• Patient has signed the Informed Consent (ICF) prior to any screening procedures being performed and is able to comply with protocol requirements. 
• Age > 18 years at time of study entry. 
• Willingness and ability to comply with study and follow-up procedures. 
• Histological confirmation of diagnosis of low-grade serous carcinoma of ovary, fallopian tube or peritoneum; original diagnosis of de novo low-grade serous carcinoma or original diagnosis of serous borderline tumor with subsequent diagnosis of low-grade serous carcinoma:
  • In order to prevent inclusion of patients with high-grade serous carcinoma, diagnosis of low-grade serous carcinoma will be verified as part of screening review by a gynecologic pathologist. Tissue for confirmation can be from primary tumor or recurrence.
• Patient must have recurrent, measurable disease by RECIST v1.1. 
• There are no restrictions on number of prior therapies. 
• Patient cannot have previously received a prior cyclin dependent kinase inhibitor (CDKi). Patients who were treated with letrozole or another aromatase inhibitor for other indications must have not taken the drug for 6 months prior to initiating letrozole for this trial and may not have progressed on treatment.
• Patients must not have remaining ovarian function to be included. In women who have at least one retained ovary, menopause must be confirmed with laboratory confirmation. Women who have ovarian function are eligible but must be placed on hormonal suppression. Menopause must be confirmed with laboratory confirmation, to include an estradiol level as this is assessed within 8 weeks of patient having been on tamoxifen. 
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2.
• Resolution of all acute toxic effects of prior therapy or surgical procedures to National Cancer Institute (NCI) CTCAE Grade ≤ 1. 
• Patient has adequate bone marrow and organ function as defined by the following laboratory values at screening:
  • Absolute neutrophil count ≥ 1.5 × 10^9/L;
  • Platelets ≥ 100 × 10^9/L;
  • Hemoglobin ≥ 9.0 g/dL;
  • Potassium, total calcium (corrected for serum albumin), magnesium, sodium and phosphorus within normal limits for the institution or corrected to within normal limits with supplements before first dose of study medication;
  • INR ≤ 1.5;
  • Serum creatinine < 1.5 mg/dL or creatinine clearance ≥ 50 mL/min;
  • In the absence of liver metastases, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 2.5 x ULN. If the patient has liver metastases, ALT and AST < 5 x ULN;
  • Total bilirubin < ULN or total bilirubin ≤ 3.0 x ULN or direct bilirubin ≤ 1.5 x ULN in patients with well-documented Gilbert's Syndrome.
• Patient with available standard 12-lead ECG with the following parameters at screening: 
  • QTcF interval at screening < 450msec (using Fridericia's correction);
  • Resting heart rate 50-90 bpm.
• Must be able to swallow ribociclib and letrozole capsules/tablets.
• Patients receiving tamoxifen or toremifine must have washout period of 5 half-lives prior to randomization.

• Patient has a known hypersensitivity to any of the excipients of ribociclib or letrozole. 
• Patient has a concurrent malignancy or malignancy within 3 years prior to starting study drug, with the exception of adequately treated, basal or squamous cell carcinoma, non-melanomatous skin cancer or curatively resected cervical cancer. Patients with known brain metastases are excluded.
• Patients with central nervous system (CNS) involvement unless they meet ALL of the following criteria:
  • At least 4 weeks from prior therapy completion (including radiation and/or surgery) to starting the study treatment;
  • Clinically stable CNS tumor at the time of screening and not receiving steroids and/or enzyme inducing anti-epileptic medications for brain metastases.
• Patient has impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of the study drugs (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection).
• Patient has a known history of HIV infection (testing not mandatory).
• Patient has any other concurrent severe and/or uncontrolled medical condition that would, in the investigator’s judgment, cause unacceptable safety risks, contraindicate patient participation in the clinical study or compromise compliance with the protocol (e.g., chronic pancreatitis, chronic active hepatitis, active untreated or uncontrolled fungal, bacterial or viral infections, etc.). 
• Clinically significant, uncontrolled heart disease and/or cardiac repolarization abnormalities, including any of the following:
  • History of acute coronary syndromes (including myocardial infarction, unstable angina, coronary artery bypass grafting, coronary angioplasty, or stenting) or symptomatic pericarditis within 6 months prior to screening;
  • History of documented congestive heart failure (New York Heart Association functional classification III-IV);
  • Documented cardiomyopathy;
  • Left Ventricular Ejection Fraction (LVEF) < 50% as determined by Multiple Gated acquisition (MUGA) scan or echocardiogram (ECHO);
  • Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), complete left bundle branch block, high-grade AV block (e.g., bifascicular block, Mobitz type II and third degree AV block);
  • Long QT syndrome or family history of idiopathic sudden death or congenital long QT syndrome, or any of the following: 
    • Risk factors for Torsades de Pointe (TdP) including uncorrected hypocalcemia, hypokalemia or hypomagnesemia, history of cardiac failure, or history of clinically significant/symptomatic bradycardia;
    • Concomitant use of medication(s) with a known risk to prolong the QT interval and/or known to cause Torsades de Pointe that cannot be discontinued (within 5 halflives or 7 days prior to starting study drug) or replaced by safe alternative medication;
    • Inability to determine the QT interval on screening (QTcF, using Fridericia’s correction);
    • Systolic blood pressure (SBP) >160 mmHg or <90 mmHg at screening;
• Patient is currently receiving any of the following medications and cannot be discontinued 7 days prior to starting study drug:
  • Known strong inducers or inhibitors of CYP3A4/5, including grapefruit, grapefruit hybrids, pummelos, star-fruit, and Seville oranges;
  • That have a narrow therapeutic window and are predominantly metabolized through CYP3A4/5;
  • Herbal preparations/medications, dietary supplements.
• Participation in other studies involving investigational drug(s) within 30 days prior to randomization or within 5 half-lives of the investigational product (whichever is longer) or participation in any other type of medical research judged not to be scientifically or medically compatible with this study. If the patient is
  enrolled or planned to be enrolled in another study that does not involve an investigational drug, the agreement of Novartis study medical lead is required to establish eligibility.
• Patient is currently receiving warfarin or other coumadin-derived anticoagulant for treatment, prophylaxis or otherwise. Therapy with heparin, low molecular weight heparin (LMWH) or fondaparinux is allowed. Direct-Acting Oral Anticoagulants (DOACS) are permitted. 
• Patient is currently receiving or has received systemic corticosteroids ≤ 2 weeks prior to starting study drug, or who have not fully recovered from side effects of such treatment. The following uses of corticosteroids are permitted: a short duration (<5 days) of systemic corticosteroids; any duration of topical applications (e.g., for rash), inhaled sprays (e.g., for obstructive airways diseases), eye drops or local injections (e.g., intra-articular).
• Patient who has received radiotherapy ≤ 4 weeks or limited field radiation for palliation ≤ 2 weeks prior to starting study drug, and who has not recovered to grade 1 or better from related side effects of such therapy (exceptions include alopecia) and/or in whom ≥25% of the bone marrow (Ellis, 1961) was irradiated.
• Patient has had major surgery within 14 days prior to starting study drug or has not recovered from major side effects (tumor biopsy is not considered as major surgery).
• Patient with a Child-Pugh score B or C.
• Patients who are pregnant or breastfeeding. 
• Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception throughout the study and for 3 weeks after study drug discontinuation. Highly effective contraception methods include:
  • Total abstinence when this is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of
    contraception;
  • Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy, or tubal ligation at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment.
• Women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g., age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks ago. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential.
• Current use of food or drugs known to be potent CYP3A4 inhibitors, drugs known to be potent CYP3A4 inducers, and drugs that are known to prolong the QT interval unless the prohibited concomitant medication can be replaced by other drugs of less potential to inhibit or induce CYP3A4 or prolong QT interval
• Patients whose tumors contain both low-grade serous carcinoma (LGSC) and high-grade serous carcinoma (HGSC).
• Patients with history of haemopoietic stem cell or bone marrow transplant.

