Background: At least 30% of Americans have fatty liver disease. This means that they store too much fat in the liver. At the moment lifestyle changes are the only way to treat this problem. Objective: To test how (1) a low-carbohydrate diet and (2) a supplement called nicotinamide riboside (NR) affect how a person s body uses dietary fat. Eligibility: Men aged 18 to 65 and women aged 18 to 50 who are healthy volunteers with a body mass index (height to weight ratio) of 25 or more. Adults with maturity-onset diabetes of the young type 2 (MODY2) are also needed. Design: Participants with diabetes will have 1 screening visit and a 9-day clinic stay. Healthy volunteers will have 1 screening visit and 2 clinic stays of 1 to 2 weeks each. During screening, all participants will have a physical exam with blood and urine tests. They will have their heart rhythm measured while riding a gym bike. NR is a pill taken by mouth. Only healthy volunteers will take the NR, for 14 days at a time, during 1 clinic stay. During their other stay, they will take placebos; these are pills that look like the study supplement but contain no NR. During each clinic stay, all participants will eat a normal American diet. Then they will eat a ketogenic "low-carb" diet for 5 days. Participants will have many tests, including: Sleeping every night and having two 24-hour stays in a special room that measures the gases their body uses and produces. Drinking a high-fat shake, then remaining seated for 5 hours while their blood and breath are monitored. Having a substance injected into the arm and remaining seated for 3 hours while their blood is measured. Wearing monitors to measure their activity levels. Another monitor will measure their blood glucose levels. Having imaging scans. ...

Type: Interventional

Start Date: Jan 2024

open study

Background: People living with HIV(PLWH) are at a higher risk for cancers that may be curable with a bone marrow transplant. HIV infection itself is no longer a reason to not get a transplant, for patients who otherwise have a standard reason to need transplant. Objective: This study is being done to see if a new combination of drugs (cyclophosphamide, maraviroc, and bortezomib) is both safe and effective at protecting against graft-versus-host disease after bone marrow transplant. The study will also test the transplant s impact on your survival and control of your cancer. Eligibility: People aged 18 years and older living with HIV and a blood cancer that is eligible for a transplant. Healthy family members aged 12 or older who are half matched to transplant recipients are also needed to donate bone marrow. Design: The study will be done in 2 phases. The first phase will be to see if we can safely use a new combination of drugs to prevent GVHD. If the combination is safe in the first phase, the study will proceed to the second phase. In the second phase, we will see if this new combination can better protect against GVHD after transplant. Participants will be screened. Their diagnoses, organ function and eligibility will be confirmed. Participants will have a catheter inserted into a vein in their chest or neck. Medications and transfusions will be given through the catheter; blood will be drawn from it. Participants will be in the hospital for 6 weeks or longer. They will receive various drugs for 2 weeks to prep their body for the transplant. The transplant cells will be administered through the catheter. Participants will continue to receive drug treatments after the transplant. Blood transfusions may also be needed. Participants will return 1-2 times per week for follow-up visits for 3 months after discharge. Participants will have visits 6, 12, 18, 24 months after transplant, then once a year for 5 years....

Type: Interventional

Start Date: Jan 2023

open study

Background: A movement disorder is a condition that causes a person s body to move in ways that are not normal. There are different types. Some disorders cause movements people can t control, such as tics or shaking. Some cause reduced or slow movements. Movement disorders can cause disability in people. Sometimes members of the same family will have the same disorder. Researchers want to learn more about how people develop these disorders. This research could lead to better treatments. Objective: This natural history study will collect data on people with different types of movement disorders. It will also collect data on their family members. The data will support further research. Eligibility: Children and adults aged 2 years and older who have a movement disorder. Family members of people with movement disorders are also needed. Design: Participants will undergo screening. They will have a physical exam. Researchers will look at their existing medical images. Any photographs or videos of their movements will also be reviewed. Most participants will come to the NIH clinic for only 1 visit. They will answer questions about their condition. They will have normal tests used to diagnose their condition. They may have blood tests and different types of imaging scans. They may have tests to see how well their nerves function. The tests used will depend on the type of disorder they have. Family members will have some of the same tests as people with disorders. Participants will not receive any new treatments. Some participants may be asked to return for a follow-up visit. Up to 4000 people may participate.

Type: Observational

Start Date: Oct 2022

open study

Background: Some genetic diseases put increase the risk of heart and blood diseases, which are the number one cause of death and disability in the U.S. Researchers want to study diseases of the heart and/or blood vessels. They want to collect data and specimens from affected people, their family members, and healthy people. Objective: To study diseases of the heart and/or blood vessels. Eligibility: People age 2 and older who may have genetic disease affecting the heart and/or blood vessels Their relatives Healthy volunteers Design: Participants will be screened with a medical history, physical exams, and imaging tests. Participants may have a few visits or visits for 2 weeks or more. This will depend on their age and disease status. Visits may include: Photographs of the face and body Heart tests Samples taken of blood, urine, saliva, skin, and/or tissue Scans. For some, a dye may be injected into a vein. A six-minute walk test Lung tests. For some, participants will blow into a tube. For others, they will breathe in a gas from a mask, have a small injection, then have a scan. Stress tests while walking on a treadmill or riding a stationary bike Ultrasound of veins and arteries Devices outside the body testing the stiffness and function of arteries Eye exam and eye tests. For some, a dye may be injected in a vein. Blood pressure tests Measurements of blood flow under the skin and in the arms and fingernail blood vessels Devices outside the body testing flexibility of the blood vessels and skin, and skin temperature

