Blockchain Papers

Akila Rekima, Lieke van den Elsen, Charlotte Isnard, Danielle J. Smyth · 19 authors

Colostrum is the physiological food for the first 72 h of a newborn.1 Its window of intake and high content in microbiota-shaping and growth factors1 suggest that colostrum is critical in guiding gut immune development. To address this hypothesis, we developed a mouse model of colostrum deprivation (Figure 1A). Like humans, mice have different lactation stages.2 We compared pups nursed immediately after birth by dams that no longer produced colostrum (Day 9 of lactation, a well-defined lactation stage in mice that is distinct from colostrum2) with control pups. This allowed us to assess the causal role of colostrum in the perinatal expansion of two cell types important in gut immune regulation, namely ILCs and CD4+ T cells. While we found a major increase in small intestine ILC2 frequency and numbers between Days 7 and 14 in control mice, ILC2 expansion was severely compromised when mice were deprived of colostrum (Figure 1B). Colostrum deprivation did not impact gut ILC, ILC1, ILC3, CD4+ T cells, Th1, Th2, Th17 and Treg cells representation in 2-week-old mice (Figure S1), suggesting a selective effect of colostrum on ILC2 ontogeny. The low numbers of Th1, Th2 and Th17 cells are consistent with the predominantly naïve T cell compartment at this time point of life.3 A more detailed analysis of CD4 T-cell phenotype including T-cell activation and their response to inflammatory signals remains to be performed to fully elucidate the role of colostrum in T-cell ontogeny. To verify that the decreased representation of ILC2 in 14-day-old mice was due to the imprinting of a different trajectory due to the absence of colostrum at birth, we performed two additional experiments. First, we investigated whether the impact of the intervention on ILC2 at Day 14 was due to changes in diet at birth versus at later time points. Therefore, pups were cross-fostered at Day 10, instead of Day 0, to dams that gave birth 9 days earlier than their biological mothers. As shown in Figure S2A, their percentage and number of ILC2 at Day 14 were similar to ctrl mice demonstrating that ILC2 ontogeny is not affected by exposure to ‘old’ milk at the time when ILC2 massively expands. We then investigated whether the reduced ILC2 expansion in mice nursed from birth by dams at Day 9 of lactation was due to colostrum deprivation versus exposure to mature milk at birth. We cross-fostered pups at birth to dams that had delivered only 3 days earlier. Similar to mice nursed by mothers at Day 9 of lactation, we found a major decrease in the representation of ILC2 compared to control mice (Figure S2B), supporting the hypothesis that colostrum at birth is required for ILC2 ontogeny. Given the importance of the microbiota in gut immune ontogeny, we next evaluated whether colostrum shaped the gut microbiota.3 Both the alpha and beta diversity of the gut microbiota significantly differed between control and colostrum-deprived 2-week-old mice (Figure S3A,B). To address whether this difference played a causal role in decreased ILC2 expansion in colostrum-deprived mice, experiments were repeated in germ-free mice. As observed in specific pathogen-free mice, we found that colostrum deprivation resulted in a 30% decrease in small intestine ILC2 compared to control germ-free mice (Figure S3C), indicating that the role of colostrum in ILC2 ontogeny is microbiota independent. The alarmins, IL-33, IL-25 and TSLP, play a major role in ILC2 proliferation and/or activation.4 During the first days of lung alveolarization, transient high levels of IL-33 were found to promote ILC2 accumulation.5 We also observed a transient increase in IL-33 secretion in the gut of 4-day-old control mice, which was two-fold lower in colostrum-deprived mice (Figure 1C). In addition to IL-33, IL-25, which is known to be important for gut ILC2 expansion/activation was significantly reduced in colostrum-deprived mice at Day 4 (Figure 1C). TSLP has a synergistic effect on the proliferation and Type 2 cytokine production of ILC2 and may be particularly important in early life where IL-33 alone is not sufficient to activate cytokine secretion.4 We also found a trend towards reduced TSLP secretion in colostrum-deprived mice (Figure 1C). Altogether, these data strongly suggest an important role for colostrum in alarmins-driven perinatal ILC2 expansion. Whereas we found that colostrum intake affected neither the circulating pool of ILC2 nor the expression of gut-homing molecules CCR9 and α4β7 on small intestine ILC2 nor their proliferation (Figure S4A–C), we found a threefold increase in apoptotic ILC2 in colostrum-deprived 2-week-old mice compared to controls (Figure 1D). The reduction in alarmins secretion in colostrum-deprived mice may contribute to their increased apoptotic death of ILC2.4 Finally, we evaluate the functional consequences of a decreased representation of small intestine ILC2 in colostrum-deprived mice by measuring their gut content in IL-13 and their