• Midlife women, ages 45-60 years old.
• Non-smokers.
• Non-obese.
• Have at least one ovary.
• Free from cardiovascular disease.
• Not taking medications influencing cardiovascular function.

• None.

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

Eligibility last updated 9/7/22. Questions regarding updates should be directed to the study team contact.

• Patients 18 years and older.
• Patient with a suspected Vestibular Schwannoma (VS).
• Recurrent VS with prior microsurgical resection or radiation therapy.
• Clinical indication for microsurgical resection.

• Children (patients less than 18 years of age).
• History of allergy to Fluorescein Sodium (FS).
• History of renal failure.
• Pregnant women.
• Those with inability to give informed consent or the legally authorized representative is unable to give informed consent.
• Prisoners and inmates.

• Male and female junior high and high school athletes presenting to the annual Mayo Clinic Sports Pre Participation exam day.

• Current injury or recent injury within that past 1 month to the upper or lower extremity that required evaluation by a medical provider.
   

Current musculoskeletal injury or recent injury to the upper or lower extremity within the past 1 month that required evaluation by a medical provider.

• 18 years or older.
• Willing and able to comply with the study procedures and provide written informed consent to participate in the study.
• Scheduled for a clinically indicated ERCP or other duodenoscope-based procedure.

• Potentially vulnerable subjects, including, but not limited to pregnant women.
• Subjects for whom endoscopic techniques are contraindicated.
• Patients who are currently enrolled in another investigational study that would directly interfere with the current study, without prior written approval from the sponsor.
• Investigator discretion.

• Age ≥ 18 years old.
• Known cardiac ischemia, who are non revascularizable, or have not and will not be undergo coronary intervention for the duration of their participation in the study.
• Evidence of ischemia from previous clinical tests (echo, nuclear, standard ECG from past 6 months).
• Left Ventricular Ejection fraction > 40% by echo (evaluated last 3 months).
• Able to complete a cardiopulmonary exercise test without significant non cardiac limitations, primarily orthopedic.
• On guideline directed optimal therapy for stable ischemia.

• Anemia (< 7 mg/dl).
• Low potassium (< 3 mmol/L).
• Creatinine (> 5.0 mg/dl or < 0.6 mg/dl).
• Unable to exercise due primarily to orthopedic limitation.
• Severe lung disease.
• Morbid obesity (BMI > 42).
• Pregnant.
• Breast feeding.
• Significant arrhythmia (Vtach, Vfib, frequent PVCs, persistent afib, or 2nd or 3rd degree AV block).
• Seizures.
• Unstable angina.
• Coronary spasm.
• Recent MI (< 90 days).
• Recent PTCA (<90 days).

