability. Under the action of multiple factors, such as the abnormal expression of tight junction proteins, diet, drugs and physiological factors , and abnormal changes in the composition of intestinal flora, the intestinal mucosal barrier function is impaired, and intestinal permeability occurs. The change promotes the translocation of the flora and the entry of LPS into the blood, induces inflammation, and then NAFLD.(I) Some immune cells in the lamina propria of the intestinal mucosa  and their secreted immune molecules  can serve as a line of defense to enhance the function of the intestinal barrier. When the immune system is unbalanced, the IgA secreted by plasma cells produced by B cell differentiation decreases, which will aggravate the translocation of intestinal bacteria and the entry of LPS into the blood.(II) Helper T cells (Th1 and Th17) derived from initial T cell differentiation participate in the pro-inflammatory response, which in turn accelerates intestinal barrier damage and causes bacterial antigens to enter the liver through the intestinal barrier, eventually promoting the occurrence and development of NAFLD.In recent years, polysaccharides have attracted wide-spread attention for their physiological properties, such as anti-virus , anti-tuGastrodia elata Blume polysaccharides could exert a protective effect on a high-fat diet (HFD)-induced NAFLD by improving liver function in mice, regulating lipid metabolism, alleviating hepatic oxidative stress injury, inhibiting inflammation, and inhibiting hepatocyte apoptosis [Lycium barbarum polysaccharides on NAFLD is mainly reflected in the promotion of mitochondrial biogenesis, the regulation of energy balance, a reduction in intracellular lipid accumulation, and a reduction in oxidative damage in NAFLD cell models [Studies have also shown that polysaccharides play a significant role in ameliorating NAFLD, a multi-factor-induced liver injury disease recently. For example, poptosis . Chicorypoptosis . Lentinapoptosis . It has l models . These sBased on the above understanding of the induction mechanism of NAFLD, it is possible to further explore the active molecules that prevent and treat NAFLD through the gut–liver axis. Due to the potential role of polysaccharides in NAFLD, the effect and mechanism of polysaccharides on improving NAFLD via the gut–liver axis have been investigated in recent years based on NAFLD disease models and changes in relevant biochemical indicators and histology, as well as in the species and composition of intestinal flora. The relevant results are shown in Astragalus polysaccharides (APS) on HFD-induced NAFLD mice by using targeted metabolomics and metagenomics. It was found that compared with the high-fat diet model group, the abundance and uniformity of intestinal bacteria in the APS group were significantly increased. Furthermore, in the APS group, the abundance of Firmicutes decreased while that of Bacteroides increased, in that the F/B ratio decreased. These results indicated that the NAFLD hepatic steatosis may be improved by APS in a microbiota-dependent manner. Similarly, Chen et al. [Sarcodon aspratus polysaccharide (SATP) in improving NAFLD based on the micro-ecological balance of gut microbiota. The results showed that the diversity of intestinal flora in NAFLD mice was reduced, and the ratio of F/B was significantly higher than that of normal mice. GM diversity increased and the F/B ratio decreased after SATP administration. Additionally, the abundance of beneficial bacteria including Lactobacillus (Firmicutes), Bacteroides and Akkermansia (Verrucomicrobia) increased significantly, indicating that the GM disorder was improved. This study also indicated that the gut microbiome is a complex formed by the interaction of various bacterial groups, not just dominated by F/B.As the two largest phyla of GM, Firmicutes and Bacteroidetes ratio  is one of the focuses of many pieces of research. Due to the complexity of the gut microbiome, the use of F/B as a biomarker for gut dysbiosis remains controversial . Analysin et al.  used a hTherefore, GM and its gut microbiome are key components of the gut–liver axis and are closely related to the host glucose and lipid metabolism, immunity, oxidative stress and other processes . AccordiPoria cocos polysaccharide (PCP) on NAFLD and explored its underlying mechanism. The results showed that PCP could effectively improve the liver injury of NAFLD. In comparison with the model group, the expressions of tight junction proteins (ZO-1 and occludin) were significantly up-regulated, while the expression of the intestinal vascular barrier (GVB) damage marker protein PV1 was significantly decreased, suggesting that PCP could protect the integrity of GVB and reduce the transfer of LPS to the liver. A further