Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Eligibility last updated 5/4/23. Questions regarding updates should be directed to the study team contact.

Inclusion Criteria
•RISK Primary

• New onset refractory status epilepticus with or without fever.
• Failure to respond to 2 or more first-line anti-seizure drugs.
• Age 0 to 18 years.
• Etiology for status epilepticus unknown:
  • No history of pre-existing epilepsy;
  • No pre-existing major developmental impairment;
  • No evidence of prodromal dyskinesia, hallucinations, or psychiatric symptoms;
  • No evidence of structural, cerebrovascular, neoplastic, metabolic, traumatic, or toxic etiology.

Inclusion Criteria
•RISK Primary

• Epileptiform abnormality on EEG.
• Seizure frequency at least weekly.
• Failure to respond to 2 or more first-line anti-seizure drugs.
• Age 0 to 18 years.
• Clinical and electrophysiological profile not consistent with:
  • self-limited focal epilepsy syndrome;
  • unifocal epilepsy.
• Normal 3T epilepsy protocol MRI (if available).
• Normal epilepsy panel or no evidence of known epilepsy mutations by whole exome sequencing (if available).
• No evidence of autoimmune, cerebrovascular, neoplastic, metabolic, traumatic, or toxic etiology.

Inclusion Criteria
•RISK Retrospective Recruitment Inclusion Criteria (~100 patients):

• Prior diagnosis consistent with NORSE or DRE.
• No evidence of autoimmune, infectious, structural, cerebrovascular, neoplastic, metabolic, or toxic etiology.
• Negative genetic epilepsy panel.
  • Note: No exclusions based on disease-modifying therapies, including immunomodulatory or immunosuppressive treatments (e.g., IV corticosteroids, plasma exchange, intravenous immunoglobulin, and anti-cytokine drugs such as anakinra or tocilizumab).

• Validated autoimmune disorder.
• Smoker.
• Pregnant.
• Weight < 9 kg.

Eligibility last updated 1/21/22. Questions regarding updates should be directed to the study team contact.

Inclusion Criteria
•Group 1:

• Mayo Clinic nurses, nurse managers, and/or nurse administrators (APRN, RN, LVN, CNA, or equivalent).

Inclusion Criteria
•Group 2:

• TBD.

• Subjects currently enrolled in “Wearable Augmented Prediction of Burnout in Nurses: A Synergy of Engineering, Bioethics, Nursing and Wellness Sciences” study (IRB #22-000447).

Note: Other protocol defined Inclusion/Exclusion Criteria may apply.

Eligibility last updated 2/8/23. Questions regarding updates should be directed to the study team contact.

• Assenting adolescents (13-17 years).
• Consenting adolescents (18-21 years).
• Parent / legal guardian of assenting or  consenting adolescent.
• Ability to participate in remote study visits, if applicable.

• Individuals who do not meet inclusion criteria.
• Those who do not communicate in English.
• Individuals with developmental disabilities that interfere with their ability to make independent decisions.
• Participants whose permanent address is more than 100 miles from Cincinnati Children's Hospital Medical Center.

Note: Other protocol defined Inclusion/Exclusion Criteria may apply.

Eligibility last updated 5/11/23. Questions regarding updates should be directed to the study team contact.

• Diagnosis of one of one of the syndromes/diagnoses of interest using established criteria.
• Age ≥ 40 to ≤ 90 inclusive.
• STMS score above 10.
• No active medical disorder that could preclude participation.
• Stable medication regimen over previous four weeks.
• Absence of certain medications that could significantly impact the myocardial 123I-MIBG.
• For those with dementia, caregiver that is with the patient at least four hours/day for at least five days per week.
• For those with dementia , or severe parkinsonism, patient and caregiver willing and able to participate in all study-related procedures.
• Patient is capable of giving informed consent, or if apropriate, has caregiver capable of giving consent on the subject's behalf.

• Does not fulfill criteria for any of the desired diagnoses.
• Age > 40 or < 90.
• Women with intact uterus and not post-menopausal unless pregnancy test performed at screening is negative.
• Women who are pregnant or are breast-feeding an infant.
• STMS score < 10.
• Active medical disorder that could preclude participation in this protocol:
  • Hypersensitivity to the radioligand or iodine;
  • Myocardial infarction or cerebral infarct over preceding year, stable or unstable angina, known symptomatic coronary artery disease;
  • Renal disease viewed by the physician to be too severe to warrant myocardial 123I-MIBG scintigraphy imaging;
  • History of significant alcohol or drug abuse;
  • Any other medical disorder considered by the study physicians as inappropriate for enrollment in this protocol.
• Patient or caregiver unwilling or unable to participate in all study-related procedures.
• Caregiver is not with a patient with dementia or severe parkinsonism at least 4 hours/day for at least 5 days/week.
• Patient or caregiver unwilling or unable to provide informed consent.

Eligibility last updated 1/4/22. Questions regarding updates should be directed to the study team contact.

• Participants must be female and have Stage I, II, or III hormone receptor positive breast cancer based on clinical or pathologic evaluation.
• Participants must have been pre- or peri-menopausal at the time of breast cancer diagnosis by satisfying one of the following:
  • had a menstrual period (by self-report) within the 12 months before breast cancer diagnosis; or
  • had a serum or plasma estradiol and/or follicle stimulating hormone (FSH) concentration consistent with premenopausal status (based on institutional standards) within the 12 months before breast cancer diagnosis or when checked after breast cancer diagnosis.
• Participants must have started initial treatment with standard of care oral endocrine therapy (ET) (i.e., tamoxifen, anastrozole, exemestane, or letrozole; within 14 days prior to randomization or be planning to start initial treatment with standard of care oral ET within 14 days after randomization.
• Participants who currently have ovarian function (estradiol above the postmenopausal range) must be planning to undergo ovarian suppression or ablation concomitantly with oral ET medication, starting before or at the same time as oral ET initiation.
• Participants with chemotherapy-induced amenorrhea or ovarian failure at time of registration must be planning to start ovarian suppression or ablation if they have recurrence of ovarian function during study participation (circulating estradiol concentration in the premenopausal range or recurrence of menses).
• Participants must have completed surgery for treatment of breast cancer at least 14 days prior to randomization NOTE: Concomitant radiotherapy at the time of randomization and/or during study participation is allowed.
• Participants who received chemotherapy must have finished it at least 14 days prior to randomization.
  • NOTE: Concomitant maintenance targeted or biologic therapy (e.g., human epidermal growth factor receptor 2 [anti-HER2] therapy, poly-ADP ribose polymerase [PARP] inhibitor therapy, CDK4/6 inhibitor therapy, osteoclast inhibitor therapy) at the time of randomization and/or during study participation is allowed.
• Participants must be ≥ 18 years of age.
• Participants must have a complete medical history within 60 days prior to randomization.
• Participants must be able to complete Patient-Reported Outcome (PRO) instruments in English or Spanish.
• Participants must:
  • agree to complete PROs at all scheduled assessments; and
  • complete the pre-registration (baseline) PRO forms within 14 days prior to randomization.
• Participants must be able to complete symptom questions on a web browser (on a smartphone, tablet, or computer) or respond via voice on a telephone in English or Spanish. Participants must agree to complete symptom questions at all scheduled assessments.
  • NOTE: Participants who do not have access to the internet and who cannot receive telephone calls for interactive voice response system (IVRS) assessments are not eligible.
• Participants must be offered the opportunity to participate in specimen banking for translational medicine. With participant consent, specimens must be collected and submitted via the Southwest Oncology Group (SWOG). specimen tracking system.
• Participants must be informed of the investigational nature of this study and must sign and give informed consent in accordance with institutional and federal guidelines.