Type: Observational

Start Date: Jul 2018

open study

Background: Allogeneic blood or marrow transplant is when stem cells are taken from one person s blood or bone marrow and given to another person. Researchers think this may help people with immune system problems. Objective: To see if allogeneic blood or bone marrow transplant is safe and effective in treating people with primary immunodeficiencies. Eligibility: Donors: Healthy people ages 4 or older Recipients: People ages 4-75 with a primary immunodeficiency that may be treated with allogeneic blood or marrow transplant Design: Participants will be screened with medical history, physical exam, and blood tests. Participants will have urine tests, EKG, and chest x-ray. Donors will have: Bone marrow harvest: With anesthesia, marrow is taken by a needle in the hipbone. OR Blood collection: They will have several drug injections over 5-7 days. Blood is taken by IV in one arm, circulates through a machine to remove stem cells, and returned by IV in the other arm. Possible vein assessment or pre-anesthesia evaluation Recipients will have: Lung test, heart tests, radiology scans, CT scans, and dental exam Possible tissue biopsies or lumbar puncture Bone marrow and a small piece of bone removed by needle in the hipbone. Chemotherapy 1-2 weeks before transplant day Donor stem cell donation through a catheter put into a vein in the chest or neck Several-week hospital stay. They will take medications and may need blood transfusions and additional procedures. After discharge, recipients will: Remain near the clinic for about 3 months. They will have weekly visits and may require hospital readmission. Have multiple follow-up visits to the clinic in the first 6 months, and less frequently for at least 5 years.

Type: Interventional

Start Date: Nov 2015

open study

Without an explanation for severe and sometimes life-threatening symptoms, patients and their families are left in a state of unknown. Many individuals find themselves being passed from physician to physician, undergoing countless and often repetitive tests in the hopes of finding answers and insight about what the future may hold. This long and arduous journey to find a diagnosis does not end for many patients- the Office of Rare Diseases Research (ORDR) notes that 6% of individuals seeking their assistance have an undiagnosed disorder. In 2008, the National Institutes of Health (NIH) Undiagnosed Diseases Program (UDP) was established with the goal of providing care and answers for these individuals with mysterious conditions who have long eluded diagnosis. The NIH UDP is a joint venture of the NIH ORDR, the National Human Genome Research Institute Intramural Research Program (NHGRI-IRP), and the NIH Clinical Research Center (CRC) (1-3). The goals of the NIH UDP are to: (1) provide answers for patients with undiagnosed diseases; (2) generate new knowledge about disease mechanisms; (3) assess the application of new approaches to phenotyping and the use of genomic technologies; and (4) identify potential therapeutic targets, if possible. To date, the UDP has evaluated 3300 medical records and admitted 750 individuals with rare and undiagnosed conditions to the NIH Clinical Center. The NIH UDP has identified more than 70 rare disease diagnoses and several new conditions. The success of the NIH UDP prompted the NIH Common Fund to support the establishment of a network of medical research centers, the Undiagnosed Diseases Network (UDN), for fiscal years 2013-2020. The clinical sites will perform extensive phenotyping, genetic analyses, and functional studies of potential disease-causing variants. The testing performed on patients involves medically indicated studies intended to help reach a diagnosis, as well as research investigations that include a skin biopsy, blood draws, and DNA analysis. In addition, the UDN will further the goals of the UDP by permitting the sharing of personally identifiable phenotypic and genotypic information within the network. By sharing participant information and encouraging collaboration, the UDN hopes to improve the understanding of rare conditions and advance the diagnostic process and care for individuals with undiagnosed diseases.

Type: Observational

Start Date: Sep 2015

open study

Background: - In deep brain stimulation (DBS), a device called a neurostimulator is placed in the chest. It is attached to wires in parts of the brain that affect movement. DBS might help people with movement disorders like Parkinson s disease (PD), dystonia, and essential tremor (ET). Objective: - To provide DBS treatment to people with some movement disorders. Eligibility: - Adults 18 years and older with PD, ET, or certain forms of dystonia. Design: - Participants will be screened with medical history and physical exam. They will have blood and urine tests and: - MRI brain scan. The participant will lie on a table that slides in and out of a metal cylinder with a magnetic field. They will be in the scanner about 60 minutes. They will get earplugs for the loud noises. During part of the MRI, a needle will guide a thin plastic tube into an arm vein and a dye will be injected. - Electrocardiogram. Metal disks or sticky pads will be placed on the chest, arms, and legs. They record heart activity. - Chest X-ray. - Tests of memory, attention, concentration, thinking, and movement. - Eligible participants will have DBS surgery. The surgery and hospital care afterward are NOT part of this protocol. - Study doctors will see participants 3 4 weeks after surgery to turn on the neurostimulator. - Participants will return every month for 3 months, then every 3 months during the first year, and every 6 months during the second year. Each time, participants will be examined and answer questions. DBS placement will be evaluated with MRI. The neurostimulator will be programmed. At two visits, participants will have tests of movements, thinking, and memory.

