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| ID | Type | Description | Link |
|---|---|---|---|
| 1R01CA196762-01A1 | U.S. NIH Grant/Contract | View source |
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| Name | Class |
|---|---|
| National Institutes of Health (NIH) | NIH |
| National Cancer Institute (NCI) | NIH |
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This randomized control trial will examine whether a well-controlled and monitored exercise intervention improves cognitive function in postmenopausal women with early-stage breast cancer and will explore whether neuroimaging metrics of brain health, pro-inflammatory biomarkers and symptoms (fatigue, sleep problems, depression, anxiety) mediate the effects of exercise on cognitive function. Furthermore, the study will explore whether the magnitude of the improvements in cognitive function are modified by estradiol levels.
The specific aims include:
Compared to usual care, examine whether the 6-month exercise intervention improves cognitive function in postmenopausal women with early stage breast cancer.
Hypothesis 1. Exercise will improve cognitive function in women in a domain specific fashion such that attention, executive and memory functions will be influenced more than other domains.
Compared to usual care, examine the direct effects of exercise on neuroimaging metrics of brain health including regional gray matter volume, white matter architecture and functional dynamics of the brain and the pro-inflammatory biomarkers (IL-6 as primary outcomes; TNF-α as secondary), and explore the direct effects of exercise on symptoms (fatigue, sleep problems, depression, anxiety).
Hypothesis 2. Exercise will improve neuroimaging metrics of brain health and pro-inflammatory biomarkers.
Compared to usual care, explore whether the effects of exercise on cognitive function are mediated by a) neuroimaging metrics of cognitive function, b) IL-6 and TNF-α levels and c) symptoms (fatigue, sleep problems, depression, anxiety), and moderated by E2 levels.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Moderate-intensity aerobic exercise | Experimental | Participants engage in a supervised 6-month moderate-intensity aerobic exercise intervention. |
|
| Usual Care | No Intervention | Physical activity neither limited nor withheld. Participants engage in activity in the same manner as if they were not part of an active intervention. |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Moderate-Intensity Aerobic Exercise Intervention | Behavioral | The intervention is moderate-intensity aerobic exercise. Walking on a motorized treadmill will be the encouraged mode of exercise; however participants may use other equipment or home exercise. Participants will begin by exercising 10-15 minutes for 3 days/week during the first 2 weeks and gradually increase the duration for the following 4 weeks until they reach 40-50 minutes per session/3 days per week. This level is then maintained for the remainder of the 6 months. The rate of increase will be tailored based on baseline cardiorespiratory fitness and response to exercise. All sessions start and end with a vital sign check (in-person) and 5-10 minutes warm-up/cool-down. Trained exercise physiologists will supervise all exercise sessions and closely monitor adherence, intensity, and safety when sessions are completed in-person, or through regular communication when home-based exercise is warranted (due to COVID-19). |
| Measure | Description | Time Frame |
|---|---|---|
| Change in Cognitive Function | Cognitive function was assessed with a battery of 14 measures. A data reduction technique, exploratory factor analysis with principal component extraction and varimax (orthogonal) rotation, was used to create summary factors. The cognitive factors identified included processing speed, attention, mental flexibility, working memory, learning and memory, verbal memory, and executive function were derived via this factor analysis. Individual measures with the highest loadings were included in each factor. All measures had factor loadings >0.400. Scores from the individual measures for each factor were normed based on healthy controls of similar age and education to yield a z-score and these were summed to yield an average z-score for each factor. Z-scores range from -4 to +4, where higher z-scores indicate better performance for each factor. | Baseline to 6 months |
| Measure | Description | Time Frame |
|---|---|---|
| Total Brain Size | High-resolution anatomical MPRAGE (1mm3 voxels, 256 slices) images will be used for volumetric analyses. The FreeSurfer pipeline using its longitudinal option will be employed to compute cortical volumes. | Baseline and 6 months |
| Pro-inflammatory Cytokines |
| Measure | Description | Time Frame |
|---|---|---|
| Change in White Matter Microstructure | Baseline and 6 months | |
| Changes in Prefrontal Cortex | Baseline and 6 months | |