• Participants must not have distant metastatic breast cancer.
• Participants who have started or plan to start treatment with tamoxifen during study participation must not have received prior tamoxifen for treatment or prevention of breast cancer.
• Participants who have started or plan to start treatment with an aromatase inhibitor during study participation must not have received prior aromatase inhibitor therapy for treatment or prevention of breast cancer.
• Participants must not be taking or planning to take oral estrogen-or progesterone-containing treatments during study participation.

NOTES: 

• Participants who start or plan to start treatment with an aromatase inhibitor may have previously received tamoxifen for prevention of breast cancer or treatment of a prior cancer.
• Participants may have received prior treatment with an aromatase inhibitor for infertility treatment.
• Participants must not be planning to become pregnant during the 80 weeks of study participation.
• Participants must not receive additional anti-cancer treatments (i.e., experimental therapy, immunotherapy, biologics, etc.) as part of another clinical trial.
• Participants must not have a non-breast malignancy for which they are currently receiving treatment.

Note: Other protocol defined Inclusion/Exclusion Criteria may apply.

Eligibility last updated 3/16/23. Questions regarding updates should be directed to the study team contact.

•  Histologic or pathologic documentation: well-differentiated pancreatic neuroendocrine tumor (G1, G2, or well-differentiated G3) confirmed by local histology and/or pathology.
• Functional or nonfunctional tumors are allowed.
• Stage: locally unresectable or metastatic disease.
• Tumor Site: neuroendocrine tumor of pancreatic primary site.
• Radiologic evaluation: tumor must have shown somatostatin receptor (SSTR) positivity on 68Ga-DOTATATE PET or other SSTR-PET scan in the 12 months prior to  registration; however, documentation of SSTR positivity in the 6 months prior to registration is preferred. SSTR positivity is defined as uptake greater than background liver in all measurable lesions.
• Patients are eligible if they meet one of the following criteria:
  • Previously untreated patients with grade 2 or 3 disease AND with symptoms of either disease bulk causing pain, anorexia, early satiety, large effusions/ ascites, abdominal pain, abdominal fullness due to hepatomegaly, dyspnea) OR incompletely controlled symptoms of hormone excess despite somatostatin analogue (SSA) and supportive care (including but not limited to:  diarrhea, hypercalcemia, hypoglycemia, hyperglycemia, flushing, Cushing's syndrome). Patient may have been started on SSA for up to 2 months for attempted symptom control without disease progression prior to registration;
  • Patients previously treated with SSA only and with disease progression by RECIST in prior 12 months;
  • Patients previously treated with SSA and one or more prior systemic therapy must have received prior anti-vascular endothelial growth factor (VEGF) pathway therapy inhibitor OR have contraindication to anti-VEGF therapy (including but not limited to: uncontrolled hypertension [systolic blood pressure [SBP] > 150 and/or diastolic blood pressure [DBP] > 90 despite medical management], stage IIB or greater heart disease, angina pectoris, prior arterial [ATE] and venous thromboembolic [VTE] events in the past 6 months, gastrointestinal [GI] bleed in the last 6 months) and disease progression by RECIST in prior 12 months;
  • Patients previously treated with more than 2 lines of therapy, not including anti VEGF therapy, but with NET related symptoms as outlined in first bullet (pain, anorexia, early satiety, large effusions/ascites, abdominal pain, abdominal fullness due to hepatomegaly, anorexia, early satiety, dyspnea) OR incompletely controlled symptoms of hormone excess despite somatostatin analogue (SSA) and supportive care (including but not limited to: diarrhea,hypercalcemia, hypoglycemia, hyperglycemia, flushing, Cushing's syndrome);
  • Any patient with disease progression by RECIST criteria in < 4 months.
• Patients must have measurable disease per RECIST v1.1 by computer tomography (CT) scan or magnetic imaging (MRI). Any lesions which have undergone percutaneous therapies or radiotherapy after starting protocol therapy should not be considered measurable unless the lesion has clearly progressed since the procedure.
• * Lesions must be accurately measured in at least one dimension (longest diameter to be recorded) as ≥ 1 cm with CT or MRI (or shortest diameter ≥ 1.5 cm for lymph nodes). Non-measurable disease includes disease smaller than these dimensions or lesions considered truly non- measurable including: leptomeningeal disease, bone metastases, ascites, pleural or pericardial effusion, lymphangitic involvement of skin or lung.
• Prior treatment with tyrosine kinase inhibitors (TKIs) such as mammalian target of rapamycin (mTOR) inhibitors (e.g., everolimus, temsirolimus, etc.) or VEGF pathway inhibitors (e.g., sunitinib, pazopanib, cabozantinib, bevacizumab, etc.) are allowed.
• Prior treatment with hepatic intra-arterial embolic therapies is allowed if there is recovery from all toxicities, measurable lesions do not include embolized liver unless there has been clear subsequent progression, all measurable lesions are somatostatin receptor avid, and treatment completed at least 2 months prior to registration.
• Prior treatment with cryoablation or thermal/radiofrequency ablation of metastases is allowed if there is recovery from all toxicities, measurable lesions do not include treated metastases, and treatment completed at least 2 months prior to registration.
• Age ≥ 18 years.
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2.
• Absolute neutrophil count (ANC) ≥ 1,500/mm^3.
• Platelet count ≥ 100,000/mm^3.
• Hemoglobin ≤ 9.0 g/dL.
• Creatinine ≤ 1.5 x upper limit of normal (ULN) OR calculated (calc.) creatinine clearance ≤ 30 mL/min (calculated by the Cockcroft-Gault equation).
• Total bilirubin ≤ 1.5 x ULN (in patients with liver metastases or known Gilbert's syndrome, total bilirubin must be ≤ 3.0 x ULN).
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) ≤ 3.0 x ULN.
• Albumin ≥ 3.0 g/dL.
• Concurrent somatostatin analog use while on protocol therapy is allowed provided that the patient:
• Has a functional tumor (evidence of peptide hormones and/or bioactive substances associated with a clinical hormone syndrome such as carcinoid syndrome or Cushing's syndrome).
• Has been on a stable dose of somatostatin analog therapy for at least three months.
• Has previously demonstrated radiographic disease progression while on somatostatin analog therapy. For subjects receiving lutetium Lu 177 dotatate, there should be a minimum of 14 days between long-acting somatostatin analogue and lutetium Lu 177 dotatate dosing. Short-acting somatostatin analogs should not be administered within 24 hours of lutetium Lu 177 dotatate dosing. Following lutetium Lu 177 dotatate dosing, long-acting somatostatin analogs may be administered between 4 and 24 hours after each dose.