Type: Interventional

Start Date: Apr 2014

open study

Researchers are looking for a better way to treat people with advanced colorectal cancer. Colorectal cancer (cancer of the colon or rectum) is one of the most common cancers worldwide. Treatments include surgery, chemotherapy, radiotherapy, and immunotherapy; however, these treatments do not work for everyone, may cause serious adverse events or may stop working eventually. New treatments and treatment combinations are needed, especially for cancers that cannot be removed with surgery or that have spread to other parts of the body (called advanced or metastatic cancer). Cells normally repair themselves when mistakes happen as they divide. But in some people with cancer, the repair system does not work properly because of a problem called dMMR (deficient mismatch repair). As a result, mistakes build up in the cell's DNA, leading to a condition called MSI (microsatellite instability). Over time, these changes can cause cells to grow and behave abnormally, contributing to the development and growth of cancer. To survive, some cancer cells with dMMR or MSI rely on a protein called Werner helicase. This protein helps repair some of the DNA damage allowing them to keep growing. Because these cancer cells depend more on Werner helicase than healthy cells, blocking this protein may help stop cancer cells from surviving while having less effect on healthy cells. The study drug, VVD-133214, is designed to block the Werner helicase protein. Blocking this protein may help stop cancer cells from growing, while causing less harm to healthy cells. VVD-133214 is being studied in combination with pembrolizumab, an approved immunotherapy that helps the immune system recognize and attack cancer cells. This study will test the combination of VVD-133214 and pembrolizumab in people with advanced colorectal cancer with MSI and/or dMMR who have not yet received treatment for their advanced disease. The study aims to find the best dose of VVD-133214 in combination with pembrolizumab and to test whether the combination is more effective than pembrolizumab alone. Participants will receive treatment with VVD-133214 for as long as it can help them and does not cause serious adverse events. Treatment with pembrolizumab will stop after two years. Participants can also stop treatment at any time. During the study, participants will have regular visits with the study doctor for tests, scans, and check-ups. These visits help check how well the cancer is responding to the treatment and monitor the participants' health. The study will also monitor adverse events, which are any new or worsening medical problems that can happen during the study. Doctors record all adverse events, irrespective of whether the study doctor believes they are related to the study treatments, to help ensure participants' safety throughout the study. After stopping treatment, participants will return for follow-up visits: 30 days after their last dose of VVD-133214 and/or 100 days after their last dose of pembrolizumab. After that, participants will have long-term follow-up visits every 90 days for as long as they agree to continue participating in follow-up.

Type: Interventional

Start Date: Sep 2026

open study

Background: People who have lung transplants often survive 6 or 7 years. But some people develop donor-specific antibodies (DSA) after their transplants; antibodies are proteins that attack foreign invaders in the body. Antibodies typically kill viruses and other agents that can cause disease. But when the antibodies attack a transplanted organ, they can cause the body to reject the new tissues. People who develop DSA after a transplant have a higher risk of death within 1 year. Objective: To test a drug called fostamatinib in people who develop DSA after a lung transplant. Eligibility: Adults aged 18 and older who developed DSA after a lung transplant. Design: Participants will continue with their standard care after a transplant. Fostamatinib is a pill taken by mouth. Some participants will take the study drug along with their standard care; others will take a placebo. A placebo is a pill that looks just like the real drug but contains no medicine. All participants will take 1 pill per day for 2 weeks. Then they will take 2 pills per day for the next 6 weeks. Participants will have clinic visits every 2 weeks while taking their pills. They will have a physical exam, with blood and urine tests, during each visit. If participants have fluid samples collected from their airways during their standard treatment, some extra fluid may be collected for this study. Participants will have a follow-up visit 4 weeks after they stop taking their pills.

Type: Interventional

Start Date: Sep 2026

open study

Background: The current standard treatment of prostate cancer is either surgery or radiation. Typically, this includes either the removal or radiation of the whole prostate gland. Many people now seek out focal therapy options to decrease the side effects of treatment. Until now, several forms of physical destruction with heat (thermal ablation), cold (cryotherapy), sound waves (HIFU), laser (FLA), and electrical energy (IRE). A new type of radiation (SBRT) may be an effective way to cure men of early-stage prostate cancer with fewer side effects than standard treatments. Objective: To see how people with untreated localized prostate cancer will respond to focal therapy with SBRT. Eligibility: People aged 18 years and older with untreated localized prostate cancer (prostate cancer which has not spread outside of the prostate gland). Design: - Participants will undergo screening including blood tests, an MRI, a PSMA PET/CT (18F-DCFPyL), and a biopsy. - Small, non-radioactive, gold seeds about the size of a grain of rice will be placed in and/or around the tumor to help target the radiation treatment. - Radiation (SBRT) will occur in 2 separate sessions about 1 week apart. No sedation is used, these sessions are painless. Each session will take about 1-2 hours. Participants can go home afterwards. - Follow-up will continue for 2 years with repeat scans (MRI and PSMA PET/CT) and blood (PSA) tests. - After two years, a biopsy will be done to understand the impact of this new treatment on prostate cancer.

