In recent years, more than 120 million people each year have needed urgent humanitarian assistance and protection. Armed conflict has profoundly negative consequences in communities. Destruction of civilian infrastructure impacts access to basic health services and complicates widespread emergency responses. The number of conflicts occurring is increasing, lasting longer and affecting more people today than a decade ago. The number of children living in conflict zones has been steadily increasing since the year 2000, increasing the need for health services and resources. This review systematically synthesised the indexed and grey literature reporting on the delivery of trauma and rehabilitation interventions for conflict-affected populations.A systematic search of literature published from 1 January 1990 to 31 March 2018 was conducted across several databases. Eligible publications reported on women and children in low and middle-income countries. Included publications provided information on the delivery of interventions for trauma, sustained injuries or rehabilitation in conflict-affected populations.A total of 81 publications met the inclusion criteria, and were included in our review. Nearly all of the included publications were observational in nature, employing retrospective chart reviews of surgical procedures delivered in a hospital setting to conflict-affected individuals. The majority of publications reported injuries due to explosive devices and remnants of war. Injuries requiring orthopaedic/reconstructive surgeries were the most commonly reported interventions. Barriers to health services centred on the distance and availability from the site of injury to health facilities.Traumatic injuries require an array of medical and surgical interventions, and their effective treatment largely depends on prompt and timely management and referral, with appropriate rehabilitation services and post-treatment follow-up. Further work to evaluate intervention delivery in this domain is needed, particularly among children given their specialised needs, and in different population displacement contexts.CRD42019125221. Armed conflict causes direct harm to civilians and has detrimental consequences for health systems, with impacts on infrastructure and health facilities affecting the provision of and access to health service including trauma and rehabilitation care.Acts of violence in the context of contemporary armed conflict are increasingly occurring in urban areas among civilian populations, with implications for the kinds of injuries sustained and the types of trauma and rehabilitation services needed at the population level.Traumatic injury from exposure to violence, land mines and other explosive remnants of war can cause devastating and long-lasting physical and psychological disability. Prompt management of traumatic injuries, and long-term follow-up care and rehabilitative services are vital to improve quality of life.Very little of the existing literature on the delivery of trauma and rehabilitation interventions to conflict-affected women and children focuses on the delivery of interventions targeted at women or children specifically, and no intervention effectiveness evidence for either of these populations is reported.Most of the literature on the delivery of trauma and rehabilitation interventions to conflict-affected women and children documents the use of highly skilled or specialised health staff providing surgical management in inpatient or fixed outpatient facilities, but the delivery of a range of interventions through mobile or outreach modes was also documented. The availability (or lack) of specialised expertise for treating paediatric patients, and of medical supplies and surgical equipment appropriate for paediatric patients, was reported as an important factor affecting intervention delivery.There is very little documentation in the literature of the delivery of relevant community-based interventions, with a single publication reporting on a mine risk reduction programme delivered by community health workers, teachers and civic leaders.As the number of women and children affected by armed conflict continues to increase, the lack of evidence on effective approaches for reaching these populations with appropriate trauma and rehabilitation services remains a significant knowledge gap.Further work is needed to evaluate trauma and rehabilitation intervention effectiveness among women and children and to identify effective intervention delivery approaches for these populations in different population displacement contexts.Landmine Monitor, an initiative that provides systematic monitoring and assessment of the international community’s response to the issues caused by land mines, cluster munitions and other explosive remnants of war (ERW), reported that in 2017, children accounted for 47% of all civilian casualties where the age was known, and women and girls made up 13% of all casualties where the sex was known.7 8As the nature of conflict is changing, acts of violence in the context of contemporary armed conflict are increasingly occurring in urban areas among civilian populations leading to deaths and life-changing injuries as a result of trauma.Physical trauma in any setting often occurs suddenly, causing life-threating and life-altering injuries which can require extensive measures for survival and a range of subsequent rehabilitation services aimed at improving quality of life, sustaining and maintaining functionality and developing adaptive capacity. In development settings in low and middle-income countries (LMIC), trauma and rehabilitation capacity are often already highly deficient,11Armed conflict provokes a wide variety of injuries, and while everyday trauma still persists, conflict-specific injuries differ from those seen in everyday trauma practice.15A previous systematic review examined the quantity and quality of the literature on the provision of injury and rehabilitation services in humanitarian crises. Sixty-two per cent of the reviewed studies were conducted in conflict settings or with patients who had suffered conflict-related injuries, and 98% of the papers described interventions for the general population.16This current review is one of a set of eight systematic reviews examining the delivery of health and nutrition interventions to conflict-affected women and children. Here we aimed to systematically synthesise the indexed and grey literature reporting specifically on the delivery of trauma and rehabilitation interventions to women and children in conflict settings, to identify how, where and by whom these interventions have been and are being delivered and to better understand existing intervention gaps in this domain. We ultimately aim for this review to help inform future implementation and delivery guidance in this domain.A systematic search of literature published from 1 January 1990 to 31 March 2018 was conducted in MEDLINE, Embase, CINAHL and PsycINFO using Medical Subject Headings terms and keywords related to three concepts: (A) conflict; (B) women and children; and (C) trauma and rehabilitation. Conflict-related search terms included war, crisis, refugees, internally displaced person (IDP) and stateless. Population-related words included women, children, pregnant, adolescents and newborn. Terms related to trauma and rehabilitation included war-related trauma, amputation, traumatic brain injury, orthopaedics, physiotherapy, and so on. The complete search syntax used for the MEDLINE database is included in online supplementary appendix B. We also screened reference lists of key systematic reviews conducted previously in the field of humanitarian health.For grey literature, we searched the websites of 10 major humanitarian agencies and organisations that are actively involved in humanitarian health research or response for women and children in conflict situations for reports on the implementation of health interventions in our population of interest. These websites included: Emergency Nutrition Network, International Committee of the Red Cross, International Rescue Committee, Médecins Sans Frontières, Save the Children, United Nations Population Fund, United Nations High Commissioner for Refugees, UNICEF, Women’s Refugee Commission and World Vision. We used broad terms for conflict and health interventions tailored to the search functionality of each website. Documents published from 1 January 2013 to 30 November 2018 were reviewed.Eligible publications were those reporting on populations affected by conflict in low or middle-income countries, as classified by the World BankNon-English publications; case reports of single patients; publications reporting on military personnel, refugee populations bound for a high-income country, economic or mathematical modelling; and editorials and opinion pieces were excluded from our review. Other excluded publications included systematic reviews, guidelines and publications where no specific health intervention was described .All identified indexed records were downloaded into EndNote and duplicates were removed. Unique records were subsequently imported into Covidence for screening. Titles and abstracts were reviewed in duplicate, and the full text of each potentially relevant publication was then screened by one reviewer, with reasons for exclusion noted at this stage.Data and information from the indexed and grey literature publications that met the review eligibility criteria were extracted in duplicate into a customised Research Electronic Data Capture form. Key variables with regard to authors and publication year, setting, target population, study design and intervention descriptions were extracted. The double-entered data were matched and any inconsistencies identified were corrected.Descriptive statistics were generated to summarise key characteristics of the population and intervention, including population displacement status and intervention delivery characteristics, and we narratively synthesised reported information on the factors impeding or facilitating intervention delivery. We tabulated any reported data on intervention coverage and effectiveness measured in relation to our population of interest; given the scarcity of such data, no meta-analysis was attempted.Neither patients nor the public were involved in the conduct of this systematic review.We identified 13 040 unique citations from indexed databases, 220 of which were screened as potentially relevant and assessed in full text, with 72 meeting our inclusion criteria . Six addPublications ranged from January 1991 to March 2018. Despite yearly variations in the frequency of publications by year, these numbers remained low. The greatest number of publications from a single year was seen in 2013, with a total of 9. The number of publications shows a peak in 2010 and again in 2013. No eligible publications were identified during 1990, 1998 and 2005. The start years of interventions reported spanned from 1975 to 2015, with peaks in 1990-91 and 2006, and remained relatively high in comparison to the previous years .Of the included publications, 16% (13/81) reported the delivery of interventions specifically targeted at child and