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| Name | Class |
|---|---|
| Northwestern University | OTHER |
| University of Alabama at Birmingham | OTHER |
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Salt sensitivity of blood pressure (SSBP) is defined as the change in blood pressure (BP) in relation to change in salt intake. An increase in BP from low- to high-salt diet is common and associated with an increased risk of cardiovascular morbidity and mortality, even among normotensive individuals. Yet, the pathophysiology of SSBP is not well understood. The prevailing paradigm is that abnormalities of neurohormones that regulate sodium (Na+) retention and excretion and/or Na+ transporting pathways create Na+ imbalances that underlie susceptibility to SSBP. As a homeostatic mechanism, BP fluctuates to maintain Na+ balance, i.e. higher BP is needed for pressure natriuresis to excrete excess Na+. An alternate framework emphasizes vascular dysregulation as the inciting mechanism. In both constructs, how Na+ itself influences BP remains incompletely understood. Our preliminary work suggests that excess Na+ induces a pro-inflammatory state that sustains higher BP. Interleukin-6 (IL-6) drives the induction of interleukin-17 (IL-17) secreting T helper 17 cells that were recently demonstrated to be pathogenic in response to Na+ exposure. IL-6, IL-17 and related cytokines regulate renal Na+ transporters and raise BP through vascular inflammation, fibrosis, and impaired vasodilation. The immune response to high- and low-salt diet in humans, however, is not completely understood, emphasizing the need for more detailed human studies, with deeper immune profiling under controlled salt conditions and with neurohormonal assessment. Our overarching postulate is that the inflammatory response to excess dietary salt intake is associated with SSBP. The Coronary Artery Risk Development in Young Adults (CARDIA) study is the ideal cohort in which to translate our preliminary findings. Investigators propose to investigate SSBP in CARDIA using standardized low- and high-salt diets and 24-hour ambulatory BP monitoring. Investigators will quantify SSBP in a total of 500 participants from the Chicago and Birmingham field centers during the upcoming year 35 exam (beginning in 2020). Our specific aims are: 1) to define the distribution of SSBP and its clinical correlates in a contemporary community-based US cohort of middle-aged individuals; 2) to investigate the immune response to dietary salt loading, and 3) to investigate the association between the immune and BP responses to dietary salt loading. The proposed study represents a unique opportunity to leverage a large, well-phenotyped cohort to test novel hypotheses regarding SSBP. Phenotyping SSBP using standardized high- and low-salt diets in CARDIA will be novel as this has never been performed in any of the existing US based NHLBI sponsored cardiovascular epidemiologic cohorts. The proposed work has the potential to yield a more readily available approach for differentiating an individual as salt-sensitive or resistant. New insights into the pathophysiology of SSBP should also provide a foundation for investigating high-impact clinical applications, by informing future studies of therapies directed at SSBP. The scientific rigor is further enhanced by the rich clinical, genetic, and biochemical data available in CARDIA.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| High Salt Diet then Low Salt Diet | Other | The high-salt diet will be achieved through the supplementation of each participant's usual diet with Na+ bullion packets (2 packets per day). This will increase Na+ intake by approximately 2,200 mg (≈100 mEq Na+) to a total greater than 5,000 mg Na+ per day based on prior estimates of Na+ intake (see section C1.2). In addition, 1,000 mg of calcium carbonate (provided via Tums tablets) will be taken daily on the high Na+ diet to reduce the potential impact of changes in calcium intake on blood pressure. The low-salt diet is comprised of 7 days of freshly prepared frozen meals, snacks, and Na+ free water. All low-salt meals will be prepared in each site's Metabolic Kitchen, with standardization of diets across sites. The low-salt diet includes: 20 mEq Na+ (±2 mEq) (460 mg/day), 100 mEq potassium (±2 mEq), and 1,000 mg calcium (±50 mg). |
|