• Male and female subjects ≥ 18 years old.
• Diagnosis of dcSSc according to the 2013 American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) criteria.
• Must have disease duration (defined as interval from first non-Raynaud disease manifestation) of ≤ 5 years.
• Must have mRSS of ≥ 15 but ≤ 35.
• Active disease defined as any of the following within the 6 months prior to screening:
  • Increase in mRSS by ≥ 3 units;
  • Increase in mRSS by ≥ 2 units with involvement of 1 new body area;
  • Involvement of 2 new body areas;
  • Symptoms indicative of skin activity such as severe cutaneous itching or burning.
• Subjects receiving concomitant immunosuppression must be on a stable dose for at least 3 months prior to screening.
• Adequate organ and bone marrow functions evaluated during the 28 days prior to enrollment as follows:
  • Absolute neutrophil count ≥ 1.5 × 10^9 /L;
  • Platelet count ≥ 100 × 10^9 /L;
  • Total bilirubin ≤ 1.0 × upper limit of normal (ULN);
  • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) within normal limits; and
  • Serum creatinine ≤ 1.5 × ULN. 
• Female subjects of childbearing potential have a negative pregnancy test at screening. Females of childbearing potential are defined as sexually mature women without prior hysterectomy or who have had any evidence of menses in the past 12 months. However, women who have been amenorrheic for 12 or more months are still considered to be of childbearing potential if the amenorrhea is possibly due to prior chemotherapy, anti-estrogens, or ovarian suppression:
  • Women of childbearing potential (i.e., menstruating women) must have a negative urine pregnancy test (positive urine tests are to be confirmed by serum test) documented within the 24-hour period prior to the first dose of study drug;
  • Sexually active women of childbearing potential enrolled in the study must agree to use two forms of accepted methods of contraception during the course of the study and for 3 months after their last dose of study drug. Effective birth control includes:
    • IUD plus one barrier method;
    • on stable doses of hormonal contraception for at least 3 months (e.g., oral, injectable, implant, transdermal) plus one barrier method; or
    • 2 barrier methods. Effective barrier methods are male or female condoms, diaphragms, and spermicides (creams or gels that contain a chemical to kill sperm), or a vasectomized partner.
• For male patients who are sexually active and who are partners of premenopausal women: agreement to use 2 forms of contraception as in criterion above during the treatment period and for at least 3 months after the last dose of study drug.
• Male subjects must not donate sperm for 3 months after last dose of study drug.
• Able to provide written informed consent prior to the performance of any study-specific procedures.

• Subject has corrected QT interval using Fredericia’s formula (QTcF) > 450 ms.
• Ongoing use or current use of concomitant medication known to have the potential for QTc prolongation.
• Female subject who is pregnant or breastfeeding.
• Participated in another study with an investigational drug within 28 days of study entry (for studies involving biologics, within three half-lives of the biologic).
• History or other evidence of severe illness or any other conditions that would make the subject, in the opinion of the Investigator, unsuitable for the study.
• Chronic heart failure with New York Heart Association Classes II, III, or IV.
• Acute or chronic liver disease (e.g., cirrhosis).
• Positive human immunodeficiency virus (HIV) test.
• Active hepatitis C virus (HCV), hepatitis B virus (HBV), or positive whole blood tuberculin test
• Diagnosed with any malignancy within 3 years of enrollment, with the exception of basal cell or completely resected squamous cell carcinoma of the skin, resected in situ cervical malignancy, resected breast ductal carcinoma in situ, or low-risk prostate cancer after curative resection
• Has had previous exposure to belumosudil or known allergy/sensitivity to belumosudil, or any other ROCK2 inhibitor.
• Scleroderma renal crisis within 4 months prior to enrollment.
• FVC ≤ 50% Predicted.

• All patients undergoing surgery by Dr. Bakri.
• Any waste tissue will be saved.

• None.

• Adults, age ≥ 40 years old.
• Clinical diagnosis of Chronic Obstructive Pulmonary Disease (COPD).
• At least 10 pack years of smoking.

• Unable to do mild exercise (orthopedic-neurologic problems or confined to a bed).
• Unable to follow commands (cognitive impairment).
• Have a high likelihood of being lost to follow-up (active alcohol or drug abuse).
• Live in an area that does not have cellular service (Verizon).

Eligibility last updated 8/27/21. Questions regarding updates should be directed to the study team contact.

• Provided informed consent.
• Age 18 years or older.
• Has an underlying enteric disorder associated with malabsorption with known or suspected history of hyperoxaluria (e.g., history of kidney stones or oxalate nephropathy).
• Urinary oxalate ≥ 50 mg/24 hr.
• Has at least 1 documented kidney stone within 2 years.

• Acute renal failure or estimated glomerular filtration rate (eGFR) < 30 mL/minute/1.73 m^2.
• Has a known genetic, congenital, or other cause of kidney stones.
• Unable or unwilling to discontinue Vitamin C supplementation.
• Cannot establish baseline kidney stone burden.

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

Eligibility last updated 9/20/22. Questions regarding updates should be directed to the study team contact.

• Males and females, age 18 years or older.
• Clinical diagnosis of localized (clinical AJCC stage Ta-T4N0M0) low- and high-grade UC of the renal pelvis and/or ureter.
• Plan to undergo RNU.
• Adequate bone marrow, renal and hepatic function:
  • Creatinine < 2.2 mg/dL (194 mmol/L);
  • Adequate hematologic function (hemoglobin > 9 g/dL; white blood cell count ≥ 3000/μL; platelet count >75,000/μL and <500,000/μL);
  • Serum bilirubin, alkaline phosphatase, aspartate aminotransferase, and alanine aminotransferase levels below 2 times the institution’s upper limits of normal.
• Easter Cooperative Oncology Group (ECOG) performance status score 0
  •2.
• Suitable candidate for surgery at the discretion of the investigator.
• Patient must be capable of giving appropriate approved informed consent or have an appropriate representative available to do.
• Patient with a prior malignancy allowed if adequately treated > 3 years ago with no current evidence of disease.
• Patient with any current malignancy except for basal or squamous cell skin cancers, noninvasive cancer of the cervix, or any other cancer deemed to be of low-risk for progression or patient morbidity during the trial period (i.e. Gleason 6 prostate cancer, renal mass < 3 cm).
• Women of childbearing potential (WOCBP) must have a negative pregnancy urine test within 28 days of registration, and be using an adequate method of contraception to avoid pregnancy prior to and for at least 6 months after gemcitabine instillation to minimize the risk of pregnancy.
• Male patient who has a partner that is a WOCBP must agree to use physician-approved contraceptive methods (e.g., abstinence, condoms, vasectomy) and should avoid conceiving children prior to and for 6 months following gemcitabine instillation.

