A Predictive Model for Thiamine Responsive Disorders Among Infants and Young Children: Results from a Prospective Cohort Study in Lao People's Democratic Republic.

OBJECTIVE: To develop a predictive model for thiamine responsive disorders (TRDs) among infants and young children hospitalized with signs or symptoms suggestive of thiamine deficiency disorders (TDDs) based on response to therapeutic thiamine in a high-risk setting. STUDY DESIGN: Children aged 21 days to <18 months hospitalized with signs or symptoms suggestive of TDD in northern Lao People's Democratic Republic were treated with parenteral thiamine (100 mg daily) for ≥3 days in addition to routine care. Physical examinations and recovery assessments were conducted frequently for 72 hours after thiamine was initiated. Individual case reports were independently reviewed by three pediatricians who assigned a TRD status (TRD or non-TRD), which served as the dependent variable in logistic regression models to identify predictors of TRD. Model performance was quantified by empirical area under the receiver operating characteristic curve. RESULTS: A total of 449 children (median [Q1, Q3] 2.9 [1.7, 5.7] months old; 70.3% exclusively/predominantly breastfed) were enrolled; 60.8% had a TRD. Among 52 candidate variables, those most predictive of TRD were exclusive/predominant breastfeeding, hoarse voice/loss of voice, cyanosis, no eye contact, and no diarrhea in the previous 2 weeks. The area under the receiver operating characteristic curve (95% CI) was 0.82 (0.78, 0.86). CONCLUSIONS: In this study, the majority of children with signs or symptoms of TDD responded favorably to thiamine. While five specific features were predictive of TRD, the high prevalence of TRD suggests that thiamine should be administered to all infants and children presenting with any signs or symptoms consistent with TDD in similar high-risk settings. The usefulness of the predictive model in other contexts warrants further exploration and refinement. TRIAL REGISTRATION: Clinicaltrials.gov NCT03626337.

Creating a data dictionary for pediatric autonomic disorders.

PURPOSE: Whether evaluating patients clinically, documenting care in the electronic health record, performing research, or communicating with administrative agencies, the use of a common set of terms and definitions is vital to ensure appropriate use of language. At a 2017 meeting of the Pediatric Section of the American Autonomic Society, it was determined that an autonomic data dictionary comprising aspects of evaluation and management of pediatric patients with autonomic disorders would be an important resource for multiple stakeholders. METHODS: Our group created the list of terms for the dictionary. Definitions were prioritized to be obtained from established sources with which to harmonize. Some definitions needed mild modification from original sources. The next tier of sources included published consensus statements, followed by Internet sources. In the absence of appropriate sources, we created a definition. RESULTS: A total of 589 terms were listed and defined in the dictionary. Terms were organized by Signs/Symptoms, Triggers, Co-morbid Disorders, Family History, Medications, Medical Devices, Physical Examination Findings, Testing, and Diagnoses. CONCLUSION: Creation of this data dictionary becomes the foundation of future clinical care and investigative research in pediatric autonomic disorders, and can be used as a building block for a subsequent adult autonomic data dictionary.

Assessment of comorbid symptoms in pediatric autonomic dysfunction.

PURPOSE: Pediatric patients with autonomic dysfunction and orthostatic intolerance (OI) often present with co-existing symptoms and signs that might or might not directly relate to the autonomic nervous system. Our objective was to identify validated screening instruments to characterize these comorbidities and their impact on youth functioning. METHODS: The Pediatric Assembly of the American Autonomic Society reviewed the current state of practice for identifying symptom comorbidities in youth with OI. The assembly includes physicians, physician-scientists, scientists, advanced practice providers, psychologists, and a statistician with expertise in pediatric disorders of OI. A total of 26 representatives from the various specialties engaged in iterative meetings to: (1) identify and then develop consensus on the symptoms to be assessed, (2) establish committees to review the literature for screening measures by member expertise, and (3) delineate the specific criteria for systematically evaluating the measures and for making measure recommendations by symptom domains. RESULTS: We review the measures evaluated and recommend one measure per system/concern so that assessment results from unrelated clinical centers are comparable. We have created a repository to apprise investigators of validated, vetted assessment tools to enhance comparisons across cohorts of youth with autonomic dysfunction and OI. CONCLUSION: This effort can facilitate collaboration among clinical settings to advance the science and clinical treatment of these youth. This effort is essential to improving management of these vulnerable patients as well as to comparing research findings from different centers.

Physical Symptoms, Distress, and Functional Disability in Youth With Chronic Orthostatic Intolerance.