| Low Salt Diet then High Salt Diet | Other | The low-salt diet is comprised of 7 days of freshly prepared frozen meals, snacks, and Na+ free water. All low-salt meals will be prepared in each site's Metabolic Kitchen, with standardization of diets across sites. The low-salt diet includes: 20 mEq Na+ (±2 mEq) (460 mg/day), 100 mEq potassium (±2 mEq), and 1,000 mg calcium (±50 mg). The high-salt diet will be achieved through the supplementation of each participant's usual diet with Na+ bullion packets (2 packets per day). This will increase Na+ intake by approximately 2,200 mg (≈100 mEq Na+) to a total greater than 5,000 mg Na+ per day based on prior estimates of Na+ intake (see section C1.2). In addition, 1,000 mg of calcium carbonate (provided via Tums tablets) will be taken daily on the high Na+ diet to reduce the potential impact of changes in calcium intake on blood pressure. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| High Salt Diet | Dietary Supplement | Patients will be randomized to be on a high salt diet for 7 days. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Salt Sensitivity of Blood Pressure | The change in 24-hour ambulatory mean arterial pressure (MAP) following one week of high-salt and following one week of low-salt diet. This is calculated as the 24 hour ambulatory MAP on the high-salt diet minus the 24 hour ambulatory MAP on the low-salt diet. | 14 days total which is 7 days each of high- and low-salt diet |
| Immune Response to Dietary Salt Loading, Change in Circulating Levels of IL-6 | The change in circulating levels of interleukin-6 (IL-6) following one week of high-salt and following one week of low-salt diet. This is calculated as the IL-6 level on the high-salt diet minus the IL-6 level on the low-salt diet. | 14 days total which is 7 days each of high- and low-salt diet |
| Immune Response to Dietary Salt Loading, Change in Circulating Levels of IL-17 | The change in circulating levels of interleukin-17 (IL-17) following one week of high-salt and following one week of low-salt diet. This is calculated as the IL-17 level on the high-salt diet minus the IL-17 level on the low-salt diet. | 14 days total which is 7 days each of high- and low-salt diet |
| Immune Response to Dietary Salt Loading, IL-10, Change in Circulating Levels of IL-10 | The change in circulating levels of interleukin-10 (IL-10) following one week of high-salt and following one week of low-salt diet. This is calculated as the IL-10 level on the high-salt diet minus the IL-10 level on the low-salt diet. | 14 days total which is 7 days each of high- and low-salt diet |
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Inclusion Criteria:
Potentially eligible individuals must consent to and be willing to adhere to the study protocol. We will include individuals not taking anti-HTN medications, i.e. normotensives and untreated hypertensives, and individuals with controlled HTN by use of ≤ 3 anti-HTN medications.
Exclusion Criteria:
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Alabama Birmingham | Birmingham | Alabama | 35294 | United States | ||
| Northwestern University |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 37950918 | Derived | Gupta DK, Lewis CE, Varady KA, Su YR, Madhur MS, Lackland DT, Reis JP, Wang TJ, Lloyd-Jones DM, Allen NB. Effect of Dietary Sodium on Blood Pressure: A Crossover Trial. JAMA. 2023 Dec 19;330(23):2258-2266. doi: 10.1001/jama.2023.23651. |
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Research data will be shared according to the most recent NIH guideline. The data collected will be made available by the CARDIA Data Coordinating Center (DCC) both to the study for use by other investigators and to NHLBI for inclusion in the NHLBI's Data Repository Program, in accordance with the NHLBI Policy for Data Sharing from Clinical Trials and Epidemiological Studies, http://www.nhlbi.nih.gov/funding/datasharing.htm. Through the conduct of the study and in resource sharing, attention will be given to protect private health information; thus, we will make data available to others through the CARDIA DCC under a data use agreement specifying (1) to use the data only for research purposes and not to identify an individual participant; (2) to secure the data using appropriate computer technology; and (3) to destroy or return the data after analyses are completed. The overall CARDIA DCC at the UAB will be responsible for overseeing approval and sharing of research data.
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A total of 281 individuals consented (were enrolled). Of these 228 actually started the study, i.e., were assigned to a study group. The 53 that were consented/enrolled but did not start the study, either did not schedule study start dates, or no longer wanted to participate prior to assignment of study diet order. This study investigates salt-sensitivity of BP (SSBP), measured as change in BP between one-week of high-salt minus one-week of low-salt diet. SSBP was determined in 213.
