A comparative study on prophylactic efficacy of cinnarizine and amitriptyline in childhood migraine: a randomized double-blind clinical trial.

BACKGROUND: Pediatric migraine prophylaxis is indicated when headaches are frequent and/or disabling. We aimed to conduct a study to compare the efficacy of cinnarizine and amitriptyline in pediatric migraine prophylaxis. METHODS: In a randomized, double-blind trial, patients aged 4-17 years with migraine who were eligible for prophylaxis enrolled. The primary outcome was a reduction response rate of ≥50% with p < 0.005 with respect to headache characteristics. The secondary outcome was migraine disability assessment. We evaluated patients every four weeks for three months: T1: week 4, T2: week 8 and T3: week 12. The safety profile was also assessed. RESULTS: Thirty patients were randomly assigned to each group. However, 43 patients completed the trial. Headache frequency decreased in amitriptyline group more effectively in T1 (p = 0.004). Amitriptyline was more successful in reducing the headache duration in all three periods (p < 0.005). There was no significant difference in severity improvement and reducing disability score between the two groups (p > 0.005). No serious adverse events were observed. CONCLUSIONS: Both medications are effective in ameliorating migraine headaches and related disabilities. However, amitriptyline appears be a preferable option over cinnarizine, given its faster onset of action, efficacy in reducing headache duration and longer-lasting effects.Trial Registration: The study was registered with the Iranian Registry of Clinical Trials (IRCT) under the code IRCT-20191112045413N1.

Advances in the Acute and Preventive Treatment of Pediatric Migraine.

PURPOSE OF REVIEW: Headaches are common in children and adolescents. Treatments for debilitating migraine are often not FDA approved or lack evidence of efficacy for children. This narrative review looks at the evidence for acute and preventative pharmacologic and non-pharmacologic treatment of pediatric migraine, as well as reviewing any recent or ongoing clinical trials. RECENT FINDINGS: Studies have been published on pharmacological treatments for headache, as well as non-pharmacological treatments. Recent findings in pediatric migraine using onabotulinumtoxinA, calcitonin gene related peptide antagonists, interventional procedures, and devices are reviewed. Pharmacologic as well as non-pharmacologic approaches for the prevention and treatment of migraine show safety and efficacy data that is promising. These treatments should be incorporated in a multi-modal approach to the management of pediatric migraine. Continued studies, prospective and randomized, are needed to further assess these newer treatments for migraine in the pediatric setting.

Practical implementation insights from 2 population health pharmacist project approaches to improve blood pressure control.

BACKGROUND: Population health pharmacists (PHPs) can optimize medication regimens for blood pressure (BP) control using various approaches based on the timing of medication recommendations sent to providers. OBJECTIVE: To identify the contextual factors and implementation insights from 2 PHP approaches to consider when implementing PHP initiatives. PRACTICE DESCRIPTION: A federally qualified health center with 14 sites throughout Connecticut. PRACTICE INNOVATION: A centralized PHP performed medication reviews and sent recommendations to providers. The providers reviewed the recommendations for implementation into patients' care plans. The 2 PHP approaches used were: JUST-IN-TIME (JIT) APPROACH: A part-time, contracted PHP used weekly reports to identify 204 patients with uncontrolled hypertension (BP ≥140/90 mm Hg) and same-week provider appointments. ANYTIME (ANY) APPROACH: A full-time staff PHP used a registry report to identify 41 patients with uncontrolled hypertension (systolic BP: 140-150 mm Hg) and diabetes (glycosylated hemoglobin: 9%-10%) regardless of the next appointment date. EVALUATION METHODS: Four of the 5 Reach, Effectiveness, Adoption, Implementation, and Maintenance framework dimensions were used to assess the JIT and ANY approaches. Quantitative data were analyzed using descriptive statistics and chi-square or Fisher exact tests. RESULTS: The contextual factors that affected the reach, effectiveness, adoption, and implementation of the 2 projects included the timing of PHP recommendations, PHP employment status, and PHP's prior work experience. The PHP insights to consider when implementing these projects include the need to (1) build trusted relationships with providers/other team members; (2) demonstrate sensitivity and respect for providers' workload/workflow; (3) send concise, actionable, and timely recommendations; and (4) measure value/impact of PHP interventions with defined metrics. The organizational implementation insights to consider include clearly defining the role of the PHP, providing clinical/administrative buy-in and support, fostering a strong organizational culture for team-based care, and collaboration with the data analytics team to identify patients classified as high impact. CONCLUSION: The contextual factors and implementation insights identified can be used pragmatically by primary care clinical leaders to integrate a limited PHP resource on an existing population health team.