• Patients with poorly differentiated neuroendocrine carcinoma (large cell histology or small cell histology) are not eligible.
• No prior temozolomide, dacarbazine, capecitabine, 5-FU, or any PRRT for treatment of the pNET.
• Not pregnant and not nursing, because this study involves an agent that has known genotoxic, mutagenic, and teratogenic effects.
• * Therefore, for women of childbearing potential only, a negative pregnancy test done ≤ 14 days prior to registration is required.
• No known brain metastases unless adequately treated, demonstrated to be stable, and off all treatment (including steroids) for at least 2 months prior to registration.
• No uncontrolled congestive heart failure (New York Heart Association [NYHA] II, III, IV).
• No significant medical, psychiatric, or surgical condition, currently uncontrolled by treatment, which may pose a risk to patient safety.
• No "currently active" second malignancy other than non-melanoma skin cancers or cervical carcinoma in situ. Patients are not considered to have a "currently active" malignancy if they have completed therapy or are on adjuvant hormonal therapy and are free of disease for ≥ 3 years.
• No known medical condition causing an inability to swallow and no known impairment of gastrointestinal function that may significantly alter the absorption of an oral agent.

Eligibility last updated 5/8/23. Questions regarding updates should be directed to the study team contact.

• ≥ 18 years.
• Enrolled in cardiac rehabilitation program to start within 3 months from hospital discharge.
• Owns a smartphone.
• Willing to download and use a smartphone app.
• Able to read, write, and speak English.

• Actively treated for an anxiety or depressive disorder through psychotherapy or pharmacologic treatments.
• Cardiac transplant.
• Active substance use.
• Neurocognitive disorder.
• Active psychosis.
• Mania diagnosis.
• Active suicidality.

Note: Other protocol defined Inclusion/Exclusion Criteria may apply.

Eligibility last updated 12/26/23. Questions regarding updates should be directed to the study team contact.

• Age ≥ 18 years.
• Cytologically or histologically confirmed colorectal cancer.
• Undergoing biopsy or surgical procedures as part of routine clinical care.

• Individuals < 18 years.
• Vulnerable patients.
• Unable to provide informed consent.

Eligibility last updated 1/7/22. Questions regarding updates should be directed to the study team contact.

Eligibility last updated 5/6/22. Questions regarding updates should be directed to the study team contact.

Inclusion Criteria
•General: 

• The subject (or, when applicable, the subject’s legally acceptable representative) signs an informed consent form indicating that the subject has been informed of the procedures to be followed, the experimental nature of the therapy, alternatives, potential benefits, side effects, risks, and discomforts.
• The subject is an outpatient of either sex, at least 40 years old, at the time of consent.
• Subjects must, in the opinion of the investigator, be able to participate in all scheduled evaluations, likely to be compliant, and likely to complete all required tests, including neuroimaging brain scans and lumbar punctures.
• The subject has a body mass index (BMI) ≥ 18 and ≤ 35 kg/m^2 at screening.

Inclusion Criteria
•Diagnostic:

• The subject has a diagnosis of possible or probable MSA using the modified Gilman et al, 2008 diagnostic criteria (Gilman et al. 2008).
• The subject’s onset of first MSA symptoms (including parkinsonism, cerebellar symptoms, orthostatic or urinary symptoms) occurred ≤ 4 years before screening, as assessed by the investigator.
• The subject’s anticipated life expectancy is ≥ 3 years, per investigator judgment.
• The subject has an UMSARS Part I score of ≤ 21 (excluding Item #11, sexual function), and additionally has:
  • Severity score ≤ 2 on the swallowing item (#2);
  • Severity score ≤ 2 on the ambulation item (#7);
  • Severity score ≤ 2 on the falling item (#8).
• The subject has an UMSARS Part IV disability score ≤ 3.
• Subject has a MoCA ≥ 18. Additionally, subject has sufficiently intact cognition to complete study assessments and follow study instructions, per investigator's judgment.
• A male subject who is nonsterilized and sexually active with a female partner of childbearing potential is eligible to participate if he agrees to use a barrier method of contraception (i.e., condom with or without spermicide) from the signing of informed consent throughout the study and for 90 days plus 5 half-lives (total of 190 days) after the last dose.
• Female subjects are eligible to participate if:
  • they are not pregnant or nursing; and
  • they are of nonchildbearing potential or agree to use highly effective contraception from the signing of informed consent throughout the study and for 30 days plus 5 half-lives (total of 130 days) after the last dose of study drug.

Exclusion Criteria
•Medical History:

• The subject has serious or unstable clinically significant illness including hepatic, renal, gastroenterologic, respiratory, cardiovascular, endocrinologic, immunologic or autoimmune (e.g., multiple sclerosis), hematologic, or other major disease, which, in the judgment of the investigator, is poorly controlled or otherwise likely to deteriorate, compromises the subject’s safety or ability to complete the study, or compromises the interpretation of the study results.
• The subject has other medical problems (neurological, visual, orthopedic, psychiatric) that, in the opinion of the investigator, may significantly interfere with completion of the study or interpretation of study endpoints.
• The subject has a disorder that is likely to interfere with drug disposition and elimination.
• In the opinion of the investigator, the subject has a diagnosis of depression or other psychiatric disorder, as defined by the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5), AND this disorder is poorly controlled AND of sufficient severity to interfere with completion of the study or interpretation of the endpoints.
• The subject is considered by the investigator to be at imminent risk of suicide or injury to self, others, or property, or the subject has attempted suicide within the past year before screening. Subjects who have positive answers on Item 4 or 5 on the C-SSRS (based on the past year) before randomization are excluded.
• The subject has a history of alcohol or substance use disorder (except tobacco use disorder), as defined by the DSM-5, within 1 year before screening or between screening and randomization, or, in the opinion of the investigator, the subject’s current or past use of substances may interfere with performance on the assessments.
• The subject has a positive finding on an alcohol or illicit drug screen. A positive result for cannabis or prescription medications does not require exclusion.
• The subject has undergone surgery for the treatment of MSA (e.g., pallidotomy, deep brain stimulation, fetal tissue transplantation).
• The subject has a history of epilepsy or seizures, except self-limited febrile childhood seizures.
• The subject has any contraindication to lumbar puncture including but not limited to thrombocytopenia or other coagulation disorders (including subjects who are receiving anticoagulants and cannot safely stop them), the absence of cutaneous or soft-tissue infection overlying or adjacent to the site of lumbar puncture, previous spinal surgery that could complicate access to the subarachnoid space, or conditions associated with raised intracranial pressure such as a closed head injury within 3 months or benign intracranial hypertension, or any spinal abnormality or other aspects (e.g., tattoos in the midline lumbar area) or other clinical findings (papilledema seen with ophthalmoscopy) that may complicate or contraindicate lumbar puncture, as judged by the investigator. Subjects who are using low-dose aspirin, low molecular weight heparin, coumadin, or other anticoagulants may still participate if use of these medications can be safely suspended before lumbar puncture, per investigator judgment and local medical practices.