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| ID | Title | Description |
|---|---|---|
| FG000 | High Salt Diet Then Low Salt Diet | The high-salt diet will be achieved through the supplementation of each participant's usual diet with Na+ bullion packets (2 packets per day). This will increase Na+ intake by approximately 2,200 mg (≈100 mEq Na+) to a total greater than 5,000 mg Na+ per day based on prior estimates of Na+ intake (see section C1.2). In addition, 1,000 mg of calcium carbonate (provided via Tums tablets) will be taken daily on the high Na+ diet to reduce the potential impact of changes in calcium intake on blood pressure. The low-salt diet is comprised of 7 days of freshly prepared frozen meals, snacks, and Na+ free water. All low-salt meals will be prepared in each site's Metabolic Kitchen, with standardization of diets across sites. The low-salt diet includes: 20 mEq Na+ (±2 mEq) (460 mg/day), 100 mEq potassium (±2 mEq), and 1,000 mg calcium (±50 mg). High Salt Diet: Patients will be randomized to be on a high salt diet for 7 days. Low Salt Diet: Patients will be randomized to be on a low salt for 7 days. |
| FG001 | Low Salt Diet Then High Salt Diet | The low-salt diet is comprised of 7 days of freshly prepared frozen meals, snacks, and Na+ free water. All low-salt meals will be prepared in each site's Metabolic Kitchen, with standardization of diets across sites. The low-salt diet includes: 20 mEq Na+ (±2 mEq) (460 mg/day), 100 mEq potassium (±2 mEq), and 1,000 mg calcium (±50 mg). The high-salt diet will be achieved through the supplementation of each participant's usual diet with Na+ bullion packets (2 packets per day). This will increase Na+ intake by approximately 2,200 mg (≈100 mEq Na+) to a total greater than 5,000 mg Na+ per day based on prior estimates of Na+ intake (see section C1.2). In addition, 1,000 mg of calcium carbonate (provided via Tums tablets) will be taken daily on the high Na+ diet to reduce the potential impact of changes in calcium intake on blood pressure. High Salt Diet: Patients will be randomized to be on a high salt diet for 7 days. Low Salt Diet: Patients will be randomized to be on a low salt for 7 days. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
As this was a cross-over trial, the number of baseline participants presented reflects those that completed the cross-over, rather than all enrolled.
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| ID | Title | Description |
|---|---|---|
| BG000 | High Salt Diet Then Low Salt Diet | The high-salt diet will be achieved through the supplementation of each participant's usual diet with Na+ bullion packets (2 packets per day). This will increase Na+ intake by approximately 2,200 mg (≈100 mEq Na+) to a total greater than 5,000 mg Na+ per day based on prior estimates of Na+ intake (see section C1.2). In addition, 1,000 mg of calcium carbonate (provided via Tums tablets) will be taken daily on the high Na+ diet to reduce the potential impact of changes in calcium intake on blood pressure. The low-salt diet is comprised of 7 days of freshly prepared frozen meals, snacks, and Na+ free water. All low-salt meals will be prepared in each site's Metabolic Kitchen, with standardization of diets across sites. The low-salt diet includes: 20 mEq Na+ (±2 mEq) (460 mg/day), 100 mEq potassium (±2 mEq), and 1,000 mg calcium (±50 mg). High Salt Diet: Patients will be randomized to be on a high salt diet for 7 days. Low Salt Diet: Patients will be randomized to be on a low salt for 7 days. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Median |
| 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 | Salt Sensitivity of Blood Pressure | The change in 24-hour ambulatory mean arterial pressure (MAP) following one week of high-salt and following one week of low-salt diet. This is calculated as the 24 hour ambulatory MAP on the high-salt diet minus the 24 hour ambulatory MAP on the low-salt diet. | Participants were randomized to one of two arms: either a high salt diet first, then low salt diet, or low salt diet first then low salt diet. The goal of the study was to quantify the within individual change in mean arterial pressure between high- and low-sodium diet. Therefore, arms are presented according to randomized diet order rather than overall high- or low-sodium diet at any point. In total it took 14 days to complete the high- and low-sodium diets that lasted for one-week each. | Posted | Median | Inter-Quartile Range | mm Hg | 14 days total which is 7 days each of high- and low-salt diet |
|
7 days during high-salt diet week and 7 days during low-salt diet week
At the end of the high- or low-salt diet, participants self-reported symptoms or events. If one diet week was completed, but not the other, adverse events were still ascertained during the completed diet week. Thus, adverse events were ascertained in relation to diet, which differs from the outcome measures of changes from high- to low-salt diet. For adverse events, the number at risk is based on an "as treated" analysis, i.e., those exposed to either study diet.