Non-pharmacologic and Mindful-Based Approaches for Pediatric Headache Disorders: a Review.

PURPOSE OF REVIEW: Headache disorders in children and adolescents are common. Among the different headache disorders, migraine and tension headache are highly prevalent and often debilitating. Pharmacological treatments for pediatric patients are often not approved or effective. Practice guidelines for prevention of pediatric headache and migraine are now incorporating information and recommendations regarding non-pharmacologic therapeutic options. Understanding the mechanism of action, safety, and efficacy of the non-pharmacologic as well as mindful-based therapeutic alternatives currently available for the management and treatment of headache and migraine may allow additional treatment alternatives for children with these conditions. RECENT FINDINGS: Studies have been published looking at non-pharmacologic treatments, and mindful-based approaches, namely relaxation, mindfulness meditation, yoga, and hypnosis as options for the treatment of headache and migraine, although there are few that examine these in children and adolescents. Several recent studies that have relevance to the care of children with headache and migraine are reviewed. Non-pharmacologic and mindful-based approaches for the prevention and treatment of headache and migraine in children show safety and efficacy data that is promising. Consider incorporating these multi-modal approaches into the therapeutic management strategies for the child or adolescent with headache and migraine. Additional prospective studies and/or randomized-controlled trials are necessary to further assess the efficacy and cost-effectiveness of these methods.

Management of Episodic Migraine in Children and Adolescents: a Practical Approach.

PURPOSE OF REVIEW: Episodic migraine is very common in children and adolescents, seen by primary care and specialists. In kids, this can greatly affect quality of life, including significant disability, specifically in terms of missed school and other activities. The goal of this paper is to give an overview of the most up-to-date thoughts on episodic migraine in the pediatric population. RECENT FINDINGS: Current options for both abortive and preventative treatments in kids, as well as specific non-pharmacological and lifestyle management recommendations for children, will be reviewed, as well as options for status migrainosus in the pediatric patient. Migraine pathophysiology is similar in adults and children with episodic migraine, but the approach to the management needs to be modified and adjusted in kids. Recognizing the impact on quality of life especially with regard to school and knowing appropriate treatment options can improve treatment and decrease the disability from this disorder.

Prevention for Pediatric and Adolescent Migraine.

Children and adolescents can experience significant disability from frequent migraine. A number of tools have been developed to help quantify the impact of migraine in this population. Many preventative medications used in adults are routinely used to prevent migraines in children, although there has been less rigorous study. This article reviews the indications and evidence for the use of migraine preventatives, such as antidepressants, antihypertensives, anticonvulsants, antihistamines, and botulinum toxin, in this population.

Prebiotics and the health benefits of fiber: current regulatory status, future research, and goals.

First defined in the mid-1990s, prebiotics, which alter the composition and activity of gastrointestinal (GI) microbiota to improve health and well-being, have generated scientific and consumer interest and regulatory debate. The Life Sciences Research Organization, Inc. (LSRO) held a workshop, Prebiotics and the Health Benefits of Fiber: Future Research and Goals, in February 2011 to assess the current state of the science and the international regulatory environment for prebiotics, identify research gaps, and create a strategy for future research. A developing body of evidence supports a role for prebiotics in reducing the risk and severity of GI infection and inflammation, including diarrhea, inflammatory bowel disease, and ulcerative colitis as well as bowel function disorders, including irritable bowel syndrome. Prebiotics also increase the bioavailability and uptake of minerals and data suggest that they reduce the risk of obesity by promoting satiety and weight loss. Additional research is needed to define the relationship between the consumption of different prebiotics and improvement of human health. New information derived from the characterization of the composition and function of different prebiotics as well as the interactions among and between gut microbiota and the human host would improve our understanding of the effects of prebiotics on health and disease and could assist in surmounting regulatory issues related to prebiotic use.