OBJECTIVE: Youth with chronic orthostatic intolerance (OI) can experience significant physical, social, and academic functional debilitation. Previous studies have indicated associations among symptom severity, psychosocial factors, and functional disability. However, empirically tested models explaining how different medical and psychosocial factors may contribute to functional disability are lacking. The current cross-sectional study aimed to evaluate mediation, moderation, and additive models of the effect of physical symptoms and psychological distress on functional disability. METHODS: One hundred and sixty-five youth (13-22 years old) undergoing medical evaluation of chronic OI symptoms completed measures of autonomic dysfunction symptom severity, depressive and anxiety symptoms, and functional disability. Models were evaluated using tests of indirect effects and linear and logistic regression analyses. RESULTS: Results supported the mediation and additive effects models for depressive symptoms. Mediation, moderation, and additive models for hypothesized effects of anxiety symptoms were not supported. CONCLUSIONS: Results provide preliminary support for models in which OI symptoms affect functional debility via their effects on mood and in which depressive symptoms have unique and additive effects on functioning. Findings lay the foundation for longitudinal and experimental evaluation of biopsychosocial models of functional disability in youth with chronic OI and related conditions. Implications include the importance of a biopsychosocial conceptualization of OI symptoms and debility as a complex interplay of factors rather than as a purely physiological or psychological process.

Understanding and Managing Adolescents with Conversion and Functional Disorders.

A functional disorder is a constellation of bothersome physical symptoms that compromise regular function but for which there is no identifiable organic or psychiatric pathology. Functional disorders can present with various symptoms. Common forms of functional disorders include functional neurologic symptom disorder (also referred to as "conversion disorder"), functional gastrointestinal disorders, chronic pain syndromes, and chronic fatigue. One-third to one-half of outpatient consultations in many practices are due to functional disorders. Functional disorders must be distinguished from structural and psychiatric disorders but should not be considered diagnoses of exclusion. Recovery is facilitated by good relationships between patients and practitioners, with good explanations of the pathophysiology of functional disorders and effective encouragement and education of patients.

Population-Based Incidence of Potentially Life-Threatening Complications of Hypocalcemia and the Role of Vitamin D Deficiency.

OBJECTIVES: To determine the incidence of potentially life-threatening complications of hypocalcemia in infants and children in Olmsted County, Minnesota; and to determine if vitamin D deficiency contributed to these events and was, at the time of clinical presentation, considered as a possible cause. STUDY DESIGN: In this population-based descriptive study, data were abstracted from the Rochester Epidemiology Project, a medical record linkage system covering 95% of patients in Olmsted County, Minnesota. Participants were children aged 0-5 years who resided in Olmsted County between January 1, 1996 and June 30, 2017, and who received diagnoses of seizures, cardiomyopathy, cardiac arrest, respiratory arrest, laryngospasm, and/or tetany. The incidence of hypocalcemia plus a potentially life-threatening complication was calculated. RESULTS: Among 15 419 patients aged 0-5 years in Olmsted County during the study period, 1305 had eligible complications: 460 had serum calcium checked within 14 days of presentation and 85 had hypocalcemia. Patients were excluded when causes other than hypocalcemia likely triggered the complication, leaving 16 children whose complication was attributed to hypocalcemia. Three of these 16 patients had a serum 25-hydroxyvitamin D measurement and 2 were deficient (≤6 ng/mL [15 nmol/L]). Among children aged 0-5 years, the incidence of hypocalcemia plus a potentially life-threatening complication was 6.1 per 100 000 person-years (95% CI, 3.5-10.0). CONCLUSIONS: Vitamin D deficiency is an underinvestigated cause of complications of hypocalcemia in children. Serum calcium and 25-hydroxyvitamin D should be measured in children with these complications to identify possibly life-threatening vitamin D deficiency.

Thiamin deficiency in low- and middle-income countries: Disorders, prevalences, previous interventions and current recommendations.

BACKGROUND: Thiamin deficiency is a major public health concern in several low- and middle-income countries (LMICs)-current attention to the problem is lacking. AIM: This review discusses prevalence of thiamin insufficiency and thiamin-deficiency disorders (TDDs) in LMICs, outlines programmatic experience with thiamin interventions, and offers recommendations to improve public-health and research attention to thiamin in LMICs. DISCUSSION: Thiamin insufficiency, i.e. low-blood-thiamin status, is endemic among several Southeast Asian countries: Cambodia (70-100% of infants and 27-100% of reproductive-age women); Laos (13% of hospitalized infants); Thailand (16-25% of children and 30% of elderly adults). Thiamin deficiency accounts for up to 45% of under-5 deaths in Cambodia, 34% of infant deaths in Laos, and 17% of infant deaths in Myanmar. Deficiency also exists in Africa, Asia, and the Americas, but these instances have typically been isolated. Exclusively breastfed infants of thiamin-deficient mothers are at highest risk for TDD and related death. Intervention strategies that have been employed to combat thiamin deficiency include food processing, fortification, supplementation, dietary diversification, and dietary behaviors, all of which have shown varying levels of effectiveness. CONCLUSIONS: We recommend universal thiamin-fortification of context-specific staple-foods in LMICs as a promising solution, as well as thiamin supplementation, particularly for pregnant and lactating women. Food processing regulations, dietary diversification, and modification of dietary behaviors to increase consumption of thiamin-rich foods may provide benefits in some circumstances, especially in countries without universal fortification programs or in populations dependent on food aid.