Type: Interventional

Start Date: Oct 2023

open study

Background: Transcranial magnetic stimulation (TMS) is form of non-invasive brain stimulation. It is approved to treat depression. TMS may help decrease drug craving. It is important to understand how TMS affects the brain. Such a better understanding would help to design ways to treat drug addiction. Objectives: To learn how TMS affects the brain when it stimulates an area in the front of the brain. Also, to see how the stimulation affects the area stimulated and other connected areas. Eligibility: Healthy, right-handed adults ages 18-60 who are non-drug users. Design: Participants will be screened under protocol 06-DA-N415. Participants will have at least 3 visits. The first visit will last about 3 hours. All other visits will last up to 6 hours. Participants cannot use drugs or alcohol at least 24 hours before a visit. They cannot have more than half a cup of a caffeinated drink at least 12 hours before a visit. Each visit will include a brief medical history update, urine test for drugs and pregnancy (if female), a breath test for alcohol and smoking, and questionnaires. Participants will have a TMS orientation visit. A wire coil will be placed on the head. An electrical current will pass through the coil to create a magnetic pulse that stimulates the brain. The other visits will include 2 sessions of TMS-MRI. Participants will lie on a table that slides into a cylinder. The TMS coil and the MRI coil will be placed over the head. Pictures will be taken of the brain with and without stimulation. Participants will complete a questionnaire about how they feel before and after each TMS session and in a follow-up call 1-3 days after their last session. ...

Type: Interventional

Start Date: Sep 2018

open study

Background: - The rare disease melorheostosis causes bones to thicken. This may lead to pain, and can affect bones, joints, and muscles. Researchers want to learn more about the disease and how it progresses. Objective: -To see what happens to people with melorheostosis over time and understand the causes of the disease. Eligibility: - People 18 and over with melorheostosis. - Their unaffected relatives. Design: - All participants will have a medical history and physical exam. - Participants who are relatives will give samples of blood or cheek cells. - Other participants will be in the study for about 1 week. - They will have blood and urine collected. - Strength, walking, and range of motion will be measured. - Participants may also have - X-rays and scans. - A pain and neurological evaluation. - Their skin evaluated by a dermatologist. - A small sample of bone taken. - Nerve conduction studies. Small electrodes with to wires will be put on the skin. A metal probe will give a small electrical shock. - Electromyography. A thin needle will be placed into the muscles. - An ultrasound, which uses sound waves to examine the muscles and nerves. An ultrasound probe will be placed over the skin. - A bone scan. They will get a small amount of radioactive fluid through a needle in an arm vein. This fluid travels to the bones. The bones will be photographed in a machine. - Bone Densitometry, a low-level x-ray. - Photographs taken. - A small circle of skin removed with a surgical instrument. - Questionnaires about their quality of life. - Participants will be asked to return about every 2 years. At these visits, participants may have blood and urine tests and x-rays.

Type: Observational

Start Date: Aug 2015

open study

Objective: The objective of this study is to identify genetic causes of inherited eye conditions through whole exome or whole genome sequencing (referred to as exome sequencing and genome sequencing in the remainder of the document). This includes identifying mutations in known genes or novel genes for recognized conditions, as well as identifying mutations in novel genes for previously uncharacterized genetic conditions involving the eye. Study Population: We plan to recruit 2,000 participants, to include both participants with an eye condition under study and unaffected family members. Ideally unaffected family members will be parents of an affected participant. Design: Participants will be self-referred or referred by an outside clinician. They will preferably be evaluated at the National Institutes of Health (NIH), but the option to participate offsite will be offered. Participants evaluated onsite will be recruited through other pre-existing NIH protocols, such as the National Eye Institute (NEI) Screening protocol (08-EI-0102), the NEI Ocular Natural History protocol (16-EI-0134), the Genetics of Inherited Eye Disease protocol (15-EI-0128), and the Pathogenesis and Genetics of Microphthalmia, Anophthalmia and Uveal Coloboma (MAC) protocol (13-EI-0049). Offsite participants will be screened via phone or secure videoconference, and records will be requested for evaluation of affected participants. Both affected and unaffected eligible participants will undergo genetic counseling and will provide a blood sample and/or saliva sample for exome or genome sequencing. Biological relationships will be confirmed prior to exome or genome sequencing. Sequence data will be analyzed for primary variants and secondary findings, unless participants choose to opt-out of secondary analysis and reporting. All sequence variants deemed clinically relevant will be validated in a Clinical Laboratory Improvement Amendment (CLIA)-certified laboratory. The results will be returned to the participant in-person, secure videoconference, or by telephone. Outcome Measures: This is an etiologic study that will generate molecular information about previously-recognized conditions for which participants did not have a molecular diagnosis, as well as molecular information for previously uncharacterized conditions involving the eye.