• Pure non-urothelial histology; urothelial carcinoma with differentiation allowed.
• Evidence of nodal or distant metastases; enlarged retroperitoneal lymph nodes > 2cm or histologically positive lymph nodes.
• History of UC of the bladder within 12 months preceding RNU, or receipt of intravesical therapy within 6 months.
• History of or current prostatic urethral, urethral, or contralateral upper tract UC.
• History of radical cystectomy or partial cystectomy.
• Planned radical cystectomy at time of RNU.
• Symptomatic urinary tract infection of bacterial cystitis (once satisfactorily treated, patients can enter the study).
• Women who are pregnant or breastfeeding.
• Prisoners or subjects who are involuntarily incarcerated.
• Subjects who are involuntarily incarcerated.
• Inability for adequate follow-up, including concerns for patient compliance or geographic proximity.

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

Eligibility last updated 10/12/22. Questions regarding updates should be directed to the study team contact.

• Histologically confirmed diagnosis of previously untreated locally advanced unresectable or metastatic HER2+ GC or GEJ adenocarcinoma:
  • Cohort A: HER2-positive (by IHC 3+) and PD-L1-positive (by IHC with 22C3 CPS ≥ 1%), and non-MSI-H per central review 1%), and non-MSI-H per central review;
  • Cohort B: HER2-positive (by IHC 3+ or IHC 2+ in combination with FISH+) by local review. PD -L1 status is not required for enrollment. 
• Availability of formalin-fixed, paraffin-embedded tumor specimen, unstained slides or contemporaneous biopsy for tumor target testing.
• Eastern Cooperative Oncology Group performance status of 0 or 1, verified within 3 days of Day 1.
• Life expectancy ≥ 6 months.
• At least one radiographically measurable target lesion.
• Acceptable laboratory parameters and adequate organ function.

• Other malignancy that is progressing or required treatment within the past 5 years, with certain exceptions.
• Patients with MSI-H status by central test in Cohort A, or patients with known MSI-H status in Cohort B.
• History of allogeneic stem cell or tissue/solid organ transplant.
• Central nervous system metastases.
• Clinically significant cardiovascular disease, gastrointestinal disorders, pulmonary compromise.
• Prior neoadjuvant or adjuvant treatment with immunotherapy.

• Adult patients, 18 years or older.
• Patients who underwent an endovascular intervention with stenting of the mesenteric vasculature for chronic atherosclerotic mesenteric ischemia.

• Subjects < 18 years of age.
• Patient who underwent endovascular intervention without stent placement.
• Patients who underwent open mesenteric revascularization.
• Patient who underwent mesenteric stenting as a part of other procedures including fenestrated or branched endografting.
• Patients who underwent mesenteric stenting for other indications other than chronic atherosclerotic mesenteric ischemia, including vasculitis, aneurysm, dissection, or acute mesenteric ischemia.

• Provision of signed and dated informed consent form.
• Subject agrees to be compliant with study requirements and adhere to post-operative dietary and exercise recommendations for the duration of the study.
• Subjects between the ages of 22-60 years.
• If female, be either post-menopausal, surgically sterile, or agree to practice birth control during year of study and have negative serum HCG at screening/baseline.
• Have a Body Mass Index (BMI) of ≥ 35 and < 40 with one or more obesity related co-morbid conditions (defined by 1991 NIH Guidelines (Appropriateness Criteria for Bariatric Surgery: Beyond the NIH Guidelines)):
  • Pre-diabetes – Fasting plasma glucose test >100 mg/dl but ≤ 125 or oral glucose tolerance test ≥ 140 mg/dl but < 200;
  • Diabetes – Individuals taking insulin and/or oral hypoglycemic medications or have a fasting glucose >126 mg/dl;
  • Hypertension – SBP > 140 or DBP > 90 or the use of an anti-hypertensive medication;
  • Dyslipidemia – Triglycerides > 250 mg/dl or cholesterol > 220 mg/dl or HDL < 35 mg/dl or LDL > 200 or use of lipid lowering medications;
  • Sleep Apnea – A formal sleep study test consistent with this diagnosis; Epworth sleepiness scale ≥ 6;
  • Polysomnography with respiratory disturbance index ≥ 10 hyponeic and/or apneic episodes per hour of sleep;
  • Venous Stasis Disease – Presence or history of pretibial venous stasis ulcers;
  • Chronic Joint Disease – Deterioration of joint cartilage and the formation of new bone (bone spurs) at the margins of the joints.
• Absence of current severe systemic disease (including, but not limited to: coronary artery disease, chronic obstructive pulmonary disease, congestive heart failure, cancer, and chronic renal disease).
• Agrees not to undergo any additional weight loss interventional procedures or liposuction for 12 months following study enrollment.
• Have not taken any prescription or over the counter weight loss medications OR those that can suppress appetite/induce weight loss for at least 6 months and agrees not to utilize for 12 months following study enrollment (including all stimulant medication).
• Subjects must be willing to possibly forego any future weight loss procedures (i.e., Vertical Sleeve Gastrectomy) given the unknown long-term effects.
• Residing within a reasonable distance from the Investigator’s treating office (~ 50 miles) and willing and able to travel to the Investigator’s office to complete all routine follow-up visits.