adolescents, but no publications reported on interventions specifically targeting women. The majority of publications  reported interventions that included the general population. In regard to displacement status, half of the publications  reported on intervention delivery in conflict-affected populations that were not displaced, 6% (7/81) reported on intervention delivery in refugee populations and 4% (4/81) in internally displaced populations (IDP). The existing healthcare system and military-based healthcare were the most commonly reported platforms involved in the delivery of interventions, reported by 49% and 33% of publications, respectively.The vast majority of publications  reported the results of observational research studies employing retrospective chart reviews in facility settings. Only one publication provided quantitative data on intervention coverage or effectiveness among women or children, reporting the proportion of children and adolescents admitted to a trauma centre in Afghanistan who received physiotherapy.40Explosive devices and remnants of war  were the most commonly reported mechanism of injury, reported in 73 publications, 53 publications reported on injuries due to high-velocity/high-energy weapons and firearms. Burn injuries were reported in 13 publications, blunt trauma in 11 publications and crush injuries in 3 publications .Reported interventions were grouped into four types or stages: (1) prehospital/triage/non-surgical management, which included wound management, burn care, pain management and fracture fixation; (2) surgical management, including amputations, abdominal surgery, cardiothoracic surgery, general surgery, neurosurgery, ophthalmic surgery and orthopaedic/reconstructive surgery; (3) rehabilitative services and management; and (4) training or education programmes.The most frequently reported interventions delivered were orthopaedic/reconstructive surgeries, described in 53 publications, while 44 publications discussed amputations and 34 publications discussed fracture fixations. The delivery of prehospital/triage care was reported in 37 publications, and wound care was reported in 34 publications . The delWe classified sites of intervention delivery by their corresponding levels of care: inpatient, outpatient, outreach and community based . SurgicaWith respect to the personnel reported to be involved in the delivery of trauma and rehabilitation interventions, we found that highly specialised medical personnel were commonly reported across virtually all categories of interventions, including both civilian and military general and subspecialty surgeons, along with physicians, nurses and other trained health workers . ParamedOur review identified multiple elements that posed either as barriers or facilitators during the delivery of trauma and rehabilitation interventions . Commonl46 88Surgical procedures require trained personnel and injuries sustained due to warfare require specialised expertise for treatment, especially among paediatric patients. The availability of such skills and expertise, including through collaboration with other service providers, was another key determinant of intervention delivery reported in multiple publications. The availability of medical supplies and surgical equipment, including those appropriate for treating children, and the capacity to provide appropriate follow-up care were also commonly reported as important factors affecting intervention delivery.This systematic review included 81 publications reporting on the delivery of trauma or rehabilitation interventions to conflict-affected populations including women, children and/or adolescents in 26 countries. Surgical interventions were the most commonly reported interventions, particularly orthopaedic surgeries, followed by prehospital care and wound management interventions. Relatively few publications reported on the delivery of rehabilitation interventions, and very few reported on the delivery of pain management interventions. Specialised medical personnel and skilled health workers, including both civilian and military, featured in the delivery of the whole range of trauma and rehabilitation interventions reported, with the exception of the few education interventions captured in this review. Most reported interventions were delivered in inpatient settings, but multiple examples of outpatient intervention delivery and delivery through mobile surgical units and other outreach modalities were also reported. The availability of emergency transport and access to health facilities was a major determinant of effective intervention delivery, as well as the availability of specialised medical personnel and supplies, and capacity for patient follow-up. Quantitative data on intervention coverage or effectiveness among women, children or adolescents particularly were generally unreported.Our findings suggest a number of key gaps in the literature with respect to the kinds of trauma and rehabilitation interventions and delivery modalities reported, as well as the kinds of conflict-affected populations featured in the literature.reporting of such interventions is simply less frequent than the reporting of, for example, surgical interventions. Given the predominance in the literature of observational studies based on retrospective chart review particularly, the latter is certainly possible.Given the increase in both warfare and population displacement, prehospital management may now be more crucial than ever for the immediate management of trauma. Violent attacks are often unpredictable and designed to inflict maximum damage, causing widespread havoc in urban and rural areas and mass casualties that can quickly overwhelm local health facilities as well as transport and referral systems. The WHO-recommended trauma pathwayRecently, during the humanitarian health response to the siege of Mosul, Iraq, between October 2016 and July 2017, WHO identified the centrality of transport in its trauma management planning, noting that functioning referral pathways require viable ambulance networks with ‘care providers at the paramedic level or above during transport’ to provide en route care.Trauma and injuries due to armed conflict remain a major cause of morbidity and mortality worldwide,Of the 81 publications included in our review, only 14 focused on children or adolescents as the target population for trauma or rehabilitation intervention delivery . Even from within this limited literature, however, some potentially useful insights emerge. The availability or lack of paediatric expertise and of medical supplies and surgical equipment appropriate for paediatric patients was reported as an important factor affecting intervention delivery, for example. An analysis of children with blast injuries in Afghanistan and Iraq concluded that documenting the particular surgical operative needs of child injuries promotes the development of plans to provide appropriate surgical care, helps guarantee the availability of age-appropriate surgical equipment and helps ensure predeployment education of the personnel who will provide humanitarian surgical care to paediatric populations.In addition to the apparently limited documentation in the literature of trauma and rehabilitation intervention delivery for women and children in conflict settings, this review has other limitations. For logistical reasons, we restricted our review to reports published in English, and we conducted a comprehensive but not exhaustive search of the grey literature; both of these methodological decisions may have led to the exclusion of relevant publications providing different information on intervention delivery than what we have currently captured.Traumatic injuries require an array of medical and surgical interventions, and their effective treatment largely depends on prompt and timely management and referral, with appropriate rehabilitation services and post-treatment follow-up. The findings of our review provide some insight into where and how humanitarian health responders have been able to deliver this continuum of care to conflict-affected populations including women and children, and the challenges of doing so. However, the actual extent of trauma and rehabilitation intervention delivery in the field, the full range of delivery modalities being used and the effectiveness of those modalities are not comprehensively documented in the literature and remain largely unknown. Further work to evaluate intervention delivery in this domain is needed, particularly among children given their specialised needs, and in different population displacement contexts.10.1136/bmjgh-2019-001980.supp1Supplementary data


A growing body of evidence supports the importance of marginal or even supramarginal resection in cases of high- but also of low-grade gliomas ,2. SeverMany strategies have been recently developed for maximizing the extent of resection. The wide employment of neuro-navigation, the utilization of intraoperative imaging (ultrasound and/or MRI), the exponential increase in the application of intraoperative direct electrical stimulation and cortical and subcortical mapping techniques via an awake craniotomy, as well as the usage of fluorescent guided surgery have provided the opportunity to maximize the extent of resection in glioma cases, while at the same time, the patients’ safety and their functional neurological status remain intact.Maugeri et al.  accurateThe authors in their in-depth analysis also examine the future perspectives of fluorescent-guided surgery (FGS), identifying the necessity for performing randomized controlled studies for further evaluating the exact accuracy of FS . They alSpecial emphasis needs to be given to the potential role of FGS in the management of patients with recurrent glioblastoma multiforme (GBM) ,13,14,15Another subgroup of glioma cases demonstrating special interest is that of patients with low-grade gliomas (LGGs) ,18,19,20The development of novel fluorescent substances, which may target LGG cells could provide the opportunity for a more extensive resection, especially in diffuse, non-enhancing gliomas. Additionally, the importance of combining the method of fluorescent surgery along with all other developed and emerging surgical strategies for maximizing glioma resection cannot be overemphasized. The combination of FGS and intraoperative cortical/subcortical stimulation and mapping might further facilitate the goal of supramarginal resection in LGG cases, and thus improve the patient’s overall outcome. Moreover, the employment of FGS along with intraoperative Raman spectroscopy may even identify metabolically active areas, which cannot be visualized by the conventional preoperative imaging studies . NeverthFinally, the issue of the overall cost of FGS needs to be seriously taken into consideration. In an era in which health expenses are constantly expanding and most health systems struggle, emerging technologies need to be of low cost in order to be easily accessible and widely available. The cost of each of these adjuvant methodologies has to be counterweighted by its positive effect on the patient’s survival and overall outcome, as well as the long-term, associated health expenditures.