Type: Observational

Start Date: Aug 2014

open study

Background: - Researchers who are studying hairy cell leukemia, and how the disease compares with other disorders, are interested in obtaining additional samples from leukemia patients and healthy volunteers. The investigators are particularly interested in samples from individuals who have diseases that can be treated with a new type of drug called immunotoxin, in which an antibody carrying a toxin binds to a cancer cell and allows the toxin to kill the cell. Objectives: - To collect a variety of clinical samples, including blood, urine, lymph samples, and other tissues, in order to study the samples and develop new treatments for leukemia. Eligibility: - Individuals 18 years of age and older who have been diagnosed with leukemia or other kinds of blood and lymphatic system cancers, or who are healthy volunteers. Design: - Individuals who have leukemia will be asked to provide blood, bone marrow, urine, and tumor tissue samples as requested by the researchers. Healthy volunteers will provide only blood and urine samples. - No treatment will be given as part of this protocol.

Type: Observational

Start Date: Mar 2010

open study

This study will allow National Eye Institute (NEI) doctors the opportunity to examine people with eye disease, whether the diagnosis is known or not, to determine if they are eligible for other NEI research studies. No treatment is offered in this study. People of all ages with various eye conditions, including genetic conditions, eye movement disorders, inflammatory eye diseases, retinal diseases and external eye diseases, may be eligible for this study. Participants undergo various tests and procedures to diagnose or evaluate their eye disease. The procedures may include the following: - Personal and family medical history - Physical examination and blood tests, including genetic testing. - Eye examination with dilation to measure visual acuity and eye pressure and to examine the front and back parts of the eye. - Questionnaire about vision and daily activities. - Conjunctival swab or lacrimal bland biopsy, or both: A sample of cells from the eyes is collected by swabbing the surface of the eye or by surgically removing a small sample of the surface of the eye or tear gland. - Electroretinogram to examine retinal function: The subject sits in the dark with his or her eyes patched for 30 minutes. The patches are removed, the surface of the eyes is numbed, and contact lenses that can sense signals from the retina are placed on the eyes. The subject then watches flashing lights. - Fluorescein angiography to examine the blood vessels in the eye: A dye is injected into a vein in the arm. The dye travels through the veins to the blood vessels in the eyes. A camera takes pictures of the dye as it flows through the blood vessels. - Optical coherence tomography to measure retinal thickness: A machine used to examine the eyes produces cross-sectional pictures of the retina. - Microperimetry to test how sensitive different parts of the retina are to changing levels of light. The subject sits in front of a computer and presses a button when he or she sees a light on the screen. - Oculography to record eye movements: Eye movements are measured by contact lenses or goggles that the subject wears while watching a series of spots on a computer screen.

Type: Observational

Start Date: Aug 2008

open study

Background: Less toxic and more effective treatments are needed for cancers caused by viruses. These cancers include Hodgkin and non-Hodgkin lymphoma, hepatocellular carcinoma, head and neck cancer, nasopharyngeal carcinoma, gastric cancer, anal cancer, cervical cancer, vaginal cancer, vulvar cancer, penile cancer, Merkel cell carcinoma, Kaposi sarcoma, and leiomyosarcoma. Researchers want to see if a combination of drugs can help. Objective: To find a safe dose of pomalidomide plus nivolumab in people with cancers caused by viruses. Eligibility: Adults ages 18 or older who have cancers caused by Epstein Barr virus (EBV), human herpes virus 8/Kaposi sarcoma herpesvirus (HHV8/KSHV), human papilloma virus (HPV), hepatitis B or C virus (HBV/HCV), and Merkel cell polyomavirus (MCPyV) that have not responded to previous treatments or have relapsed, or in adults who do not want to have surgery because of disfigurement or other risks. Adults who have HIV with any CD4 T cell count are eligible. Design: Participants will be screened with blood and urine tests, scans, and heart tests. They will have a physical exam. Their ability to perform normal daily activities will be assessed. They may have a tumor biopsy. Treatment will be given in 28-day cycles. Participants will take pomalidomide as a tablet by mouth for 21 days of each cycle, for up to 24 cycles. They will get nivolumab by intravenous infusion once each cycle. They will take an aspirin each day until 30 days after their last dose of the study drugs. Participants will keep a pill diary. They will bring it to their study visit at the end of each cycle. At these visits, some screening tests will be repeated. Participants with Kaposi sarcoma will have pictures taken of their lesions. Participants will give blood and saliva samples for research. They may have optional anal and/or cervical swabs. They may have optional biopsies. Participants will have a follow-up visit 30 days after they stop taking the study drugs, then every month for 100 days. Some screening tests will be repeated. Then they may by contacted by phone every 3 months for 9 months, and then every 6 months thereafter.

