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| Name | Class |
|---|---|
| The Hospital for Sick Children | OTHER |
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This is a pilot, randomized, placebo-controlled trial of omega-3 fatty acids in autism. Autism, originally described by Kanner in 1943, is among the most severe of neurodevelopmental disorders. It is a Pervasive Developmental Disorder (PDD) affecting social and communicative functions and is also characterized by repetitive behaviors/restricted interests. It is also frequently accompanied by significant aggression, self-injury, irritability and hyperactivity, making care for these individuals an even greater challenge for families or institutional settings. Autism severely impacts the affected individual and family members, causing life-long functional impairment. In this protocol the investigators will use the terms "autism" and "autism spectrum disorder (ASD)" interchangeably to refer to Autistic disorder, Asperger Syndrome and PDD-Not Otherwise Specified (NOS).
Currently risperidone is the only medication approved the by Food and Drug Administration (FDA) for this disorder, and specifically for irritability associated with autism, although not all patients with autism respond to risperidone. No pharmacologic treatments have been approved for use in preschool children, although it is clear that early intervention is associated with improved outcomes. Behavioral and educational therapies play a significant role in the management of autistic symptoms. The history of alternative treatments in autism is notable for the exaggerated benefit of a variety of supplements, such as high dose vitamins (e.g. B6, magnesium), and secretin. The current widespread use of alternative/nutritional supplements to patients with autism without scientifically demonstrated efficacy, underscores the necessity for scientifically sound studies to be conducted. Complementary and alternative medical therapies (CAM) are commonly employed by families of autistic children. Recent surveys have estimated the prevalence of such use to be between 30% and 95% (1,2,3). Omega-3 fatty acids were reported to be used in 28.7% of patients (1). However, only two small case series and a very small randomized study have been reported in this population to date. The investigators propose to conduct a randomized controlled trial of omega-3 fatty acids in preschoolers with ASD.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Omega-3 Fatty Acids | Active Comparator | Children will be administered 3.75ml of the liquid formulation of Nutra Sea high-EPA (HP) (containing 1.5 gr of EPA+DHA). The starting dose will be 1.875ml (0.75 gr of EPA+DHA) and the dose will be doubled on week 2. |
|
| Placebo | Placebo Comparator | Children will be administered 3.75ml of the liquid formulation of Placebo. The starting dose will be 1.875ml and the dose will be doubled on week 2. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Omega-3 Fatty Acids | Dietary Supplement | Children will be administered 3.75ml of the liquid formulation of Nutra Sea HP (containing 1.5 gr of EPA+DHA). The starting dose will be 1.875ml (0.75 gr of EPA+DHA) and the dose will be doubled on week 2. The parents may choose to give this as a single dose or split it to two doses if stomach upset occurs. This formulation is double distilled and has very little fishy taste, which will make it more palatable for children and will make creating a matching placebo a simpler process. |
| Measure | Description | Time Frame |
|---|---|---|
| Change From Baseline in the Pervasive Developmental Disorder-Behavioral Inventory (PDDBI) - Autism Composite Score | The PDDBI measures autism symptomology. The autism composite score was used as the primary outcome measure for autism symptom severity. PDDBI Autism Composite Scale Range: Minimum Range = 10 (lower autism symptom severity) Maximum Range = 100 (higher autism symptom severity) The Autism Composite is calculated from the sum of T-scores of the Sensory/Perceptual Approach Behaviours, Ritualisms/Resistance to Change, Social Pragmatic Problems, and Semantic/Pragmatic Problems domains subtracted by the sum of T-scores of the Social Approach Behaviours, and Expressive Language domain then converted into the Autism Composite as a T-score. Mean change between baseline and week 24 is reported. A negative change indicates improvement | Baseline and 24 Weeks |
| Change From Baseline in the Behaviour Assessment System for Children (BASC-2) - Externalizing Problems Composite | The BASC-2 externalizing problems composite measures hyperactivity and aggressive behaviours. Primary Outcome domain: Externalizing Problems composite Externalizing Problems Composite T-Score Range: Minimum Range: 10 (lower externalizing problems) Maximum Range: 120 (higher externalizing problems) The Externalizing Problems composite is computed from the sum of t-scores from the hyperactivity and aggression subscales then converted into the externalizing problems composite t-score. Mean change between baseline and week 24 is reported. A negative change indicates improvement. | Baseline and 24 Weeks |
