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| ID | Type | Description | Link |
|---|---|---|---|
| U01DK072146 | U.S. NIH Grant/Contract | View source |
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| Name | Class |
|---|---|
| National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) | NIH |
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We have completed patient enrollment in the the double blind, randomized, placebo-controlled trial of intravenous (IV) N-acetylcysteine (NAC) vs. placebo for the treatment of non-acetaminophen ALF. The purpose of this study is to examine the safety and efficacy of intravenous NAC in children with ALF for whom no antidote or other specific treatment is available. Inclusion in the NAC Study required enrollment in the Pediatric Acute Liver Failure (PALF) Study Registry.
The Pediatric Acute Liver Failure (PALF) Study Group to identify, characterize, and develop management strategies for infants, children and adolescents who present with acute liver failure. The PALF study group includes 20 sites (17 in the United States, 2 in the United Kingdom, and 1 in Canada). The primary objective of the Pediatric Acute Liver Failure (PALF) study is to collect, maintain, analyze, and report clinical, epidemiological, and outcome data in children with ALF, including information derived from biospecimens.
Patients enrolled in the PALF study registry were able to enroll in the NAC study providing they met the additional required inclusion/exclusion criteria.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| N-acetylcysteine (NAC) | Active Comparator | Eligible children were adaptively allocated by age (less than 2 years of age or at least 2 years old) and hepatic encephalopathy (grade 0-1 or 2-4) to receive N-acetylcysteine (150 mg/kg/d) in 5% dextrose (D5W) infused over 24 hours for up to 7 consecutive days |
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| placebo | Placebo Comparator | Eligible children were adaptively allocated within strata defined by age (less than 2 years of age or at least 2 years old) and hepatic encephalopathy (grade 0-1 or 2-4) to receive 5% dextrose (D5W) infused over 24 hours for up to 7 consecutive |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| N-acetylcysteine | Drug | The study drug is administered as a continuous infusion at a dose of 150 mg/kg/day for up to 7 days following entry into the study. The infusion is discontinued at the time of death, liver transplant or discharge. |
| Measure | Description | Time Frame |
|---|---|---|
| Survival | Spontaneous survival without transplant plus survival following transplantation | One year following randomization |
| Measure | Description | Time Frame |
|---|---|---|
| Spontaneous Recovery | Survival without liver transplantation | One year following randomization |
| Cumulative Percent Incidence of Transplantation by 1 Year | Within 1 year of randomization |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Robert H Squires, M.D. | Children's Hospital of Pittsburgh, University of Pittsburgh | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of California, San Francisco | San Francisco | California | 94143 | United States | ||
| University of Colorado, Denver Children's Hospital |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 19643443 | Background | Narkewicz MR, Dell Olio D, Karpen SJ, Murray KF, Schwarz K, Yazigi N, Zhang S, Belle SH, Squires RH; Pediatric Acute Liver Failure Study Group. Pattern of diagnostic evaluation for the causes of pediatric acute liver failure: an opportunity for quality improvement. J Pediatr. 2009 Dec;155(6):801-806.e1. doi: 10.1016/j.jpeds.2009.06.005. Epub 2009 Jul 29. | |
| 18643912 | Background | Rudnick DA, Dietzen DJ, Turmelle YP, Shepherd R, Zhang S, Belle SH, Squires R; Pediatric Acute Liver Failure Study Group. Serum alpha-NH-butyric acid may predict spontaneous survival in pediatric acute liver failure. Pediatr Transplant. 2009 Mar;13(2):223-30. doi: 10.1111/j.1399-3046.2008.00998.x. Epub 2008 Jul 17. |
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Participants were from an established registry of children with acute liver failure. Entry criteria: children <18 years, absence of a known chronic liver disease, biochemical evidence of acute liver injury, and a liver-based coagulopathy. Evidence of hepatic encephalopathy was required if the prothrombin time (PT) was between 15-19.9 seconds
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| ID | Title | Description |
|---|---|---|
| FG000 | Placebo | Eligible children were adaptively allocated within strata defined by age (less than 2 years of age or at least 2 years old) and HE (grade 0-1 or 2-4) to placebo consisting of D5W alone. Volumes were adjusted for small children. Study medications were infused over 24 hours for up to 7 consecutive days in a dedicated line without other medications. Treatment was stopped earlier than 7 days in the case of hospital discharge, liver transplantation, or death within 7 days of randomization. Dextrose in water: Eligible children were adaptively allocated within strata defined by age (less than 2 years of age or at least 2 years old) and HE (grade 0-1 or 2-4) to receive N-acetylcysteine (150 mg/kg/d) in 5% dextrose (D5W) and water or placebo consisting of an equal volume of D5W alone. Volumes were adjusted for small children. Study medications were infused over 24 hours for up to 7 consecutive days in a dedicated line without other medications. |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| Placebo | Drug | Eligible children were adaptively allocated within strata defined by age (less than 2 years of age or at least 2 years old) and hepatic encephalopathy (grade 0-1 or 2-4) to receive N-acetylcysteine (150 mg/kg/d) in 5% dextrose (D5W) and water or placebo consisting of an equal volume of D5W alone. Volumes were adjusted for small children. Study medications were infused over 24 hours for up to 7 consecutive days in a dedicated line without other medications. Treatment was stopped earlier than 7 days in the case of hospital discharge, liver transplantation, or death within 7 days of randomization. |