study on the mechanism found that PCP could inhibit the pyroptosis of small intestinal macrophages by regulating PARP-1 to protect the integrity of the intestinal barrier under a high-fat diet, and thus play a role in improving NAFLD.As previously mentioned, increased intestinal permeability resulting from impaired intestinal mechanical and immune barriers is one of the important mechanisms promoting the progression of NAFLD. LPS produced by intestinal flora metabolism might activate intestinal mucosal adenylate cyclase, affect mitochondria and lysosomes in epithelial cells, and then cause damage to the top of intestinal villi and epithelial cells ; on the Clostridium subcluster XIVa), suggesting that the polysaccharide mediate the production of SCFAs, play a role in protecting the intestinal barrier function, and ultimately achieve the purpose of alleviating NAFLD. From the perspective of source, Hu et al. [Human small intestinal glucoamylase is suitable for digesting and degrading food-derived starch, lactose and sucrose, while the remaining complex polysaccharides  that are not digested are mainly decomposed by GM fermentation, and are the main carbon source of GM ,117. Wheu et al.  used psySCFAs are not only an essential energy source for the body but also function as signaling molecules. In recent years, the role of SCFAs in lipid metabolism, inflammation, and oxidative stress has attracted the attention of many scholars. Yao et al.  found thCholesterol forms BAs through the action of enzymes such as cholesterol synthesis rate-limiting enzyme CYP7A1 in the liver, and this amphiphilic molecule is released in the biliary tract after binding to glycine or taurine. In the intestine, BAs are involved in the digestion of emulsified fat, cholesterol, and fat-soluble vitamins, and promote the absorption of meals in the small intestine. Although most BAs are reabsorbed back into the liver, a small fraction of BAs can be uncoupled, dehydrogenated, and dehydroxylated by GM to form secondary bile acids ,35,130. Grifola frondosa heteropolysaccharide (GFP) as the treatment substance and NAFLD rats formed by HFD as the modelling group to study the improvement effect of GFP on NAFLD and explored the potential mechanism. Compared with the model group, the polysaccharide group could change the GM composition ratio, reduce F/B, significantly increase beneficial bacteria such as Allobaculum, Bacteroides and Bifidobacterium, and reduce the abundance of harmful bacteria such as Acetatifactor, Alistipes, Flavonifractor, Paraprevotella and Oscillibacter. In addition, the study also found that the gene expression of CYP7A1 was significantly increased after GFP intervention compared with the model group, and the expression of ACC, TNF-α and SOCS2 was effectively reduced. These results indicated that GFP could promote the conversion of hepatic cholesterol to BAs, improve cholesterol utilization, and reduce its accumulation to improve NAFLD. At the same time, it is suggested that GFP may play a certain role in promoting fat metabolism, reducing liver lipid levels and being anti-inflammatory. Huang et al.  exploredRegulation of bile acid cycle-related receptors  and their signaling pathway can affect the occurrence and development of NAFLD ,47,48. PGanoderma lucidum polysaccharide peptide (GLPP) (polysaccharide-peptide ratio of 95%: 5%) in improving NAFLD. GLPP could reverse the low expression of CYP7A1, FXR, SHP  and other proteins and the high expression of FGFR4 in the liver of ob/ob mice and ApoC3 transgenic mice to regulate bile acid synthesis, and inhibit fatty acid synthesis by down-regulating the expression of SREBP1c, FAS, ACC, thereby ultimately improving NAFLD. During the bile acid cycle, most of the primary bile acids converted from hepatic cholesterol flow into the intestine through BSEP, then can be reabsorbed by intestinal ASBT, and enter the portal vein through OSTα/β. Finally, bile acids are taken up by NTCPs and OATPs into the liver [Zhong et al.  investighe liver . Therefohe liver ,134. Wanhe liver  studied These studies suggested that polysaccharides could reduce the levels of harmful metabolites of gut flora , increase the type and abundance of beneficial metabolites , and regulate the related signaling pathways of the bile acid cycle through the flora, thereby playing an active role in anti-NAFLD. Polysaccharides can not only regulate the composition and proportion of intestinal flora, increase the diversity of flora and increase the abundance of beneficial bacteria, but also regulate flora metabolites and affect their related signaling pathways, thereby improving or preventing NAFLD.