Toxicological assessment of dihydroberberine.

A battery of studies was conducted to examine the toxicological potential of dihydroberberine (DHBBR), a derivative of berberine (BBR). The genotoxicity studies conducted on DHBBR, including the bacterial reverse mutation test, the mouse lymphoma assay, and the in vivo micronucleus test, showed that DHBBR is non-mutagenic and non-clastogenic. An acute oral toxicity study revealed that the LD50 of DHBBR in female Sprague Dawley rats was greater than 2000 mg/kg bw. In a 14-day oral dose range finding study, the maximum tolerated dose was the high dose, 120 mg/kg bw/day. Based on a 90-day oral toxicity study in male and female Sprague Dawley rats, it was concluded that the NOAEL for DHBBR is 100 mg/kg bw/day, the highest dose tested.

The role of innovation and technology in meeting individual nutritional needs.

Few Americans meet the recommendations of the Dietary Guidelines for Americans and many do not know how to apply food and nutrition information to develop a personal approach to preventing diet/lifestyle-related diseases. In a time of rapid technologic advancement and rewards for innovation, a critical opportunity in food and nutrition science exists for improving health and reducing disease risk. The National Center for Food Safety and Technology (NCFST) recently established the Health Promoting Foods research platform to support the availability of safe food by using emerging technologies for improving food quality and consumer choice. A workshop convened with leading regulators and nutrition, genetic, medical, toxicological, behavioral, and consumer scientists to: discuss challenges facing personalized nutrition and health, develop strategies to overcome challenges using innovations in food and information technology, and define and prioritize a short- and long-term research agenda for the research platform. The workshop included presentations and in-depth discussions on the state of the science in genomics, behavior, food, and information technology. Workshop participants identified gaps, intersections, and new opportunities for delivering individualized food-based solutions that would be more accessible, affordable, and convenient. The research agenda, which was developed within a framework of providing information and guidance to the food and associated industries, supporting the process for health-related claims, building consumer confidence in data and food-health information, and providing a pathway for implementation of the US Dietary Guidelines for Americans and other public policies, reflects the commitment of the community, government, food industry, health organizations, and academia to improving health.

Applying the FDA definition of whole grains to the evidence for cardiovascular disease health claims.

The U.S. FDA defines whole grains as consisting of the intact, ground, cracked, or flaked fruit of the grains whose principal components, the starchy endosperm, germ, and bran, are present in the same relative proportions as they exist in the intact grain. We evaluated the effect of applying the FDA definition of whole grains to the strength of scientific evidence in support of claims for risk reduction of cardiovascular disease (CVD). We concluded that using the FDA definition for whole grains as a selection criterion is limiting, because the majority of existing studies often use a broader meaning to define whole grains. When considering only whole grain studies that met the FDA definition, we found insufficient scientific evidence to support a claim that whole grain intake reduces the risk of CVD. However, a whole grain and reduced risk of CVD health claim is supported when using a broader concept of whole grain to include studies that considered intake of fiber-rich bran and germ as well as whole grain. This type of analysis is complicated by diversity in nutrients and bioactive components among different types of whole grains.

Epidemiology of Pediatric Traumatic Brain Injury and Hypothalamic-Pituitary Disorders in Arizona.