Adolescence is an important ontogenetic period that is characterized by behaviors such as enhanced novelty-seeking, impulsivity, and reward preference, which can give rise to an increased risk for substance use. While substance use rates in adolescence are generally on a decline, the current rates combined with emerging trends, such as increases in e-cigarette use, remain a significant public health concern. In this review, we focus on the neurobiological divergences associated with adolescent substance use, derived from a cross-sectional, retrospective, and longitudinal studies, and highlight how the use of these substances during adolescence may relate to behavioral and neuroimaging-based outcomes. Identifying and understanding the associations between adolescent substance use and changes in cognition, mental health, and future substance use risk may assist our understanding of the consequences of drug exposure during this critical window. Adolescence is characterized by a series of developmental changes occurring roughly between 10–19 years, with the timing of onset highly impacted by social, cultural, and nutritional influences Spear, . During Substance use  by adolescents remains a significant public health concern. According to the most recent National Epidemiologic Survey on Alcohol and Related Conditions, more than 50% of substance use initiation cases occur between the ages 15–19 , this approach helps to contrast the similarities and differences between the different drugs. We focus on findings from studies of substances most commonly used during adolescence, namely tobacco and e-cigarettes, alcohol, and cannabis , and pipe tobacco  were negatively correlated with the number of cigarettes smoked per day, that performance deficits were more pronounced in current smokers than non-smokers and former smokers, and that cognitive performance was lower in former smokers than non-smokers  looking at the markers of neurobiological function  before the appearance of substance use could help uncover the mechanistic underpinnings of the long-term consequences of substance use that have been reviewed here. Importantly, as studies indicate compounding detrimental effects of adolescent and prenatal drug exposure on neurological and cognitive outcomes  delivery methods are largely unknown outside of future drug use susceptibility. To date, only one neuroimaging study investigating young adult e-cigarette experimenters and those at risk to try e-cigarettes exists in the literature (Garrison et al., Moreover, through the reverse translation of findings from clinical populations, the causal underpinnings of the consequences of adolescent substance use can be uncovered. Related to the emerging trends such as the increases in vaping, the availability of animal models of self-administration using electronic devices, combined with pre-clinical neuroimaging methods, will help establish the direct causal consequences of adolescent vaping (Hines et al., Despite the overall recent downward trends in adolescent substance use the prevalence of adolescent substance use remains a significant public health concern, largely due to the consequences of this use and the especially vulnerable window of neurodevelopment during this period. In this review, we highlighted the neurobiological and behavioral changes that arise from adolescent nicotine, alcohol, cannabis, and opioid use or their combination. Specifically, adolescent drug exposure may contribute to increased risk for the development of cognitive deficits, psychopathology, or subsequent substance use disorders that may be related to the structural and functional changes in the brain. Investigating mechanisms underlying these alterations may provide novel avenues for the development of therapeutics that target these mechanisms to prevent and reduce the harm associated with substance use in adolescence.SH drafted the cannabis and alcohol literature review and the “Limitations” section. Besides, SH was responsible for consolidating the review, formatting 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.


In general, our results show that the frequency of health-seeking across a range of service providers  does not significantly correlate with prudent or non-prudent use practices or the levels of antimicrobials used. Instead, we find that patterns of antimicrobial use are linked to how much farmers invest in biosecurity  and the following vaccination protocols. Our results emphasize that more research is required to understand the interactions between animal health service providers and farmers regarding antimicrobial use and antimicrobial resistance. Addressing these gaps will be crucial to inform antimicrobial stewardship training, curriculums and, guidelines whose ultimate purpose is to limit the selection and transmission of antimicrobial resistance.International organizations and governments have argued that animal health service providers can play a vital role in limiting antimicrobial resistance by promoting the prudent use of antimicrobials. However, there is little research on the impact of these service providers on prudent use at the farm level, especially in low- and middle-income countries where enforcement of prudent-use regulations is limited. Here, we use a mixed-methods approach to assess how animal health-seeking practices on layer farms in Ghana ( Animal health service providers (AHSP) can play a critical role in limiting the emergence and global spread of antimicrobial resistance (AMR). As the World Organization for Animal Health (OIE) states; “Being in contact with both animals and farmers, you are the frontline on the battlefront of antimicrobial resistance.” (emphasis added) . AcknowlWithin most low- and middle-income countries (LMICs), and particularly sub-Saharan Africa, the lack of prescription tracking systems means that national-level assessments of the impact of AHSPs and stewardship programs on prudent use over time are unfeasible. Instead, these relationships need to be ascertained from cross-sectional surveys. Most surveys provide evidence of the relationship between AHSPs and prudent use through assessing self-reported knowledge, attitudes, and practices (KAP) of AHSPs and those in-training ,11. For To advance the understanding of the role of AHSPs in antimicrobial stewardship within LMICs, we used a mixed-methods approach to assess how animal health-seeking practices on layer farms in Ghana and Kenya impact self-reported antimicrobial usage, engagement in prudent administration and withdrawal practices and perceptions of AMR. We define AHSPs as individuals who have received formal training in veterinary sciences and/or receive compensation for services linked to animal health, including attendants at shops who sell veterinary medicines (agrovets). Our main objective was to assess how the frequency of health-seeking from government veterinarians, private veterinarians, community/extension officers, agrovets, and feed distributors was associated with self-reported AMU across an average month of production, adherence to withdrawal practices, and AMR-relevant knowledge and perceptions on the farm controlling for other potential factors that could impact these practices . Both qualitative and quantitative results suggest that the frequency of seeking advice from AHSPs is largely unrelated to prudent practices and attitudes, and that monthly AMU was more strongly associated with biosecurity, disease pressures, and vaccination rates than health-seeking practices. We discuss potential reasons underlying the lack of association between health-seeking and AMU practices and perceptions. Building upon these reasons, we conclude by providing guidance on the future efforts required to ensure AHSPs can play a major role in limiting the emergence and spread of AMR.Study locations in Ghana and Kenya were chosen given the prominence of layer production in the area and evidence from previous studies of the self-administration of antimicrobials as well as AMR in fecal samples and residues in eggs and water in drinkers ,15,16. TThe study was designed by an interdisciplinary research team comprising animal health experts and social scientists from FAO, the Directorate of Veterinary Services, Directorate of Livestock Production, and Sub County animal healthcare workers in Kenya; and the Veterinary Services Directorate of Ministry of Food and Agriculture, and Regional and Municipal Veterinary Officers in Ghana. A mixed-methods approach combining qualitative and quantitative data collection methods was used to develop the KAP survey. In Kenya, this included conducting separate focus group discussions (FGDs) with male and female farmers (2), and key informant interviews (KIIs) with agrovets (2), government and private veterinary officers (2), and animal health assistants (1). In Ghana, qualitative methods included FGDs among two mixed-gender groups of farmers and veterinary officers in the municipality. Seven KIIs were also conducted among the following stakeholders: agrovets (2), feed millers (2), animal health assistants (1), and government veterinary staff (2). In both countries, FGDs and KIIs were concentrated around twelve major themes relating to AMU and AMR including farm management and economic practices, disease histories, and knowledge, attitudes, and practices relating to AMU and AMR, including governance, regulations, policies, and enforcement.n = 4 in Ghana and n = 6 in Kenya) using tablets with the Kobo Collect® application. Enumerators were taken through a comprehensive four-day training and piloting of the KAP questionnaire. The survey was administered in English, Kiswahili or Kikuyu (Kenya), or Twi (Ghana) with the respondent indicating what language they were most comfortable in using. Interviews lasted around one hour.Thematic analysis of qualitative interviews was used to develop a KAP survey instrument of over 200 items that included a broad range of questions covering demographics, livelihood, health, and hygiene and biosecurity topics related to factors that could drive AMU and AMR. . In Kenya, enumerators conducted a door-to-door survey within local neighborhoods, generating a list of households from which a random selection of households was done and provided to enumerators. This census did not include all layer farmers in Gatundu North as some residents incorrectly believed that enumerators were a part of the county’s efforts to count the number of livestock for tariff calculation and therefore, refused to participate. In Ghana, a snowball sampling approach was used whereby veterinary officers were initially contacted to provide names of individuals currently engaged in layer production. Farmers that were listed during the snowball sampling were then consulted during the KAP survey to provide names of individuals who were currently engaged in layer production. This process was conducted until the data collection period ended .Ethical approvals were obtained in each country. In Kenya, the study was approved by the AMREF Health Africa Ethics and Scientific Review Committee (AMREF-ESRC P551/2018). This research was also approved by the Institutional Animal Care and Use Committee of KALRO-Veterinary Science Research Institute, Muguga, upon compliance with all provision vetted under and coded: KALRO-VSRI/IACUC016/28092018. In Ghana, permission to conduct the study was approved by the Ministry of Health Ethical Review Board (ID No. 014/10/18).In both countries an information sheet (IS) containing a detailed narrative of the study and its aims was provided to potential participants who could read and was read out to those who could not. Participants were informed of the research purposes including the benefits and risks of participation. The respondents were assured of their right to withdraw from study participation at any point, and necessary precautions were made to ensure and maintain confidentiality, anonymity, and voluntarism throughout the study. Written informed consent was sought and obtained from all study participants that could write. For those who could not write, a thumbprint signature was requested.A multivariate ordinal logistic model was used to assess associations between the number of times a farmer reported using antimicrobials during an average production month and health-seeking practices see . Health asdoc 1], and tOur results also provide evidence-based insights into the potential content of AMU/AMR training, curriculums, and guidelines by identifying factors that promote AMU on poultry farms in Ghana and Kenya. For example, we found that AMU was negatively associated with vaccination rates and farm biosecurity levels. While these relationships are expected, training content should be developed emphasizing communication strategies to link vaccines, biosecurity, AMU, and AMR more explicitly, including the economic trade-offs of initial investments in biosecurity  and vaccinations versus later costs for antimicrobials. To develop this targeted content, more research is needed on the specific biosecurity practices, vaccines, and diseases that are associated with AMU across different types of production systems and farm scales. In the current study, the small sample size meant that the number of variables that could be entered into models was limited and scales of vaccines, disease, and biosecurity had to be used. As such, we could not determine what specific practices, vaccines, or diseases drove the correlation with AMU or whether each exhibited similar effects. Likewise, to disentangle potential explanations behind the lack of association between health-seeking frequency and prudent AMU practices, larger-scale studies are needed to permit statistical regression techniques that can control for confounding factors  as well as assessments of the quality of advice received from AHSPs, which were not possible in the current study. More research on the knowledge, attitudes, and practices of common sources of animal health advice will allow a better understanding of whether the frequency of utilization will translate to behavioral change on the farm.In addition, to link health-seeking and farm dynamics with AMU and AMR, better measures of AMU are needed to assess the impact of AHSPs on antimicrobial stewardship. Our measure of use, the self-reported number of times antimicrobials are used in an average production month, may have been affected by recall biases, as has been shown in other health-related studies . StudiesFinally, while stewardship training will be needed to improve the quality of advice from AHSPs, the success of these efforts will also depend heavily on parallel efforts to increase access to AHSPs in LMICs. Across the last 30–40 years, privatization of the animal healthcare sector within these countries, which was meant to improve the quality, efficiency, and coverage of services, has largely not compensated for service reductions in the public sector, ,28. AccoAHSPs will play an important role in impacting prudent antimicrobial use and thus reducing the emergence and spread of antimicrobial resistance globally. However, there is limited research attempting to understand the impacts of AHSPs on prudent use practices on the farm, especially in LMICs. Using ethnographic data from layer farmers in Ghana and Kenya, we showed that AHSP seeking frequency, to a large extent, was not associated with prudent use practices. Our results highlight that more research is required to understand the interactions between AHSPs and farmers, especially the quality of animal health advice receive.. Filling the gaps in these interactions will inform antimicrobial stewardship training, curriculums, and guidelines whose ultimate purpose is to limit the spread and transmission of AMR.