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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 | High Salt Diet | The high-salt diet will be achieved through the supplementation of each participant's usual diet with Na+ bullion packets (2 packets per day). This will increase Na+ intake by approximately 2,200 mg (≈100 mEq Na+) to a total greater than 5,000 mg Na+ per day based on prior estimates of Na+ intake. In addition, 1,000 mg of calcium carbonate (provided via Tums tablets) will be taken daily on the high Na+ diet to reduce the potential impact of changes in calcium intake on blood pressure. Adverse events were ascertained in relation to any exposure to high-salt diet regardless of diet-sequence or completion of both high- and low-salt diets. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Headache | General disorders | Systematic Assessment | Headache |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Deepak Gupta | Vanderbilt University Medical Center | 615-936-2530 | d.gupta@vumc.org |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | May 18, 2022 | Apr 28, 2026 | Prot_SAP_001.pdf |
| ICF | No | No | Yes | Informed Consent Form | Apr 13, 2022 | Jul 14, 2025 | ICF_000.pdf |
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| ID | Term |
|---|---|
| D006973 | Hypertension |
| ID | Term |
|---|---|
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
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| ID | Term |
|---|---|
| D004039 | Diet, Sodium-Restricted |
| ID | Term |
|---|---|
| D004035 | Diet Therapy |
| D044623 | Nutrition Therapy |
| D013812 | Therapeutics |
| D004032 | Diet |
| D009747 |
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| Low Salt Diet | Dietary Supplement | Patients will be randomized to be on a low salt for 7 days. |
|
| Chicago |
| Illinois |
| 60611 |
| United States |
| BG001 | Low Salt Diet Then High Salt Diet | The low-salt diet is comprised of 7 days of freshly prepared frozen meals, snacks, and Na+ free water. All low-salt meals will be prepared in each site's Metabolic Kitchen, with standardization of diets across sites. The low-salt diet includes: 20 mEq Na+ (±2 mEq) (460 mg/day), 100 mEq potassium (±2 mEq), and 1,000 mg calcium (±50 mg). The high-salt diet will be achieved through the supplementation of each participant's usual diet with Na+ bullion packets (2 packets per day). This will increase Na+ intake by approximately 2,200 mg (≈100 mEq Na+) to a total greater than 5,000 mg Na+ per day based on prior estimates of Na+ intake (see section C1.2). In addition, 1,000 mg of calcium carbonate (provided via Tums tablets) will be taken daily on the high Na+ diet to reduce the potential impact of changes in calcium intake on blood pressure. High Salt Diet: Patients will be randomized to be on a high salt diet for 7 days. Low Salt Diet: Patients will be randomized to be on a low salt for 7 days. |
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
The high-salt diet will be achieved through the supplementation of each participant's usual diet with Na+ bullion packets (2 packets per day). This will increase Na+ intake by approximately 2,200 mg (≈100 mEq Na+) to a total greater than 5,000 mg Na+ per day based on prior estimates of Na+ intake (see section C1.2). In addition, 1,000 mg of calcium carbonate (provided via Tums tablets) will be taken daily on the high Na+ diet to reduce the potential impact of changes in calcium intake on blood pressure. The low-salt diet is comprised of 7 days of freshly prepared frozen meals, snacks, and Na+ free water. All low-salt meals will be prepared in each site's Metabolic Kitchen, with standardization of diets across sites. The low-salt diet includes: 20 mEq Na+ (±2 mEq) (460 mg/day), 100 mEq potassium (±2 mEq), and 1,000 mg calcium (±50 mg). High Salt Diet: Patients will be randomized to be on a high salt diet for 7 days. Low Salt Diet: Patients will be randomized to be on a low salt for 7 days. |
| OG001 | Low Salt Diet Then High Salt Diet | The low-salt diet is comprised of 7 days of freshly prepared frozen meals, snacks, and Na+ free water. All low-salt meals will be prepared in each site's Metabolic Kitchen, with standardization of diets across sites. The low-salt diet includes: 20 mEq Na+ (±2 mEq) (460 mg/day), 100 mEq potassium (±2 mEq), and 1,000 mg calcium (±50 mg). The high-salt diet will be achieved through the supplementation of each participant's usual diet with Na+ bullion packets (2 packets per day). This will increase Na+ intake by approximately 2,200 mg (≈100 mEq Na+) to a total greater than 5,000 mg Na+ per day based on prior estimates of Na+ intake (see section C1.2). In addition, 1,000 mg of calcium carbonate (provided via Tums tablets) will be taken daily on the high Na+ diet to reduce the potential impact of changes in calcium intake on blood pressure. High Salt Diet: Patients will be randomized to be on a high salt diet for 7 days. Low Salt Diet: Patients will be randomized to be on a low salt for 7 days. |