Traumatic brain injury (TBI) in children can result in long-lasting social, cognitive, and neurological impairments. In adults, TBI can lead to endocrinopathies (endocrine system disorders), but this is infrequently reported in children. Untreated endocrinopathies can elevate risks of subsequent health issues, such that early detection in pediatric TBI survivors can initiate clinical interventions. To understand the risk of endocrinopathies following pediatric TBI, we identified patients who had experienced a TBI and subsequently developed a new-onset hypothalamic regulated endocrinopathy (n = 498). We hypothesized that pediatric patients who were diagnosed with a TBI were at higher risk of being diagnosed with a central endocrinopathy than those without a prior diagnosis of TBI. In our epidemiological assessment, we identified pediatric patients enrolled in the Arizona Health Care Cost Containment System (AHCCCS) from 2008 to 2014 who were diagnosed with one of 330 TBI International Classification of Diseases (ICD)-9 codes and subsequently diagnosed with one of 14 central endocrinopathy ICD-9 codes. Additionally, the ICD-9 code data from over 600,000 Arizona pediatric patients afforded an estimate of the incidence, prevalence, relative risk, odds ratio, and number needed to harm, regarding the development of a central endocrinopathy after sustaining a TBI in Arizona Medicaid pediatric patients. Children with a TBI diagnosis had 3.22 times the risk of a subsequent central endocrine diagnosis compared with the general population (±0.28). Pediatric AHCCCS patients with a central endocrine diagnosis had 3.2-fold higher odds of a history of a TBI diagnosis than those without an endocrine diagnosis (±0.29). Furthermore, the number of patients with a TBI diagnosis for one patient to receive a diagnosis of a central endocrine diagnosis was 151.2 (±6.12). Female subjects were more likely to present with a central endocrine diagnosis after a TBI diagnosis compared to male subjects (64.1 vs. 35.9%). These results are the first state-wide epidemiological study conducted to determine the risk of developing a hypothalamic-pituitary disorder after a TBI in the pediatric population. Our results contribute to a body of knowledge demonstrating a TBI etiology for idiopathic endocrine disorders, and thus advise physicians with regard to TBI follow-up care that includes preventive screening for endocrine disorders.

Clinical spectrum of POLR3-related leukodystrophy caused by biallelic POLR1C pathogenic variants.

OBJECTIVE: To determine the clinical, radiologic, and molecular characteristics of RNA polymerase III-related leukodystrophy (POLR3-HLD) caused by biallelic POLR1C pathogenic variants. METHODS: A cross-sectional observational study involving 25 centers worldwide was conducted. Clinical and molecular information was collected on 23 unreported and previously reported patients with POLR3-HLD and biallelic pathogenic variants in POLR1C. Brain MRI studies were reviewed. RESULTS: Fourteen female and 9 male patients aged 7 days to 23 years were included in the study. Most participants presented early in life (birth to 6 years), and motor deterioration was seen during childhood. A notable proportion of patients required a wheelchair before adolescence, suggesting a more severe phenotype than previously described in POLR3-HLD. Dental, ocular, and endocrine features were not invariably present (70%, 50%, and 50%, respectively). Five patients (22%) had a combination of hypomyelinating leukodystrophy and abnormal craniofacial development, including 1 individual with clear Treacher Collins syndrome (TCS) features. Brain MRI revealed hypomyelination in all cases, often with areas of pronounced T2 hyperintensity corresponding to T1 hypointensity of the white matter. Twenty-nine different pathogenic variants (including 12 new disease-causing variants) in POLR1C were identified. CONCLUSIONS: This study provides a comprehensive description of POLR3-HLD caused by biallelic POLR1C pathogenic variants based on the largest cohort of patients to date. These results suggest distinct characteristics of POLR1C-related disorder, with a spectrum of clinical involvement characterized by hypomyelinating leukodystrophy with or without abnormal craniofacial development reminiscent of TCS.

Developmental and reproductive toxicological evaluation of arachidonic acid (ARA)-Rich oil and docosahexaenoic acid (DHA)-Rich oil.