|
|
| Length of Hospital Stay | Randomization to hospital discharge |
| Categorized Length of ICU Stay | The length of ICU stay was categorized as number of days in ICU within 7 days of randomization, unless participant either died or received an LTx within this time period. Special categories were created for these cases. | Within 7 days of randomization |
| Number of Organ Systems Failing | Within 7 days of randomization |
| Highest Coma Grade of Hepatic Encephalopathy | West Haven Criteria for hepatic encephalopathy (Grade 0 - IV ) is used for participants > 3 year of age. Coma grade IV indicates a participant who is comatose , with no reflexes, is decerebrate and has abnormal EEG changes with very slow delta activity. For participants less than 3 years the Whittington Scale was used. The Whittington scale does not use EEG changes and has only 3 levels, early (grades I and II), Mid (III) with somnolence, stupor, combativeness and Late (IV) for participants who are comatose with absent reflexes and decerebrate or decorticate posturing. | Within 7 days of randomization |
| Infectious Complication | Within 7 days of randomization |
| Denver |
| Colorado |
| 80218 |
| United States |
| Emory University, Children's Healthcare of Atlanta | Atlanta | Georgia | 30322 | United States |
| Children's Memorial Hospital | Chicago | Illinois | 60614 | United States |
| Riley Children's Hospital | Indianapolis | Indiana | 46202 | United States |
| Johns Hopkins University | Baltimore | Maryland | 21287 | United States |
| Harvard University, Boston Children's Hospital | Boston | Massachusetts | 02115 | United States |
| University of Michigan | Ann Arbor | Michigan | 48109 | United States |
| St. Louis Children's Hospital | St Louis | Missouri | 63110 | United States |
| Mount Sinai Hospital | New York | New York | 10029 | United States |
| Columbia-Presbyterian | New York | New York | 10032 | United States |
| University of Cincinnati, Cincinnati Children's Hospital | Cincinnati | Ohio | 45229 | United States |
| Children's Hospital of Philadelphia | Philadelphia | Pennsylvania | 19104 | United States |
| Children's Hospital of Pittsburgh of UPMC | Pittsburgh | Pennsylvania | 15224 | United States |
| Children's Medical Center of Dallas | Dallas | Texas | 75235 | United States |
| Baylor College of Medicine | Houston | Texas | 77030 | United States |
| University of Washington | Seattle | Washington | 98105 | United States |
| Hospital for Sick Children | Toronto | Ontario | M5G 1X8 | Canada |
| Birmingham Children's Hospital | Birmingham | B4 6NH | United Kingdom |
| King's College Hospital (London, UK) | London | SE59RS | United Kingdom |
| 16950959 | Background | James LP, Alonso EM, Hynan LS, Hinson JA, Davern TJ, Lee WM, Squires RH; Pediatric Acute Liver Failure Study Group. Detection of acetaminophen protein adducts in children with acute liver failure of indeterminate cause. Pediatrics. 2006 Sep;118(3):e676-81. doi: 10.1542/peds.2006-0069. |
| 16737880 | Background | Squires RH Jr, Shneider BL, Bucuvalas J, Alonso E, Sokol RJ, Narkewicz MR, Dhawan A, Rosenthal P, Rodriguez-Baez N, Murray KF, Horslen S, Martin MG, Lopez MJ, Soriano H, McGuire BM, Jonas MM, Yazigi N, Shepherd RW, Schwarz K, Lobritto S, Thomas DW, Lavine JE, Karpen S, Ng V, Kelly D, Simonds N, Hynan LS. Acute liver failure in children: the first 348 patients in the pediatric acute liver failure study group. J Pediatr. 2006 May;148(5):652-658. doi: 10.1016/j.jpeds.2005.12.051. |
| 15789368 | Background | Alonso EM. Acute liver failure in children: the role of defects in fatty acid oxidation. Hepatology. 2005 Apr;41(4):696-9. doi: 10.1002/hep.20680. No abstract available. |
| 15791615 | Background | Shneider BL, Rinaldo P, Emre S, Bucuvalas J, Squires R, Narkewicz M, Gondolesi G, Magid M, Morotti R, Hynan LS. Abnormal concentrations of esterified carnitine in bile: a feature of pediatric acute liver failure with poor prognosis. Hepatology. 2005 Apr;41(4):717-21. doi: 10.1002/hep.20631. |
| 21621221 | Background | Sundaram SS, Alonso EM, Narkewicz MR, Zhang S, Squires RH; Pediatric Acute Liver Failure Study Group. Characterization and outcomes of young infants with acute liver failure. J Pediatr. 2011 Nov;159(5):813-818.e1. doi: 10.1016/j.jpeds.2011.04.016. Epub 2011 May 31. |
| FG001 | N-acetylcysteine (NAC) | Eligible children were adaptively allocated within strata defined by age (less than 2 years of age or at least 2 years old) and HE (grade 0-1 or 2-4) to receive NAC (150 mg/kg/d) in 5% dextrose (D5W) and water. Volumes were adjusted for small children. Study medications were infused over 24 hours for up to 7 consecutive days in a dedicated line without other medications. Treatment was stopped earlier than 7 days in the case of hospital discharge, LTx, or death within 7 days of randomization. N-acetylcysteine: The study drug is administered as a continuous infusion at a dose of 150 mg/kg/day for up to 7 days following entry into the study. The infusion is discontinued at the time of death, liver transplant or discharge. |
