Role of Pediatricians in Promoting and Supporting Breastfeeding: A Position Paper of the International Pediatric Association Strategic Advisory Group on Infant, Child, and Adolescent Nutrition.

BACKGROUND: Promoting and supporting breastfeeding is an important public health intervention with multiple benefits for both infants and mothers. Even modest increases in the prevalence and duration of breastfeeding could significantly reduce healthcare costs and improve maternal and child health outcomes. However, widespread adoption of breastfeeding recommendations remains poor in most settings, which contributes to widening health and social inequalities. Pediatricians have a duty to advocate for improving child health, including promoting and supporting breastfeeding. SUMMARY: This paper, from the International Pediatric Association Special Advisory Group on Nutrition, considers common barriers to breastfeeding and addresses how pediatricians can better promote and support breastfeeding, both at an individual level and by influencing practice and policy. All pediatricians need to understand the basics of breastfeeding, including lactation physiology, recognize common breastfeeding problems, and advise mothers or refer them for appropriate support; training curricula for general pediatricians and all pediatric subspecialties should reflect this. Even in the situation where their day-to-day work does not involve direct contact with mothers and infants, pediatricians can have an important influence on policy and practice. They should support colleagues who work directly with mothers and infants, ensuring that systems and environments are conducive to breastfeeding and, where appropriate, milk expression. Pediatricians and pediatric organizations should also promote policies aimed at promoting and supporting breastfeeding at local, regional, national, and international levels. KEY MESSAGES: Pediatricians have a duty to promote and support breastfeeding, regardless of their day-to-day role and responsibilities. Pediatric training curricula should ensure that all trainees acquire a good understanding of breastfeeding so they are able to effectively support mothers in their personal practice but also influence breastfeeding practice and policy at a local, regional, national, and international level.

Ochratoxin a in breast milk in Morocco: the affecting dietary habits of the lactating mothers and the degree of exposure of newborns "CONTAMILK study".

The aim of the present study is to evaluate the level of contamination of breast milk (BM) by ochratoxin A, among Moroccan lactating mothers in the city of Rabat, and to identify the associated factors of exposure, also to estimate the degree of exposure of the breastfeed infant. The analysis of ochratoxin A (OTA) was accomplished by ELISA method on 82 colostrum samples. OTA was detectable (>0.08 ng/mL) in 55% of samples with a maximum concentration of 10.04 ng/mL, and the levels exceeded 0.5 ng /mL in 50 % of the samples. In addition, several factors and dietary habits affect significantly the level of OTA in the analyzed samples of breast milk including, the consumption of industrial dairy products, the frequency of consumption of canned foods, dried fruits and legumes, also the period of breast milk collection. Besides, OTA was higher than the tolerable daily intake for 49% newborns. However, these results need to be confirmed by multicenter studies to more broadly estimate the levels of exposition of Moroccan population to OTA. Furthermore, awareness campaigns are recommended to inform the public, especially pregnant women and lactating women about appropriate preventive measures to limit exposure to this mycotoxin.

Levels of mercury in Moroccan breast milk and the affecting factors: CONTAMILK study.

This study aims to evaluate the level of mercury in the breast milk of Moroccan mothers and its association with several maternal parameters and habits, and to estimate the daily intake of the newborns. Inductively coupled plasma mass spectrometry (ICP-MS) was used to determine the concentrations of mercury in 70 colostrum samples. Indeed, a structured questionnaire was administrated during milk collection to report data concerning the maternal socioeconomic and anthropometric parameters, as well as dietary habits and smoking habits in the family, etc. The median of mercury in breast milk was 3,56 µg/L (range 1.64-124 µg/L) and exceeded normal levels of 1.7 µg/l, suggested by the World health organization in 99% of milk samples. Significant associations were found between mercury levels and the occurrence of previous miscarriages, anemia before pregnancy and vitamin & mineral supplementation during pregnancy, as well the frequency of consumption of cereals and the use of lipstick. The estimated daily intake was higher than the tolerable daily intake of the World health organization and the European food safety authority in 30% of newborns. These results need to be confirmed by multicenter studies to investigate the levels of mercury in the breast milk of the Moroccan population.

Systematic Review of the Literature of Factors Affecting the Exposure and the Levels of Lead in Human Breast Milk.