The purpose of this study was to investigate the reproductive and developmental toxicity of dietary exposure to DHA-rich oil from Schizochytrium sp. and ARA-rich oil from Mortierella alpina. In a developmental toxicity study, pregnant Wistar rats were untreated (control) or administered corn oil (vehicle control), 1000, 2500, or 5000 mg/kg bw/day of DHA-rich oil or ARA-rich oil via gavage from gestation days 6 through 20. In the reproductive toxicity study, male and female Wistar rats were administered vehicle control (corn oil), or 1000, 2500, or 5000 mg/kg bw/day of DHA- or ARA-rich oil via gavage throughout the mating period, pregnancy, and the nursing and lactation period. Differences in the number of fetuses, fetal skeletal malformations, and external and visceral anomalies in the developmental study and mortality, clinical signs, fertility indices, physical observations, gross necropsy findings, and gestation period length in the reproductive toxicity study were not dose-related or significantly different from control groups, and were not considered to be treatment related. The no observed adverse effect level (NOAEL) for maternal toxicity and embryo/fetal development and for paternal or maternal treatment-related reproductive toxicity for the DHA-rich oil and ARA-rich oil administered by gavage, was 5000 mg/kg bw/day.

Migrainous Aura, Visual Snow, and "Alice in Wonderland" Syndrome in Childhood.

Migraine is a condition that is common in the pediatric and adolescent population. Among children with migraine, visual aura can consist of either negative or positive features or both. Reports of sensory auras can also be elicited with a careful history. The understanding of the types of aura, as well as their relation to the more typical features of migraine, are discussed. The similar phenomena of visual snow and Alice in Wonderland syndrome in children are also described in detail.

Toxicological evaluation of arachidonic acid (ARA)-rich oil and docosahexaenoic acid (DHA)-rich oil.

The safety of DHA-rich oil from Schizochytrium sp. and ARA-rich oil from Mortierella alpina was separately evaluated by testing for gene mutations, clastogenicity, and aneugenicity, and by conducting 28-day and 90-day dietary studies in Wistar rats. The results of all genotoxicity tests were negative. The 28-day and 90-day studies involved dietary exposure to 1000, 2500, and 5000 mg per kg bw of the DHA-rich and ARA-rich oils and two control diets: water and corn oil (vehicle control). There were no treatment-related effects of either the DHA-rich or ARA-rich oils on clinical observations, body weight, food consumption, behavior, hematology, clinical chemistry, coagulation, urinalysis parameters, or necropsy findings. Increases in cholesterol and triglyceride levels were considered related to a high oil diet and non-adverse. The no observable adverse effect level (NOAEL) for both the DHA-rich and ARA-rich oils was 5000 mg per kg bw, the highest dose tested. The results confirm that these oils possess toxicity profiles similar to those of other currently marketed oils and support the safety of DHA-rich oil from Schizochytrium sp. and ARA-rich oil from Mortierella alpina for their proposed uses in food.

Effects of tree nuts on blood lipids, apolipoproteins, and blood pressure: systematic review, meta-analysis, and dose-response of 61 controlled intervention trials.

BACKGROUND: The effects of nuts on major cardiovascular disease (CVD) risk factors, including dose-responses and potential heterogeneity by nut type or phytosterol content, are not well established. OBJECTIVES: We examined the effects of tree nuts (walnuts, pistachios, macadamia nuts, pecans, cashews, almonds, hazelnuts, and Brazil nuts) on blood lipids [total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein, and triglycerides], lipoproteins [apolipoprotein A1, apolipoprotein B (ApoB), and apolipoprotein B100], blood pressure, and inflammation (C-reactive protein) in adults aged ≥18 y without prevalent CVD. DESIGN: We conducted a systematic review and meta-analysis following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Two investigators screened 1301 potentially eligible PubMed articles in duplicate. We calculated mean differences between nut intervention and control arms, dose-standardized to one 1-oz (28.4 g) serving/d, by using inverse-variance fixed-effects meta-analysis. Dose-response for nut intake was examined by using linear regression and fractional polynomial modeling. Heterogeneity by age, sex, background diet, baseline risk factors, nut type, disease condition, duration, and quality score was assessed with meta-regression. Publication bias was evaluated by using funnel plots and Egger's and Begg's tests. RESULTS: Sixty-one trials met eligibility criteria (n = 2582). Interventions ranged from 3 to 26 wk. Nut intake (per serving/d) lowered total cholesterol (-4.7 mg/dL; 95% CI: -5.3, -4.0 mg/dL), LDL cholesterol (-4.8 mg/dL; 95% CI: -5.5, -4.2 mg/dL), ApoB (-3.7 mg/dL; 95% CI: -5.2, -2.3 mg/dL), and triglycerides (-2.2 mg/dL; 95% CI: -3.8, -0.5 mg/dL) with no statistically significant effects on other outcomes. The dose-response between nut intake and total cholesterol and LDL cholesterol was nonlinear (P-nonlinearity < 0.001 each); stronger effects were observed for ≥60 g nuts/d. Significant heterogeneity was not observed by nut type or other factors. For ApoB, stronger effects were observed in populations with type 2 diabetes (-11.5 mg/dL; 95% CI: -16.2, -6.8 mg/dL) than in healthy populations (-2.5 mg/dL; 95% CI: -4.7, -0.3 mg/dL) (P-heterogeneity = 0.015). Little evidence of publication bias was found. CONCLUSIONS: Tree nut intake lowers total cholesterol, LDL cholesterol, ApoB, and triglycerides. The major determinant of cholesterol lowering appears to be nut dose rather than nut type. Our findings also highlight the need for investigation of possible stronger effects at high nut doses and among diabetic populations.