• History of (or intra-operative evidence of) prior bariatric, gastric or esophageal surgery.
• Esophageal stricture or other anatomy and/or condition that could preclude passage of endoluminal instruments or procedure execution.
• Moderate gastro-esophageal reflux disease (GERD), defined as symptoms that cause subject severe discomfort, compromise performance of daily activities, and/or condition is not entirely controlled with drug therapy.
• Large hiatal hernia (> 3 cm) by history or as determined by pre-enrollment endoscopy.
• Pancreatic insufficiency/disease.
• History of gastroparesis or symptoms that would be suggestive of gastroparesis or generalized dysmotility (e.g., esophago-gastric motility issues and lower esophageal sphincter abnormalities).
• Pregnancy or plans of pregnancy in the next 12 months.
• History of a known diagnosis or pre-existing symptom of rheumatoid arthritis, scleroderma, system lupus, or other autoimmune connective tissue disorder.
• Immunosuppressive medications or systemic steroids (i.e., oral prednisone) within 6 months of Visit 1.  Intranasal/inhaled steroids are acceptable.
• Unable or unwilling to avoid use of aspirin and/or non-steroidal anti-inflammatory drugs (NSAIDs), or other medications known to be gastric irritants beginning two weeks prior to enrollment and throughout the entire study.
• History of inflammatory disease of the GI tract; coagulation disorders; hepatic insufficiency or cirrhosis.
• Active gastric erosion, lesion, or gastric/duodenal ulcer.
• History of or current platelet or coagulation dysfunction, such as hemophilia.
• History or present use of insulin or insulin derivatives for treatment of diabetes.
• Type II Diabetes Mellitus (as defined by HgbA1c > 6.5%) for greater than 11 years at the time of enrollment.
• If smoker, plans to quit smoking in the year after enrollment.
• Portal hypertension and/or varices.
• Patient has a history of drug or alcohol abuse or positive at screening for drugs of abuse.
• Patient is currently using marijuana/cannabis for either medicinal or recreational use, or has plans to start using over the next 12 months.
• Present or history of psychosis, bipolar disease, or obsessive-compulsive disorder after pre-enrollment history and medical/ psychological assessment.
• Beck Depression Inventory (Short) Score ≥ 12 and/or uncontrolled depression after pre-enrollment psychological and medical assessment. 
• Patient score > 2 in any of the 9 identified symptoms on the Gastroparesis Cardinal Symptom Index (GCSI)
• Patient with a 13C-Spirulina Gastric Emptying Breath Test (GEBT) result that is less than a kPCD/min of 34.4 at 120 minutes or 43 at 180 minutes
• Non-ambulatory or has significant impairment of mobility (i.e., cannot ambulate for 30 minutes).
• Known hormonal or genetic cause for obesity including untreated hypothyroidism (TSH > 5.0 U/ml).
• Participating in another clinical study.
• Subjects with a personal history of allergic/anaphylactic reactions including hypersensitivity to the drugs or materials that will be utilized in the study procedure.
• Physician’s assessment that the subject is not an appropriate candidate.

Eligibility last updated 10/7/21. Questions regarding updates should be directed to the study team contact.

Any patient implanted with or receiving an Inspire implant, who meets the following criteria, is eligible to participate in the registry:

• Must be a legal adult, ≥ 22 years old.
• Capable of giving informed consent, as required per institution.
• Willing to return for routine clinic visits as required for Inspire therapy management.

Any patient who meets any of the following criteria will not be eligible to participate in the registry:

• Has a life expectancy of less than 1 year.
• Any reason the clinician deems patient is unfit for participation in the study.

• Adults between 18 and 65 years of age.
• Bipolar I or II disorder as confirmed by structured clinical interview for DSM-IV-TR.
• Major depressive episode unresponsive to steady and stable (i.e., at least 2 weeks) mood stabilization (e.g., lithium, valproate, lamotrigine, carbamazepine/oxcarbamazepine, and/or atypical antipsychotic therapy) and non-psychotropic medication.
• Antidepressant therapy is allowed in the study as long as patients are also on a mood stabilizer. Patients will be enrolled provided that any needed modifications to the antidepressant would be made at least two weeks prior to randomization.
• Patients receiving psychotherapy will be allowed to be randomized provided therapy frequency does not change during the 8-week blinded phase.  
• Symptom severity score on the Quick Inventory for Depressive Symptomatology – Clinician (QIDS-C16) ≥ 9, and the Clinical Global Impression for Bipolar Illness (CGI-BP) Depression Severity Scale ≥ 3.
• Patients on stimulants for comorbid attention deficit disorder (ADHD) and/or binge eating disorder (BED) will be enrolled provided that the stimulant can be tapered and discontinued at least one week prior to randomization; symptom severity inclusion criteria must be met again prior to randomization.
• Patients with a prescribed opiate (e.g.. hydroxicodone) or other pain intervention for acute or chronic pain management will be allowed provided they:
  • use a prescribed opiate or other pain intervention at a recommendation dose and established duration;
  • show no evidence of prescription misuse;
  • do not meet abuse or dependence criteria by SCID;
  • no known significant pharmacological interactions.
• Ability to travel for the assessment visits.  