Human milk may sometimes contain chemical contaminants, which could have adverse effects on neonates or nursing infants. Lead (Pb) is of considerable interest due to its toxicity and occurrence. Furthermore, it has been suggested that human milk is a significant potential source of lead exposure to nursing infants. A systematic literature search in PubMed, Science Direct, and Google Scholar databases was performed to identify relevant studies, published in English until 2017, that investigated and explored common factors affecting the level of lead in human milk among lactating women around the world. Forty-nine papers were rated and explored the effect of one or several factors on the level of lead in human milk from 28 countries and carried out over a wide time frame from 1983 to 2017 and through Europe, Asia, America, and Africa, reviewing more than 5,000 subjects. Place of residence, maternal age, stage of lactation, smoking habits, maternal dietary intakes, and parity were the mostly assessed factors among the studies and considered as the main factors affecting Pb levels in BM. Other factors were not studied well enough and considered minor because few surveys evaluated their impacts. However, the literature findings are very controversial.

Prevention of Childhood Obesity: A Position Paper of the Global Federation of International Societies of Paediatric Gastroenterology, Hepatology and Nutrition (FISPGHAN).

Global childhood obesity increased more than 8-fold over 40 years, inducing a very large personal, societal, and economic burden. Effects of available treatments are less than satisfactory; therefore, effective prevention is of high priority. In this narrative review, we explore preventive opportunities. The available evidence indicates large benefits of improving nutrition and lifestyle during early life, such as promoting breast-feeding and improving the quality of infant and early childhood feeding. Promoting healthy eating patterns and limiting sugar-containing beverage consumption from early childhood onwards are of great benefit. Regular physical activity and limited sedentary lifestyle and screen time alone have limited effects but are valuable elements in effective multicomponent strategies. The home environment is important, particularly for young children, and can be improved by educating and empowering families. School- and community-based interventions can be effective, such as installing water fountains, improving cafeteria menus, and facilitating regular physical activity. Reducing obesogenic risk factors through societal standards is essential for effective prevention and limiting socioeconomic disparity; these may comprise food, drink, and physical activity standards for day cares and schools, general food quality standards, front-of-pack food labeling, taxation of unhealthy foods, restriction of food advertisements to children, and others. Effective prevention of childhood obesity is not achieved by single interventions but by integrated multicomponent approaches involving multiple stakeholders that address children, families, and societal standards. Pediatricians and their organizations should be proactive in supporting and empowering families to support their children's health, and in promoting societal measures that protect children.

Total, organic, and inorganic mercury in human breast milk: levels and maternal factors of exposure, systematic literature review, 1976-2017.

This systematic review summarizes the finding of 58 studies from 33 countries, which assessed mercury concentrations in breast milk and the factors related to the level of contamination. We performed a literature search in Pubmed, Science Direct, and Google Scholar databases for studies published between 1976 and 2017 that are monitoring and measuring mercury in human breast milk and investigating the associated factors. Then, we extracted more information about the aim of the study, the country, samples size, time of lactation, mercury concentration, and other data. Most of the studies used mature milk or colostrum for analysis and in about 60% of them, the concentrations exceed significantly the limit set by the World Health Organization (WHO) of 1.7 µg/l; In addition, many factors and parameters were related to the level of mercury contamination in breast milk. Periodic monitoring surveys are recommended in each country to evaluate the level of mercury in milk of lactating women and to estimate the level of exposure of newborns.

Chapter 9. Words From Partner Societies.

On the occasion of the 50th anniversary of the European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN), its close partner associations submitted comments and felicitations which are presented here. These include words from the Latin American (LASPGHAN), North American (NASPGHAN) and Panarabian Societies (PASPGHAN) and the Commonwealth Association (CAPGHAN) of Paediatric Gastroenterology, Hepatology and Nutrition, the Federation of International Societies of Paediatric Gastroenterology, Hepatology and Nutrition (FISPGHAN), the European Academy of Pediatrics (EAP), the European Pediatric Association/Union of National Pediatric Societies (EPA-UNEPSA), the International Pediatric Association (IPA), the European Crohn's and Colitis Organisation (ECCO), European Society for Clinical Nutrition and Metabolism (ESPEN) , the Federation of European Nutrition Societies (FENS), and United European Gastroenterology (UEG).