ability to clear helminth infection, which is known to involve ILC2.5 IL-13 levels in gut tissues form colostrum-deprived mice were significantly reduced compared to control mice (Figure 1E). When 3-week-old colostrum-deprived mice were infected with Heligmosomoides polygyrus, twice as many worms in the intestine and threefold more eggs in the faeces were found 21 days later, compared to control mice (Figure 1F), showing the decreased ability of colostrum-deprived mice to efficiently control helminth infection later in life. Our data suggest that the reduced representation of ILC2 underlies this increased susceptibility to helminth infection. Future studies will establish whether other characteristics of colostrum-deprived mice may explain this observation. As a first step in translating our findings to humans, we analyzed the association between delayed initiation of breastfeeding (based on WHO guidelines recommending initiation within 1 h6), a practice that deprives the newborn of the full dose of colostrum, and the susceptibility to helminth infection in young children. Three-hundred mothers and their children (aged 1–3 years) were recruited in Uganda, and data on early feeding practices were collected retrospectively (Table 1). Among mothers who initiated breastfeeding after 1 h, 78% initiated breastfeeding on the first day of life, 17% on Day 2 and 5% after 1 week. Delayed initiation of breastfeeding was strongly associated with an increased risk for helminth infection [OR (95% CI): 5.3 (1.9–15.06, p = .009)] (Figure 1G). Data remained significant after adjustment for maternal and child age, which differed between the two groups [aOR (95% CI): 6.6 (2–22)]. A limitation of this proof-of-concept study is the recall bias on early feeding practice. To fully establish the importance of colostrum in the prevention of helminth infections, prospective studies specifically addressing the relationship between the amount of colostrum feeding and helminth infections will be required. Mouse and human data show there is a massive infiltration of ILC2 in the infant small intestine7, 8; however, factors involved in this process remained unknown. This work uncovers a critical role for colostrum in gut ILC2 ontogeny and reveals its importance for anti-helminth defence. Given the importance of ILC2 in the regulation of allergic responses,5 future research will need to address the impact of colostrum deprivation at birth on allergy risk. Despite WHO guidelines, more than half of newborns globally are non-optimally colostrum-fed,6 which deprives the newborn of colostrum bioactives at a time of both high vulnerability and critical developmental change. There is strong evidence that optimal colostrum feeding has a major impact on the prevention of neonatal mortality, especially in low-and middle-income countries.9 Our data provide evidence that colostrum may also be fundamental in imprinting healthy immune development. Expanding the knowledge on colostrum bioactives responsible for ILC2 expansion should lead to a major impact on child health. Project design and supervision: VV. Conceptualization: VV (whole project), AR (whole project), ML (GF exp), DL (GF exp), RL (ILC2 ontogeny), RM (helminth mice), TE (helminth human) and RB (microbiota). Mice experiments, data analysis and interpretation: AR, LvdE, CI, SM, ND, CT, ML, NS, TY and VV. Human data collection and analysis: MB, CR and TE. Microbiota data analysis: FS, RB and VV. Writing—original draft: AR and VV. Writing—review and editing: All. The authors would like to thank Simone Ross and Caitlin Murray at the Harry Perkins Institute for Medical Research, the Gnotobiotic facilities and the technical assistance of staff in the South Australian Health and Medical Research Institute (SAHMRI) Preclinical Imaging and Research Laboratories (PIRL) and Translational Research Institute (TRI). Flow cytometry analysis was performed with the help of Catherine Rinaldi from the Cytometry Centre of Microscopy Characterisation, and Analysis (CMCA, UWA) and at the ACRF Cellular Imaging and Cytometry Core Facility in SAHMRI. The ACRF Facility is generously supported by the Detmold Hoopman Group, Australian Cancer Research Foundation and Australian Government through the Zero Childhood Cancer Program. We also thank Benjamin Lelouvier from Vaiomer for the data analysis. VV, LE, AR, SM, MB and ND were supported by the Larsson-Rosenquist Foundation. AR and LE were supported by a Raine collaborative grant award. DJL was supported by an EMBL Australia Group Leader award. RMM thanks the Wellcome Trust for support through an Investigator Award (Ref 219530), and core-funded Wellcome Centre for Integrative Parasitology (Ref: 104111). Florence Servant declares she is an employee of the “Vaiomer SAS” company. All the other authors declare they have no conflict of interest related to this publication. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions. Data S1. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Sylvain Carré, Franck Gabriel

No abstract is available for this record.