(1) Polysaccharides regulate the composition and proportion of intestinal flora, such as reducing Firmicutes (F)/Bacteroidetes (B) ratio, promoting the colonization of beneficial flora , and improving the microecology of intestinal flora, thereby play a role in prevention and treatment NAFLD.(2) Polysaccharide inhibits the increase in LPS level, on the one hand, it reduces its stimulation to intestinal epithelial cells, reduces the inflammatory response of intestinal epithelial cells, reduces the damage of tight junction proteins, and improves intestinal barrier function; On the other hand, it reduces the entry of LPS into the liver through the portal vein and the production of LPS–LBP conjugates, which subsequently reduces the response of CD-14 and inhibits the activation of the TLR4 pathway, thereby reducing liver inflammation and relieving NAFLD ((3) Polysaccharides act as prebiotics to increase SCFAs in the body. Such metabolites are not only beneficial to repairing the intestinal barrier and reducing harmful substances entering the liver, but also bind to receptors such as GPR41 and GPR43 in the liver after entering the blood through the portal vein, regulate the AMPK signaling pathway, increase lipid oxidation, decrease the expression of PPARγ and SREBP1c and reduce the synthesis and accumulation of hepatic lipid ((4) Primary bile acids can be biotransformed to secondary bile acids under the action of GM. Polysaccharides affect bile acid metabolism and regulate the ratio between each bile acid. For example, polysaccharides can reduce FXR antagonist BAs  and increase FXR agonist BAs ; polysaccharides may also reduce the synthesis of cytotoxic BAs  and increase the synthesis of cytoprotective BAs . The absorption of BAs into the liver can enhance the FXR-related signaling pathway, which not only induces the expression of the downstream target gene SHP, negatively regulates SREBP1c, and downregulates the expression of genes related to fatty acid syntheses, such as FAS and ACC, to reduce hepatic lipogenesis, but also reduces insulin resistance (IR) to ameliorate NAFLD ((5) Bile acids can be synthesized by CYP7A1, transported by BSEP, and reabsorbed into the liver by ABST and OSTα/β. Polysaccharides may have a certain regulatory effect on the bile acid cycle and excretion. Polysaccharides can indirectly upregulate the activity of CYP7A1 through bile acid cycling, increase the conversion of liver cholesterol to bile acids, and increase the utilization of cholesterol; at the same time, up-regulate the expression of BSEP and down-regulate the expression of intestinal ASBT, which may promote bile acid transport and inhibit the reabsorption of bile acids by the intestinal wall, thereby reducing intrahepatic bile acid accumulation and resulting liver damage  need to be carried out on the lead compounds of polysaccharides, which have not been reported yet.The incidence of NAFLD is increasing year by year, and long-term development can lead to liver cirrhosis and hepatocellular carcinoma. Moreover, NAFLD is closely related to chronic kidney disease, cardiovascular disease, and diabetes, all of which seriously threaten and affect public health and quality of life ,135. WitThis article reviews the pathogenesis of NAFLD from the perspective of the gut–liver axis, and mainly expounds on its correlation with NAFLD from the perspective of intestinal flora imbalance and intestinal barrier permeability. Compared with healthy individuals, NAFLD patients have an imbalanced gut microbiome and impaired gut permeability. On the one hand, the beneficial metabolites of GM, such as SCFAs, are relatively reduced, while the proportion of harmful metabolites, such as LPS, is increased. LPS enters the portal vein through the damaged intestinal barrier, causing inflammation and energy metabolism disorders in the liver. At the same time, under the action of GM, the ratio of different types of bile acids in the body may be changed, which will eventually adversely affect the metabolism of glucose and lipids in the liver through enterohepatic circulation. On the other hand, impaired intestinal mucosal barrier function, increased intestinal permeability, immune imbalance, decreased IgA secretion, and inflammatory responses involving immune cells promote bacterial translocation and LPS entry into the blood, which further induces hepatic inflammatory responses. On this basis, the mechanism of action of polysaccharides in improving or preventing NAFLD by regulating the gut–liver axis was analyzed. On the one hand, polysaccharides can regulate the type and proportion of GM through the gut–liver axis, guide the body to change in a beneficial direction, improve NAFLD via maintaining the ecological balance of the flora and exerting a certain intestinal barrier repair function. On the other hand, polysaccharides can promote the production of SCFAs and the proliferation of beneficial bacteria, and inhibit the