• Inability to provide written informed consent.
• Inability to understand English.
• Score less than 86% correct (i.e., one wrong) on comprehension assessment that reviews study goals.
• Clinically significant signs of acute suicidality from any of the following assessments:
  • Response of > 2 on question #12 of QIDS-C; or
  •  Response = 3 on the SCID Module A- #A19.
• Suicide attempt within the past year.
• Concomitant treatment with monoamine oxidase inhibitors (MAOIs); also, within 14 days following discontinuation of treatment with a monoamine oxidase inhibitor.
• Baseline Young Mania Rating Scale (YMRS) score ≥ 12.
• Patients with active psychosis (measured by a score > 4 on YMRS question #8) or a diagnosis of schizophrenia, schizoaffective disorder, delusional, or schizophreniform disorder identified by structured clinical interview for DSM-IV-TR.
• Active abuse or dependence of alcohol, opiates, or cannabis (nicotine dependence will be an exception) by structured clinical interview for DSM-IV-TR; patients meeting full remission for at least 3 months can be randomized. 
• Positive toxicology screen for drugs of abuse (i.e., cocaine, methamphetamine, illegal opiates).
• Positive toxicology screen for cannabis and a cannabis use disorder by structured clinical interview for DSM-IV-TR.  Participants who use cannabis for recreational or medicinal purposes and fail the toxicology screen can potentially be included in the study only if they take the CUDIT-R and score a 12 or less.
• Known lifetime history of cocaine or methamphetamine abuse or dependence identified by structured clinical interview for DSM-IV-TR.
• Active stimulant prescription abuse or dependence by structured clinical interview for DSM-IV-TR; patients meeting full remission for at least 6 months can be randomized.
• Known lifetime history of stimulant-induced mania.
• Known hypersensitivity, such as angioedema or anaphylaxis, to amphetamines or other ingredients of MYDAYIS.
• Clinically unstable medical disease.
• Known history of a structural cardiac abnormality, cardiomyopathy, serious heart rhythm abnormality, coronary artery disease, stroke, or other serious cardiovascular problems.
• ECG with clinically significant arrhythmias, conduction abnormalities, or voltage criteria met for left ventricular hypertrophy (unless cleared by cardiology consultation).
• Uncontrolled hypertension (> 160/100) or tachycardia (heart rate > 110).
• History of grand mal seizure; history of febrile seizure as infant permitted.
• Established vasculopathy or history of Raynaud’s phenomena.
• Narrow angle glaucoma.
• Chronic kidney disease (CKD) > stage IIIa (GFR 40-59).
• Tourette syndrome.
• Women who are pregnant, lactating or of child-bearing potential not using at least one adequate contraceptive measure (i.e., hormonal contraception-birth control pills, intrauterine devices (IUD), tubal ligation or condoms during sexual intercourse).
• Current positive test for SARS-CoV-2; those with previous COVID-19 illness and those who test positive for SARS-CoV-2 any time after starting study drug or placebo will be included.
• Otherwise excluded for administrative reasons and/or clinician judgment.

Eligibility last updated 3/22/22. Questions regarding updates should be directed to the study team contact.

• Participants will be enrolled for this study from patients attending the Mayo Clinic Depression Center, Mayo Clinic Family Medicine clinics at Rochester and Kasson, MN;, Behavioral Health and Primary Care Clinic at Mayo Clinic Health System, Austin and Albert Lea, MN, with a diagnosis of major depression with a current moderate episode, with PHQ-9 scores 10-23.
• Participants will be required to be between 25 and 80 years old.
• Able to speak English.
• Able to provide written informed consent to participate in the study.
• Participants must have DSM-V diagnostic confirmation of major depressive disorder (MDD) (American Psychiatric Association 2013). 
• Participants will continue taking any prescribed medications from their clinical treatment team. 
• Participants with co-morbid secondary diagnoses of persistent depressive disorder and generalized anxiety disorders will be included in the study.
• Participants must consent to audio recording of random group sessions which will be disclosed at the final study session.
• Participants are willing to use the Mayo Clinic Patient Portal for communication purposes during the study.

• Participants with bipolar disorder, active psychosis, active suicidal ideations, and active substance abuse meeting criteria for substance use disorders except nicotine, obsessive compulsive disorder, active panic disorder with agoraphobia or other phobic disorder, active posttraumatic stress disorder, active severe personality disorders will be excluded.
• Participants with a severe major depressive episode- HAM-D scores ≥ 23.
• Pregnant women – because of time duration of the study.

• Is able to provide written informed consent.
• Willing to comply with all study procedures and be available for the duration of the study.
• Ability to take oral medication.
• Male or female, at least 18 years of age.
• Is a solid organ transplant (SOT) recipient.
• Has recurrent C. difficile infection. A C. difficile recurrence is defined as:
  •  Positive C. difficile testing in stool (confirmed via medial record review) AND
  •  Diarrhea (≥3 loose stools over 24 hours) during the 180-day period following completion of treatment for prior CDI episode.
• History of positive IgG testing to cytomegalovirus (CMV) and Epstein Barr Virus (EBV) for subject.
• Clinical response to 4-10 days of C. difficile treatment for the current CDI episode. Clinical response is defined as ≥5% reduction of diarrhea.
• Females of childbearing potential must have a negative urine or serum pregnancy test at baseline and prior to randomization. A female of child-bearing potential is any woman (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria:
  • Has not undergone a hysterectomy or bilateral oophorectomy; or
  • Has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months).
• Women of childbearing potential in sexual relationships with men must use an acceptable method of contraception§ from 30 days prior to enrollment until 4 weeks after completing study treatment. Males must agree to avoid impregnation of women during and for four weeks after completing study treatment through use of an acceptable method of contraception.
  • Note: Acceptable method of contraception is defined as those, alone or in combination, that result in a low failure rate [i.e. less than 1% per year] or in conjunction with their sexual partner(s), use 2 forms of medically acceptable contraceptive methods that have a reported failure rate of >1% per year. Includes, but is not limited to, barrier with additional spermicidal foam or jelly, intrauterine device, hormonal contraception (started at least 30 days prior to study enrollment), intercourse with men who underwent vasectomy.