Kinins and their receptors have been implicated in a series of pathological alterations, representing attractive pharmacological targets for several diseases. The present review article aims to discuss the role of the kinin system in infectious diseases. Literature data provides compelling evidence about the participation of kinins in infections caused by diverse agents, including viral, bacterial, fungal, protozoan, and helminth-related ills. It is tempting to propose that modulation of kinin actions and production might be an adjuvant strategy for management of infection-related complications. Th. Th22]. f kinins . These rfor Sap7 ,190. An ell wall . Sewerynell wall . The affalbicans . Thus, kPlasmodium infections in the 1970s, passing through the elegant contributions by Dr. Regoli about the effects of bacterial LPS on de novo induction of kinin B1 receptors in the 1980s, we arrived in the 1990s with a massive development of kinin antagonists, reaching the 2000s with the approval of icatibant for the treatment of hereditary angioedema, finally meeting the year of 2020 with startling evidence about the relevance of ACE2 and kinins for Covid-19 burden. For every infectious agent—bacteria, virus, fungus, protozoan or helminth—the mechanisms of invasion and escaping from the immune system involve one or more components of the kinin system. A huge number of preclinical studies and some pieces of clinical evidence clearly indicate that pharmacological modulation of kinin precursors, active peptides, kinin receptors and/or related enzymes might provide benefits for managing infectious diseases, including life-threatening situations. Despite this, the number of approved drugs targeting the kinin system is still low. Definitely, there is an urgent need for new options to treat infectious diseases, and the reasons involve the emerging resistance of pathogens and the high toxicity of most antimicrobial drugs, besides unmet clinical needs, such as complex cases of Covid-19. It is about time to reassess the available molecules and to develop novel tools targeting the kinin system as part of the endeavors against infectious diseases.From the pioneer studies showing the relevance of the kinin system in


The Commentary reports on our experience in Centro di Riferimento Oncologico IRCCS Aviano about the integrated and combined treatment with percutaneous endoscopic gastrostomy and lanreotide in patients with bowel obstructions by ovarian cancer and peritoneal carcinomatosis. We treated patients with gynecological cancers and bowel obstruction with percutaneous endoscopic gastrostomy and, when patients were partially responsive, with lanreotide. We registered a constant overall benefit for the quality of life and for the control of symptoms, which is very important especially during the home care follow-up of terminal patients. Ovarian cancer is the eighth most common type of cancer in the world and it has the lowest survival rate of all gynecological cancers. In 2020, there is an estimation of about 21.750 new cases diagnosed per year and about 13,940 ovarian cancer deaths in the USA [Almost all the patients with gynecological cancer have undergone multiple surgical treatments as well as a number of cycles of chemo- or radiotherapy . The patTo date, gastrointestinal decompression through a nasogastric tube is the first-line procedure in patients with disseminated peritoneal carcinomatosis and small bowel obstruction, but this treatment is poorly tolerated and it has many side effects, involving wing necrosis, laryngeal disorders, esophageal-gastric lesions, or aspiration pneumonia.Percutaneous endoscopic gastrostomy (PEG) is a simple method for achieving nonsurgical gastric decompression in patients suffering from metastatic abdominal tumors and upper gastrointestinal tract obstruction .Decompressive PEG is an endoscopic medical procedure in which a tube is passed into the patient’s stomach through the abdominal wall . PEG is PEG offers advantages over the commonly used nasogastric tube and is not as invasive as the traditional gastrostomies, thus reducing the risk related to the classical surgical procedure that is performed only in few selected cases .From our past experience, with the study of Zucchi et al., we showed that, although these patients often have ascites, advanced carcinomatosis and multiple gastrointestinal treatments, PEG, and percutaneous endoscopic jejunostomy (PEJ) were positioned with few side effects. Results showed an improvement of symptomatology, assessed for the first time through a subjective score, Symptom Distress Score (SDS), proving that the PEG treatment is appropriate in terminal patients unfit for surgery .In terminal patients with gynecological cancers, the placement of decompressive PEG can be associated with analogues of somatostatin, a molecule that inhibits the secretion of different hormones, such as insulin and gastrointestinal hormones. In vivo, somatostatin has a biological half-life of 2–3 min, allowing only intravenous infusion .The development of analogues of somatostatin, such as lanreotide and octreotide with long-acting formulations, administered at 4- or 2-week intervals, respectively, minimizes the discomfort of the patient. These drugs also modulate gastrointestinal function by reducing gastric and intestinal secretions and slowing the intestinal motility . In partWe studied 27 patients with gynecological cancer, peritoneal carcinomatosis, and small bowel obstruction, treated at the Department of Gynecological Surgical Oncology of the Centro di Riferimento Oncologico IRCCS Aviano, Italy.The majority of them had surgical treatment and received also two or three cycles of chemotherapy. They were hospitalized with clinical and radiological diagnosis of complete intestinal obstruction.PEG was performed when there were no other solutions than palliative derivation. When symptoms worsened, we introduced lanreotide, at the starting dose of 30 mg.Most patients received at least two doses of lanreotide at 14-day intervals. After one or two administrations, we observed reduction of nausea in 68.8% of them, of vomiting in 50.7% of cases, and of distension or abdominal pain in 42.8% of cases (Fig. The positioning of PEG facilitates the home care follow-up in those patients with neoplastic small bowel obstruction, and lanreotide is the drug of choice to be associated in the control of symptoms.In conclusion, based on our experience, the association of PEG and lanreotide is a valid tool for the palliation of malignant inoperable bowel obstruction in gynecological cancer patients and shows a better cost-benefit ratio than other options. During the home care follow-up, this treatment increases the chances of avoiding hospitalization and permitting, potentially, a better quality of life.