Cerebellar infarction: an unrecognized complication of very low birthweight.

We evaluated 13 children with cerebral palsy who had birthweights under 1085 g. A magnetic resonance image (MRI) of the head was obtained, the findings were compared, and the neonatal records were reviewed. The individual children were classified as to the type of cerebral palsy. On MRI, all had severe injury to the inferior cerebellar hemispheres, mostly symmetric, and in some there was injury to the inferior vermis. The average birthweight was 668 g, and the gestational ages were 24 to 27 weeks. No other outstanding prenatal or postnatal problems were identified. The children had different types of severe cerebral palsy, with only 3 being able to walk. Almost all were mentally retarded and microcephalic. All had visual problems. This report defines a previously underappreciated injury to the cerebellum in extremely premature infants. Further clinical, laboratory, and pathologic studies are needed to better define the underlying mechanisms.

Meta-analysis of attention-deficit/hyperactivity disorder or attention-deficit/hyperactivity disorder symptoms, restriction diet, and synthetic food color additives.

OBJECTIVE: The role of diet and of food colors in attention-deficit/hyperactivity disorder (ADHD) or its symptoms warrants updated quantitative meta-analysis, in light of recent divergent policy in Europe and the United States. METHOD: Studies were identified through a literature search using the PubMed, Cochrane Library, and PsycNET databases through February 2011. Twenty-four publications met inclusion criteria for synthetic food colors; 10 additional studies informed analysis of dietary restriction. A random-effects meta-analytic model generated summary effect sizes. RESULTS: Restriction diets reduced ADHD symptoms at an effect of g = 0.29 (95% CI, 0.07-0.53). For food colors, parent reports yielded an effect size of g = 0.18 (95% CI, 0.08-0.24; p = .0007), which decreased to 0.12 (95% CI, 0.01-0.23; p < .05) after adjustment for possible publication bias. The effect was reliable in studies restricted to food color additives (g = 0.21, 95% CI = 0.06-0.36) but did not survive correction for possible publication bias and was not reliable in studies confined to Food and Drug Administration-approved food colors. Teacher/observer reports yielded a nonsignificant effect of 0.07 (95% CI = -0.03 to 0.18; p = .14). However, high-quality studies confined to color additives yielded a reliable effect (g = 0.22, 95% CI = 0.10-0.41, p = .030) that survived correction. In psychometric tests of attention, the summary effect size was 0.27 (95% CI = 0.07-0.47; p = .007) and survived correction. An estimated 8% of children with ADHD may have symptoms related to synthetic food colors. CONCLUSIONS: A restriction diet benefits some children with ADHD. Effects of food colors were notable were but susceptible to publication bias or were derived from small, nongeneralizable samples. Renewed investigation of diet and ADHD is warranted.