Practices of Introduction of Complementary Feeding and Iron Deficiency Prevention in the Middle East and North Africa.

BACKGROUND: Iron deficiency (ID) with or without anemia is associated with impaired mental and psychomotor development. Given the paucity of information on physicians' knowledge and practices on iron (Fe) supplementation and impact of ID in the Middle East and North Africa, it was felt important to conduct a survey. METHOD: A group of expert physicians developed a questionnaire that was randomly distributed among Middle East and North Africa doctors to assess their knowledge and practices on introduction of complementary feeding, impact of ID, its prevention, and their impression on prevalence of ID. Descriptive statistics were used. RESULTS: We received 2444 completed questionnaires. Thirty-nine percent of physicians do not follow the European Society for Paediatric Gastroenterology, Hepatology and Nutrition guidelines regarding age of introduction of complementary feedings. Approximately 62% estimate the prevalence of ID anemia to be 40% to 70%; however, only 17% always monitor hemoglobin between 9 and 12 months of age, 43% do so "almost" always, whereas 36% do so "rarely" or (4%) "never." For the prevention of ID in infants older than 6 months of age, almost all recommend introducing Fe supplements. Ninety-seven percent agree that untreated ID during infancy may have long-term negative effects on cognitive function, whereas 53.26% consider that Fe-enriched infant cereals result in staining of the baby teeth, constipation, and dark stools. CONCLUSIONS: Although there is awareness of the impact of ID, there are some misconceptions regarding age of introduction of complementary feedings, surveillance of Fe status, and side effects of Fe-enriched infant cereals. There is a need for educational initiatives focusing on prevention of Fe deficiency.

Assessment of cadmium levels in human breast milk and the affecting factors: A systematic review, 1971-2014.

BACKGROUND: This is a first systematic review summarizing 43 years of research from 36 countries for the assessment of cadmium in breast milk, a suitable matrix in human biomonitoring. OBJECTIVES: To report from the published literature the levels of cadmium in breast milk, and the affecting factors causing increase in cadmium concentrations. In addition, to gather several quantitative data that might be useful to evaluate the international degrees of maternal and infant exposure. METHODS: We reviewed the literature published between 1971 and 2014, available on Pubmed, Science Direct, and Google Scholar, reporting quantitative data about cadmium levels in human breast milk. Information about the aim of the study, name of the country, period of collection of samples, size of samples, sampling method, time of lactation, mother's age, area of residence, cadmium concentration, and other data were extracted. RESULTS: Sixty-seven studies were selected and included in this systematic review. Some concentrations greatly exceed the limit set by the World Health Organization (WHO); however, about 50% of the studies had less than 1 µg/L cadmium concentration (recommended by the WHO); as well as many factors have shown their implication in breast milk contamination. CONCLUSIONS: Breast milk is a pathway of maternal excretion of cadmium. It is also a biological indicator of the degree of environmental pollution and cadmium exposure of the lactating woman and the nourished infant. Therefore, preventive measures and continuous monitoring are necessary.

Early childhood obesity: a survey of knowledge and practices of physicians from the Middle East and North Africa.

BACKGROUND: Childhood obesity is one of the most serious public health issues of the twenty-first century affecting even low- and middle-income countries. Overweight and obese children are more likely to stay obese into adulthood. Due to the paucity of data on local practices, our study aimed to assess the knowledge and practices of physicians from the Middle East and North Africa region with respect to early-onset obesity. METHODS: A specific questionnaire investigating the perception and knowledge on early-onset obesity was circulated to healthcare providers (general physicians, pediatricians, pediatric gastroenterologist, neonatologists) practicing in 17 Middle East and North African countries. RESULTS: A total of 999/1051 completed forms (95% response) were evaluated. Of all respondents, 28.9% did not consistently use growth charts to monitor growth during every visit and only 25.2% and 46.6% of respondents were aware of the correct cut-off criterion for overweight and obesity, respectively. Of those surveyed, 22.3, 14.0, 36.1, 48.2, and 49.1% of respondents did not consider hypertension, type 2 diabetes, coronary heart disease, fatty liver disease, and decreased life span, respectively, to be a long-term complication of early childhood obesity. Furthermore, only 0.7% of respondents correctly answered all survey questions pertaining to knowledge of early childhood overweight and obesity. CONCLUSION: The survey highlights the low use of growth charts in the evaluation of early childhood growth in Middle East and North Africa region, and demonstrated poor knowledge of healthcare providers on the short- and long-term complications of early-onset obesity. This suggests a need for both continued professional education and development, and implementation of guidelines for the prevention and management of early childhood overweight and obesity.