|
|
| Primary | Immune Response to Dietary Salt Loading, Change in Circulating Levels of IL-6 | The change in circulating levels of interleukin-6 (IL-6) following one week of high-salt and following one week of low-salt diet. This is calculated as the IL-6 level on the high-salt diet minus the IL-6 level on the low-salt diet. | Participants were randomized to one of two arms: either a high salt diet first, then low salt diet, or low salt diet first then low salt diet. The goal of this aim was to quantify the within individual change in interleukin-6 between high- and low-sodium diet. Therefore, arms are presented according to randomized diet order rather than overall high- or low-sodium diet at any point. In total it took 14 days to complete the high- and low-sodium diets that lasted for one-week each. | Posted | Median | Inter-Quartile Range | pg/ml | 14 days total which is 7 days each of high- and low-salt diet |
|
|
|
| Primary | Immune Response to Dietary Salt Loading, Change in Circulating Levels of IL-17 | The change in circulating levels of interleukin-17 (IL-17) following one week of high-salt and following one week of low-salt diet. This is calculated as the IL-17 level on the high-salt diet minus the IL-17 level on the low-salt diet. | Participants were randomized to one of two arms: either a high salt diet first, then low salt diet, or low salt diet first then low salt diet. The goal of this aim was to quantify the within individual change in interleukin-17 between high- and low-sodium diet. Therefore, arms are presented according to randomized diet order rather than overall high- or low-sodium diet at any point. In total it took 14 days to complete the high- and low-sodium diets that lasted for one-week each. | Posted | Median | Inter-Quartile Range | pg/ml | 14 days total which is 7 days each of high- and low-salt diet |
|
|
|
| Primary | Immune Response to Dietary Salt Loading, IL-10, Change in Circulating Levels of IL-10 | The change in circulating levels of interleukin-10 (IL-10) following one week of high-salt and following one week of low-salt diet. This is calculated as the IL-10 level on the high-salt diet minus the IL-10 level on the low-salt diet. | Participants were randomized to one of two arms: either a high salt diet first, then low salt diet, or low salt diet first then low salt diet. The goal of this aim was to quantify the within individual change in interleukin-10 between high- and low-sodium diet. Therefore, arms are presented according to randomized diet order rather than overall high- or low-sodium diet at any point. In total it took 14 days to complete the high- and low-sodium diets that lasted for one-week each. | Posted | Median | Inter-Quartile Range | pg/ml | 14 days total which is 7 days each of high- and low-salt diet |
|
|
|
| 0 |
| 217 |
| 0 |
| 217 |
| 21 |
| 217 |
| EG001 | Low Salt Diet | The low-salt diet is comprised of 7 days of freshly prepared frozen meals, snacks, and Na+ free water. All low-salt meals will be prepared in each site's Metabolic Kitchen, with standardization of diets across sites. The low-salt diet includes: 20 mEq Na+ (±2 mEq) (460 mg/day), 100 mEq potassium (±2 mEq), and 1,000 mg calcium (±50 mg). Adverse events were ascertained in relation to any exposure to low-salt diet regardless of diet-sequence or completion of both high- and low-salt diets. | 0 | 215 | 0 | 215 | 17 | 215 |
| GI Upset | Gastrointestinal disorders | Systematic Assessment | Nausea, Heartburn, Vomiting |
|
| Cramp | Musculoskeletal and connective tissue disorders | Systematic Assessment |
|
| Edema | General disorders | Systematic Assessment | Edema or swelling |
|
| Oral symptoms | General disorders | Systematic Assessment | Dry/sore mouth |
|
| Lightheaded | General disorders | Systematic Assessment | Lightheaded, Dizziness, Weakness, or Lethargy |
|
| Pain | General disorders | Systematic Assessment | Pain |
|
| Dyspnea | General disorders | Systematic Assessment | Shortness of breath |
|
| Diarrhea | Gastrointestinal disorders | Systematic Assessment |
|
| Constipation | Gastrointestinal disorders | Systematic Assessment |
|
| Hypoglycemia | Endocrine disorders | Systematic Assessment | Low blood sugar |
|
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| Nutritional Physiological Phenomena |
| D000066888 | Diet, Food, and Nutrition |
| D010829 | Physiological Phenomena |