Ricardo Uauy, Jehan‐François Desjeux, Tahmeed Ahmed, Muttaquina Hossain · 8 authors

Childhood malnutrition encompasses a plethora of nutritional disorders that include stunting, underweight, wasting, severe acute malnutrition (SAM), and micronutrient deficiency disorders. Overweight and obesity, at the other end of the nutritional spectrum, are also manifestations of childhood malnutrition. Nearly 24 million children (younger than 5 years) worldwide experience SAM. The vast majority is located in Africa and Asia (8 million are in India alone). A child with SAM is 10 times more likely to die than a well-nourished child. SAM is one of the top 3 nutrition-related causes of death in children younger than 5 years. Estimates of deaths directly attributable to SAM varied from 0.5 to 2 million annually. Moderate and severe child malnutrition account for 40% to 50% of all deaths in children younger than 5 years. If the United Nations Millennium Development Goals (http://www.un.org/millenniumgoals) of reducing children malnutrition and mortality by 50% by 2015 are to be met, SAM needs to be prevented and controlled effectively. UN SYSTEM (UNICEF-WHO-WFP) ACTIVITIES IN PREVENTION AND TREATMENT OF SAM Support countries with high levels of SAM to scale up coverage for treatment through community-based management of acute malnutrition (CMAM) Preventing acute malnutrition in children and women through increasing coverage of high-effect interventions (eg, micronutrients) Inpatient treatment is reserved for the smaller group that requires close medical monitoring and therapies that are exclusive to medical facilities: parenteral hydration, treatment of hypotension, shock, metabolic alterations (hypoglycemia, hypothermia), or severe infections Integrated management of PEM considers both inpatient and outpatient treatment of SAM; whenever possible outpatient treatment should be used based on the following advantages: Minimizes effect on family and requires limited health services support Simpler treatment: no food preparation is required, can be eaten directly Broad coverage: eliminates primary barriers to “scaling up” (need for doctors and health facilities) Active case finding relies on community outreach The support for using community-based treatment is also based on equal or lower mortality rates and reduced cost (US$∼450–∼$130/child).Policy formulation at country level is progressing rapidly; 95% countries have national guidelines/protocols for acute malnutrition as evidenced by: Visible policy documents and joint statements Increasing coverage and scaling-up of programs: 55 countries implementing CMAM; an additional 7 countries are in the planning stages. Integration of CMAM with other primary health progress in at least 50% to integrate activities: integrated management of childhood illness, infant and young child feeding, human immunodeficiency virus/acquired immune deficiency syndrome Increasing adherence to a comprehensive integrated approach into health system Global guidelines and training resources are available including incorporation of infant feeding orientation into trainings.Challenges encountered in the implementation of the CMAM include Weakness in existing intersectoral linkages; stronger links with food security and other sectors are required in support of long-term solutions and prevent short-term emergencies Unpredictable funding; most resources still derived from humanitarian response for acute emergencies averting multiyear planning Difficulties in setting up long-term supply plans to ensure that ready to use therapeutic food (RUTF) needs are met and buffer stocks are in place. Geographical distance of manufacturers from the final beneficiaries is a problem; however, proliferation of unreliable local suppliers with poor quality control systems is not the answer. UN SYSTEM ACTIVITIES IN PREVENTION AND TREATMENT OF SAM The WHO Electronic Library of Evidence for Nutrition Actions (eLENA) has been released (www.who.int/elena). This updated version of the site includes new nutrition intervention topics such as food supplementation for children with moderate acute malnutrition, vitamin D supplementation in infants, multiple micronutrient supplementation in pregnant women, and community-based feeding for the promotion of child growth. Updates of the eLENA site have been launched and include translations into the 5 official WHO languages. The Spanish site was launched during the World Health Assembly in May 2012 (www.who.int/elena/es). Updated guidelines on the integrated management of SAM in children are expected to be released in the upcoming edition of eLENA. The Global Database on the Implementation of Nutrition Action is a complementary Web-based tool in which governments and organizations can upload and share information on their nutrition activities. The Global Database on the Implementation of Nutrition Action will have a user-friendly interface with interactive maps, lists, and fact sheets that show what is being done where, when, with whom, why, and how to scale up and improve nutrition. Users are invited to continue to upload nutrition action information via the online form at www.who.int/nutrition/gina. CHALLENGES FOR HEALTH PROFESSIONALS CONCERNED WITH GASTROINTESTINAL DISEASES AND NUTRITION IN ADDRESSING SAM Clearly, there is a need for all concerned parties to join forces; pediatricians and especially those with interest in gastrointestinal (GI) diseases and nutrition have an important role to play. Key challenges ahead and potential approaches in addressing them are summarized in the next section. Lack of political commitment: Nutrition is often a low priority on the political agenda resulting in limited funding or in some cases no secure budget allocation being made. SAM in many cases is not even recognized as a health problem (not included in surveillance systems). Health professionals should also be strong in advocacy efforts and lead the battle against SAM calling the attention of all concerned parties, not only on moral grounds but also as a key investment for national development. The implementation of known solutions requires a strong delivery system, such as infant and young child feeding. Thus, a well-supported health care service with broad coverage is fundamental, particularly in hard-to-reach areas and for population groups living in poverty or emergency conditions. Resistance of some governments to use imported ingredients, that is, RUTF or other costly supplies, limits implementation of CMAM programs in some areas of the world. The concerns are commonly based on sustainability and having to depend on imported commodities. These can be circumvented by using local ingredients and/or local blending of ingredients depending on circumstances. The appropriate design and effective implementation of CMAM requires local capacity to design, implement, and evaluate programs. Limited local capabilities impede progress in controlling and preventing malnutrition in many countries. The effectiveness of CMAM program requires local institutional capacity to ensure the delivery of a comprehensive package of services in emergencies (CMAM and micronutrients); in addition, information needs to be collected and reported to assess cost-effectiveness