| Changes in Task-evoked Functional MRI Outcomes |
Inclusion Criteria:
Exclusion Criteria:
1. Prior treatment with cancer chemotherapy, central nervous system radiation, or intrathecal therapy 2. Clinical evidence of distant metastases 3. Self-report of hospitalization for psychiatric illness within the last two years 4. History of neurologic illness 5. Any of the following breast cancer surgery complications unless approved by the participant's health care provider: persistent seroma requiring aspiration, wound dehiscence, infection, prolonged drain output, lymphedema 6. Reconstructive surgery unless approved by the participant's health care provider 7. Any significant medical condition that would preclude them from exercising (e.g., uncontrolled diabetes, congestive heart failure, angina, uncontrolled arrhythmia or other symptoms that indicate increased risk for an acute cardiovascular or respiratory event) If necessary, we will verify this information with a participant's health care provider 8. Eating disorders or a history of substance abuse 10. Any use of an assisted walking device 11. Recent history of falls or balance problems
Additional Exclusion Criteria for Neuroimaging subgroup:
1. Presence of metal implants (i.e., pacemaker, some stents)
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| Name | Affiliation | Role |
|---|---|---|
| Catherine M Bender, PhD | University of Pittsburgh | Principal Investigator |
| Kirk I Erickson, PhD | University of Pittsburgh | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Pittsburgh | Pittsburgh | Pennsylvania | 15261 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 42421660 | Derived | Gentry AL, Sereika SM, Erickson KI, McCall MK, Belcher SM, Cummings MC, Cho MG, Brufsky E, Rosenzweig MQ, Bender CM. The relationship of neighborhood socioeconomic disadvantage and pretreatment cancer-related cognitive impairment in women with breast cancer: A post hoc analysis of a randomized controlled trial. Cancer. 2026 Jul 15;132(14):e70506. doi: 10.1002/cncr.70506. | |
| 40768266 | Derived | Liu S, Liu D, Bender CM, Erickson KI, Sereika SM, Shaffer JR, Weeks DE, Conley YP. DNA methylation associations with cognitive function in early-stage hormone receptor-positive breast cancer patients. Epigenomics. 2025 Sep;17(13):879-889. doi: 10.1080/17501911.2025.2542116. Epub 2025 Aug 6. |
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At the completion of the intervention, after investigators have been un-blinded to group status, and after the testing and publication of the primary aims and hypotheses, the investigators will provide de-identified data to interested investigators provided that they closely consult with Drs. Bender and Erickson with respect to study design, analytical procedures, and to avoid overlapping research in analyses or manuscript preparation. The primary investigative team will be given priority in addressing scientific questions of interest with the collected data, but will work closely with any interested investigators in maximizing the data to address other questions of interest that could be answered by these data.
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| ID | Title | Description |
|---|---|---|
| FG000 | Moderate-intensity Aerobic Exercise | Participants engage in a supervised 6-month moderate-intensity aerobic exercise intervention. Moderate-Intensity Aerobic Exercise Intervention: The intervention is moderate-intensity aerobic exercise. Walking on a motorized treadmill will be the encouraged mode of exercise; however participants may use other equipment or home exercise. Participants will begin by exercising 10-15 minutes for 3 days/week during the first 2 weeks and gradually increase the duration for the following 4 weeks until they reach 40-50 minutes per session/3 days per week. This level is then maintained for the remainder of the 6 months. The rate of increase will be tailored based on baseline cardiorespiratory fitness and response to exercise. All sessions start and end with a vital sign check (in-person) and 5-10 minutes warm-up/cool-down. Trained exercise physiologists will supervise all exercise sessions and closely monitor adherence, intensity, and safety when sessions are completed in-person, or through regular communication when home-based exercise is warranted (due to COVID-19). |