Exclusion Criteria
•Diagnostic Assessments:

• Any clinically significant abnormality as determined by investigator at screening or between screening and randomization in physical examination findings, vital signs, ECGs, or clinical laboratory test results that may compromise the subject’s safety or ability to complete the study or compromise the interpretation of the study results.
• Presence of any of the following contraindications to MRI:
  • claustrophobia that would contraindicate brain MRI or the presence of a pacemaker;
  • cardiac defibrillator; spinal cord or vagus nerve stimulator;
  • aneurysm clip;
  • artificial heart valve; recently placed (within 1 year) coronary or carotid stent; ear implant;
  • CSF shunt; other implanted medical device (e.g., insulin pump); or
  • metal fragments or foreign objects in the eyes, skin, or body.
• Ophthalmic abnormalities. The following are considered exclusionary:
  • Ophthalmic abnormalities and conditions that, in the judgment of the investigator and/or ophthalmologist, would affect subject safety and/or impair the ability to perform a quality ophthalmological evaluation;
  • Congenital or acquired ophthalmic conditions (primary or secondary) that are considered poorly controlled within the last 12 months before screening, with or without treatment, or otherwise expected to lead to significant deterioration in visual acuity in the next 12 months after randomization;
  • Any ocular opacities that may prevent quality fundus assessment;
  • Neovascular or exudative (wet) form of age-related macular degeneration.
• The subject has any of the following at the screening visit:
  • estimated glomerular filtration rate (determined with the Chronic Kidney Disease Epidemiology Collaboration equation) < 50 mL/min; QT interval with Fridericia correction method > 450 ms for male subjects and > 470 ms for female subjects;
  • a serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) value > 1.5 × the upper limit of normal (ULN).
• Clinically significant vital sign abnormalities at screening, defined as:
  • Systolic blood pressure ≥ 160 mm Hg;
  • Diastolic blood pressure ≥ 90 mm Hg (blood pressure assessed with the subject at rest in the seated position; may be repeated up to 3 times), or;
  • Pulse rate 100 beats per minute (subject at rest in the seated position).
• The subject has a positive hepatitis B surface antigen test result, known or suspected active hepatitis C infection, or known history of HIV infection:
  • Note: Subjects with positive hepatitis C virus (HCV) serology results may be enrolled if results from a quantitative polymerase chain reaction for HCV RNA is negative, to exclude active hepatitis C infection, and if the investigator agrees that the subject can safely participate in the study.
• The subject has a brain MRI that shows clinically significant evidence of malignant, ischemic, demyelinating, structural, or degenerative brain disease (other than MSA) that may confound diagnosis or subject safety during the study, or the subject has findings that compromise the safety of lumbar puncture per investigator judgment.
• The subject has a current blood clotting or bleeding disorder, including clinically significant abnormal findings in laboratory tests of coagulation.

Exclusion Criteria
•Other:

• The subject has poor venous access such that IV drug delivery or PK/safety blood sampling would be difficult.
• The subject has participated in another study investigating active or passive immunization against αSYN for PD or MSA, or has had immunoglobulin G therapy, within 6 months before screening.
• The subject’s participation in a previous study of a disease-modifying therapy (with proven receipt of active treatment) will compromise the interpretability of the data from the present study, per consultation with medical monitor or designee. For example, subjects who participated in a study of gene therapy and antisense oligonucleotides (or other disease-modifying treatment) and received active treatment would be excluded.
• The subject has received any investigational compound that, in the opinion of the investigator or sponsor, may not have completely washed out before the screening visit or may affect the safety or efficacy evaluations.
• The subject has a positive pregnancy test result at screening.
• The subject is an immediate family member, is a study site employee, or is in a dependent relationship (e.g., as a spouse, parent, child, or sibling) with a study site employee who is involved in the conduct of this study.
• The subject has donated 400 mL or more of his or her blood volume within 90 days before the start of the screening visit.  

Eligibility last updated 8/10/22. Questions regarding updates should be directed to the study team contact.

Inclusion Criteria
•Primary Care Patient Cohort:

• All adult patients ≥ 18 years of age currently in the panel for participating Family Medicine providers within the Mayo Clinic Family Practice.
• Valid MN research authorization.

• Age < 18 years of age.

Inclusion Criteria
•Family Practice Provider Cohort:

• Mayo Clinic Family Practice providers.

• Not willing to provide consent.

Eligibility last updated 4/28/22. Questions regarding updates should be directed to the study team contact.

• ≥ 18 years of age.
• No additional confounding cardiorespiratory, metabolic, or musculoskeletal conditions.   
• All inclusion criteria will be at the discretion of the principal investigator.

• < 18 years of age.

Note: Other protocol defined Inclusion/Exclusion Criteria may apply.

Eligibility last updated 1/31/23. Questions regarding updates should be directed to the study team contact.

• Adult male and female patients undergoing lower extremity orthopedic surgery at the study institutions (St. Mary Hospital and Rochester Methodist Hospital within the Mayo Clinic Rochester hospital system).
• Patients 18 years or older at time of surgery.

• Patients who refuse research participation.
• Patients who are pregnant.
• Patients with known pulmonary pathology (COPD, asthma requiring routine treatment).

1. Willing and able to provide written informed consent
2. Age ≥ 18 years
3. Diagnostic coronary angiography/left heart catheterization or percutaneous coronary intervention via the transradial approach

1. Presence of a palpable hematoma or clinical concern of hemostasis at the transradial access site in which bleeding risk would be prohibitive
2. Access or attempted access site – including contralateral radial artery, brachial artery, or femoral artery or vein as switching of access could be attributed to arterial injury
3. Planned staged procedure, coronary artery bypass grafting or noncardiac surgery, within 30 days
4. Pregnant or lactating females
5. Contraindication or high risk of bleeding with anticoagulation
   1. bleeding requiring medical attention in the previous 6 months
   2. thrombocytopenia (platelets < 50 x 10^9/L)
   3. any prior intracranial hemorrhage
   4. use of glycoprotein IIb/IIIa inhibitors during percutaneous coronary intervention
   5. administration of thrombolytic therapy in the preceding 24 hours
   6. use of regular non-steroidal anti-inflammatory medications excluding Aspirin < 100mg/day
   7. ischemic stroke or transient ischemic attack diagnosed in the last 3 months
6. Cardiogenic shock
7. Ventricular arrhythmias refractory to treatment
8. Liver dysfunction (Child-Pugh class B or C)
9. Unexplained anemia with a Hgb below 100 g/L
10. History of medication noncompliance or risk factor for noncompliance
11. Active malignancy
12. Allergy to rivaroxaban
13. Another indication for anticoagulation
14. Strong CYP3A4 and P-glycoprotein inhibitor use which increase rivaroxaban levels (ketoconazole, itraconazole, lopinavir/ritonavir, ritonavir, diltiazem, verapamil and conivaptan, carbamazepine, phenytoin, rifampin, St.John’s wort)
15. Life expectancy <30 days
16. Women capable of pregnancy not on birth control
17. Chronic kidney disease with creatinine clearance of less than 30mL/min
18. History of antiphospholipid syndrome, in particular triple positive (lupus anticoagulant, anticardiolipin antibodies, and anti-beta 2-glycoprotein I antibodies)

Note: Other protocol defined Inclusion/Exclusion Criteria may apply.

Eligibility last updated 8/22/23. Questions regarding updates should be directed to the study team contact.

Inclusion Criteria - Surveillance Population:

- Undergoing surveillance endoscopy for a diagnosis of non-dysplastic Barrett's
esophagus (NDBE, based on last endoscopic procedure; patients with prior history of
low-grade dysplasia/indefinite for dysplasia with NDBE at last endoscopy can be
included).

- Barrett's esophagus (BE) length of at least M1.

- English and Spanish speaking.

- Able to comprehend and complete the consent form.

- Age18-89 years.

- Life-expectancy of at least 2 years.

Inclusion Criteria
•Screening Population:

- Undergoing endoscopy for screening of BE.

- BE length of at least M1.

- English and Spanish speaking.

- Able to comprehend and complete the consent form.

- Age 18-89 years.

- Expected life-expectancy of at least 2 years.

Inclusion Criteria - Physicians:

-All participating sites will include physicians who are trained in the use of WATS3D and
certified by the site PI. All endoscopists will need to complete a minimum of three cases
to be eligible to participate in the study.