Physician practice in food allergy prevention in the Middle East and North Africa.

BACKGROUND: A number of scientific organisations have developed guidelines for the primary prevention of allergic disease through nutritional interventions. However, even if the best evidence-based guidelines are available, these guidelines do not necessarily lead to adherence and improved health outcomes. METHOD: To determine how closely the practice of physicians in select Middle Eastern and North African countries compares with the current recommendations on the primary prevention of allergy a survey study was performed using a structured questionnaire and convenience sampling. RESULTS: A total of 1481 physicians responded, of which 66.1% were pediatricians. A total of 76.6% of responding physicians routinely identify infants who are at risk for developing allergy. In infants at risk for developing allergy, 89.1% recommend exclusive breastfeeding for at least 4 months. In contrast to current recommendations, 51.6% routinely recommend avoidance of any allergenic food in the lactating mother. In infants at risk of developing allergy who are completely formula fed, standard infant formula was recommended by 22.5% of responders. Of the responding physicians, 50.6% would recommend delaying the introduction of complementary food in infants at risk of allergy compared to those not at risk, whereas 62.5% would recommend postponing the introduction of potentially allergenic foods. Only 6.6% stated they follow all current recommendations on food allergy prevention. CONCLUSION: The results of this survey suggest that a substantial part of responding physicians from select Middle Eastern and North African (MENA) countries do not follow current recommendations on primary prevention of allergic disease through nutritional interventions.

Phenotype and molecular characterization of Wilson's disease in Morocco.

BACKGROUND AND STUDY AIMS: In Morocco the prevalence of Wilson disease (WD) and the spectrum of mutations are not known. The aim of the present study was to estimate the prevalence of WD in Morocco, to evaluate the phenotype among a large cohort of WD patients, and to characterize ATP7B variants in a subgroup of WD patients. PATIENTS AND METHODS: We collected data from 226 patients admitted to five university hospital centers in Morocco between 2008 and 2020. The diagnosis was based on clinical manifestations, function tests and biochemical parameters. The genotype was characterized in 18 families diagnosed at the University Hospital Center of Marrakesh, by next generation sequencing. RESULTS: The mean annual prevalence in Morocco was 3.88 per 100,000 and the allele frequency was 0.15 %. Among the 226 patients included (121 males and 105 females), 196 were referred for a hepatic or neurological involvement and 30 were asymptomatic. The mean age at diagnosis was 13 ± 5.1 years (range: 5 - 42 years). Consanguinity was found in 63.3 % of patients. The mean duration of illness was 2.8 ± 1.9 years. Kayser-Fleischer rings were found in 131 (67.9 %) of 193 patients. Among the 196 symptomatic patients, 141/159 (88.7 %) had low serum ceruloplasmin (<0.2 g/L) and a high 24-hours urinary copper (>100 µg/day) was found in 173/182 (95.1 %) patients. The initial treatment was D-penicillamine in 207 patients, zinc acetate in five, zinc sulfate in five, and nine patients were not treated; 60/207 (29 %) patients have stopped treatment. A total of 72 patients died; the mortality rate was 31.9 %. Eight different ATP7B variants were identified among the 18 patients studied, of which two were novel (p.Cys1104Arg and p.Gln1277Hisfs*52), and six previously published (p.Gln289Ter, p.Cys305Ter, p.Thr1232Pro, p.Lys1020Arg, p.Glu583ArgfsTer25 and c.51+4A>T). All informative patients were homozygous for the disease-causing mutation. CONCLUSION: In Morocco, a high prevalence due to consanguinity and a high mortality rate due to the difficulty of diagnosis and lack of treatment were observed in WD patients. NGS sequencing identified new ATP7B variants in WD patients from Morocco.