| FG001 | Usual Care | Physical activity neither limited nor withheld. Participants engage in activity in the same manner as if they were not part of an active intervention. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Moderate-intensity Aerobic Exercise | Participants engage in a supervised 6-month moderate-intensity aerobic exercise intervention. Moderate-Intensity Aerobic Exercise Intervention: The intervention is moderate-intensity aerobic exercise. Walking on a motorized treadmill will be the encouraged mode of exercise; however participants may use other equipment or home exercise. Participants will begin by exercising 10-15 minutes for 3 days/week during the first 2 weeks and gradually increase the duration for the following 4 weeks until they reach 40-50 minutes per session/3 days per week. This level is then maintained for the remainder of the 6 months. The rate of increase will be tailored based on baseline cardiorespiratory fitness and response to exercise. All sessions start and end with a vital sign check (in-person) and 5-10 minutes warm-up/cool-down. Trained exercise physiologists will supervise all exercise sessions and closely monitor adherence, intensity, and safety when sessions are completed in-person, or through regular communication when home-based exercise is warranted (due to COVID-19). |
| 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 in Cognitive Function | Cognitive function was assessed with a battery of 14 measures. A data reduction technique, exploratory factor analysis with principal component extraction and varimax (orthogonal) rotation, was used to create summary factors. The cognitive factors identified included processing speed, attention, mental flexibility, working memory, learning and memory, verbal memory, and executive function were derived via this factor analysis. Individual measures with the highest loadings were included in each factor. All measures had factor loadings >0.400. Scores from the individual measures for each factor were normed based on healthy controls of similar age and education to yield a z-score and these were summed to yield an average z-score for each factor. Z-scores range from -4 to +4, where higher z-scores indicate better performance for each factor. | Posted | Least Squares Mean | Standard Error | z-score | Baseline to 6 months |
|
6 months
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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 | Moderate-intensity Aerobic Exercise | Participants engage in a supervised 6-month moderate-intensity aerobic exercise intervention. Moderate-Intensity Aerobic Exercise Intervention: The intervention is moderate-intensity aerobic exercise. Walking on a motorized treadmill will be the encouraged mode of exercise; however participants may use other equipment or home exercise. Participants will begin by exercising 10-15 minutes for 3 days/week during the first 2 weeks and gradually increase the duration for the following 4 weeks until they reach 40-50 minutes per session/3 days per week. This level is then maintained for the remainder of the 6 months. The rate of increase will be tailored based on baseline cardiorespiratory fitness and response to exercise. All sessions start and end with a vital sign check (in-person) and 5-10 minutes warm-up/cool-down. Trained exercise physiologists will supervise all exercise sessions and closely monitor adherence, intensity, and safety when sessions are completed in-person, or through regular communication when home-based exercise is warranted (due to COVID-19). |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Catherine Bender, Principal Investigator | University of Pittsburgh | 412-624-3594 | cbe100@pitt.edu |
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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 | Jun 14, 2023 | Jan 3, 2024 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D001943 | Breast Neoplasms |
| D009043 | Motor Activity |
| ID | Term |
|---|---|
| D009371 | Neoplasms by Site |
| D009369 | Neoplasms |
| D001941 | Breast Diseases |
| D012871 | Skin Diseases |
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|
Cytokine levels for interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) were determined using high-sensitivity, quantitative sandwich enzyme immunoassay run according to manufacturer's directions. Greater pgs/ML indicate higher levels of both IL-6 and TNF-aplha. |
| Baseline to 6 months |
| Peak VO2 | Fitness will be measured by submaximal VO2 test. The submaximal test is similar to the full test, but stops at 85% of the age-predicted heart rate. The protocol involves walking at a self-selected pace between 2.0-4.0 mph with increasing grade increments of 2% every two minutes. The test is terminated when the subject reaches 85% of their age-predicted heart rate or at volitional exhaustion. Higher levels (ml/kg/minute) indicate better peak VO2. | Baseline and 6 months |
| Estradiol (E2) Levels | E2 was determined by a competitive binding immunoassay, according to manufacturer's directions. Greater pgs/ML indicate higher levels of estradiol. | Baseline to 6 months |
| Fatigue | The Fatigue 8a Patient Reported Outcomes Measurement Information System (PROMIS) short form was used to measure fatigue. It consists of 8 items on which participants respond using a 5-point Likert scale. The scores range from 0 to 24 with higher scores indicating greater fatigue. | Baseline and 6 months |