Exclusion Criteria - Surveillance Population:

- BE patients undergoing surveillance or evaluation for endoscopic eradication therapy
(EET) for prior diagnosis of BE related dysplasia or esophageal adenocarcinoma (EAC).

- Active erosive esophagitis with LA Grade B or higher.

- Esophageal varices.

- Prior history of EET.

- Prior history of esophageal or gastric surgery, except for uncomplicated
fundoplication.

- Pregnancy.

Inclusion Criteria - Screening Population:

- BE patients undergoing surveillance or evaluation for EET for prior diagnosis for
BE-related dysplasia or EAC.

- Active erosive esophagitis with LA Grade B or higher.

- Esophageal varices.

- Prior history of esophageal or gastric surgery, except for uncomplicated
fundoplication.

- Pregnancy.

Note: Other protocol defined Inclusion/Exclusion Criteria may apply.

Eligibility last updated 9/12/22. Questions regarding updates should be directed to the study team contact.

• Age ≥ 18.
• Cytologically or histologically confirmed GI cancers.
• Able to consent.

• Individuals < 18 years.
• Vulnerable patients.
• Unable to provide informed consent.
   

• Hospitalized adult (≥ 18 years) patients.
• Community acquired pneumonia.

• Contraindications or unwillingness to use corticosteroids by patient or provider.
• History of adrenal insufficiency, septic shock, or another absolute indication for steroid use.
• Suspected pulmonary vasculitis or other autoimmune pulmonary disorder.
• Positive pregnancy test
• Comfort care.

Eligibility last updated 8/24/21. Questions regarding updates should be directed to the study team contact.

• Pregnant patients seen for prenatal care within the Mayo Clinic Health Systems.
• Ability to provide informed written consent.
• Singleton pregnancies.

• Mothers < 18 years of age.
• Fetal anomalies.
• Concern for intraamniotic infection on admission.
• Preterm labor on admission.
• Other conditions precluding expectant management.

Eligibility last updated 4/27/23.  Questions regarding updates should be directed to the study team contact.

• Male or female adults ages 21 and older at the time of enrollment.
• Received at least one COVID-19 vaccination (Johnson &Johnson, Pfizer, Moderna, Novavax; subjects with any number of prior vaccine doses are eligible) and would like to receive an mRNA booster vaccine.
• No immunosuppression or immunodeficiency.
• Determined by medical history and clinical judgment to be eligible for the study, by being generally healthy, with no autoimmune or immunosuppressive conditions and having stable current medical conditions (subjects with preexisting stable disease, defined as disease not requiring significant change in therapy or hospitalization for worsening disease 12 weeks before receipt of the booster vaccine, will be eligible. A change in dose or therapy within a category (e.g., change from one nonsteroidal anti-inflammatory drug to another) is allowed. A change to a new therapy category (e.g., surgery or addition of a new pharmacological class) is only allowed if it is not caused by worsening disease. A change to a new therapy category caused by worsening disease is considered significant and therefore ineligible for enrollment.
• Patients with diabetes mellitus are eligible for inclusion if they have had a hemoglobin A1c measurement of < 8.0 within the past 6 months prior to enrollment. These hemoglobin A1c measurements are recommended at least twice yearly by the American Diabetes Association (ADA), and the target levels here are representative of the goals of the ADA. These hemoglobin A1c levels will ensure that these participants have good glycemic control. (American Diabetes Association. American Diabetes Association Position Statement: Standards of Medical Care in Diabetes— 2015. Diabetes Care 2015;38(Suppl. 1): S1–S94).
• Able to follow study procedures in the opinion of the investigator.
• Expected to be available for the duration of the study.
• Weighs > 110 lbs.

• Known or suspected immunodeficiency or receiving treatment with immunosuppressive therapy including cytotoxic agents (e.g., for cancer, HIV, or autoimmune disease).
• Subjects on corticosteroids will be excluded if ≥ 20mg of Prednisone (or equivalent drug) has been (or will be) administered daily for 2 weeks or more. Subjects will be eligible if corticosteroid therapy has been discontinued for at least 30 days.
• Serious chronic medical conditions including metastatic malignancy, severe chronic obstructive pulmonary disease requiring supplemental oxygen, end-stage renal disease with or without dialysis, clinically unstable cardiac disease, or any other disorder that, in the investigator’s opinion, precludes the subject from participating in the study. Diabetic patients will be excluded if they do not have a hemoglobin A1c measurement within the past 6 months or if they had a hemoglobin A1c measurement of an A1c  > 8.0.
• Receipt of any blood products, including immunoglobulin, within 6 months of study enrollment.
• Current anticoagulant therapy or a history of bleeding diathesis that would contraindicate intramuscular (IM) injection:
  • Note: antiplatelet drugs such as aspirin and clopidogrel are permitted.
• Receipt of any COVID-19-specific monoclonal antibodies within the past 90 days prior to enrollment.
• Any acute illness within the last 30 days.
• Blood donation within the last 56 days prior to study enrollment and within 56 days following the last study visit.
• Pregnancy, Nursing or trying to conceive at the time of the study or for 28 days following the baseline visit.
• Currently taking antibiotics to treat a serious infection. Preventative use of antibiotics (i.e. oral surgery) is not an exclusion criterion.
• Diagnosis of a cognitive disorder (e.g., Alzheimer’s, Dementia).
• Anemia.
• Any medical condition that would, in the opinion of the investigator, interfere with the evaluation of the study objectives.

Note: Other protocol defined Inclusion/Exclusion Criteria may apply.

Eligibility last updated 1/25/23. Questions regarding updates should be directed to the study team contact.

- Participant has a current diagnosis of epilepsy  with myoclonic-atonic seizures (EMAS), also known as Doose syndrome, myoclonic-astatic epilepsy, or myoclonic-atonic epilepsy, consistent with the International League Against Epilepsy (ILAE) guidelines.  Presence of myoclonic-atonic seizures is mandatory to support a diagnosis of EMAS as determined by medical history and independent approval by The Epilepsy Study Consortium (TESC).

- Participant's initial seizure onset occurred from ≥ 6 months to < 6 years of age, with normal or mildly impaired/delayed neurodevelopment reported prior to onset of seizures. During the first year of seizure onset, the majority of seizures experienced by the participant were myoclonic-atonic seizures or generalized tonic-clonic seizures as determined by medical history.

- Participant is currently treated with one or more antiepileptic drug (AED) on a stable regimen (≥ 28 days prior to starting the baseline period [Part A Visit 2]) or on a stable ketogenic diet (≥ 3 months prior to starting the baseline period [Part A Visit 2]) and no changes to treatment are planned for the duration of the study.

- Participant is refractory to anticonvulsant medication and failed at least 1 AED (e.g., valproic acid, clobazam, clonazepam, and levetiracetam) at therapeutic doses.

- Participant is able to provide a historical electro-encephalogram (EEG) report, which was performed within 12 months of Screening (Part A Visit 1), or is willing to complete an EEG at Screening (Part A Visit 1), that confirms a 3 to 6 Hertz (Hz) generalized spike-and-slow-wave or polyspike-and-slow-wave pattern.

- Contraceptive use by male and female participants should be consistent with Clinical Trial Facilitation Group (CTFG) guidelines and any applicable local regulations regarding the methods of contraception for those participating in clinical studies.

- Fertile male participants with partners of childbearing potential (CBP) must be willing to use a male barrier method of contraception in addition to a second method of  acceptable contraception used by their female of CBP partners, from the time of Screening (Part A Visit 1) until 3 months after the follow-up visit.