Youth with Chronic Pain and Postural Orthostatic Tachycardia Syndrome (POTS): Treatment Mediators of Improvement in Functional Disability.

Intensive pain rehabilitation programs are effective in increasing functioning for youth with chronic pain (CP). However, the utility of such programs for youth with CP and co-morbid postural orthostatic tachycardia syndrome (POTS) is rarely examined. In addition, studies examining mediators of treatment for CP are sparse. This paper compares treatment outcomes for youth with CP (n = 117) and youth with CP + POTS (n = 118). Additionally, depression and pain catastrophizing were tested as potential mediators of treatment effects. Significant treatment improvements were found for functional disability, depression, pain catastrophizing, and perceived pain intensity but with no differences between groups. Improvements in depressed mood, pain catastrophizing (helplessness subscale), and pain severity partially mediated functioning improvement. Pain severity was not a significant mediator in the CP + POTS group. We concluded that depression and pain catastrophizing, especially the helplessness domain, can impact functioning improvement in adolescents with CP and POTS and are particularly important to target in treatment.

Outcomes of Adolescent-Onset Postural Orthostatic Tachycardia Syndrome.

OBJECTIVES: To determine the clinical course of adolescent-onset postural orthostatic tachycardia syndrome (POTS) and to assess health-related quality of life, 2-10 years after diagnosis. STUDY DESIGN: Pediatric patients, 13-18 years of age, diagnosed with POTS at Mayo Clinic, Rochester, from 2003 to 2010 were mailed a questionnaire if they were at least 18 years of age at the time of the mailing. The primary outcome measures were norm-based, age- and sex-adjusted, 36-Item Short Form Health Survey physical composite score and mental composite score. RESULTS: The survey was mailed to 502 patients with a response rate of 34% (n = 172). The mean duration from diagnosis to survey completion was 5.4 (SD, 1.9) years; the mean age of the respondents at the time of the survey was 21.8 (2.2) years. The responders were predominantly females (84% vs 68% of nonresponders; P < .001). Only 33 (19%) respondents reported complete resolution of symptoms, and an additional 51% reported persistent but improved symptoms, and 28 (16%) had only intermittent symptoms. The majority (71%) consider their health at least "good." The mean physical composite score was significantly lower than the population norm (mean [SD], 36.6 [15.8] vs 50; P < .001), however, the corresponding mean mental composite score was normal (50.1 [11.2]). CONCLUSIONS: Overall, 86% of adolescents with POTS report resolved, improved, or just intermittent symptoms, when assessed via questionnaire at an average of 5 years after initial treatment. Patients with persistent symptoms have more physical than mental health concerns.

Interdisciplinary Treatment of Maladaptive Behaviors Associated with Postural Orthostatic Tachycardia Syndrome (POTS): A Case Report.

The prevalence of postural orthostatic tachycardia syndrome (POTS) in adolescents and young adults has been increasing during the past decade. Despite this increase, documentation regarding treatment of these patients is just beginning to emerge. In addition, despite a call for a multidisciplinary or interdisciplinary approach, no studies have examined the efficacy of such an approach to treatment. This paper describes a case study of a 19-year-old male with debilitating POTS seen at a tertiary clinic for evaluation and subsequent intensive interdisciplinary treatment. The treatment approach is described and outcomes are presented.

Comparison of Limestone and Ground Fish for Treatment of Nutritional Rickets in Children in Nigeria.