In the present review, we highlight the possible “extra-immunological” effects of maternal immunoglobulins (Ig) transferred to the blood circulation of offspring, either via the placenta before birth or via the colostrum/milk across the gut after birth in different mammalian species. Using the newborn pig as a model, since they are naturally born agammaglobulinemic, intravenously (i.v.) infused purified serum Ig rapidly improved the vitality, suckling behavior, and ensured the survival of both preterm and term piglets. In further studies, we found that proper brain development requires i.v. Ig supplementation. Studies have reported on the positive effects of i.v. Ig treatment in children with epilepsy. Moreover, feeding newborn pigs an elementary diet supplemented with Ig improved the gut structure, and recently a positive impact of enteral or parenteral Ig supplementation on the absorption of polyunsaturated fatty acids (PUFAs) was observed in the newborn pig. Summarized, our own results and those found in the literature, indicate the existence of important extra-immune effects of maternal Ig, in addition to the classical protective effects of transferred maternal passive immunity, including effects on the development of the brain, gut, and possibly other organ systems in the neonate. These additional properties of circulating Ig could have an impact on care guidelines for human neonates, especially those born prematurely with low plasma Ig levels. Human infants receive the majority of maternal immunoglobulins (Ig), predominantly immunoglobulin G (IgG), via the placenta. Maternal antibody transfer to the fetus starts as early as during the 13th week of gestation. The level of IgG in the fetal circulation is relatively low  between weeks 17 and 22, reaching 50% of maternal levels by week 32 and usually exceeding the maternal plasma IgG level at birth  later in life. Patients with classical PID, as a result of various gene defects, develop various immune disorders later in life  with varMaternal Ig, transferred to the offspring's blood stream, either before birth (in the case of human infants) or after birth (in the case of ungulates), are omnipresent and may function as regulators for those organs and systems undergoing drastic developmental changes after birth, e.g., the gut, brain, immune system, etc. However, any extra-immune regulatory effects of Ig are difficult to recognize at “first glance,” and are probably often overlooked because of “the most obvious role of Ig in protecting the offspring from infections during the first few weeks of life.” Hence, the aim of our review is to highlight and summarize the knowledge obtained from previous studies by our lab, as well as previous literature concerning the possible extra-immunological effects of maternal Ig transfer during the early post-natal period and their (Ig) role in further development of the offspring.In the case of livestock praxis with regard to goat breeding, it is well-known that careful surveillance of the pasture should be carried out during delivery time in order to locate newborn kids. If the kids do not receive colostrum containing high levels of IgG timeously, they become apathetic and die within a few hours after birth, with no obvious symptoms of infection . SimilarTo study this inexplicable effect of colostrum, we performed some simple experiments to determine whether provision of purified Ig, the major protein in colostrum whey, using different approaches, would be beneficial for term and preterm newborn piglets . A prepaNeurological disorders are among the main clinical problems affecting preterm children and often cause communication problems and learning disabilities later on in life , 8. SeveThus, the main objective in a study performed in our lab , was to in vitro leads to an increase in intracellular calcium  in the newborn pig . The higThe extra-immunological effects of circulating maternal Ig, presumably more specifically IgG, in the newborn are summarized in this review highlighting the importance of maternal Ig transfer in stimulating organ growth and maturation after birth. The classical immune-protecting features of maternal Ig can be replaced by, e.g., antibiotics and sterile conditions, while the extra-immunological stimulatory effects probably cannot be replaced. Thus, the properties and role of maternal Ig transmitted to the offspring in late pregnancy or directly after birth need to be further explored and recognized as vital components of early development with possible long-lasting effects on health and performance later in life.KP, JW, BW, and SP were responsible for preparing the manuscript. KP, SP, and BW designed the review and critically reviewed the manuscript. All authors contributed to manuscript revision, have read, and approved the submitted version.SP is the owner of SGP+ Group, Sweden; KP is employed by the SGP+ Group, Sweden. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The network pharmacology method was used to predict the active components of Banxia Xiexin decoction, its targets and the key signalling pathways that are activated in the treatment of depression and ulcerative colitis to explore the common mechanism.The active components and targets of Banxia Xiexin decoction were obtained by searching the ETCM,TCMSP and TCMIP database. The disease targets of depression and ulcerative colitis were obtained by combining the following the DisGeNET, OMIM,Drugbank,CTD and PharmGKB disease databases. The drug and disease target genes were obtained from the intersection of the herbal medicine targets and the disease targets and were imported into the STRING platform for the analysis of PPI network. The network modules were constructed using Cytoscape software. An analysis of the functional annotations of GO terms and KEGG signalling pathways was performed for each network module. Then, the tissue distribution, sub-cellular distribution and protein attributes of the key targets in the pathway were analysed by the BioGPS, Genecards and DisGeNET databases.The mechanism of Banxia Xiexin Decoction in the treatment of depression and ulcerative colitis is related to drug reaction, steroid metabolism, lipid metabolism, inflammatory response, oxidative stress response, cell response to lipopolysaccharide, insulin secretion regulation, estradiol response and other biological functions, mainly through the regulation of 5-hydroxytryptamine synaptic, arachidonic acid metabolism, HIF-1 signaling pathway and NF-kappa B signaling pathway can achieve the effect of same treatment for different diseases.The mechanism of Banxia Xiexin Decoction in treating different diseases involves direct or indirect correlation of multiple signal pathways, mainly involved in drug metabolism and lipid metabolism, but also through comprehensive intervention of the body’s nervous system, immune system, digestive system and other systems. The effective components of Banxia Xiexin Decoction are mainly act on eight key target proteins  to carry out multi-target effect mechanism, biological mechanism of treating different diseases with the same treatment, and related mechanism of overall treatment, which provide theoretical reference for further research on the material basis and mechanism of Banxiaxiexin decoction on antidepressant and prevention and treatment of ulcerative colitis. Depression is a chronic and recurrent mental disorder. The main clinical characteristics of patients are marked and lasting depression, accompanied by physical symptoms of gastrointestinal diseases, which can impair social functions and lead to suicidal tendencies. Thus, depression is very harmful to the physical and mental health of patients –3. Ulcer8+ and regulate CD4 + / CD8 + balance in UC model rats [With the rapid development of modern society and the economy, the accelerated pace of life, and the intense pressure of competition, the number of patients with the two diseases has shown an increasing trend, which not only seriously distress the normal life and work of patients but also imposes a heavy burden on the family and society. Currently, Standard treatment often uses an aminosalicylic acid preparation, corticosteroid hormones, and immunosuppressants as the main treatment, combined with antidepressants. Although these drugs display short-term clinical efficacy, different degrees of side effects occur with the prolongation of the treatment, which will seriously reduce the compliance of patients with the treatment process and the curative effect of the disease. Traditional Chinese medicine has the unique advantages of overall regulation, safety and effectiveness in the treatment of depression and ulcerative colitis. Traditional Chinese medicine not only has a profound foundation in clinical practice but also has led to the development of a large number of classic prescriptions for treatment. Thus, traditional Chinese medicine has gradually become more widely used. Banxia Xiexin decoction, which was first published in the Treatise on Cold Damage and Miscellaneous Disease, is composed of seven herbs, namely, Banxia, Ganjiang, Scutellaria, Coptis, ginseng, liquorice and jujube. This prescription can effectively improve gastrointestinal inflammation, regulate gastrointestinal motility and anti-ulcer effectively in clinical –12. Reladel rats . It can del rats . Relevandel rats . At the del rats , 17. Accdel rats , 19.Based on previous clinical experience, modern clinical practice and animal experiments using traditional Chinese medicine, Banxia Xiexin decoction effectively displays the comprehensive advantages of treating different diseases, treating the viscera and treating specimens with the same formulation through component coordination, target coordination and efficacy coordination among various herbs. However, there is a lack of comprehensive and systematic understanding on the material basis and molecular mechanism of its efficacy, and there is no study on the biological mechanism of Banxia Xiexin decoction in treating depression and ulcerative colitis with different diseases. Therefore,this study aims to screen the active components and predicted targets of the herbs contained in Banxia Xiexin decoction by using the biological module analysis of network pharmacology to better understand the common targets, molecular mechanism, tissue localization and subcellular distribution of the traditional Chinese medicine in the treatment of different diseases. In addition, the relevant networks and biological functions are analysed to explore the multi-target mechanism, the biological mechanism of simultaneously treating different diseases, and the related mechanism of the overall treatment with the classical prescriptions in a comprehensive, multi-level and systematic manner. We aim to provide a reliable