- Female participants of CBP will not be pregnant or lactating and have a confirmed negative highly sensitive serum pregnancy test at Screening (Part A Visit 1).

- Female participants must also have a confirmed negative urine pregnancy test prior to receiving their first dose of blinded investigational medicinal product (IMP) at Part A Visit 3.

- Female participants who are continuing to Part B must have a confirmed negative urine pregnancy test prior to receiving their first dose of open-label GWP42003-P at Part B Visit 1.

- Female participants of CBP must be willing to use a highly effective method of contraception from the time of signing the Informed Consent Form (ICF) until 3 months after the follow-up visit.

- Participant or participant's caregiver(s) (according to local laws) is/are willing and able to give signed informed consent for participation in the study including compliance with the requirements and restrictions listed in the ICF and in the
protocol.

- Participant's caregiver(s) are willing to allow the responsible authorities to be notified of participation in the study, if mandated by local law.

- Participant's caregiver completes at least 89% of Seizure eDiary entries during the first 28 days of the Baseline period (≥ 25 days of entries).

Part B only:

- Has completed Part A of this study.

- Was compliant with all requirements of Part A (e.g., dosing, seizure eDiary, visits/procedures), in the judgement of the investigator and sponsor

• alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 5 × upper limit of normal (ULN);
• total bilirubin (TBL) (serum) ≥ 2 × ULN or International Normalized Ratio (INR) > 1.5 (TBL ≥ 2 × ULN exclusion will not apply for participants diagnosed with Gilbert's disease);
• serum ALT or AST ≥ 3 × ULN with the presence of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (> 5%);
• elevated ALT or AST at Screening (Part A Visit 1), should be discussed with the medical monitor prior to Randomization (Part A Visit 3); the medical monitor may allow for a  confirmatory re-draw prior to randomization.

This criterion can only be confirmed once the laboratory results are available.

- Has clinically significant impaired renal function at Screening (Part A Visit 1), as evidenced by an estimated creatinine clearance lower than 60 milliliters per minute
(mL/min).

- Is a female participant of CBP, who is pregnant (positive pregnancy test), lactating or planning pregnancy during the course of the study and for 3 months thereafter.

- Participant has any known or suspected history of alcohol or substance abuse.

- Any clinically significant abnormalities identified following a physical examination or laboratory assessments of the participant that, in the opinion of the investigator, would jeopardize the safety of the participant if they take part in the study.

- Participant has any other clinically significant disease or disorder which, in the opinion of the investigator, may either put the participant, other participants, or site staff at risk because of participation in the study, may influence the result of the study, or may affect the participant's ability to take part in the study.

- Has a change in anticonvulsant therapies within 28 days of starting the baseline period (Part A Visit 2), including AEDs or settings on vagal nerve stimulator.

- Has any planned clinical interventions or intends to change any or all medications that may impact seizures during the study.

- Has been treated with a general anesthetic in the 28 days prior to screening (Part A Visit 1) or randomization (Part A Visit 3 [Week 0]).

- Has undergone surgery for epilepsy in the 6 months prior to Screening (Part A Visit 1).

- Is being considered for epilepsy surgery or any procedure involving general anesthesia during the study.

- Has initiated a ketogenic diet within 3 months prior to the Baseline period (Part A Visit 2). Participants who are stable on a ketogenic diet for ≥ 3 months and willing to remain on a stable epilepsy dietary therapy (e.g., ketogenic diet, Atkins diet, low glycemic index diet) during the study, are eligible for inclusion.

- Has initiated felbamate within 12 months prior to screening (Part A Visit 1).  Participants who are stable on a felbamate for ≥ 12 months are eligible for inclusion.

- Is currently being treated with or had previously (within 3 months prior to screening [Part A Visit 1] received intravenous immunoglobulin treatment or plasma exchange for the treatment of seizures

- Has participated in a clinical study involving administration of an IMP (new chemical entity) or medical device (e.g., vagal nerve stimulator) within 1 month prior to screening (Part A Visit 1)

- Have previously been randomized, completed, or withdrawn from this study.

- Is currently using a drug of abuse or current non-prescribed use of any prescription drug.

- Is currently using or has used recreational or medicinal cannabis, cannabinoid-based medications, products, or supplements (botanical or synthetic) within 28 days prior to
screening (Part A Visit 1).

- Mother (if breastfeeding the participant) is currently using or has used recreational or medicinal cannabis, cannabinoid-based medications, products, or supplements (botanical or synthetic) within 28 days of screening (Part A Visit 1).

- Has any history of suicidal behavior or serious suicidal ideation, defined as Category 4 or greater on the Columbia Suicide Severity Rating Scale (C-SSRS) at any visit prior
to dosing with IMP. This criterion applies only to participants 4 to 18 years of age.

- Is unwilling or unable to comply with all study requirements, including accurate eDiary completion.

- Participants who, in the opinion of the investigator (or designee), should not participate in this study.

- Has travel planned outside their country of residence during the study, unless the participant has confirmation that the IMP is permitted in the destination country and all stops along the way.

Part B only:

- Has significantly impaired hepatic function at Part A Visit 9, defined as any of the following:

• ALT or AST > 5 × ULN;
• TBL (serum) ≥ 2 × ULN or INR > 1.5 (TBL ≥ 2 × ULN exclusion will not apply for participants diagnosed with Gilbert's disease;
• Serum ALT or AST ≥ 3 × ULN with the presence of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (> 5%). The medical monitor may allow for a confirmatory redraw prior to rollover.

- Meets any exclusion criteria at Part B Visit 1.

Eligibility last updated 8/24/23. Questions regarding updates should be directed to the study team contact.

• At least 22 years of age and up to 85 years of age.
• Diagnosed with paroxysmal atrial fibrillation, as documented on ECG, trans-telephonic monitoring (TTM), cardiac event monitoring, Holter monitoring, or implantable loop recording (episodes must be longer than 30 seconds to qualify).
• At least two symptomatic or asymptomatic atrial fibrillation episodes over the last month, or at least one symptomatic or asymptomatic atrial fibrillation episode in the last two weeks.
• On anticoagulants if indicated by treatment guidelines.
• Willing to stay on stable medications for the duration of the study ● Competent and willing to provide written, informed consent to participate in the study

• Prior cardiac ablation, or cardiac ablation planned within 6 weeks of Visit 1.
• Cardioversion procedure performed within the last 12 weeks.
• Valvular atrial fibrillation by transthoracic echocardiography.
• Abnormal left atrial enlargement, as measured by left atrial anteroposterior diameter greater than 5.5 cm or left atrial volume index greater than 48 mL/m^2.
• Prior or planned cardiac transplantation or cardiac surgery.
• Cerebral ischemic event (stroke or transient ischemic attack) within the last 6 months.
• Myocardial infarction within the last 6 months.
• Heart failure (NYHA class III or IV).
• Left ventricular ejection fraction less than 35%.
• Recurrent vaso-vagal syncopal episodes.
• Unilateral or bilateral vagotomy.
• Hemodynamic instability.
• Structural heart damage.
• Implanted active electrical medical device, such as pacemaker, implantable loop recorders, defibrillator, or deep brain stimulator.
• Implanted metal or electrical devices in the head or treated hand,.
• Not currently on anticoagulants.
• History of epilepsy or seizures.
• Peripheral neuropathy affecting the upper left extremity.
• Pregnancy, anticipated pregnancy, or nursing during the study.
• Unable or unwilling to comply fully with study procedures and follow-up, including atrial fibrillation diary requirements.
• Known allergy to any of the device materials that are in contact with prospective subject’s skin.
• Current participation, or previous participation within the last 30 days, in another interventional clinical trial that may confound the results of this study, unless otherwise approved by the Sponsor.
• Subjects unable to communicate with the Investigator and study staff.
• Presence of any health condition that should preclude participation in this study, per the Investigator’s opinion.