of the interventions. Successful sustained control of SAM requires intersectoral linkages beyond health; at the very least, they should include agriculture (food and nutrition security), water and sanitation, women's and children rights, community participation and empowerment. Creating sustainable livelihoods allows communities to meet their basic needs. Only then can governments be held accountable and responsible in addressing the social and economic determinants of SAM. Sustained funding for activities, programs, development of institutional and human capacity is fundamental to avert acute emergencies. Predictable medium- and long-term funding and multiyear planning are essential to prevent malnutrition in all its forms and avert the consequences on human and social development. Long-term supply to ensure that raw materials to produce RUTF are met and buffer stocks are in place and available to cover local needs. This requires appropriate quality control and distribution systems. Systematic collection of local, regional, and national data collection and information systems should be in place to guide CMAM activities, map SAM, and focus efforts on most-affected areas. Information flow from field to national level should be established; consistent use of WHO reference growth standards should be used within and between countries, defining common performance indicators for regional- and country-level reports. This report is a short account of present efforts in addressing SAM; what we do or fail to accomplish in the next few years will have major significance if we are to achieve the millennium development goals 1 and 4. Halving hunger by 2015 most likely will not be achieved on a global basis; however, with appropriate support, this may be achieved by many countries in Africa and southeast Asia. Similarly, reducing by two-thirds the mortality of children younger than 5 years unless we make this a global priority for action and do not leave this to action by local governments that may or may not see this as a top priority. It is time that we consider child health and well-being a global priority subject to commitments by global governance; sooner or later we must face that “children's needs cannot be postponed.” We must act now to secure their basic needs—the future of humanity is at stake. All JPGN readers are concerned with malnutrition in children because most diseases of the GI tract have a negative effect on nutrition. Because they are common all over the world, essentially as a consequence of infection, they represent a major cause of malnutrition. Malnutrition, A Risk to All Children and Humanity Nutrition is essential for all life to be perpetuated through reproduction. Childhood is the period in which growth and psychosocial development are supported by use of food through metabolic processes genetically determined. Malnutrition is a generic term that covers the results of any deviation that impairs growth and development. It may be so severe that it may remove the life of the child. Most often the child recovers after proper treatment, but in too many children, it will last for years. Many girls reach reproductive age in poor nutritional condition. The millions of children born to malnourished women are more likely to face cognitive impairments, short stature, lower resistance to infections, and a higher risk of diseases throughout their lives, thus perpetuating the cycle of malnutrition. Select Realistic Target At the global scale, the most prevalent situation is deficit rather than abundance in food availability or food use or both, for example, as a consequence of GI disorder, infectious disease, or low birth weight (LBW). According to UNICEF, 1 in 4 children in the developing world are underweight. Because pediatricians are facing such a disaster, it is difficult to imagine what can be done to solve it; however, by targeting specific population, it may be possible to envisage proper treatment. First, it is important to define the different states of malnutrition. Malnutrition may be the results of general or selective food deprivation, essentially iron, iodine, zinc, and vitamin A. The most common clinical conditions are underweight, stunting, and wasting. All of these conditions occur in different context that need to be analyzed. Second, it is important to identify the regions of the world that need context-specific approaches. More than 10 million children die each year, most from preventable causes and almost all in poor countries. Six countries account for 50% of worldwide deaths in children younger than 5 years, and 42 countries for 90%. The causes of death differ substantially from one country to another. A better understanding of child health epidemiology could contribute to more effective approaches to saving children's lives (1). Severe Acute Malnutrition SAM is defined by an extremely low weight for height, by visible severe wasting, or by the presence of nutritional edema. Until the end of the 20th century, the median under-5 case-fatality rate for SAM typically ranges from 30% to 50%. It was reduced substantially (typically <5%) when physiological and metabolic changes were taken into account and a standardized protocol was initiated (2). The use of F100 as a milk powder reconstituted with water to obtain 100 kcal/100 mL was effective but its use was limited to medical structures. The RUTF was a major step in overcoming the limitation of F100 (3–5). In 1997, André Briend, who was the initiator of such treatment, conducted the first clinical trial in Tchad as a proof of concept. In 2005, in Niger, Médecins Sans Frontières treated at home 60,000 children with a success rate of 90%. Such a therapeutic approach is expected to save millions of children. Linear Programming One approach to prevent malnutrition and maintain healthy nutritional status is to use locally available food. However, many limits need to be taken into account, including food availability, composition, and cost, which must cover the nutrient recommendations for that population. Historically, such an approach was at on trial and The of nutrition has been with a tool The is The more a child a for example, the more or and such a is The for and and cost of the This is what can solve an program was then more user-friendly programs were for example, In a program was being and should be released more pediatricians and to proper recommendations that are as food rather than Such an approach could be used in many different in both and developing Childhood Malnutrition in Asia defined as the reference is the most common of childhood malnutrition and malnutrition. It is with cognitive and reduced the million of all of the under-5 children in the developing world, Asia for million The of children in Asia is than in the acute malnutrition and is defined as a children are to infections and have a 3 to 4 of death from or More than million children experience the form of wasting, SAM, which is by any one of the or edema. India is home to million children with SAM Africa has million children with SAM, which a risk of death with well-nourished is a of and wasting. The of at birth is with of other and the between children in different regions after 24 when with a healthy