| Measure | Description | Time Frame |
|---|---|---|
| Number of Participants Classified as Responders by the Clinical Global Impression - Improvement (CGI-I) | The CGI-I is a seven-point scale that provides a clinician rating of global improvement and as such is already inherently a measure of change. It requires the clinician to assess the degree to which the participant's illness has improved or worsened relative to a baseline state before the intervention. Change is rated as: 0- Not assessed
Participants are classified as responders if their CGI-I score was 1 or 2 and non-responders for CGI-I scores of 3 to 7. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Evdokia Anagnostou, M.D. | Holland Bloorview Kids Rehabilitation Hospital | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Holland Bloorview Kids Rehabilitation Hospital | Toronto | Ontario | M4G 1R8 | Canada |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 25798215 | Derived | Mankad D, Dupuis A, Smile S, Roberts W, Brian J, Lui T, Genore L, Zaghloul D, Iaboni A, Marcon PM, Anagnostou E. A randomized, placebo controlled trial of omega-3 fatty acids in the treatment of young children with autism. Mol Autism. 2015 Mar 21;6:18. doi: 10.1186/s13229-015-0010-7. eCollection 2015. |
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Participants were randomized to the two arms in a 1:1 fashion by the pharmacy, based on a randomization schedule produced by the study biostatistician. They were stratified into one of four strata based on the PDDBI score obtained at screening (four quartiles).
Participants were recruited from the hospital clinical database, as well as presentations at local conferences and media. Diagnosis was established using the Diagnostic and Statistical Manual, Fourth Edition for an Autism Spectrum Disorder supported by the Autism Diagnostic Observations Schedule and the Autism Diagnostic Interview - Revised.
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| ID | Title | Description |
|---|---|---|
| FG000 | Omega-3 Fatty Acids | Participants started at 0.75 g of EPA + DHA (1.875 ml once a day) of liquid formulation of NutraSea HP. If this was well tolerated, the dose was doubled to 1.5 g (3.5 ml) after 2 weeks, as per Health Canada guidelines for maximum dose for this age group. The NutraSea HP formulation is a naturally derived fish oil that is extracted, isolated, and processed to contain EPA/DHA in the ratio of 3:1. It has a lemon flavor. |
| FG001 | Placebo | Participants started at 0.75 g (1.875 ml once a day) of liquid formulation of placebo. If this was well tolerated, the dose was doubled to 1.5 g (3.5 ml) after 2 weeks, as per Health Canada guidelines for maximum dose for this age group. The placebo had the same physical characteristics as the medication (NutraSea HP) but contained refined olive oil and medium chain triglycerides. The placebo has a lemon flavor. |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
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| ID | Title | Description |
|---|---|---|
| BG000 | Omega-3 Fatty Acids | Participants started at 0.75 g of EPA + DHA (1.875 ml once a day) of liquid formulation of NutraSea HP. If this was well tolerated, the dose was doubled to 1.5 g (3.5 ml) after 2 weeks, as per Health Canada guidelines for maximum dose for this age group. The NutraSea HP formulation is a naturally derived fish oil that is extracted, isolated, and processed to contain EPA/DHA in the ratio of 3:1. It has a lemon flavor. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Change From Baseline in the Pervasive Developmental Disorder-Behavioral Inventory (PDDBI) - Autism Composite Score | The PDDBI measures autism symptomology. The autism composite score was used as the primary outcome measure for autism symptom severity. PDDBI Autism Composite Scale Range: Minimum Range = 10 (lower autism symptom severity) Maximum Range = 100 (higher autism symptom severity) The Autism Composite is calculated from the sum of T-scores of the Sensory/Perceptual Approach Behaviours, Ritualisms/Resistance to Change, Social Pragmatic Problems, and Semantic/Pragmatic Problems domains subtracted by the sum of T-scores of the Social Approach Behaviours, and Expressive Language domain then converted into the Autism Composite as a T-score. Mean change between baseline and week 24 is reported. A negative change indicates improvement | 1 participant was dropped from the analysis in the Omega-3 group as there was insufficient data due to early termination. | Posted | Mean | 95% Confidence Interval | units on a scale | Baseline and 24 Weeks |