Type: Interventional

Start Date: Dec 2021

open study

Background: Trisomy 8 mosaicism is a genetic disorder that can increase inflammation in the body. Symptoms include fevers; sores or ulcers in the mouth, digestive tract, or genital area; skin rashes; problems in organs or tissues; and changes in bone marrow cells. Researchers want to conduct a natural history study to learn more about these symptoms and what causes them. Objective: To gather data and samples from people with and without the trisomy 8 mosaicism. Eligibility: People of any age with the trisomy 8 gene mosaicism. Their healthy relatives are also needed. Design: Affected participants will have visits every 1 to 2 years for 30 years at NIH. Each visit will take 1 to 5 days and may be in-person or remote. With remote visits, participants may have a video call with the study team and samples may be sent to researchers by mail. Participants may have these procedures: Physical exam, with blood tests. Tests of brain function and motor skills. Sensory tests. Researchers will see how participants respond to sensations such as pinpricks, heat, cold, and pressure. Magnetic resonance imaging (MRI) scan of the brain and/or spine. X-ray of the spine. Ultrasound test of heart function (echocardiogram). Tissues samples (biopsies) collected from the skin, inside of the mouth, and bone marrow. Swabs to collect cells from the mouth, skin, and vagina. Collection of blood, stool, urine, saliva, hair, and fingernail samples. X-rays, MRI, and heart tests will be done only once. Other procedures may be repeated at each visit. All tests and procedures are voluntary. Healthy relatives who enroll will have a baseline visit and then follow-up visits as needed. They will have a physical exam. The inside of their mouth may be swabbed. Samples of blood, stool, urine, and saliva may be taken.

Type: Observational

Start Date: Sep 2026

open study

Background: Injury or diseases of the heart and lung can sometimes cause scar tissue (fibrosis) to build up in those organs. Current imaging scans can see this scar tissue once it has formed, but researchers want to find a way to detect the fibrosis in its earliest stages, while there might still be time to prevent serious damage. A new tracer (a radioactive substance injected during imaging scans) may be able to help. Objective: To test a new tracer (18F-FAPI-74) during imaging scans in people with heart or lung disease. Eligibility: People aged 18 years and older with lung or heart disease that may cause scarring in those organs. Design: Participants will have 6 clinic visits over 2 years. Participants will be screened: They will have blood tests and tests of their heart and lung function. Those with heart disease will have a magnetic resonance imaging (MRI) scan of the heart. The study tracer will be used with positron emission tomography (PET)/computed tomography (CT) scans. The study tracer will be injected into a vein in the arm. Participants will lie on a padded bed that slides through a donut-shaped machine. Participants will have scans with the study tracer 2 times, 8 to 12 months apart. They will also have standard CT scans and blood tests during these visits. They will also have blood tests at 3 and 6 months between these visits. Participants will have a follow-up visit after 18 to 24 months. The study scans, MRI and standard CT scans, and lung function tests may be repeated....

Type: Interventional

Start Date: Sep 2026

open study

Background: Allergic and inflammatory conditions have been increasing over the years. Many factors may play a role in this. Every day, people are exposed to pollution and chemicals in our foods, clothing, and all of the cleaning, hygiene, and other products we use. Studies have suggested there may be links between these environmental exposures and allergic and inflammatory illnesses. Researchers want to know more about how these exposures affect our health. Objective: To learn how everyday exposure to common substances affects people's health. Eligibility: Healthy people aged 18 to 80 years. Design: Participants will have 2 stays in the hospital. Each stay will last 7 days, and the stays will be spaced 4 to 6 weeks apart. During both stays, participants will remain confined to their room. They will eat only food from the menu, and they will use only provided products for personal care. (They may bring their own electronic devices, such as their phone and computer.) One stay will be in a pure room. Participants will breathe filtered air, eat unprocessed foods, and use personal care products with fewer chemicals. One stay will be in a room that allows exposure to common environmental chemicals. Some participants will be limited to only 1 type of exposure: chemicals thought to affect only skin, gut, or respiratory health. Some participants will be exposed to all 3 types. Participants will undergo testing. Blood, skin cell, urine, mouth swabs, and stool samples will be taken. They will have lung tests, smell tests, and tests that measure the health of their skin. These tests will be repeated in outpatient visits 2 weeks after each hospital stay....

Type: Interventional

Start Date: Apr 2026

open study

Background: Each year, more than 32,000 people in the United States are diagnosed with colorectal cancer that has returned or progressed after treatment and spread to other organs. This is called metastatic colorectal cancer (mCRC). Most people with mCRC survive only about 2 years. Objective: To test the ability of a combination of up to 4 experimental anti-cancer drugs treat mCRC. The names of these drugs are retifanlimab, TriAdeno vaccine, N-803, and SX-682. They are described below. Eligibility: Adults aged 18 years or older with mCRC. Participants must have Design: Participants will be screened. This includes having a physical exam, blood tests, urine tests, and imaging tests. If signed on to the study, participants will have 2 tumor biopsies. One when starting the study and once about 8 weeks after bring on the study. Participants will receive $500 for each biopsy. Participants will be treated with either 3 or 4 drugs and will receive a detailed calendar explaining when each drug is given. Retifanlimab is given every 4 weeks through an IV (an IV is tube attached to a needle inserted into a vein in the arm). N-803 is injected under the skin on the abdomen every 4 weeks. TriAdeno vaccine is injected under the skin of the upper arm or thigh once a month for 3 doses and then once every 3 months. Some participants will also receive a 4th drug. SX-682 is a pill taken by mouth. Participants will take this drug 2 times a day at home for about 3 weeks of each month. Study treatment will continue up to 2 years. Follow-up phone calls/emails may continue for 3 more years.