reference value for subsequent experimental verification, clinical application, and new drug research and development.Panax ginseng C. A. Mey), ginger , jujube (Ziziphus jujuba Mill) and liquorice . The active components and targets of Banxia Xiexin decoction were obtained by searching the Encyclopedia of Traditional Chinese Medicine  [http://lsp.nwu.edu.cn/tcmsp.php) database was used to search all the chemical composition information of the single Chinese medicine. According to the recommended screening threshold conditions of the platform, when OB ≥ 30% and DL ≥ 0.18, get the key active ingredients of the Chinese medicine were obtained [https://pubchem.ncbi.nlm.nih.gov/) database to search and download the molecular structure formula and PubChem CID of the corresponding chemical composition, and then select the corresponding target of the compound whose species is “Homo sapiens” in SwissTargetPrediction (http://swisstargetprediction.ch/) platform according to the chemical similarity between the active compound ligands. Seven herbs were added to TCMIP (http://www.tcmip.cn/) database to establish the chemical composition database of Banxia Xiexin Decoction. According to the target prediction interface of traditional Chinese medicine, all chemical composition prediction targets with drug similarity score ≥ 0.8 were selected [http://www.uniprot.org/) database was used to input the names of the predicted target proteins, and the species was set to Homo sapiens. Then, the target protein of each herbal medicine was corrected to the official symbol.Banxia Xiexin decoction contains seven Chinese herbal medicines: Banxia (Arum Ternatum Thunb), Scutellaria , Coptis (Coptis chinensis Franch), ginseng (0/ETCM/) , 21, thiobtained . The canselected –25. The Using the disease databases gene disease association database (DisGeNET), comprehensive human Mendelian genetics database (OMIM), drug target database (Drugbank), comparative toxicogenomic database (CTD), and pharmacogenetics and pharmacogenomics database (PharmGKB), we input the disease gene keywords for depressive disorder, depression and ulcerative colitis. The target genes of the two diseases were searched and screened, and the target genes of each disease database were combined to eliminate the repeated disease targets. Finally, the known disease targets of depression and ulcerative colitis were obtained.The herbal medicine targets in Banxia Xiexin decoction and the disease targets of depression and ulcerative colitis were separately imported into the OmicShare online tool to generate a Venn diagram. The target genes of Banxia Xiexin decoction for treating depression and ulcerative colitis were mapped, and the target gene database of compounds for treating depression and ulcerative colitis was constructed by extracting the intersecting target genes. The disease target genes that were not related to the components of Banxia Xiexin decoction were removed from the table, and the components that did not match the components of depression and ulcerative colitis were removed. Finally, the disease target genes of the herbs were obtained, and a common target database was established.Homo sapiens”, and the minimum interaction threshold was set to “Medium Confidence”. The data for the protein-protein interactions were obtained, listed in columns, and saved in. TSV format, and the PPI network was visualized by constructing a graph.The PPI was constructed and clarified using the STRING network database platform to further elucidate the interactions of the common target genes in the treatment of depression and ulcerative colitis with Banxia xiexin decoction. The protein species was set to “P-value of each function and pathway was obtained by the method and was corrected using the Benjamini-Hochberg algorithm. The biological signaling pathways with P < 0.05 were regarded as statistically significant. The results were sorted according to the P-value, and the top three results were retained.As a closely connected functional group, the biological network module performs the corresponding functions through the interactions of multiple targets in each network module. The data presented in columns of the TSV file were imported into the Cytoscape software, and the key network modules were constructed by using the MCODE Cluster analysis plug-in in the toolbar Apps. By using the online Database for Annotation, Visualization and Integrated Discovery (DAVID6.8), the target genes in the key network modules were analysed by determining the related GO biological processes and signalling pathways that were enriched in the KEGG. The DAVID database integrates various database resources and uses an improved fisher to accurately assess and calculate the results. The http://biogps.org), Genecards (http://www.genecards.org/) and DisGeNET (http://www.disenet.org) databases to obtain the tissue distribution, subcellular distribution and protein classification information, respectively.The key targets in the selected signalling pathways were imported into the STRING database to obtain the protein interaction relationship, and the protein interaction network was drawn with the Cytoscape software. According to the Degree value, the key targets were selected and imported into the BioGPS . Using the related target prediction technology in each software to screen the prediction targets of the above-mentioned active ingredients, eliminate the repeated targets, and finally obtain a total of 1551 herbal prediction targets.We searched the DisGeNET, OMIM, Drugbank, CTD and PharmGKB databases and screened the known target genes related to depression and ulcerative colitis. We combined the target genes from each database, deleted the duplicate disease targets, and retrieved 876 disease targets for depression and 914 disease targets for ulcerative colitis. The intersection of 1551 predicted herbal medicine targets and two disease targets was obtained to obtain 318 therapeutic targets of Banxia Xiexin decoction for depression and 198 therapeutic targets for ulcerative colitis. Then, 318 depression targets and 198 ulcerative colitis targets were imported into the OmicShare online tool to extract the intersecting target genes and construct a Venn diagram, as shown in Fig. The 66 intersecting target genes listed above were imported into the STRING software platform to obtain the data columns of protein-protein interactions, construct a PPI network diagram, and better understand the potential mechanism of Banxia xiexin decoction in the treatment of depression and ulcerative colitis. The network contains 65 protein-protein interaction targets and 464 edges that represent protein-protein interactions. The average node Degree value in the network is 14.30, and the average centre clustering coefficient is 0.614, as shown in Fig. P-values obtained from the enrichment analysis. Module A was mainly related to the positive regulation of biosynthesis, including pathway in cancer, proteoglycan signaling pathway in cancer and arachidonic acid metabolism pathway. Module B was mainly related to metabolism pathway, including HIF-1 signaling pathway, arachidonic acid metabolism pathway and NF-kappa B signaling Pathway. Module C was mainly related to plasma membrane regulation, mainly involving neuroactive ligand-receptor interaction signaling pathway, serotonergic synapse and calcium signaling pathway. Module D was related to related metabolic processes, mainly involving drug metabolism-cytochrome P450, metabolism of xenobiotics by cytochrome P450 and retinol metabolism signaling pathway.The protein interaction data listed above were imported into the Cytoscape software, and the protein interaction network of Banxia Xiexin decoction in the treatment of depression and ulcerative colitis was divided into modules by using the MCODE Cluster plug-in tool, involving 63 nodes and 464 edges. Four key network modules and 90 targets were finally obtained, among which the largest network module was composed of 35 target nodes. The nodal target proteins contained in these modules may play important roles in the treatment of depression and ulcerative colitis with Banxia Xiexin decoction, as shown in Fig. The 66 common target genes screened above were mapped for an enrichment analysis of the GO terms and KEGG pathways and displayed in the chart shown in Fig. The targets in the four key signaling pathways selected above were imported into the STRING platform, and the columns of protein-protein interaction data were obtained. The data columns were imported into the Cytoscape software for a network topology analysis. The targets were sorted according to the node degree value, and the frequency of the targets in each pathway was counted. Finally, the key targets with a value higher than the degree median value and the highest frequency were selected. Eight key targets meet these criteria, as shown in Table The eight key targets described above were imported into the BioGPS platform to obtain the relevant tissue distribution information. Obtain the tissue information with correlation cutoff value above 0.9 and each gene expression ranking in the top five to make a data list. The obtained data list is imported into the Cytoscape software to draw the “tissue-target”network diagram, as shown in Fig. Import the key targets into the Genecards database to obtain the subcellular distribution information. The subcellular location of Confidence = 5 of the key target was selected and included. Import the subcellular distribution information table into the Cytoscape software to draw the “subcellular-target” network diagram, as shown in Fig. Import the key targets into the DisGeNET database to obtain the protein information of each target. The results show that the key targets mainly involve transfer/carrier protein, signaling molecule, oxidoreductase, transferase and transcription factor. See Table As the basic principle of guiding the clinical diagnosis and treatment of diseases, the treatment method of “treating different diseases with the same treatment” of traditional Chinese medicine is also the essence of syndrome differentiation and treatment in traditional Chinese medicine. The explanation for the simultaneous treatment of different diseases is mainly attributed to the similar aetiology, pathogenesis, symptoms and disease location during the occurrence and development of different diseases. Therefore, different diseases can be cured with the same prescription, completely reflecting the advantages of traditional Chinese medicine in syndrome differentiation, holistic treatment and comprehensive treatment. Nowadays, the traditional Chinese medicine Banxia Xiexin Decoction is often used to treat ulcerative colitis , 11 and According to the analysis of enriched biological processes and signalling pathways of common targets of the classical prescription used to treat two diseases, the GO biological processes, KEGG pathways, and the results of the biological network module analysis are overlapped and were enriched in the 5-HT synaptic signalling pathway, arachidonic acid (AA) metabolism, HIF-1 signaling pathway and NF-kappa B signalling pathway. Thus, different diseases are able to be treated with the same prescriptions. 