production of LPS and the abundance of harmful bacteria, whilst regulating bile acid-related signaling pathways to combat NAFLD, suggesting that polysaccharides can be used as a potential prebiotic to improve or prevent NAFLD. It is worth noting that the mechanism of NAFLD improvement based on the bile acid cycling pathway has not been fully elucidated, and the effect of polysaccharide intervention on bile acid homeostasis and its GM regulation is still poorly understood, so it needs to be further explored.Studies have shown that traditional Chinese medicine has a significant effect on the treatment of NAFLD with fewer adverse reactions . PolysacAlthough polysaccharides have potential anti-NAFLD effects, there are few studies on their clinical translation and practical application. Furthermore, their efficacy and druggability are still unclear. Moreover, compared with small molecules, polysaccharides are a class of macromolecular compounds with more complex structures, the related profound research has not yet been conducted. For example, the multi-target, multi-level mechanisms of action of polysaccharides and their relationships with structure have not been elucidated. Therefore, an in-depth study and understanding of the structure–activity relationship of active polysaccharides and more precise regulation of GM and repair of the intestinal barrier using the principle of the gut–liver axis will help to improve the therapeutic effects of polysaccharides on NAFLD and contribute to the discovery of a new generation of polysaccharide prebiotics. In addition, different types of GM may have different physiological and metabolic functions, and there will also be synergistic or competitive effects between bacterial groups. Revealing the intervention effect of polysaccharides based on the metabolic mechanism of GM will help to understand the mechanism of “specific polysaccharide–corresponding bacteria (species)–liver” interactions. It may also be more helpful in the development of more precise and targeted polysaccharide drugs.


Around the world rates of self-harm vary, placing immense strain on health services. Approximately 20% of children and adolescents are thought to engage in self-harm. The systematic review aims to explore the characteristics, risks and protective factors of ethnicity and religion on self-harm in comparison to the general population. Better identification of risk factors can help professionals and local authorities develop intervention programs to mitigate the incidence of self-harm.The Population, Exposure, Outcome, Study design and setting (PEOS) was used as a framework to formulate the question for this systematic review. A literature search was conducted using EMBASE, MEDLINE and APA PsycInfo databases and all English articles published between 2010 and 2020 were screened against the inclusion and exclusion criteria.Fourteen studies which met the criteria were identified and appraised using the Joanna Briggs Institute (JBI) critical appraisal checklist.Unintentional injuries, sexual behaviours, adverse childhood experiences, health status and poverty alongside racial discrimination were associated with self-harm and or suicidal ideation in ethnically diverse populations. In African Americans, Hispanics and Whites, violence or physical altercation, illicit substance misuse, sadness and hopelessness increased the risk of self-harm and or suicidal ideation. The association of subtle forms of discrimination and suicidal ideation was noted to be statistically significant for African Americans, whereas for Latinx this was only marginally increased. Low mood and hopelessness in African American girls, substance misuse in American Indian youths, and aggression in the Caribbean cohort were also noted to present with increased self harm.Adolescent's religiosity and parental monitoring had both a direct and an indirect role for suicidal ideation reduction. Religious importance and attendance at religious services by offspring and parents decreased self-harm in female adolescents more than males.There was a wide heterogeneity in the population and factors reviewed in the different studies, hence pooling of data for meta-analysis of the quantitative studies was not appropriate to estimate prevalence or association between factors and characteristics of the population.This narrative synthesis provides evidence that minority ethnic groups have unique factors, which can increase the rate of self-harm. Religion or spirituality favours a protective role in self-harm or suicide but not for suicidal ideation, although there were only a limited number of articles exploring this.Future studies should focus on defining the ethnic groups further and exploring this and religious factors on a wider scale using standardised parameters.