reference group It is that particularly has the of childhood malnutrition. of are born each with which is a weight at In the of ranges from in to in This is important because is a major risk for malnutrition. children who have an risk of diseases in including 2 and malnutrition, of which is not and is also known as millions of children in Asia. In children 5 years, million in southeast with million in all of Africa from which is nutritional in and 2005, 50% of age children in Asia vitamin A deficiency by a level deficiency has negative on growth and development to In children in Africa with 30% in southeast Asia being in southeast at high risk for deficiency are those with a of and of of deficiency is high in Asia Overweight and are the of the Overweight in childhood is defined as a can be defined as having a it has a primary childhood health problem in countries are also to see childhood as a of children in the and WHO regions were to be or by in in the and in southeast Asia A done on children a in of from in to in The of malnutrition and the from in children of Asia for Nutrition must be treated as a development agenda and to the in national policy formulation and is a major in many countries and needs attention for more as as and This has even more for countries such as which face by interventions should be up to reach These interventions include appropriate complementary feeding, micronutrient treatment of moderate acute malnutrition and SAM These interventions will not be interventions and in water and poverty and so on need to be at It is also to have programs such as social and sanitation, and interventions. The problem in countries should be with programs for and with on of children. and in the of SAM The treatment of SAM must focus on of childhood malnutrition, with a approach including micronutrient during exclusive of human immunodeficiency for with effective use of therapeutic in the water and with most addressing the social determinants of health through within This however, on the of and management of SAM during the of treatment, which has such a high therapeutic food (RUTF) has capacity for growth in both and we need to focus more on the of children with severe malnutrition, often by acute or is for such children, as the of on children's with and milk or has feeding is but may need to be which it very difficult on with the of especially during and WHO guidelines the use of following done years we now have a of the in malnutrition, so should be to design better in may be important has an of there are with We need with to see they improve as they are being used of a new are understanding of childhood and we are the and of as a to childhood In of poverty and deprivation, it is often some children malnourished and many do Because from severe and has it be if childhood growth and nutrition not this is not likely to lead to better treatment it may improve understanding of the determinants of malnutrition and it may even be possible to identify children at risk and to prevent malnutrition. It is important for children in developing countries to from to to and in The of nutrition of children is a of social and economic with a effect on to food and nutrition. The information available the health of a to a were as of and and in the of of living and social and poverty by the Children in a cost from the in the of infectious and malnutrition. The effect of child with infection, especially infection, is the In children of the population but for of for deficiency and of for other nutritional infections, with rates up to the of the population, with poor nutrition to produce a by poor especially of and perpetuating a cycle of and malnutrition to poverty first with lower birth up to 1 than in some and with the risk of which on was than the of the community in This is by growth in the first of In the century, 30% and of were the for weight and height, increasing to and by 24 of age At the of the century, infant mortality the poor times that of higher groups at and there is a deficit of years for these and 20th health with for infections, and severe nutritional and a however, from conditions to a situation that has but has of nutritional to and 40% of to are or increasing to almost during the years This problem in childhood with more likely to be or than higher social Increasing is with increasing 2 and metabolic which occur in up to of low social of poor are and experience higher and The causes of death those of low social living in poverty are and with standardized mortality rates for to and for and metabolic to times than higher groups now for of the between higher and lower social The from diseases of nutritional deficiency to diseases of is to the nutritional experience of children, with nutritional experience into long-term health of poverty and food and food quality have resources to food and poor to a is increasing More important is in nutrition and by both and which with childhood malnutrition is with later and its long-term These nutritional of and metabolic to the in which with food. These represent major potential of intervention essential for health and well-being at the population are no solutions to the by children. The solutions are not and healthy are are they to low but common to many other and groups of the and to their of is as is and the role of women, social and and These may from nutritional and but advocacy a of and in The 2 of Malnutrition The health of childhood are and attention In countries, food not have the and it too is a global that in and countries, with for long-term health and development. In million children in poverty and million in more than one of children and are or food and are as health there is increasing there is between these conditions. children are often from in food in children who face food are more likely to report hunger Children who with hunger are more likely to be experience and have a higher of and of key and are more likely to have and The and long-term consequences of and are and include psychosocial and joint and their long-term obesity, food and hunger are often in even in in which other indicators of poverty are food programs: than of the children for a or a and of children in a program Risk for food include or the poverty children by and those located in or areas. communities at high risk for as is more prevalent those who are poor and for this of these 2 there is no some are in and have limited to healthy which to with of low cost but food. These are also to living in communities also often to and with for and more time or Thus, the food and are is is there are between food of and in children have been have particularly in of to poverty and low may be a common and food In such of limited to food may in of food for of food resulting in food food and may such as adherence to infant feeding recommendations and to healthy Thus, the between food and has both an and both important health for children in health policy to with the of childhood obesity, it must consider to with the and social conditions that in food the face of malnutrition in in other countries, from that in countries, food and have nutritional and long-term health of both of these is to the long-term health and development of children.