An international multidisciplinary consensus on pediatric metabolic dysfunction-associated fatty liver disease.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is highly prevalent in children and adolescents, particularly those with obesity. NAFLD is considered a hepatic manifestation of the metabolic syndrome due to its close associations with abdominal obesity, insulin resistance, and atherogenic dyslipidemia. Experts have proposed an alternative terminology, metabolic dysfunction-associated fatty liver disease (MAFLD), to better reflect its pathophysiology. This study aimed to develop consensus statements and recommendations for pediatric MAFLD through collaboration among international experts. METHODS: A group of 65 experts from 35 countries and six continents, including pediatricians, hepatologists, and endocrinologists, participated in a consensus development process. The process encompassed various aspects of pediatric MAFLD, including epidemiology, mechanisms, screening, and management. FINDINGS: In round 1, we received 65 surveys from 35 countries and analyzed these results, which informed us that 73.3% of respondents agreed with 20 draft statements while 23.8% agreed somewhat. The mean percentage of agreement or somewhat agreement increased to 80.85% and 15.75%, respectively, in round 2. The final statements covered a wide range of topics related to epidemiology, pathophysiology, and strategies for screening and managing pediatric MAFLD. CONCLUSIONS: The consensus statements and recommendations developed by an international expert panel serve to optimize clinical outcomes and improve the quality of life for children and adolescents with MAFLD. These findings emphasize the need for standardized approaches in diagnosing and treating pediatric MAFLD. FUNDING: This work was funded by the National Natural Science Foundation of China (82070588, 82370577), the National Key R&D Program of China (2023YFA1800801), National High Level Hospital Clinical Research Funding (2022-PUMCH-C-014), the Wuxi Taihu Talent Plan (DJTD202106), and the Medical Key Discipline Program of Wuxi Health Commission (ZDXK2021007).

Lead concentrations in breast milk of Moroccan nursing mothers and associated factors of exposure: CONTAMILK STUDY.

The aim of CONTAMILK study was to estimate levels of contamination of breast milk (BM) of Moroccan nursing mothers by some xenobiotics including, lead (Pb), to identify associated factors of exposure and to determine the daily intake of newborns. Lead concentrations were determined in 70 samples of colostrum by ICPMS and a structured questionnaire was filled during milk collection to report participants' data. The median lead concentration was 908 µg/L (range 1.38-515,39 µg/L) and in 79 % of samples, levels were higher than the normal range reported by the World Health Organization (WHO) in BM (2-5 µg/L). Indeed, preterm delivery, frequency of use of cosmetic powders and lipsticks were significantly associated with the level of lead in BM. The estimated daily intake was greater than the tolerable daily intake (TDI) of the European food safety authority (0.5 µg/kg/day) for 39 babies and 6 babies according to the WHO (3.6 µg/kg/day).

Defining paediatric metabolic (dysfunction)-associated fatty liver disease: an international expert consensus statement.

The term non-alcoholic fatty liver disease (NAFLD), and its definition, have limitations for both adults and children. The definition is most problematic for children, for whom alcohol consumption is usually not a concern. This problematic definition has prompted a consensus to rename and redefine adult NAFLD associated with metabolic dysregulation to metabolic (dysfunction)-associated fatty liver disease (MAFLD). Similarities, distinctions, and differences exist in the causes, natural history, and prognosis of fatty liver diseases in children compared with adults. In this Viewpoint we, an international panel, propose an overarching framework for paediatric fatty liver diseases and an age-appropriate MAFLD definition based on sex and age percentiles. The framework recognises the possibility of other coexisting systemic fatty liver diseases in children. The new MAFLD diagnostic criteria provide paediatricians with a conceptual scaffold for disease diagnosis, risk stratification, and improved clinical and multidisciplinary care, and they align with a definition that is valid across the lifespan.

Aflatoxin M1 prevalence in breast milk in Morocco: Associated factors and health risk assessment of newborns "CONTAMILK study".

The aim of this study was to assess the contamination of breast milk by aflatoxin M1 among nursing mothers from Rabat, Morocco, and to explore its association with several maternal parameters and dietary habits. In addition, the health risk assessment of the newborns by the estimation of the daily intake. A competitive Enzyme Linked Immunosorbent Assay method was used for the analysis of aflatoxin M1 in breast milk samples. Analytical results indicate that out of 82 total samples, 43 samples (52.4%) of milk were positive. Aflatoxin M1 levels ranged from undetectable to 13.33 ng/L, while the mean level was 5.75 ± 3.44 ng/L. Besides, several factors and foodstuffs seem to increase the level of AFM1 in breast milk. As regards the estimated daily intake of aflatoxin M1, it varies between immeasurable and a maximum of 1.16 ng/kg.bw. The degree of exposure to AFB1 and the levels of its metabolite AFM1 in breast milk were low, compared to some studies from other countries. Further investigations and periodic monitoring programs are recommended in large samples and in many cities of morocco to assess the level of exposure of the Moroccan population.