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Omega-3 Fatty Acids | Children will be administered 3.75ml of the liquid formulation of NutraSea HP (containing 1.5 gr of EPA+DHA). The starting dose will be 1.875ml (0.75 gr of EPA+DHA) and the dose will be doubled on week 2. The parents may choose to give this as a single dose or split it to two doses if stomach upset occurs. This formulation is double distilled and has very little fishy taste, which will make it more palatable for children and will make creating a matching placebo a simpler process. Omega-3 Fatty Acids: Children will be administered 3.75ml of the liquid formulation of NutraSea HP (containing 1.5 gr of EPA+DHA). The starting dose will be 1.875ml (0.75 gr of EPA+DHA) and the dose will be doubled on week 2. The parents may choose to give this as a single dose or split it to two doses if stomach upset occurs. This formulation is double distilled and has very little fishy taste, which will make it more palatable for children and will make creating a matching placebo a simpler process. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Overactivity | Psychiatric disorders | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Evdokia Anagnostou | Holland Bloorview Kids Rehabilitation Hospital | 416-425-6220 | 6005 | eanagnostou@hollandbloorview.ca |
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| ID | Term |
|---|---|
| D000067877 | Autism Spectrum Disorder |
| ID | Term |
|---|---|
| D002659 | Child Development Disorders, Pervasive |
| D065886 | Neurodevelopmental Disorders |
| D001523 | Mental Disorders |
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| ID | Term |
|---|---|
| D015525 | Fatty Acids, Omega-3 |
| ID | Term |
|---|---|
| D004042 | Dietary Fats, Unsaturated |
| D004041 | Dietary Fats |
| D005223 | Fats |
| D008055 | Lipids |
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| Placebo | Dietary Supplement | Children will be administered 3.75ml of the liquid formulation of Placebo. The starting dose will be 1.875ml and the dose will be doubled on week 2. The parents may choose to give this as a single dose or split it to two doses if stomach upset occurs. This formulation is double distilled and has very little fishy taste, which will make it more palatable for children and will make creating a matching placebo a simpler process. |
|
|
| 24 weeks |
| Change From Baseline in the Vineland Adaptive Behavioral Scales (VABS) - Adaptive Functioning Composite | The VABS is a measure of adaptive behavior in daily settings. Secondary measure domain: The adaptive functioning composite describes an individuals overall functioning Adaptive Behaviour Composite Standard Score Range: Minimum range: 20 (low adaptive functioning) Maximum range: 160 (high adaptive functioning) The adaptive behaviour composite standard score is computed from the sum of standard scores from the communication, daily living skills, socialization and motor skills domains and converted into the adaptive behavior composite standard score. Change in the adaptive behaviour composite standard score from baseline to week 24 is reported. Positive change indicates improvement. | Baseline and 24 Weeks |
| Change From Baseline in the Preschool Language Scale (PLS-4) - Total Language | The PLS-4 is a language measure that provides a global assessment of a child's language functioning abilities, receptive and expressive language. Secondary outcome measure domain: Total language standard score Total Language Standard Score Range: Minimum range: 50 (lower language abilities) Maximum range: 150 (higher language abilities) The total language standard score is computed from a sum of the auditory comprehension and expressive communication standard scores, then converted into the total language standard score. Change of total language standard scores from baseline to week 24 is reported. Positive change indicates improvement | Baseline and 24 Weeks |
| Lack of Efficacy |
|
| BG001 | Placebo | Participants started at 0.75 g (1.875 ml once a day) of liquid formulation of placebo. If this was well tolerated, the dose was doubled to 1.5 g (3.5 ml) after 2 weeks, as per Health Canada guidelines for maximum dose for this age group. The placebo had the same physical characteristics as the medication (NutraSea HP) but contained refined olive oil and medium chain triglycerides. The placebo has a lemon flavor. |
| BG002 | Total | Total of all reporting groups |
| Participants |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| OG000 |
| Omega-3 Fatty Acids |
Participants started at 0.75 g of EPA + DHA (1.875 ml once a day) of liquid formulation of NutraSea HP. If this was well tolerated, the dose was doubled to 1.5 g (3.5 ml) after 2 weeks, as per Health Canada guidelines for maximum dose for this age group. The NutraSea HP formulation is a naturally derived fish oil that is extracted, isolated, and processed to contain EPA/DHA in the ratio of 3:1. It has a lemon flavor. |