Catherine Richards, Paul Andrews

INTRODUCTION Wherever you go, there are children who vomit. Causes of acute vomiting episodes include infections, minor head injury, gastrointestinal obstruction, and other surgical conditions. Chronic vomiting or recurrent vomiting is less well categorised, but includes regurgitation due to gastroesophageal reflux, allergic and eosinophilic diseases of the gut, chronic gastrointestinal dysfunction, metabolic disturbance, disease of the central nervous system, and disorders such as cyclical vomiting syndrome. It has even been noted that in children it can be a “symptom of almost any disease system” (1). This article outlines the mechanics and mechanisms of emesis and related reflexes, such as belching and gastroesophageal reflux, and highlights how knowledge of the underlying physiology has implications for understanding functional upper gastrointestinal tract disease in children. In addition, we review a number of challenging areas of paediatric gastroenterology involving nausea and vomiting. The authors use the following terminology: Vomiting is a lay term, used by patients and their families, to describe previously swallowed food and gastrointestinal secretions coming up the oesophagus and out of the mouth by any mechanism. Regurgitation describes the apparently effortless movement of gastric contents from stomach to oesophagus and out of the mouth. Emesis describes the forceful expulsion (vomiting) of stomach contents out of the mouth by vigorous contraction of the anterior abdominal wall muscles and diaphragm following activation of the emetic reflex. It is vital that clinicians distinguish between regurgitation and emesis, because when they become pathological, the treatment for each is different. Inappropriate treatment risks failure, and surgical therapy for regurgitation due to gastroesophageal reflux is likely to worsen the symptoms of emesis. The emetic reflex is triggered by a wide range of peripheral or central stimuli (2). Inputs to the “vomiting centre” (the collection of nuclei in the brainstem coordinating the emetic motor outputs) include gastrointestinal vagal afferents, the area postrema (“chemoreceptor trigger zone,” subject to direct influence by blood and cerebrospinal fluid–borne factors), vestibular system (motion sickness and inner ear disease), and stimulation of the pharynx. Severe abdominal pain is also a potent stimulus, but the pathways by which it induces emesis are unclear; although the noxious stimuli are conveyed in the splanchnic afferents, stimulation of these afferents does not evoke reflex emesis, in contrast to stimulation of abdominal vagal afferents. The emetic reflex also can be activated by stimulation of more rostral regions of the brain (eg, hypothalamus, limbic system) and by unpleasant sights or smells. The reflex also is amenable to Pavlovian conditioning, but relatively little is known of the descending pathways involved and their clinical significance. However, it is likely that the threshold for activation of the reflex by a number of stimuli is capable of modulation from higher brain regions, and this is supported by observations that sensitivity to motion sickness is a predictor of emesis to anticancer chemotherapy, postoperative nausea, and vomiting and pregnancy sickness (2). The emetic reflex may be considered in 2 phases—the prodromal phase and the ejection phase. The prodromal phase is characterised by nausea, an unpleasant but not painful sensation related to the upper abdomen, associated with a desire to vomit or a feeling that vomiting is imminent. It may precede emesis or it may occur in isolation (2), as can emesis itself. Emesis may alleviate nausea. The physiological basis of nausea remains poorly understood, but there is a strong association with gastric antral dysrhythmia and a large increase in the plasma levels of arginine vasopressin (3). Nausea is often accompanied by autonomic events, including sweating, peripheral vasoconstriction (causing pallor), tachycardia, reduced gastric secretion and pupil dilatation due to sympathetic nervous activity, and increased salivation due to parasympathetic stimulation (2). The central nervous systemic pathways involved in the genesis of the sensation of nausea are not known, although the inferior frontal cortex has been implicated. The ejection phase consists of retching and vomiting. First, there is a vagally mediated relaxation of the stomach and the lower oesophageal sphincter. A retrograde giant contraction originating in the mid-small intestine sweeps to the stomach, and is also under vagal efferent control. This contraction probably accounts for the frequent presence of bile in vomitus, except when pyloric obstruction is present. Tonic longitudinal contraction of the pharyngoesophageal junction pulls up the oesophagus, helping to open up the gastroesophageal junction. Then retching begins, with the anterior abdominal wall muscles and entire diaphragm (including the crura) contracting synchronously, with displacement of the abdominal oesophagus and gastric cardia through the crural hiatus into the thorax. Although gastric contents may enter and leave the lower oesophagus, they are not ejected. During vomiting, the perioesophageal diaphragm (ie, the right crus) relaxes, and the expulsion of gastric contents is achieved by the somatic muscles compressing the relaxed stomach. In the dog, a retrograde-propagated pharyngoesophageal contraction promotes the forcible ejection of gastric contents from the mouth (4), but it is unclear whether this occurs in humans. The purpose of the emetic reflex is defensive: to remove contaminated food from the upper gastrointestinal tract (2). Nausea stops further ingestion and facilitates learned aversion. It is an aversive stimulus, much more so than pain (5). The emetic reflex is a protective gastrointestinal reflex and in the normal course of events should be activated only occasionally; however, chronic gastrointestinal disease or dysfunction may result in frequent activation. In some neurologically impaired children, the central neurological damage