| Anxiety | The eight-item Anxiety 8a PROMIS short form was used to measure anxiety. Participants rate each item on a scale from 1 to 5. The score is the total of the responses with higher scores indicating greater anxiety. The range of scores is 5 to 40. | Baseline to 6 months |
| Sleep Problems | Sleep problems were measured using global score of the Pittsburgh Sleep Quality Index (PSQI). The PSQI is a self-report measure that consists of 19 items. Each item is weighted on a 0-3 interval scale. The PSQI global score ranges from 0 to 21, where lower scores indicate better sleep quality, and higher scores indicate poorer sleep quality. | Baseline to 6 months |
| Depressive Symptoms | Depressive symptoms will be measured using the Beck Depression Inventory II (BDI II). The 21-item BDI II is a self-report measure on which participants rate depressive symptoms on a four-point scale. The BDI II score ranges from 0 to 63 with higher scores indicating greater depressive symptomatology. | Baseline to 6 months |
| Baseline and 6 months |
| Changes in Resting State Network | Baseline and 6 months |
| 40035875 | Derived | Bender CM, Sereika SM, Gentry AL, Zhu Y, Wagner M, Cuglewski C, Duquette J, Grove G, Cummings M, Cho MG, Brufsky AM, Diego EJ, McAuliffe PF, Marsland AL, Conley YP, Erickson KI. Aerobic exercise and aromatase inhibitor-associated musculoskeletal symptoms: results of a randomized clinical trial. Support Care Cancer. 2025 Mar 4;33(3):244. doi: 10.1007/s00520-025-09257-4. |
| 33210238 | Derived | Bender CM, Sereika SM, Gentry AL, Duquette JE, Casillo FE, Marsland A, Brufsky AM, Evans S, Gorantla VC, Grahovac TL, McAuliffe PF, Steiman JG, Zhu Y, Erickson KI. Physical activity, cardiorespiratory fitness, and cognitive function in postmenopausal women with breast cancer. Support Care Cancer. 2021 Jul;29(7):3743-3752. doi: 10.1007/s00520-020-05865-4. Epub 2020 Nov 19. |
| 29501739 | Derived | Gentry AL, Erickson KI, Sereika SM, Casillo FE, Crisafio ME, Donahue PT, Grove GA, Marsland AL, Watt JC, Bender CM. Protocol for Exercise Program in Cancer and Cognition (EPICC): A randomized controlled trial of the effects of aerobic exercise on cognitive function in postmenopausal women with breast cancer receiving aromatase inhibitor therapy. Contemp Clin Trials. 2018 Apr;67:109-115. doi: 10.1016/j.cct.2018.02.012. Epub 2018 Mar 6. |
| BG001 | Usual Care | Physical activity neither limited nor withheld. Participants engage in activity in the same manner as if they were not part of an active intervention. |
| BG002 | Total | Total of all reporting groups |
| Participants |
|
| Age, Continuous | Mean | Standard Deviation | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| BMI, Customized | Mean | Standard Deviation | kg/m^2 |
|
| Disease Stage: DCIS, I, IIa, IIb, IIIa | Breast cancer stages, defined by American College of Surgeons, retrieved from medical record. Stage 0=noninvasive Stage 1=tumor </=2cm, no lymph node spread Stage 2a=tumor</=2cm, spread to axillary lymph nodes or tumor 2-5cm, no axillary lymph node spread. Stage 2b=tumor 2-5cm, spread to 1-3 axillary lymph nodes or to lymph nodes near breastbone or tumor >5cm, no axillary lymph node spread Stage 3a=tumor >5 cm & spread to 1-3 axillary lymph nodes or to lymph nodes near breastbone. Increasing stages: >extent of cancer. Increasing stages indicate greater extent of breast cancer. | Count of Participants | Participants |
|
Participants engage in a supervised 6-month moderate-intensity aerobic exercise intervention. Moderate-Intensity Aerobic Exercise Intervention: The intervention is moderate-intensity aerobic exercise. Walking on a motorized treadmill will be the encouraged mode of exercise; however participants may use other equipment or home exercise. Participants will begin by exercising 10-15 minutes for 3 days/week during the first 2 weeks and gradually increase the duration for the following 4 weeks until they reach 40-50 minutes per session/3 days per week. This level is then maintained for the remainder of the 6 months. The rate of increase will be tailored based on baseline cardiorespiratory fitness and response to exercise. All sessions start and end with a vital sign check (in-person) and 5-10 minutes warm-up/cool-down. Trained exercise physiologists will supervise all exercise sessions and closely monitor adherence, intensity, and safety when sessions are completed in-person, or through regular communication when home-based exercise is warranted (due to COVID-19). |
| OG001 | Usual Care | Physical activity neither limited nor withheld. Participants engage in activity in the same manner as if they were not part of an active intervention. |
|
|