• Major bowel resection surgery within 90 days of randomization.
• Active chronic intestinal disease (e.g. Crohn's disease, ulcerative colitis).
• History of total colectomy or bariatric surgery.
• Known or suspected toxic megacolon and/or known small bowel ileus.
• Presence of colostomy or ileostomy.
• Concomitant antibiotic use within 48 hours of Visit 2. Topical antibiotics and SOT prophylaxis (e.g., trimethoprim-sulfamethoxazole) are permitted.
• Dysphagia: oropharyngeal, esophageal, functional, neuromuscular (e.g. stroke, multiple sclerosis, ALS), or patient shows evidence of dysphagia when the ‘safety test’ capsule is administered.
• Currently receiving medication for treatment of acute rejection and/or develop acute rejection prior to administration of FMT.
• Active, severe gastroparesis
• Unwilling to withhold probiotics for duration of study. Probiotics include supplements, prescriptions, and non-prescriptions. Foods (like yogurt) are permitted.
• Neutropenia, ≤500 neutrophils/mL [abstracted from the medical record and resulted within 7 days of Visit 2].
• Symptomatic co-infection with another intestinal pathogen as determined by chart review.
• Concurrent intensive induction chemotherapy, radiation therapy or biological treatment for active malignancy. Patients on maintenance chemotherapy may be enrolled only after consultation with medical monitor.
• Any severe food allergy, defined as a history of anaphylaxis, systemic urticarial or angioedema attributed to a food and requiring current avoidance precautions.
• Expected life expectancy <6 months.
• Use of investigational drugs, biologics, or devices within 30 days prior to randomization.
• Women who are pregnant, lactating or planning on becoming pregnant during the study.
• Not suitable for study participation due to other reasons at the discretion of the investigators        

• Able to understand the goals of the study and provide informed consent.
• Any hospitalized patient scheduled for a first-time sternotomy or thoracotomy under the care of Mayo Clinic cardiovascular inpatient service or thoracic inpatient service admitted after 1 February 2020, who is not excluded due to criteria listed below.
• Between the ages of 21 and 80 years old.
• English speaking.

• Unable to consent to study due to cognitive difficulty.
• Current diagnosis of epilepsy, dementia, or other neurological disease that may prevent use of virtual reality (VR) hardware and software.
• Sensitivity to flashing light or motion.
• Patients who received anxiolytic drugs or sedatives within the preceding 24 hours.
• Recent stroke.
• Post-transplant patient, or pre-transplant patient with severe illness.
• At the time of in-room virtual reality (VR) administration, patient on ventilator, is receiving BiPAP or CPAP, or other breathing assistance equipment.
• Injury to the eyes, face, neck, or arms that prevents comfortable use of VR hardware or software, or safe use of the hardware (e.g., open sores, wounds, or skin rash on face).
• Non-English speaking.

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

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

Eligibility last updated 7/27/22. Questions regarding updates should be directed to the study team contact.

Key

Eligibility last updated 7/12/22. Questions regarding updates should be directed to the study team contact.

• Age ≥ 18.
• Blood cancer diagnosis (including B-ALL, multiple myeloma, and lymphoma).
• Receiving a CAR-T product.
• Able to complete a written questionnaire in English either at home or with assistance at an appointment.
• Able to perform a verbal interview either in person or via phone teleconference.

• Severe cognitive deficit of neuropsychiatric condition that would prevent person from being able to provide informed consent or complete survey or interview questions.

Eligibility last updated 6/3/22. Questions regarding updates should be directed to the study team contact.

Registration
•Inclusion Criteria

• Age ≥ 18 years.
• Diagnosed with cancer and receiving chemotherapy.
• Able to provide informed consent.
• Willingness to complete questionnaires.
• ECOG Performance Status (PS) 0, 1, 2.
• One or more of the following nasal symptoms for which the patient reports they would appreciate treatment. Symptoms must have started after the initiation of systemic, antineoplastic therapies, be attributed to the systemic, antineoplastic therapies, and symptoms must be reported  as being moderate (corresponding to a score of 2) or worse on a scale from mild (1) to very severe (4) on at least one of the items below.
• Dryness;
• Discomfort/Pain;
• Bleeding;
• Scabbing;
• Sores.

 Registration
•

• Predisposition to epistaxis prior to the initiation of cancer-directed therapy (more than once a month over the previous year).
• Planned initiation or continuation of any topical nasal treatment other than the studied nasal spray,( such as nasal steroids, Ayr nasal gel, Neosporin ointment or nasal administration of petroleum jelly).  Taking Imitrex for migraines is acceptable.
• Previous exposure to rose geranium in sesame oil nasal spray.
• Concurrent upper respiratory tract infection.
• History of allergic or other adverse reactions to sesame oil or essential rose geranium oil.
• Any other reason that the study clinician or investigator feels precludes safe or appropriate inclusion in this study.

Re-Registration:

• The patient will be un-blinded and determined to have been on the saline arm, when initially randomized.

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

Eligibility last updated 8/24/22. Questions regarding updates should be directed to the study team contact.

Registration
•Inclusion Criteria

• Age ≥ 18 years.
• Diagnosed with cancer and receiving chemotherapy.
• Able to provide informed consent.
• Willingness to complete questionnaires.
• ECOG Performance Status (PS) 0, 1, 2.
• One or more of the following nasal symptoms for which the patient reports they would appreciate treatment. Symptoms must have started after the initiation of systemic, antineoplastic therapies, be attributed to the systemic, antineoplastic therapies, and symptoms must be reported  as being moderate (corresponding to a score of 2) or worse on a scale from mild (1) to very severe (4) on at least one of the items below.
• Dryness;
• Discomfort/Pain;
• Bleeding;
• Scabbing;
• Sores.

 Registration
•

• Predisposition to epistaxis prior to the initiation of cancer-directed therapy (more than once a month over the previous year).
• Planned initiation or continuation of any topical nasal treatment other than the studied nasal spray,( such as nasal steroids, Ayr nasal gel, Neosporin ointment or nasal administration of petroleum jelly).  Taking Imitrex for migraines is acceptable.
• Previous exposure to rose geranium in sesame oil nasal spray.
• Concurrent upper respiratory tract infection.
• History of allergic or other adverse reactions to sesame oil or essential rose geranium oil.
• Any other reason that the study clinician or investigator feels precludes safe or appropriate inclusion in this study.

Re-Registration:

• The patient will be un-blinded and determined to have been on the saline arm, when initially randomized.