appears to result in loss of inhibition, or hypersensitisation of the emetic reflex, which is then activated in the course of normal everyday activity. The belch is a vago-vagal reflex that permits oral expulsion of excessive intragastric air. Accumulation of gas in the gastric fundus and distension of the region of the cardia results in sudden and complete transient relaxation of the lower oesophageal sphincter (6), accompanied by relaxation of the diaphragmatic crus (7). A common cavity phenomenon occurs, attributed to reflux of air and other gastric contents into the oesophagus, with equalisation of gastric and oesophageal pressure; 1 or more belches may then take place as air is expelled (8,9) facilitated by contraction of anterior abdominal muscles. Note that the somatic motor changes during belching are similar to those occurring during vomiting, although they are considerably less forceful, and from the person's point of view, feel effortless. Unlike activation of the emetic reflex, there is no prodrome of nausea or associated autonomic events, such as sweating or vasoconstriction. Gastroesophageal reflux is the apparently effortless leakage of gastric contents (including food and gastric secretions) up into the oesophagus. It occurs when the mechanisms of oesophagogastric competence malfunction or are overcome by exceptional factors. Episodes of gastroesophageal reflux (GER) may occur in normal, healthy individuals without significant consequences. Gastroesophageal reflux disease (GERD) is present when the reflux results in significant symptoms or harm. A major factor in the occurrence of GER is dysfunction of the mechanism of lower oesophageal sphincter complex (ie, the smooth-muscle lower oesophageal sphincter [LOS] and the encircling right crus of the diaphragm). The most common mechanism of GER, in healthy individuals and in patients of all ages, is transient lower oesophageal sphincter relaxations (TLOSR); in other words, LOS resting pressure is normal but reflux occurs during episodes of a sudden, brief drop in pressure to near zero, which is not associated with primary oesophageal peristalsis induced by swallowing (10–15). This is more frequent in the immediate postprandial period and in the presence of gastric distension, and is accompanied by selective and complete inhibition of the crural diaphragm. TLOSRs can be triggered by activation of vagal afferents supplying the gastric fundus and cardia, and the resulting reflex motor responses are presumed to be coordinated in the brainstem (13,16). The normal physiological process most closely related to TLOSR is belching (8), although again the relaxation of the crural diaphragm and the LOS is reminiscent of the mechanics of emesis. Other mechanisms of GER include very low LOS resting pressure, downward drifts in resting pressure, reflux during swallow-induced relaxations, and GER due to abdominal straining (17,18). LOS length, or lack of it, especially the abdominal oesophagus, influences the effectiveness of the LOS as a reflux barrier. Sliding hiatus hernia is common in patients with GERD. This will dissociate the diaphragmatic crus from the LOS and disrupt antireflux mechanisms (19–21). Conversely, a long intraabdominal oesophagus will have antireflux properties because it is subject to intraabdominal pressure that will tend to compress it closed. In a nonvomiting species, such as the rat, the abdominal oesophagus is disproportionately long and narrow compared with humans. There is evidence that if the distal oesophagus is replaced by a tube of sufficient intraabdominal length, then reflux is prevented even in the absence of the LOS (22,23). In adults with reflux, relatively small quantities of gastric contents reach the mouth, but in children, the amounts refluxed may be much greater and may result in a large proportion of the recently ingested feed effortlessly pouring out of the mouth. Consideration of the underlying physiological processes should make clear the difference between reflux vomiting and vomiting due to activation of the emetic reflex. Reflux vomiting is akin to belching; there is no prodrome and it appears effortless. Emetic vomiting is preceded by feeling unwell with nausea, pallor, sweating, and tachycardia, and it is accompanied by violent contractions of the anterior abdominal wall muscles and diaphragm, leaving the subject feeling drained and exhausted. CLINICAL IMPLICATIONS FOR CONFUSION BETWEEN EMESIS AND GER Chronic vomiting in children may appear to be a result of GER and regurgitation. It is reported to be particularly common in neurologically impaired children and is attributed to central nervous system dysfunction (24); however, it is not always easy to get the diagnosis right. The importance of understanding the pathophysiology and the potentially devastating effects of misdiagnosis is emphasised by considering the effects of inappropriate fundoplication. Many children, particularly those with neurological impairments, do not show a full symptomatic response to antireflux medication. They are considered to have severe reflux disease and to require surgery. However, a high failure rate has been documented (25,26) and an alternative explanation must be considered. Failure to respond to antireflux therapy may not indicate severe GERD, but that some or all of the symptoms are due to another cause (eg, activation of the emetic reflex) (24). Many of the children with failure to respond to antireflux therapy have symptoms other than those of GERD. One prominent troublesome symptom that persists after fundoplication is retching (25–33), but this is a component of the emetic reflex and not a symptom of GER (24). These children may also have evidence of nausea (34). Performing fundoplication on a child whose symptoms are wholly or partly due to activation of the emetic reflex is liable to result in marked postoperative problems (35). Fundoplication does not deal with the underlying causes of emesis, and by creating a valvular mechanism at the oesophagogastric junction and obstructing the movement of gastric contents back up the oesophagus, symptoms