| OG001 | Placebo | Participants started at 0.75 g (1.875 ml once a day) of liquid formulation of placebo. If this was well tolerated, the dose was doubled to 1.5 g (3.5 ml) after 2 weeks, as per Health Canada guidelines for maximum dose for this age group. The placebo had the same physical characteristics as the medication (NutraSea HP) but contained refined olive oil and medium chain triglycerides. The placebo has a lemon flavor. |
|
|
|
| Primary | Change From Baseline in the Behaviour Assessment System for Children (BASC-2) - Externalizing Problems Composite | The BASC-2 externalizing problems composite measures hyperactivity and aggressive behaviours. Primary Outcome domain: Externalizing Problems composite Externalizing Problems Composite T-Score Range: Minimum Range: 10 (lower externalizing problems) Maximum Range: 120 (higher externalizing problems) The Externalizing Problems composite is computed from the sum of t-scores from the hyperactivity and aggression subscales then converted into the externalizing problems composite t-score. Mean change between baseline and week 24 is reported. A negative change indicates improvement. | 1 participant was dropped from the analysis in the Omega-3 group as there was insufficient data due to early termination. | Posted | Mean | 95% Confidence Interval | units on a scale | Baseline and 24 Weeks |
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|
|
| Secondary | Number of Participants Classified as Responders by the Clinical Global Impression - Improvement (CGI-I) | The CGI-I is a seven-point scale that provides a clinician rating of global improvement and as such is already inherently a measure of change. It requires the clinician to assess the degree to which the participant's illness has improved or worsened relative to a baseline state before the intervention. Change is rated as: 0- Not assessed
Participants are classified as responders if their CGI-I score was 1 or 2 and non-responders for CGI-I scores of 3 to 7. | 1 participant was dropped from the analysis in the Omega-3 group as there was insufficient data due to early termination. | Posted | Number | participants classified as responders | 24 weeks |
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|
|
| Secondary | Change From Baseline in the Vineland Adaptive Behavioral Scales (VABS) - Adaptive Functioning Composite | The VABS is a measure of adaptive behavior in daily settings. Secondary measure domain: The adaptive functioning composite describes an individuals overall functioning Adaptive Behaviour Composite Standard Score Range: Minimum range: 20 (low adaptive functioning) Maximum range: 160 (high adaptive functioning) The adaptive behaviour composite standard score is computed from the sum of standard scores from the communication, daily living skills, socialization and motor skills domains and converted into the adaptive behavior composite standard score. Change in the adaptive behaviour composite standard score from baseline to week 24 is reported. Positive change indicates improvement. | 1 participant was dropped from the analysis in the Omega-3 group as there was insufficient data due to early termination. | Posted | Mean | 95% Confidence Interval | units on a scale | Baseline and 24 Weeks |
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|
|
| Secondary | Change From Baseline in the Preschool Language Scale (PLS-4) - Total Language | The PLS-4 is a language measure that provides a global assessment of a child's language functioning abilities, receptive and expressive language. Secondary outcome measure domain: Total language standard score Total Language Standard Score Range: Minimum range: 50 (lower language abilities) Maximum range: 150 (higher language abilities) The total language standard score is computed from a sum of the auditory comprehension and expressive communication standard scores, then converted into the total language standard score. Change of total language standard scores from baseline to week 24 is reported. Positive change indicates improvement | 1 participant was dropped from the analysis in the Omega-3 group as there was insufficient data due to early termination. | Posted | Mean | 95% Confidence Interval | units on a scale | Baseline and 24 Weeks |
|
|
|
|
| 0 |
| 19 |
| 19 |
| 19 |
| EG001 | Placebo | Participants started at 0.75 g (1.875 ml once a day) of liquid formulation of placebo. If this was well tolerated, the dose was doubled to 1.5 g (3.5 ml) after 2 weeks, as per Health Canada guidelines for maximum dose for this age group. The placebo had the same physical characteristics as the medication (NutraSea HP) but contained refined olive oil and medium chain triglycerides. The placebo has a lemon flavor. | 0 | 19 | 19 | 19 |
| Decreased Energy | General disorders | Systematic Assessment |
|
| Social Communicative Intent Loss | Psychiatric disorders | Systematic Assessment |
|
| Staring Spell | Psychiatric disorders | Systematic Assessment |
|