Note: Other protocol defined Inclusion/Exclusion Criteria may apply.

Eligibility last updated 11/9/23. Questions regarding updates should be directed to the study team contact.

Subjects with known or suspected Barrett’s Esophagus (BE) (cases):

• Patient between the ages of 18 – 90.
• Patients with a BE segment ≥ 1cm in maximal extent endoscopically or suspected BE in medical record.
• Histology showing evidence of intestinal metaplasia with or without presence of dysplasia or suspected BE in medical record.
• Undergoing clinically indicated endoscopy.

Subjects without known history of BE (controls):

• Undergoing clinically indicated diagnostic endoscopy.
• Subjects with GERD and one or more additional risk factors for BE including:[IPGM1] 
  • Male sex;
  • age ≥ 50 years;
  • Caucasian race;
  • Presence of central obesity (BMI ≥ 30);
  • Current or past history of smoking.

For subjects with known BE

• Patients with prior history of ablation (photodynamic therapy, radiofrequency ablation, cryotherapy, argon plasma coagulation). Patients with history of endoscopic mucosal resection (EMR)/endoscopic submucosal dissection (ESD) alone will not be excluded.
• Patients with history of surgical resection for esophageal carcinoma. 

For subjects with or without known evidence of BE (on history or review of medical records):

• Pregnant or lactating females.
• Patients who are unable to consent.
• Patients with current history of uninvestigated dysphagia.
• History of eosinophilic esophagitis, achalasia.
• Patients on oral anticoagulation including Coumadin, Warfarin.
• Patients on antiplatelet agents including Clopidogrel, unless discontinued for three to five days prior to the Cytosponge procedure.
• Patients on oral thrombin inhibitors including Dabigatran and oral factor X a inhibitors such as rivaroxaban, apixaban and edoxaban, unless discontinued for three to five days prior to the Cytosponge procedure.
• Patients with history of known esophageal or gastric varices or cirrhosis.
• Patients with history of surgical esophageal resection for esophageal carcinoma. 
• Patients with congenital or acquired bleeding diatheses.
• Patients with a history of esophageal squamous dysplasia.
• Patient has known carcinoma of the foregut (pancreatic, bile duct, ampullary, stomach, or duodenum) within 5 years prior to study enrollment.
• Patient has received chemotherapy class drugs or radiation to treat mediastinal or esophageal cancer.

Eligibility last updated 10/5/22. Questions regarding updates should be directed to the study team contact.

Adult Patients With Two or More Chronic Conditions

• Members of Mayo Clinic Connect, the online community of patients facilitated by the Mayo Clinic Center for Social Media, who have received care in multiple settings and organizations.

People Living With One or More Chronic Conditions

•  Individual with one of more chronic conditions.

International Experts in Shared Decision Making (SDM)

• Participants will be adults that have published, peer reviewed, SDM related manuscripts.
• Affiliated with institutions eligible to support a research collaborator status with Mayo Clinic and willing to become Mayo Clinic research collaborators for the duration of their participation in this study.

Primary and Specialty Care Clinicians

• Clinicians included in the KER Unit database as having expressed interest in SDM, having participated in prior focus groups, or contributed to our work as clinical content experts in developing SDM tools.

Adult Patients With Two or More Chronic Conditions

• Minors, those with cognitive issues and/or non-English speaking.

People Living With One or More Chronic Conditions

• Minors, those with cognitive issues and/or non-English speaking.

International Experts in Shared Decision Making (SDM)

• No expertise in SDM or ability to enter into research collaborator status with Mayo Clinic , Minors, those with cognitive issues and/or non-English speaking.

Primary and Specialty Care Clinicians

• Minors, those with cognitive issues and/or non-English speaking.

Eligibility last updated 8/17/22. Questions regarding updates should be directed to the study team contact.

• Moderate or severe tricuspid valve regurgitation of primary or secondary etiology.
• Subject is adequately treated with medical therapy for heart failure 30 days prior to index procedure, including a diuretic.
• Heart Team determines patient is a recommended candidate for the VDyne System.
• Age 18 years or older.
• Clinical Screening Committee (CSC) and Imaging Core Labs confirm suitability for
• treatment with the VDyne System.

• Patient anatomy (cardiac and vascular) is not suitable for the VDyne System as assessed by Imaging Core Labs.
• Intolerance to procedural anticoagulation or post-procedural antiplatelet/anticoagulation regimen that cannot be medically managed.
• Hypersensitivity to nickel or titanium.

Clinical Exclusion Criteria (assessed by pre-procedural imaging):

• Left Ventricular Ejection Fraction (LVEF) < 30%.
• Severe RV dysfunction.
• Significant abnormalities of the tricuspid valve and sub-valvular apparatus.
• Sepsis including active infective endocarditis (IE) (within last 6 months).
• Right ventricular or atrial thrombus or vegetation.
• Severe tricuspid annular or leaflets calcification.
• Systolic pulmonary hypertension with systolic pulmonary artery pressure ≥70 mmHg.

CONCOMITANT PROCEDURES

• Significant coronary artery disease requiring treatment such as symptomatic, unresolved multi-vessel or unprotected left main coronary artery disease.
• Any planned surgery or interventional procedure within the period of 30 days prior to 30 days following the implant procedure. This includes any planned concomitant cardiovascular procedure such as CABG, PCI, pulmonary vein ablation, left atrial appendage occlusion, septal defect repair, etc.
• Unresolved severe symptomatic carotid stenosis (> 70% by ultrasound).
• Cardiac resynchronization therapy device or implantable pulse generator implanted within 60 days of planned implant procedure.
• Permanent pacing leads that will interfere with delivery or implantation of the VDyne Valve.
• Cardiogenic shock or hemodynamic instability requiring inotropes or mechanical support devices at the time of planned implant procedure.
• Prior tricuspid valve surgery or catheter-based therapy with permanent residual devices implanted that would preclude delivery or implantation of the VDyne Valve (e.g., valve replacement, edge to edge repair).
• Severe valvular heart disease requiring intervention other than the tricuspid valve.
• Known significant intracardiac shunt (e.g., septal defect) (PFO's without significant shunts are allowed).

COMORBIDITIES

• Cerebrovascular accident (stroke, TIA) within 6 months of treatment procedure.
• Severe lung disease (severe COPD or continuous use of home oxygen or oral steroids).
• Acute myocardial infarction (AMI) within 30 days.
• Significant renal dysfunction (eGFR<30 ml/min/1.73m^2) or on dialysis.
• End-stage liver disease (MELD > 11 / CHILD class C).
• Bleeding requiring transfusion within 30 days.
• Coagulopathy or other clotting disorder that cannot be medically managed.
• Chronic immunosuppression or other condition that could impair healing response.
• Any of the following: leukopenia, chronic anemia (Hgb < 9), thrombocytopenia, history of bleeding diathesis, or coagulopathy
• Unwilling to receive blood products.