are made worse. The child will retch repeatedly, and the accompanying nausea will persist. Children who retch preoperatively have a much higher chance of retching following fundoplication compared with nonretchers (35). In a report on anatomical wrap failure (eg, wrap herniation/wrap disruption) following laparoscopic fundoplication in adults, Soper and Dunnegan (36) found a significant association with forceful contraction of the diaphragm. The process that appears to generate the greatest pressures, and, moreover, the greatest pressure gradient from the abdomen to the thorax, is retching. Retching generates huge forces capable of causing wrap disruption, and in particular, forces that specifically drive the wrap through the crural hiatus (ie, wrap herniation into the thorax). Using radioopaque markers, Johnson and Laws (37) demonstrated elevation of the oesophagogastric junction through the crural hiatus just before retching and vomiting, with displacement of the cardia and distal oesophagus cranial to the crus, into the thorax. In a subsequent study of the mechanics of vomiting in the cat, McCarthy and Borison (38) described retches as a metronomic series of pulses, with brief negative-pressure pulses in the thorax mirrored by positive-pressure pulses in the abdomen, progressively building up a substantial transdiaphragmatic pressure gradient (200–300 mmHg) and culminating in a prolonged positive abdominal and thoracic pressure wave with sustained abdominal contraction and elevation of the diaphragm and vomit expulsion. During retching, there was a pulsing cephalad displacement of the oesophago-gastric junction, with the fundus of the stomach drawn through the diaphragmatic hiatus, into the thorax (38,39). These reports indicate that there is normally a substantial movement of the gastroesophageal junction during retching and vomiting, with significant pressure changes. Fundoplication in the retching child sets the scene for anatomical wrap failure. Repeated episodes of retching drive the oesophagogastric junction through the diaphragmatic hiatus into the thorax and pull the wrap apart. Patients classically present with increasing postoperative retching (wrap intact), which may later progress to retching and vomiting, associated with subsequent documentation of wrap disruption. Retching precedes wrap failure and is a cause rather than a symptom of wrap herniation. Not only does fundoplication fail to relieve emesis but there is also evidence that fundoplication may even sensitise the emetic reflex, reducing the threshold for activation of retching and emetic vomiting. Some children may develop new onset of retching after fundoplication, and parents of children who retched before surgery believe the postoperative retching is worse. Gastric dysrhythmias, as recorded by the surface electrogastrogram, may worsen after fundoplication, correlating with retching symptoms (24). In an animal model of fundoplication (the ferret), fundoplication was followed by an increased sensitivity to a low dose of the centrally acting emetic loperamide (40). A possible mechanism of sensitisation is the presence of peripheral nerve and muscle damage and scarring as a result of surgery. Histological examination of the fundoplication in the ferret shows clear evidence of scar tissue in the wall of the distal oesophagus and the inner gastric layer of the fundoplication wrap, in the region of the cardia (41). This effect may be even more marked in disrupted wraps. In ferrets with disrupted fundoplications, we observed an increased retching response to induction of general anaesthesia compared with intact fundoplications (in turn greater than controls), together with evidence of gastric dysmotility and increased scar tissue and nerve damage (41). This has implications for redoing fundoplications after wrap disruption, with a higher risk of failure, increasing damage, physiological dysfunction, and ever-increasing symptoms. CHALLENGES IN NAUSEA AND VOMITING IN PAEDIATRIC GASTROENTEROLOGY How Do We Identify Nausea in Young Children and Neurologically Impaired Children? Nausea is a self-reported subjective sensation, so how can the presence of this significant clinical symptom be established in patients who are unable to self-report, such as young children and those with severe neurological impairments? The situation is analogous to that in animals, in which behavioural changes and physiological markers have been used as surrogate markers for the presence of the sensation (2). Traditional teaching states that pain from reflux oesophagitis causes food refusal in children. In our study of children before and after Nissen fundoplication, we observed a striking association between food refusal and retching, strongly suggesting that in the context of recurrent vomiting, food refusal is a manifestation of the nausea that accompanies the emetic reflex (34). Refusal of specific foods is particularly suggestive of nausea-induced taste aversion. An infant with activation of the emetic reflex secondary to intolerance of cow's milk protein may refuse whole-protein cow's-milk formula, but will readily drink a hydrolysed formula or water. Parents of a child with emesis may say that they appear unsettled or “pull a face” immediately before emesis, again suggesting distress and nausea. Other indicators of nausea may include the surface electrogastrogram; development of a gastric dysrhythmia in response to food may indicate nausea in the same way that the appearance of tachygastria correlates with the onset of motion sickness (42). Measurements of plasma vasopressin have not been made in children with suspected nausea, but such measurements may be helpful in ensuring that this distressing symptom does not go unrecognised and hence untreated. Cyclical Vomiting Cyclical vomiting is a that is most reported in children 2 to but which can also occur in It is characterised by a of or more of acute nausea and vomiting to with to with of and central nervous system disease of this a to into the physiology and of the emetic reflex. 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