Cadmium Contamination in Breast Milk of Moroccan Lactating Women and the Associated Factors: CONTAMILK Study.

The objectives of this study were to assess levels of contamination of breast milk (BM) by cadmium (Cd) among lactating mothers from Rabat, Morocco, and to investigate its association with several maternal habits, parameters, and factors. In addition, to estimate the daily intake of the newborns. Cd concentrations were measured by inductively coupled plasma-mass spectrometry (ICP-MS) in 70 human milk samples collected between the 2nd and 5th day postpartum. Accuracy of the analysis was checked by various methods including the use of reference material. A structured questionnaire was filled during the collection of milk reporting data concerning anthropometric, sociodemographic parameters, dietary and cosmetic habits, etc. The median (range) of Cd in human milk was 0.49 µg/L (range 0.013-95.19 µg/L) respectively. In 21 (30%) of 70 samples, Cd levels were higher than the normal reported by the World Health Organization (WHO) in BM (< 1 µg/L). Indeed, several factors affect significantly Cd levels in BM of the mothers such as low maternal education level, preterm delivery, cesarean delivery, and area of residence. Also, the frequency of consumption of milk and dairy products as well dried fruits and wheat bread and the frequency of use of cosmetic powders. However, the daily intake of cadmium by the newborns was lower than tolerable daily intake of the WHO for 97% of them. Our results revealed low cadmium concentrations in human milk samples from Moroccan lactating mothers living in Rabat, also the association of some factors with the levels of contamination found in this population.

Medicines Acceptability in Hospitalized Children: An Ongoing Need for Age-Appropriate Formulations.

Although knowledge on medicine acceptability remains fragmented, this multi-faceted concept has emerged as a key factor for compliance in pediatrics. In order to investigate the acceptability of medicines used in the University Medical Centre Ibn Sina (CHIS) of Rabat, Morocco, an observational study was conducted. Using a multivariate approach integrating the many aspects of acceptability, standardized observer reports were collected for 570 medicine intakes in patients up to the age of 16, then analyzed on a reference framework. Tablets appeared to be well accepted in children greater than 6 years old, but were crushed/dissolved for 90% of the 40 children aged from 3 to 5, and 100% of the 38 patients younger than 3. Moreover, the prescribed dose was fully taken for only 52% and 16% of these younger children, respectively. Despite this, tablets represented 24% of evaluations in children from 3 to 5 and 20% in infants and toddlers. Oral liquid preparations appeared to be better accepted than tablets in preschoolers, but not for those under 3. Overall, these findings highlight the lack of suitable alternatives for the younger children, especially for formulations of antiepileptics, antithrombotic, and psycholeptic agents in the local context.

[Weber-Christian's disease: a preleukemic disorder?] / La maladie de Weber-Christian: s'agit-il d'un état pré-leucémique?

Weber christian's disease or idiopathic panniculitis is a rare condition characterized by an inflammation of the subcutaneous adipose tissue; it is a non-specific pathological condition that remains a central issue of debate and whose outcome is unpredictable. We here report the case of a 9-month-old female infant admitted in the hospital with sepsis preceded by respiratory symptoms and followed by the occurrence of small, hard, susceptible, asymmetrical erythematous subcutaneous nodes located in the arms and lower limbs. Cutaneous biopsy showed lobular hypodermitis with polymorphonuclear neutrophil infiltrations. The diagnosis of Weber Christian's disease was retained after eliminating other differential diagnoses. The patient was treated with prednisone with good outcome; during the follow-up period and during disease regression the diagnosis of B-cell acute lymphoblastic leukemia was made; this uncommon outcome has never been described in the literature. The aim of this study is to discuss any similar situation where another diagnosis was made in patients initially treated for idiopathic lobular panniculitis. This highlights the need for exhaustive etiological investigations and prolonged monitoring in order to search for a possible associated disorder.