| COMPLETED |
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| NOT COMPLETED |
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All participants who were randomized were included in the baseline analysis.
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| ID | Title | Description |
|---|---|---|
| BG000 | N-acetylcysteine (NAC) | Eligible children were adaptively allocated by age (less than 2 years of age or at least 2 years old) and HE (grade 0-1 or 2-4) to receive NAC (150 mg/kg/d) in 5% dextrose (D5W) infused over 24 hours for up to 7 consecutive days N-acetylcysteine: The study drug is administered as a continuous infusion at a dose of 150 mg/kg/day for up to 7 days following entry into the study. |
| BG001 | Placebo | Eligible children were adaptively allocated within strata defined by age (less than 2 years of age or at least 2 years old) and HE (grade 0-1 or 2-4) to receive 5% dextrose (D5W) infused over 24 hours for up to 7 consecutive Dextrose in water: placebo consisting of an equal volume of D5W alone for up to 7 days following entry into the study |
| BG002 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants | Participants |
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| Age, Continuous | Median | Inter-Quartile Range | years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Race (NIH/OMB) | Count of Participants | Participants |
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| Region of Enrollment | Number | participants |
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| Coma Grade of Hepatic Encephalopathy | West Haven Criteria for hepatic encephalopathy (Grade 0 - IV ) is used for participants > 3 year of age. Coma grade IV indicates a participant who is comatose , with no reflexes, is decerebrate and has abnormal EEG changes with very slow delta activity. For participants less than 3 years the Whittington Scale was used. The Whittington scale does not use EEG changes and has only 3 levels, early (grades I and II), Mid (III) with somnolence, stupor, combativeness and Late (IV) for participants who are comatose with absent reflexes and decerebrate or decorticate posturing. | Number | participants |
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| 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 | Survival | Spontaneous survival without transplant plus survival following transplantation | All participants who were enrolled in the study were included in the survival analysis | Posted | Number | Participants | One year following randomization |
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| Secondary | Spontaneous Recovery | Survival without liver transplantation | All participants enrolled in study | Posted | Number | participants | One year following randomization |
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| Secondary | Cumulative Percent Incidence of Transplantation by 1 Year | Posted | Number | percentage of participants | Within 1 year of randomization |
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| Secondary | Length of Hospital Stay | All participants enrolled in study with hospital stay information, 2 participants (1 in each arm) did not have hospital discharge information. | Posted | Median | Inter-Quartile Range | days | Randomization to hospital discharge |
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| Secondary | Categorized Length of ICU Stay | The length of ICU stay was categorized as number of days in ICU within 7 days of randomization, unless participant either died or received an LTx within this time period. Special categories were created for these cases. | Posted | Number | participants | Within 7 days of randomization |
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| Secondary | Number of Organ Systems Failing | Posted | Number | participants | Within 7 days of randomization |
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| Secondary | Highest Coma Grade of Hepatic Encephalopathy | West Haven Criteria for hepatic encephalopathy (Grade 0 - IV ) is used for participants > 3 year of age. Coma grade IV indicates a participant who is comatose , with no reflexes, is decerebrate and has abnormal EEG changes with very slow delta activity. For participants less than 3 years the Whittington Scale was used. The Whittington scale does not use EEG changes and has only 3 levels, early (grades I and II), Mid (III) with somnolence, stupor, combativeness and Late (IV) for participants who are comatose with absent reflexes and decerebrate or decorticate posturing. | All enrolled participants where coma grade could be assessed. Four participants (two in each randomization arm) could not have coma grade assessed during the 7 days after randomization. | Posted | Number | participants | Within 7 days of randomization |
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| Secondary | Infectious Complication | Posted | Number | Participants | Within 7 days of randomization |
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Seven day randomization treatment period
Regular investigator assessment
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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 | N-acetylcysteine (NAC) | Eligible children were adaptively allocated by age (less than 2 years of age or at least 2 years old) and HE (grade 0-1 or 2-4) to receive NAC (150 mg/kg/d) in 5% dextrose (D5W) infused over 24 hours for up to 7 consecutive days N-acetylcysteine: The study drug is administered as a continuous infusion at a dose of 150 mg/kg/day for up to 7 days following entry into the study. The infusion is discontinued at the time of death, liver transplant or discharge. | 5 | 92 | 19 | 92 | ||