OBJECTIVE: To determine whether children with calcium-deficiency rickets respond better to treatment with calcium as limestone or as ground fish. STUDY DESIGN: Nigerian children with active rickets (n = 96) were randomized to receive calcium as powdered limestone (920 mg of elemental calcium) or ground fish (952 mg of elemental calcium) daily for 24 weeks. Radiographic healing was defined as achieving a score of 1.5 or less on a 10-point scale. RESULTS: The median (range) age of enrolled children was 35 (6-151) months. Of the 88 children who completed the study, 29 (66%) in the ground fish group and 24 (55%) in the limestone group achieved the primary outcome of a radiographic score of 1.5 or less within 6 months (P = .39). The mean radiographic score improved from 6.2 ± 2.4 to 1.8 ± 2.2 in the ground fish group and from 6.3 ± 2.2 to 2.1 ± 2.4 in the limestone group (P = .68 for group comparison). In an intention to treat analysis adjusted for baseline radiographic score, age, milk calcium intake, and serum 25-hydroxyvitamin D concentration, the response to treatment did not differ between the 2 groups (P = .39). Younger age was associated with more complete radiographic healing in the adjusted model (aOR 0.74 [95% CI 0.57-0.92]). After 24 weeks of treatment, serum alkaline phosphatase had decreased, calcium and 25-hydroxyvitamin D increased, and bone mineral density increased in both groups, without significant differences between treatment groups. CONCLUSION: In children with calcium-deficiency rickets, treatment with calcium as either ground fish or limestone for 6 months healed rickets in the majority of children.

Cholecalciferol supplementation does not influence ß-cell function and insulin action in obese adolescents: a prospective double-blind randomized trial.

BACKGROUND: There is increasing interest in the extraskeletal effects of vitamin D, particularly in the obese state with regard to the development of insulin resistance and diabetes. OBJECTIVE: The objective of the study was to determine the effect of 2 doses of cholecalciferol (vitamin D3) supplementation on insulin action (Si) and pancreatic ß-cell function in obese adolescents. METHODS: We performed a 12-wk double-blind, randomized comparison of the effect of vitamin D3 supplementation on Si and ß-cell function in obese Caucasian adolescents (body mass index > 95(th) percentile). The subjects were randomly assigned to receive either 400 IU/d (n = 25) or 2000 IU/d (n = 26) of vitamin D3. Each subject underwent a 7-sample 75 g oral glucose tolerance test, with glucose, insulin, and C-peptide measurements, to calculate Si and ß-cell function as assessed by the disposition index (DI), with use of the oral minimal model before and after supplementation. A total of 51 subjects aged 15.0 ± 1.9 y were enrolled. Included for analysis at follow-up were a total of 46 subjects (20 male and 26 female adolescents), 23 in each group. RESULTS: Initial serum 25-hydroxyvitamin D [25(OH)D] was 24.0 ± 8.1 µg/L. There was no correlation between 25(OH)D concentrations and Si or DI. There was a modest but significant increase in 25(OH)D concentration in the 2000 IU/d group (3.1 ± 6.5 µg/L, P = 0.04) but not in the 400 IU/d group (P = 0.39). There was no change in Si or DI following vitamin D3 supplementation in either of the treatment groups (all P > 0.10). CONCLUSIONS: The current study shows no effect from vitamin D3 supplementation, irrespective of its dose, on ß-cell function or insulin action in obese nondiabetic adolescents with relatively good vitamin D status. Whether obese adolescents with vitamin D deficiency and impaired glucose metabolism would respond differently to vitamin D3 supplementation remains unclear and warrants further studies. This trial was registered at clinicaltrials.gov as NCT00858247.

Thiamine deficiency and cardiac dysfunction in Cambodian infants.

OBJECTIVES: To compare blood thiamine concentrations, echocardiography findings, and plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels in infants with clinically diagnosed beriberi and healthy matched controls, and to evaluate changes after thiamine treatment. STUDY DESIGN: Sixty-two Cambodian infants (20 cases and 42 controls), aged 2-47 weeks, were enrolled in this prospective study. Echocardiography and phlebotomy were performed at baseline and after thiamine treatment. RESULTS: Both cases and controls were thiamine-deficient, with median blood thiamine diphosphate (TDP) concentrations of 47.6 and 55.1 nmol/L, respectively (P = .23). All subjects had normal left ventricular ejection fraction. The median NT-proBNP concentration in cases (340 pg/mL [40.1 pmol/L]) was higher than previously reported normal ranges, but not statistically significantly different from that in controls (175 pg/mL [20.7 pmol/L]) (P = .10), and was not correlated with TDP concentration (P = .13). Two cases with the lowest baseline TDP concentrations (24 and 21 nmol/L) had right ventricular enlargement and elevated NT-proBNP levels that improved dramatically by 48 hours after thiamine administration. CONCLUSION: Only a minority of thiamine-deficient Cambodian infants demonstrate abnormal echocardiography findings. Thiamine deficiency produces echocardiographic evidence of right ventricular dysfunction, but this evidence is not apparent until deficiency is severe. NT-proBNP concentrations are mildly elevated in sick infants with normal echocardiography findings, indicating possible physiological changes not yet associated with echocardiographic abnormalities.