Type: Interventional

Start Date: Mar 2024

open study

Study Description: Despite the availability of pharmacotherapy for some substance use disorders, relapse vulnerability is still a significant issue. This suggests medications with alternative mechanisms of action should be explored to address this unmet need. Substantial preclinical research indicates that orexin antagonism blunts the internally and externally triggered motivation to attain abused substances. This research project will translate these preclinical findings into the clinical domain by administering the FDA approved orexin antagonist, suvorexant, to those with a substance use disorder. Suvorexant s ability to blunt neurobiological correlates of substance misuse will be assessed. This will be assessed following acute and repeated drug administration. Baseline individual differences will be considered to determine whether neurobiological variance influences suvorexant s impact in those with nicotine dependence. In an independent arm, the interaction between suvorexant and a dopamine agonist (methylphenidate) on cognitive function will be assessed in non-smoking individuals. Objectives: The objective is to determine the acute and chronic impact of the orexin antagonist, suvorexant, on neurobiological and behavioral factors linked with substance use disorders. Whether such effects are mediated by baseline characteristics will be tested. Given suvorexant is an FDA approved treatment for insomnia, sleep will be evaluated as well in the nicotine dependent arm. Endpoints: In nicotine-dependent individuals, suvorexant s impact on brain function will be assessed several ways by evaluating: 1) resting function, 2) reactivity to drug cues, 3) reactivity to non-drug related cognitive tasks. Sleep and nicotine use will be measured throughout the study period. In those without nicotine-dependence, the impact of suvorexant and the interaction of acute methylphenidate and suvorexant on brain function will be assessed. This arm will provide insight into how suvorexant impacts reward/cognition as well as impacts the pharmacological influence of methylphenidate on those same measures. Study Population:<TAB> Nicotine dependence arm:140 subjects; Volunteers who are between the ages of 18-60 and are daily smokers/vapers. Control arm: 80 subjects; Volunteers who are between the ages of 18-60 and are non-smokers/vapers This study will be conducted at the NIDA-IRP, Biomedical Research Center, in Baltimore, MD. Description of Study Intervention: Nicotine dependence arm: Suvorexant at 10 mg single dose, and Suvorexant at 10 mg daily for approximately 7 days. Control arm: 1. Tolerability visit with one MRI scan post-20mg methylphenidate, 4 acute drug administration (6-14 days in randomized order: 1. Placebo + placebo; 2. 20mg suvorexant + Placebo; 3. Placebo + 40mg methylphenidate; 4. 20 mg suvorexant + 40mg methylphenidate max) Study Duration: 5 years Participant Duration: 1-2 months

Type: Interventional

Start Date: Feb 2023

open study

This study will evaluate subjects with adult- and childhood-onset myositis to learn more about their cause and the immune system changes and medical problems associated with them. Myositis is an inflammatory muscle disease that can damage muscles and other organs, resulting in significant disability. Children or adults with polymyositis or dermatomyositis or a related condition may be evaluated under this study. Healthy children or adults will also be enrolled as "controls," for comparison of test results. All patients will undergo a complete history (including completing some questionnaires) and physical examination, review of medical records, and blood and urine tests. Patients may then choose to participate in an additional 1- to 5-day evaluation, which will include some or all of the following diagnostic, treatment or research procedures: 1. Standardized muscle strength testing, range of motion of joints and walking (gait) analysis by a physiotherapist; completion of a questionnaire regarding ability to perform daily tasks 2. Skin assessment, possibly including photographs of lesions and a skin biopsy (removal of a small skin sample under local anesthetic) 3. Magnetic resonance imaging (scans that use magnetic fields to visualize tissues) of leg muscles 4. Swallowing studies, including a physical examination and questionnaire on swallowing ability, studies of tongue strength, and ultrasound imaging during swallowing, and possibly, a modified barium swallow 5. Voice and speech assessment, possibly including computerized voice analysis and laryngoscopy-analysis of the larynx (voice box) using a small rigid scope with a camera placed in the mouth to view and record vocal cord function 6. Pulmonary function tests (measurement of air moved into and out of the lungs, using a breathing machine) to evaluate lung function and, possibly, chest X-ray 7. Electrocardiogram (measurement of the electrical activity of the heart) and, possibly, echocardiogram (ultrasound imaging of the heart) 8. Endocrine evaluation 9. Eye examination, in patients with vision loss or other eye symptoms 10. Nutrition assessment to evaluate muscle mass and muscle wasting, including tape measurements or bioelectric impedance testing, a painless procedure in which wires are attached to the extremities with a sticky paste. 11. Muscle ultrasound. 12. Electromyography (record of the electrical activity of muscles) 13. Muscle or skin biopsy (removal of a small piece of muscle tissue for microscopic examination) All patients may have only a one-time evaluation or may return for one follow-up evaluations (either the 1-day or 3- to 5-day evaluation) over a 1-year period. Healthy children will undergo a medical history and brief physical examination; blood and urine tests; speech and swallowing studies including questionnaires and physical examination, tongue strength, and ultrasound study; and bioelectric impedance testing. Children 8 to 18 years old may also have exercise testing.