5-hydroxytryptamine (5-HT), as an indole derivative, is mainly produced in brain tissue by tryptophan hydroxylase-2 (TPH2) and plays an important role. 95% of 5-HT is mainly produced in gastrointestinal tract of digestive system, and this process is mainly produced by further metabolism of tryptophan hydroxylase-1 (TPH1) . 5-HT noThe targets of Banxia Xiexin decoction were also significantly enriched in the HIF-1 signaling pathway and NF-kappa B signalling pathway. Studies have confirmed that acute stress can promote animals to keep excited for a certain period of time, while long time in this state of tension will make the sympathetic nerve in the body in a continuous state of tension, the hypothalamic-pituitary-adrenocortical (HPA) axis over excitation will cause human body to be in a negative state, produce anxiety and despair, reduce the ability of learning and memory, and then the nervous system and immune system of the body will be in different levels of disorder, leading to the occurrence of various diseases, and serious mental diseases such as depression, which will become a serious threat to our own and social development . HoweverActivated NF-kB, an important nuclear transcription factor in cells, participates in the mechanisms regulating the expression of various genes involved in the inflammatory response and immune response, and it regulate cell apoptosis, the stress response, synaptic plasticity and memory. In recent years, an imbalance in the intestinal flora has been reported to be closely related to the occurrence of ulcerative colitis. When ulcerative colitis occurs, it will activate the immune system in vivo and lead to the occurrence of systemic inflammation. T-lymphocytes will accumulate in the damaged intestinal mucosa and lead to a defect in intestinal barrier function. The immune system is activated by various microbial antigens after intestinal pathogens invade the submucosa. The activation of inflammatory cells leads to the inflammation of the intestinal mucosa. This process is mediated by Toll-like receptors, which activate the NF-kappa B signalling pathway, resulting in the release of the pro-inflammatory cytokines IL-1 and TNF-α. The inflammatory state caused by the abnormal immune function also plays a role in the pathogenesis of depression. The number of immune cells in patients with depression often changes the immune function of the body, disrupting the immune function of peripheral cells and increasing the levels of pro-inflammatory cytokines. Subsequently, the pro-inflammatory cytokines alter the local brain structure and neuroendocrine function. Therefore, Banxia Xiexin decoction may induce the expression of inflammatory cytokines and participate in the immune and inflammatory responses of patients with depression by activating the NF-kappa B signalling pathway to effectively improve the gastrointestinal inflammatory response and the effective regulation of the central nervous system , 54.In this study, we used the tools of BioGPS, Genecards and DisGeNET to analyze the tissue distribution, subcellular distribution, and protein attribution. It can be seen from the results that in the treatment of depression and ulcerative colitis, the tissue distribution mainly involves the amygdala, pancreas and lung of brain, while the subcellular localization mainly includes myeloid cells, monocytes, cardiomyocytes, lymphoblasts and bronchial epithelial cells. Therefore, the prediction results not only provide a reference value for the clinical application of traditional Chinese medicine in the treatment of different diseases, but also provide guidance for the next animal and cell experimental verification stage of the research group, and also open up a new research idea for the traditional Chinese medicine to study the potential pharmacological mechanism of depression and ulcerative colitis from the perspective of brain, lung and pancreas.In summary, this paper studies the common mechanism of the treatment of ulcerative colitis and depression using a network pharmacological biological module analysis by investigating biological processes, signalling pathways, tissue distribution, subcellular distribution, protein attributes, etc. Banxia Xiexin decoction not only directly participated in drug and lipid metabolism but also exerted the effect of “treating different diseases with the same treatment” by comprehensively regulating the functions of the nervous system, immune system, digestive system and other systems of the body. In addition, from the perspective of integration, we also explored the efficacy of this herbal medicine through multiple channels and effects. The results were consistent with the process of disease induction by multiple factors and interactions, and a certain correlation was observed between the key signalling pathways that work synergistically. The traditional concept of “treating different diseases with the same treatment: of traditional Chinese medicine is integrated with the research technology of modern network pharmacology to not only take full advantage of traditional Chinese medicine in overall treatment and comprehensive prevention and treatment but also systematically analyse the mechanism underlying the efficacy of ancient traditional Chinese medicine prescriptions using of modern visualization technology. Our study provides a new area of research for exploring the mechanism of synergism in the treatment of different diseases, provides a reliable reference value for the subsequent experimental verification of our findings, and ensures that the overall research results are highly credible and persuasive.


MicroRNAs (miRNAs) are small non-coding RNAs that mainly act by binding to target genes to regulate their expression. Due to the multitude of genes regulated by miRNAs they have been subject of extensive research in the past few years. This state-of-the-art review summarizes the current knowledge about miRNAs and illustrates their role as powerful regulators of physiological processes. Moreover, it highlights their aberrant expression in disease, including specific cancer types and the differential hosting-metastases preferences that influence several steps of tumorigenesis. Considering the incidence of breast cancer and that the metastatic disease is presently the major cause of death in women, emphasis is put in the role of miRNAs in breast cancer and in the regulation of the different steps of the metastatic cascade. Furthermore, we depict their involvement in the cascade of events underlying breast cancer brain metastasis formation and development. Collectively, this review shall contribute to a better understanding of the uniqueness of the biologic roles of miRNAs in these processes, to the awareness of miRNAs as new and reliable biomarkers and/or of therapeutic targets, which can change the landscape of a poor prognosis and low survival rates condition of advanced breast cancer patients. Subsequently, it was found out that they are abundant in both invertebrates and vertebrates, with estimates of 2300 true human mature miRNAs in 2019 [MicroRNAs (miRNAs or miR) are small non-coding ribonucleic acids (RNAs) that up until recently were fairly unknown, but that in the past few years have received great attention by the scientific community due to their unique properties and roles in many diseases ,2,3,4. T in 1993 . It was  in 1993  reported in 2019 . While l in 2019 . This ha in 2019 . In thisIt is predicted that up to 98% of the transcriptional output of the human genome represents RNA sequences that do not code for protein synthesis but fulfill several functions. MiRNAs are a subclass of single stranded small non coding (ncRNAs) with about 21–25 nucleotides that play important gene-regulatory roles by pairing to mRNAs of protein-coding genes to direct their posttranscriptional repression, hence having impact in crucial cellular functions . CommonlMiRNAs play an evolutionarily conserved role in regulating numerous genes involved in development  and in cBoth in physiological and pathologic conditions, miRNA expression and their targets are, in many cases, tissue specific. In fact, different miRNAs are expressed in different tissues at different levels, with characteristic patterns that play an important role in tissue identity, differentiation and function. The same applies to pathologies, as specific miRNAs are aberrantly upregulated or downregulated in different diseases and can influence or even determine the pathologic phenotypes of cells . Since tAlthough most miRNAs are found inside cells, they can also circulate in a cell-free form, commonly known as circulating or extracellular miRNAs (ECmiRNAs). These are found in body fluids, as blood, plasma, urine, cerebrospinal fluid, saliva and semen . They arCell free miRNAs can also be shielded from extracellular environment by associating with high density lipoprotein or with argonaut-2 in a ribonucleo–protein complex. Although it remains unclear if and how these miRNAs facilitate cell–cell communication, they represent most circulating miRNAs . MoreoveThe recognition of miRNAs’ impact in cancer has driven the scientific community towards the elucidation of their role in the regulation of tumorigenesis. Around 50% of human miRNA genes are thought to be located nearby chromosomal breakpoints or in regions of instability, thus prone to gene deletion, amplification and mutations, all of which are considered cancer-associated regions or fragile sites of the genome . The earMiRNAs may play a role as oncogenes (oncomiRs), the most common type, by downregulating tumor suppressor genes and/or genes controlling cell differentiation or apoptosis . In someOne of the hallmarks of tumorigenesis is the formation of metastases, an intricate process by which cells spread from a primary tumor to distant organs and tissues, forming viable secondary tumors. Recent studies showed that miRNAs have an active role in regulating metastases either presenting up- or downregulated expression, consequently decreasing or enhancing the expression of target genes . MoreoveTumor cells often release higher numbers of microvesicles than other cells, and cancer patients present a higher quantity of serum exosomes than healthy individuals . AccumulAs cell free miRNAs can reach distant sites and regulate various cellular components of the tumor microenvironment, they