General

• Known hypersensitivity or contraindication to procedural or post-procedural medications (e.g., contrast solution) which cannot be adequately managed medically.
• Life expectancy less than 12 months due to non-cardiac comorbidities.
• Treatment is not expected to provide benefit (futile).
• Current IV Drug user (must be free drug abuse for > 1 year).
• Pregnant, lactating or planning pregnancy within next 12 months. (female of child-bearing potential use two reliable contraceptive methods during the study -hormonal methods such as pill and condom).
• Vulnerable patient groups (minors, cognitively impaired persons, prisoners, persons whose willingness to volunteer could be unduly influenced by the expectation of benefits associated with participation or of retaliatory response from senior members of a hierarchy in case of refusal to participate, such as students, residents, and employees).
• Currently participating in an investigational drug or device trial that has not reached its primary endpoint or is likely to interfere with this study.
• Patient (or legal guardian) unable or unwilling to provide written informed consent before study-specific procedures are conducted.
• Patient unable or unwilling to comply with study required testing and follow-up visits.

Eligibility last updated 4/14/23. Questions regarding updates should be directed to the study team contact.

• Patients received platelet-rich plasma (PRP) for knee osteoarthritis (OA) vs patients who received standard care including total knee replacement that are found in Mayo-Epic database.

• < 18 years of age. 

Eligibility last updated 9/19/22. Questions regarding updates should be directed to the study team contact.

Inclusion Criteria
•Obese Subjects with Type 2 Diabetes:

• Age ≥ 25 or ≤ 65 years.
• HbA1c ≤ 8.5% (type 2 diabetic subjects).
• HbA1c ≤ 6.5% (obese and lean subjects).
• BMI ≥ 28 Kg/M^2 (Obese subjects with and without type 2 diabetes).
• BMI ≤ 25 Kg/M^2 (Lean subjects without type 2 diabetes).
• Use of sulfonylureas or metformin only (type 2 diabetec subjects).
• For female subjects: negative pregnancy test at the time of enrollment or study.
• No history of prior upper abdominal surgery such as adjustable gastric banding, pyloroplasty and vagotomy.
• No active systemic illness or malignancy.
• No symptomatic macrovascular or microvascular disease.
• No contraindications to MRI (e.g., metal implants, claustrophobia).
• Hematocrit > 35%.
• TSH > 0.4 or < 5.5.
• Consumption of < 2 alcohol drinks per day or < 14 per week or a negative AUDIT questionnaire.

Exclusion Criteria
•Obese Subjects with Type 2 Diabetes:

• Age ≤ 25 or ≥ 65 years (to avoid studying subjects who could have latent type 1 diabetes, or the effects of age extremes in subjects with normal or impaired fasting glucose).
• HbA1c ≥ 8.5%.
• BMI ≤ 28 Kg/M^2.
• Use of insulin or agents other than sulfonylureas or metformin.
• For female subjects: positive pregnancy test at the time of enrollment or study.
• History of prior upper abdominal surgery such as adjustable gastric banding, pyloroplasty and vagotomy.
• Active systemic illness or malignancy.
• Symptomatic macrovascular or microvascular disease.
• Contraindications to MRI (e.g., metal implants, claustrophobia).
• Hematocrit < 35%.
• TSH < 0.4 or > 5.5.
• Consumption of > 2 alcohol drinks per day or > 14 per week or a positive AUDIT questionnaire.

Inclusion Criteria
•Obese Subjects without Type 2 Diabetes:

• BMI ≥ 28 Kg/M^2.
• > 5% liver fat content, as determined by MRI using the proton density fat fraction (PDFF) technique.

Exclusion Criteria
•Obese Subjects without Type 2 Diabetes:

• Age ≤ 25 or ≥ 65 years (match subjects with T2DM).
• HbA1c ≥ 6.5%.
• BMI ≤ 28 Kg/M^2.
• Use of any glucose-lowering agents including metformin or sulfonylureas.
• For female subjects: positive pregnancy test at the time of enrollment or study.
• History of prior upper abdominal surgery such as adjustable gastric banding, pyloroplasty and vagotomy.
• Active systemic illness or malignancy.
• Symptomatic macrovascular or microvascular disease.
• Contraindications to MRI (e.g., metal implants, claustrophobia).
• Hematocrit < 35%.
• TSH < 0.4 or > 5.5.
• Consumption of > 2 alcohol drinks per day or > 14 per week or a positive AUDIT questionnaire.

Inclusion Criteria - Lean Subjects without Diabetes:

• Age ≥ 25 or ≤ 65 years (match subjects with T2DM).
• BMI ≤ 25 Kg/M^2). 

Exclusion Criteria
•Lean Subjects without Diabetes:

• Age ≤ 25 or ≥ 65 years (match subjects with T2DM).
• HbA1c ≥ 6.5%.
• BMI ≥ 25 Kg/M^2.
• Use of any glucose-lowering agents including metformin or sulfonylureas.
• For female subjects: positive pregnancy test at the time of enrollment or study.
• History of prior upper abdominal surgery such as adjustable gastric banding, pyloroplasty and vagotomy.
• Active systemic illness or malignancy.
• Symptomatic macrovascular or microvascular disease.
• Contraindications to MRI (e.g., metal implants, claustrophobia).
• Hematocrit < 35%.
• TSH < 0.4 or > 5.5.
• Consumption of > 2 alcohol drinks per day or > 14 per week or a positive AUDIT questionnaire.
• Liver fat content ≥ 5% as determined by MRI using the proton density fat fraction (PDFF) technique.

Eligibility last updated 1/12/22. Questions regarding updates should be directed to the study team contact.

• Adult patients (age 18 and over).
• Active cancer diagnosis.
• Admitted to the inpatient setting.
• Grade 3-4 oral mucositis per the World Health Organization (WHO).
• Grade 3: soreness and erythema, able to eat solid food.
• Grade 4: soreness and erythema, able to tolerate liquid diet only.
• Patient reports oropharyngeal pain.
• Able to provide informed consent.

• Pediatric age (under 18 years old).
• Any contraindication to methylene blue.
• Pregnant women.

Eligibility last updated 10/25/22. Questions regarding updates should be directed to the study team contact.

• ctDNA assay must be performed through this study or study BNT000-001 ctDNA screening protocol.

- Patients must have an Eastern Cooperative Oncology Group (ECOG) Performance Status of
0-1.

- Patients must have adequate hematologic and organ function.

- Adequate tumor material in formalin-fixed paraffin embedded (FFPE) blocks or as sectioned tissue (only upon approval by sponsor) must be available (as described in
the laboratory manual).

- The patient has started a standard of care AdCTx within 8 weeks post-surgery and has completed at least 3 months of treatment.

Note: Other protocol defined Inclusion/Exclusion Criteria may apply.

Eligibility last updated 9/15/23. Questions regarding updates should be directed to the study team contact.

• Women ≥ 18 yrs.
• Diagnosed with LAM  using one or more of the following methods:
  • Lung Biopsy;
  • Elevated VEGF-D;
  • Chylous Ascites;
  • Chylous Pleural Effusions;
  • Renal Angiomyolipomas.
• Chest imaging (X-ray or CT scan).

• Current treatment with Sirolimus for LAM.
• Diagnosis of Tuberculosis.
• History of organ transplantation.

Note: Other protocol defined Inclusion/Exclusion Criteria may apply.

Eligibility last updated 10/17/23. Questions regarding updates should be directed to the study team contact.