Type: Observational

Start Date: Jun 1995

open study

Background: During the first few decades of life, the brain changes dramatically in shape and function. Sleep lets researchers measure these changes. Researchers want to create a database of sleep and neurodevelopmental data in a group of infants and children to learn more. Objective: To address a knowledge and data gap in the field of sleep and neurodevelopment in infants and children. Eligibility: Children ages 6 months to 76 months who may or may not be at risk for neurodevelopmental and neuropsychiatric disorders. Also, children ages 6 months to 8 years who have a referral for a sleep study. Design: Participants will have neurodevelopmental testing. They will have a medical, psychiatric, and family history. They will have a physical and neurological exam. They will be interviewed and complete surveys. They will give a cheek swab and/or blood sample. Some participants will have 1 study visit that lasts 2 days. Other participants will have up to 4 study visits. Each visit will last 2 days. Visits occur every 8 months to 1 year, for a total participation time of 2 years. Participants will have a 20-minute daytime electroencephalogram (EEG), if possible. This EEG session will be used to calibrate the machine for the overnight study. Participants will take part in an inpatient overnight sleep study. Electrodes will be placed on the participants. For young children, parents will help place the EEG leads. Other sensors may also be placed. A gauze cap will be placed on participants head to protect the leads and keep the participants from moving them. 'Lights out' will occur as close to participants bedtime as possible. ...

Type: Observational

Start Date: Nov 2021

open study

Methylmalonic acidemia (MMA), one of the most common inborn errors of organic acid metabolism, is heterogeneous in etiology and clinical manifestations. Affected patients with cblA, cblB and mut classes of MMA are medically fragile and can suffer from complications such as metabolic stroke or infarction of the basal ganglia, pancreatitis, end stage renal failure, growth impairment, osteoporosis, and developmental delay. The frequency of these complications and their precipitants remain undefined. Furthermore, current treatment protocol outcomes have continued to demonstrate substantial morbidity and mortality in the patient population. Increasingly, solid organ transplantation (liver, and/or kidney) has been used to treat patients. Disordered transport and intracellular metabolism of vitamin B12 produces a distinct group of disorders that feature methylmalonic acidemia as well as (hyper)homocysteinemia. These conditions are named after the corresponding cellular complementation class - (cblC, cblD, cblF, cblJ and cblX) - and are also heterogenous, clinically and biochemically. The genetic disorders underlying cblE and cblG feature an isolated impairment of the activity of methionine synthase, a critical enzyme involved in the conversion of homocysteine to methionine and these disorders feature (hyper)homocysteinemia. Lastly, a group of patients can have increased methylmalonic acid and/or homocysteine in the blood or urine caused by variant(s) in recently identified (ACSF3) and unknown genes. In this protocol, we will clinically evaluate patients with methylmalonic acidemia and cobalamin metabolic defects. Routine inpatient admissions will last up to 4-5 days and involve urine collection, blood drawing, ophthalmological examination, radiological procedures, MRI/MRS, skin biopsies in some, and developmental testing. In a subset of patients who have or will receive renal, hepato- or hepato-renal transplants or have an unusual variant or clinical course and have MMA, a lumbar puncture to examine CSF metabolites will be performed. In this small group of patients, CSF metabolite monitoring may be used to adjust therapy. The study objectives will be to further delineate the spectrum of phenotypes and characterize the natural history of these enzymopathies, query for genotype/enzymatic/phenotype correlations, search for new genetic causes of methylmalonic acidemia and/or homocysteinemia, identify new disease biomarkers and define clinical outcome parameters for future clinical trials. The population will consist of participants previously evaluated at NIH, physician referrals, and families directed to the study from clinicaltrials.gov as well as the Organic Acidemia Association, Homocystinuria Network America and other national and international support groups. Most participants will be evaluated only at the NIH Clinical Center. However, if the NIH team decides that a patient under the age of 2 years is a candidate subject for this research protocol, that patient may enroll at the Children's National Medical Center (CNMC) site, pending approval by Dr Chapman, the Principal Investigator of the CNMC location Individuals may also enroll in the tissue collection only part of the study at the UPMC Children's Hospital of Pittsburgh or share medical history and clinical data via telemedicine visits remotely. Outcome measures will largely be descriptive and encompass correlations between clinical, biochemical and molecular parameters.

Type: Observational

Start Date: Jun 2004

open study

This study is designed to evaluate the genetics involved in the development of lung disease by surveying genes involved in the process of breathing and examining the genes in lung cells of patients with lung disease. The study will focus on defining the distribution of abnormal genes responsible for processes directly involved in different diseases affecting the lungs of patients and healthy volunteers. Optional CT Sub-study The standard CT scan will be compared to the low dose radiation CT scan for the 150 subjects enrolled in the sub-study to assess the variation between the two techniques. Specifically, the quantitative computer aided detection of lung CT abnormalities from LAM can be compared to assess whether low radiation dose CT exams is an alternative to conventional CT to monitor disease status. This optional sub-study will be offered to up to 100 adult subjects with lung disease and up to 50 children age 9 and older with CF. Children will not be enrolled in the optional CT sub-study unless they have had a standard CT scan for medical purposes to use in comparison. One additional low dose radiation CT scan of the chest may be done as part of this sub-study when these subjects have their next annual CT scan.

Type: Observational

Start Date: Sep 1996

open study