| Secondary | Total Brain Size | High-resolution anatomical MPRAGE (1mm3 voxels, 256 slices) images will be used for volumetric analyses. The FreeSurfer pipeline using its longitudinal option will be employed to compute cortical volumes. | The sample size for the total brain size analysis is smaller than the total number of participants because, imaging was planned on a subset of the overall sample, the impact of COVID precluded imaging for a time, the MRI machine was switched during the study, so it would have required some participants to use one imaging machine and another set with a second machine. Thus, the parameters of the sequences and the image quality would have been different between machines, and budget cuts. | Posted | Mean | Standard Deviation | mm-cubed | Baseline and 6 months |
|
|
|
| Secondary | Pro-inflammatory Cytokines | Cytokine levels for interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) were determined using high-sensitivity, quantitative sandwich enzyme immunoassay run according to manufacturer's directions. Greater pgs/ML indicate higher levels of both IL-6 and TNF-aplha. | The number of participants analyzed for the pro-inflammatory cytokines, IL-5 and TNF-alpha is smaller than what is reported in the participant flow module because the impact of COVID precluded securing the blood samples for IL-6 and TNF-alpha for a time. | Posted | Mean | Standard Error | pg/ML | Baseline to 6 months |
|
|
|
| Secondary | Peak VO2 | Fitness will be measured by submaximal VO2 test. The submaximal test is similar to the full test, but stops at 85% of the age-predicted heart rate. The protocol involves walking at a self-selected pace between 2.0-4.0 mph with increasing grade increments of 2% every two minutes. The test is terminated when the subject reaches 85% of their age-predicted heart rate or at volitional exhaustion. Higher levels (ml/kg/minute) indicate better peak VO2. | The number of participants analyzed for peak VO2 is smaller than what is reported in the participant flow module because the impact of COVID precluded securing VO2 for a time. | Posted | Mean | Standard Error | ml/kg/minute | Baseline and 6 months |
|
|
|
| Secondary | Estradiol (E2) Levels | E2 was determined by a competitive binding immunoassay, according to manufacturer's directions. Greater pgs/ML indicate higher levels of estradiol. | The number of participants analyzed for estradiol is smaller than what is reported in the participant flow module because the impact of COVID precluded securing blood samples for estradiol for a time. | Posted | Mean | Standard Error | pg/ML | Baseline to 6 months |
|
|
|
| Secondary | Fatigue | The Fatigue 8a Patient Reported Outcomes Measurement Information System (PROMIS) short form was used to measure fatigue. It consists of 8 items on which participants respond using a 5-point Likert scale. The scores range from 0 to 24 with higher scores indicating greater fatigue. | The sample size for the analysis of the fatigue data is smaller than the total numbers in the Participant Flow module because the impact of COVID precluded securing fatigue measurement for a time. | Posted | Mean | Standard Deviation | score on a scale | Baseline and 6 months |
|
|
|
| Secondary | Anxiety | The eight-item Anxiety 8a PROMIS short form was used to measure anxiety. Participants rate each item on a scale from 1 to 5. The score is the total of the responses with higher scores indicating greater anxiety. The range of scores is 5 to 40. | Posted | Least Squares Mean | Standard Error | units on a scale | Baseline to 6 months |
|
|
|
| Secondary | Sleep Problems | Sleep problems were measured using global score of the Pittsburgh Sleep Quality Index (PSQI). The PSQI is a self-report measure that consists of 19 items. Each item is weighted on a 0-3 interval scale. The PSQI global score ranges from 0 to 21, where lower scores indicate better sleep quality, and higher scores indicate poorer sleep quality. | Posted | Least Squares Mean | Standard Error | units on a scale | Baseline to 6 months |
|
|
|
| Secondary | Depressive Symptoms | Depressive symptoms will be measured using the Beck Depression Inventory II (BDI II). The 21-item BDI II is a self-report measure on which participants rate depressive symptoms on a four-point scale. The BDI II score ranges from 0 to 63 with higher scores indicating greater depressive symptomatology. | Posted | Least Squares Mean | Standard Error | units on a scale | Baseline to 6 months |
|
|
|
| Other Pre-specified | Change in White Matter Microstructure | Not Posted | Baseline and 6 months | Participants |
| Other Pre-specified | Changes in Prefrontal Cortex | Not Posted | Baseline and 6 months | Participants |
| Other Pre-specified | Changes in Task-evoked Functional MRI Outcomes | Not Posted | Baseline and 6 months | Participants |
| Other Pre-specified | Changes in Resting State Network | Not Posted | Baseline and 6 months | Participants |
| 0 |
| 77 |
| 0 |
| 77 |
| 0 |
| 77 |
| EG001 | Usual Care | Physical activity neither limited nor withheld. Participants engage in activity in the same manner as if they were not part of an active intervention. | 0 | 76 | 0 | 76 | 0 | 76 |
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| D017437 |
| Skin and Connective Tissue Diseases |
| D001519 | Behavior |