| Increased Emotional Lability | Psychiatric disorders | Systematic Assessment |
|
| Increased Irritability/Anger/Aggression | Psychiatric disorders | Systematic Assessment |
|
| Headache | Nervous system disorders | Systematic Assessment |
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| Stuttering | Psychiatric disorders | Systematic Assessment |
|
| Increased Appetite | Metabolism and nutrition disorders | Systematic Assessment |
|
| Decreased Appetite | Metabolism and nutrition disorders | Systematic Assessment |
|
| Decreased Dietary Variety | Metabolism and nutrition disorders | Systematic Assessment |
|
| Abdominal Pain | Gastrointestinal disorders | Systematic Assessment |
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| Regurgitation | Gastrointestinal disorders | Systematic Assessment |
|
| Vomiting | Gastrointestinal disorders | Systematic Assessment |
|
| Diarrhea | Gastrointestinal disorders | Systematic Assessment |
|
| Constipation | Gastrointestinal disorders | Systematic Assessment |
|
| Eye Swelling | Eye disorders | Systematic Assessment |
|
| Nearsightedness | Eye disorders | Systematic Assessment |
|
| Eye Surgery | Surgical and medical procedures | Systematic Assessment |
|
| Earache | Ear and labyrinth disorders | Systematic Assessment |
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| Red Eyes | Eye disorders | Systematic Assessment |
|
| Nose Bleed | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
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| Tonsillectomy | Surgical and medical procedures | Systematic Assessment |
|
| Nasal Congestion | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
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| Cough | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
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| Daytime Wetting | Renal and urinary disorders | Systematic Assessment |
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| Pain on Urination | Renal and urinary disorders | Systematic Assessment |
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| Change in Urine Colour | Renal and urinary disorders | Systematic Assessment |
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| Muscle Aches | Musculoskeletal and connective tissue disorders | Systematic Assessment |
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| Right Leg Internal Rotation | Musculoskeletal and connective tissue disorders | Systematic Assessment |
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| Left Knee Injury | Injury, poisoning and procedural complications | Systematic Assessment |
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| Rash | Skin and subcutaneous tissue disorders | Systematic Assessment |
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| Eczema | Skin and subcutaneous tissue disorders | Systematic Assessment |
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| Bruising | Skin and subcutaneous tissue disorders | Systematic Assessment |
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| Dry Skin | Skin and subcutaneous tissue disorders | Systematic Assessment |
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| Flaky Scalp | Skin and subcutaneous tissue disorders | Systematic Assessment |
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| Upper Respiratory Infection | Infections and infestations | Systematic Assessment |
|
| Fever | Infections and infestations | Non-systematic Assessment |
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| Ear Infection | Infections and infestations | Systematic Assessment |
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| Gastroenteritis | Gastrointestinal disorders | Systematic Assessment |
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| Skin Infection | Infections and infestations | Systematic Assessment |
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| Hand Mouth Foot Disease | Infections and infestations | Systematic Assessment |
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| Roseola | Infections and infestations | Systematic Assessment |
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| Initial Insomnia | Nervous system disorders |
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| Bronchiolitis | Infections and infestations |
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| Hand Mouth Foot Disease | Infections and infestations |
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| Mid-cycle Insomnia | Nervous system disorders |
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| Early Awakening | Nervous system disorders |
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| Non-restorative Sleep | Nervous system disorders |
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| Nightmares | Nervous system disorders |
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| D005231 |
| Fatty Acids, Unsaturated |
| D005227 | Fatty Acids |
| D005395 | Fish Oils |
| D009821 | Oils |