| EG001 | Placebo | Eligible children were adaptively allocated within strata defined by age (less than 2 years of age or at least 2 years old) and HE (grade 0-1 or 2-4) to receive 5% dextrose (D5W) infused over 24 hours for up to 7 consecutive Dextrose in water: Eligible children were adaptively allocated within strata defined by age (less than 2 years of age or at least 2 years old) and HE (grade 0-1 or 2-4) to receive NAC (150 mg/kg/d) in 5% dextrose (D5W) and water or placebo consisting of an equal volume of D5W alone. Volumes were adjusted for small children. Study medications were infused over 24 hours for up to 7 consecutive days in a dedicated line without other medications. Treatment was stopped earlier than 7 days in the case of hospital discharge, LTx, or death within 7 days of randomization. | 4 | 92 | 16 | 92 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Respiratory distress | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
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| Bacteremia | Infections and infestations | Systematic Assessment |
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| Bradycardiac episode | Cardiac disorders | Systematic Assessment |
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| Hypoglycemia | Endocrine disorders | Systematic Assessment |
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| Aplastic Anemia | Blood and lymphatic system disorders | Systematic Assessment |
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| Epstein-Barr virus | Infections and infestations | Systematic Assessment |
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| Fever, chills, sinusitis | Infections and infestations | Systematic Assessment |
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| Small intestine ulcerations | Gastrointestinal disorders | Systematic Assessment |
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| Fever | General disorders | Systematic Assessment |
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| Hearing loss | Ear and labyrinth disorders | Systematic Assessment |
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| Bigeminy | Cardiac disorders | Systematic Assessment |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Infection | Infections and infestations | Systematic Assessment |
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| Rash | Skin and subcutaneous tissue disorders | Systematic Assessment |
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| Bronchospasm | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
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| Arrhythmia | Cardiac disorders | Systematic Assessment |
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| Aspiration | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
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| Dilated and fixed pupils | Eye disorders | Systematic Assessment |
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| Hypertension | Vascular disorders | Systematic Assessment |
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| Pleural effusion | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
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| Sleepiness | General disorders | Systematic Assessment |
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| Bradycardia | Cardiac disorders | Systematic Assessment |
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| High Fever | General disorders | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Robert H. Squires, Jr. | University of Pittsburgh | 412-692-8648 | squiresr@upmc.edu |
| ID | Term |
|---|---|
| D017114 | Liver Failure, Acute |
| D006501 | Hepatic Encephalopathy |
| ID | Term |
|---|---|
| D017093 | Liver Failure |
| D048550 | Hepatic Insufficiency |
| D008107 | Liver Diseases |
| D004066 | Digestive System Diseases |
| D001928 | Brain Diseases, Metabolic |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
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| ID | Term |
|---|---|
| D000111 | Acetylcysteine |
| D005947 | Glucose |
| D014867 | Water |
| ID | Term |
|---|---|
| D003545 | Cysteine |
| D000603 | Amino Acids, Sulfur |
| D013457 | Sulfur Compounds |
| D009930 | Organic Chemicals |
| D000596 | Amino Acids |
| D000602 | Amino Acids, Peptides, and Proteins |
| D006601 | Hexoses |
| D009005 | Monosaccharides |
| D000073893 | Sugars |
| D002241 | Carbohydrates |
| D006878 | Hydroxides |
| D000468 | Alkalies |
| D007287 | Inorganic Chemicals |
| D000838 | Anions |
| D007477 | Ions |
| D004573 | Electrolytes |
| D010087 | Oxides |
| D017601 | Oxygen Compounds |
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| >=65 years |
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| Male |
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| Asian |
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| Native Hawaiian or Other Pacific Islander |
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| Black or African American |
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| White |
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| More than one race |
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| Unknown or Not Reported |
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| United States |
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| United Kingdom |
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| 2-4 |
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