may be important in understanding, detecting and targeting metastatic progression and, hence, valuable prognostic markers and targets for therapeutic intervention in specific types of tumorigenesis. Additionally, the presence of miRNAs that are associated with the process of metastases by regulating one or several of its steps may identify those patients that already have distant micrometastases that are too small to diagnose otherwise.https://gco.iarc.fr/). It is a malignant type of tumor that usually initiates in the epithelial cells of the mammary ducts [BC is the most frequently diagnosed cancer in women worldwide and the leading cause of death from cancer in women, with almost 2.1 million new cases and 627,000 deaths in 2018, representing about 15% of all cancer deaths among women, according to the World Health Organization  need to undergo a series of steps, commonly named as the metastatic cascade . This muUnder normal conditions, the architecture of the mammary epithelium is ensured by cell–cell and cell-basement membrane (BM) interactions. Cell–cell interactions are established through intercellular junctions, including tight junctions (TJs) and adherens junctions (AJs) . During RHOC. Thus, Twist-mediated miR-10b upregulation induces local invasion and migration of BCCs [CDH1, the gene that encodes for the epithelial cell adhesion molecule E-cadherin. The oncoproteins MYC and MYCN are responsible for the upstream regulation of miR-9 by acting on the mir-9–3 locus, causing activation of miR-9 expression in tumor cells [Numerous miRNAs have been described to regulate EMT  and to b of BCCs . MiR-373 of BCCs , a cell  of BCCs . Anotheror cells . Thus, bor cells .TGFBR2 and RELA, leading to a downregulation of transforming growth factor β (TGF-β) and nuclear factor (NF)-kB, respectively. TGF-β reduction leads to a decrease in angiopoietin-like 4, a protein known to disrupt vascular integrity through targeting vascular endothelial cadherin and claudin-5, well known components of AJs and TJs, respectively [Once malignant cells undergo EMT, detach from the primary tumor and invade the surrounding tissue, to reach distant organs they need to enter the circulatory or lymphatic system in a process named intravasation . The hemectively ,81.The several members of the vascular endothelial growth factor (VEGF) family  and its receptors promote metastases and intravasation, through augmenting tumor microvasculature availability due to the powerful angiogenic activity ,90. MoreBC metastatic cells that succeed in intravasation, either via the blood or lymphatic circulation, become circulating tumor cells (CTCs). Throughout their path, CTCs can encounter many obstacles, including shear forces of the circulation, collision with host cells and attack of the immune system. All these factors influence CTCs survival and limit their ability to establish metastases in distant sites. In fact, millions of metastatic cells are shed by the tumor to the bloodstream, but only a small percentage reaches the target and very few clinically relevant metastases are formed, compared to the number of cells released by the tumor. Thus, it is expected that a selection of the most resistant and aggressive tumor cells occurs . The firThe cells that survive the hostile intravascular environment need to cross the vascular endothelium to extravasate into the surrounding tissue. The extravasation process involves adhesion to the endothelium, modulation of the endothelial barrier and, finally, TEM to reach the surrounding tissues. Once the cells reach the tissues, they can start proliferating again to form new solid tumors. Extravasation of BCCs usually takes place in the microvasculature near the target site, in a process similar to the mechanism proposed for leucocyte extravasation during inflammatory response, from the luminal to the abluminal side of the endothelium . SimilarMiR-19b, a member of the miR-17–92 cluster, is a key oncomiR in BC by regulating the PI3 K/Akt pathway and leading to the downregulation of several tumor suppressor genes, including phosphatase and tensin homolog (PTEN) . RecentlThe last step of the metastatic cascade is the colonization and establishment of macroscopic secondary tumors at distant organs . CTCs thMARCKS that encodes for a protein responsible for the promotion of cell cycling and motility. Thus, exosomal transfer of miRNAs can promote BCC dormancy in a metastatic niche [MiRNAs seem to have an important role in the switch between dormant and activated BCCs. Exosomes released by bone marrow stem cells induce dormant phenotypes of BC metastatic cells by releasing miR-23a, which suppresses the target gene ic niche . On the ic niche , remainiic niche . Aberranic niche .Once DTCs have adapted to the microenvironment and established an accommodating metastatic niche, they start proliferating again to colonize and invade the secondary sites. In this step of the metastatic cascade, the production of MMPs and cathepsins is essential to promote the rearrangement of the ECM and drive cell invasion and migration through the stroma . To suppSOX4 and TNC [As in all stages of the metastatic cascade, miRNAs can have an active role in promoting or inhibiting the colonization of distant organs. MiR-335 is a well-known tumor suppressor that was found absent in primary breast tumors from patients who relapsed and was associated with a poor metastasis-free survival, in line with its role in inhibiting migration, invasion and metastatic colonization by regulating several metastasis-implicated genes, such as  and TNC . Accordi and TNC . Further and TNC . MiR-182 and TNC . As prev and TNC ,138. Alt and TNC .BRCA1 gene and the overexpression of Ki-67. Among the several types of BC, HER2-positive and triple negative tumors are the ones presenting the highest predisposition to brain metastases and are thus considered the most aggressive types and the ones with the lowest survival rates [With the improvements in primary BC treatment, the prognosis of patients is considerably worsened by the appearance of metastasis that are responsible for 90% of human cancer deaths . BC is tal rates ,147, as al rates ,149. Theal rates . The besal rates .Despite its clinical importance, the molecular mechanism of brain metastases is still poorly understood. The complex process of formation of brain metastases comprises all the steps of the metastatic cascade plus the colonization and growth in the brain parenchyma. This process was reported to take 3.72 years for HER2-positive and 2.07 years for triple negative BC types . Thus, BOnce BCCs enter the brain, they encounter an ideal microenvironment for metastatic growth, since the BBB provides protection against immune surveillance, chemotherapeutic agents and other harmful substances . The anaA receptor, GABA transporter and GABA transaminase). Such acquisition of a GABAergic phenotype renders the malignant cells able to take up and catabolize GABA as a biosynthetic source, indicating that they co-opt GABA as an oncometabolite to obtain energy for cell proliferation [n-methyl-d-aspartate receptor and obtain its major agonist, l-glutamate, from glutamatergic synapses where high levels of the neurotransmitter are released from excitatory pre-synaptic neurons. To access glutamate, the tripartite synapses formed by astrocytes and pre- and post-synaptic neurons are subverted by metastasizing cells that take the place of astrocytes forming pseudo-tripartite synapses [Although the brain microenvironment can be very hostile and kill most of the metastatic cells in a first response , the fewferation . Moreovesynapses . There isynapses .Considering the difficulties in the treatment of brain metastases, an early diagnosis increases the chances of survival. However, the resolution of current MRI techniques and the contrast agents currently used do not allow an efficient detection of small tumors or micrometastases, which could be targeted by first-line treatment more efficiently than macrometastases . As prevMetastatic cancer stem-like cells (CSCs), which are associated with tumor growth and metastasis initiation due to their properties like cell growth, cell cycle and self-renewal and invasiveness, are highly regulated by miRNAs . AccordiZhang et al.  demonstrMiR-509 has been described to be highly expressed in primary breast tumors whereas its expression is significantly decreased in brain metastatic lesions originated from the same tumors. Moreover, the levels of this miRNA are decreased in primary breast tumors of patients with brain metastases when compared with BC patients without this kind of metastatic lesions. The downregulation of miR-509 directly relates with the upregulation of both RhoC and TNF-α, indicating that the expression of these proteins is regulated by such miRNA . RhoC isPDPK1 and the consequent diminished expression of PDPK1 protein, leading to decreased phosphorylation of cofilin and resulting in activated cofilin-induced modulation of actin dynamics that disturbs BBB integrity [Another miRNA related with BCBM worth mentioning is miR-181c that was shown to have an active role in BBB destruction during the process of formation of brain metastases . It was ntegrity . Since tntegrity .MiR-122 has been previously identified as a marker for predicting metastatic progression in early stage BC by being highly expressed in BC patients’ serum prior to development of metastases . More reAnother stroma-derived extracellular miRNA, miR-19a, is capable of modulating BCBM microenvironment by downregulating PTEN , an impoFinally, it was recently demonstrated the downregulation of miR-802-5p and of miR-194-5p in plasma prior to the detection of brain metastases, in a mouse model of preferential formation of brain metastases from BC . Thus, mMiRNAs have arisen as important posttranscriptional regulators of possibly all the genes present in the human genome and overwhelming amounts of data have recently linked aberrant miRNA expression to the origin and development of many, if not all, types of cancer to which specific miRNAs signatures can be assigned. Moreover, some miRNAs have been specifically related to the formation of metastases and particularly from BC to the brain. However, the role of miRNAs in the cellular mechanisms and intercellular communication underlying cancer development and metastases progression remain mostly unmapped. Therefore, extending the current knowledge about miRNAs biopathology will pave the way for the establishment of miRNAs as early biomarkers and as potential targets for modulation. Hopefully, the anticipated discoveries in the years to come will open new opportunities for a timely detection and therapeutic intervention, essential to improve the expectancies in the field of oncology and particularly of neuro-oncology.