Inclusion Criteria
•Healthy Volunteers:

• Male and female volunteers aged 18-80 years old.
• No significant medical conditions or gastrointestinal symptoms by interview or questionnaire:
  • Having capacity to provide written informed consent before participating in the study;
  • Able to communicate adequately with the investigator and to comply with the requirements for the entire study.

Inclusion Criteria
•Patients:

• Male and female volunteers aged 18-80 years.
• Persistent upper gastrointestinal symptoms (nausea, vomting, bloating, post prandial fullness or post prandial pain) for > 6 months.
• Having capacity to provide written informed consent before participating in the study.
• Able to communicate adequately with the investigator and to comply with the requirements for the entire study.

Exclusion Criteria
•Healthy Volunteers and Symptomatic Patients: 

• Severe nausea or vomiting, which may preclude study assessments.
• Use of medications that, in the opinion of the investigator have the potential, to alter GI motility (e.g., narcotics, medications with significant anticholinergic effects, prokinetic agents) and which cannot be discontinued for 4 half-lives prior to the imaging studies.
• Clinical evidence of significant cardiovascular, respiratory, renal, hepatic, gastrointestinal, hematological, neurological, psychiatric or other disease that may interfere with the objectives of the study.  A history of inflammatory bowel disease (e.g, Crohn’s disease or ulcerative colitis).  However, participants with microscopic or collagenous colitis will be eligible to participate.
• Prior gastric or major intestinal (i.e., resection of > 50 cm) or colonic surgery (i.e., hemi or subtotal colectomy).  Appendectomy, cholecystectomy, tubal ligation, hysterectomy, herniorrhaphy, and limited colonic resection are permissible.
• Participants who are allergic to eggs or decline to consume milk.
• History of radiation therapy to the abdomen.
• Pregnant women, breast-feeding women, prisoners and institutionalized individuals.
• Treatment with GLP-1 agonists and amlyin which cause vagal blockade and may affect central processing of pain.
• Positive tissue transglutaminase antibodies (TTG).
• Poor peripheral venous access, if central venous access is not available.
• Any other condition or prior therapy that, in the opinion of the investigator, would make the patient unsuitable for the study.

• Pathologically (histologically or cytologically) proven diagnosis of recurrent or persistent ovarian endometrioid or clear cell carcinoma, OR recurrent or persistent endometrioid endometrial adenocarcinoma; patients with recurrent endometrial cancer must have mismatch repair (MMR) immunohistochemistry completed; if they are found to be mismatch repair deficient, they should be offered treatment with immune checkpoint inhibition before consideration for treatment on trial; primary ovarian tumors must be at least 50% endometrioid or clear cell morphology, or have histologically documented recurrence with at least 50% endometrioid or clear cell morphology; institutional pathology reports must be provided indicating at least 50% endometrioid or clear cell morphology for ovarian tumors (primary or recurrent lesions).
• All patients must have measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1; measurable disease is defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded); each lesion must be ≥ 10 mm when measured by computed tomography (CT), magnetic resonance imaging (MRI) or caliper measurement by clinical exam; or ≥ 20 mm when measured by chest x-ray; lymph nodes must be > 15 mm in short axis when measured by CT or MRI.
• Patients must have had at least one, but no more than 3, prior cytotoxic regimens for management of primary disease; unlimited prior hormonal therapy, targeted therapy (including immunotherapy) or antiangiogenic therapy will be permitted.
• Patients must have completed prior therapy:
  • Chemotherapy: cytotoxic
    • At least 28 days since last dose of chemotherapy prior to registration.
  • Chemotherapy: nitrosoureas
    • At least 6 weeks since last dose of chemotherapy prior to registration.
  • Chemotherapy: non-cytotoxic (e.g. small molecule inhibitor)
    • At least 28 days since last dose of chemotherapy prior to registration.
  • Monoclonal antibody(ies)
    • At least 28 days since last dose of monoclonal antibody prior to registration.
  • Immunotherapy
    • At least 28 days since last dose of immunotherapy prior to registration.
  • Radiotherapy (RT)
    • At least 14 days from last local site RT prior to registration,
    • At least 21 days from stereotactic radiosurgery prior to registration.
    • At least 12 weeks from craniospinal, ≥ 50% radiation of pelvis or total body irradiation prior to registration.
    • Patients with central nervous system (CNS) disease should demonstrate evidence of stabilization after the 28-day time point after definitive treatment.
    • Full recovery of radiation related side effects prior to registration.
    • All subjects must have evidence of measurable disease outside of the radiation field at the time of registration.
• Appropriate stage for study entry based on the following diagnostic workup:
  • History/physical examination within 14 days prior to registration;
  • Imaging of the chest, abdomen and pelvis within 28 days prior to registration.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2 within 14 days prior to registration.
• Platelets ≥ 100,000/mcl (within 14 days prior to registration).
• Absolute neutrophil count (ANC) ≥ 1,500/mcl (within 14 days prior to registration).
• Hemoglobin (Hgb) ≥ 8 g/dL (within 14 days prior to registration).
• Differential with no clinically significant morphologic abnormalities on complete blood count (CBC) testing; manual differential is encouraged, if clinically indicated, and in cases where an automated differential is abnormal (within 14 days prior to registration).
• Creatinine ≤ 1.5 x institutional/laboratory upper limit of normal (ULN) (within 14 days prior to registration).
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 x ULN (within 14 days prior to registration).
• Total serum bilirubin level ≤ 1.5 x ULN; direct bilirubin ≤ ULN for subjects with total bilirubin > 1.5 x ULN (patients with isolated indirect bilirubin elevations and a history of Gilbert's syndrome are eligible) (within 14 days prior to registration).
• Women of childbearing potential must be willing and able to use adequate contraception (hormonal and barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 30 days after the last dose of study agent; should a woman become pregnant or suspect she is pregnant while she is participating in this study, she should inform her treating physician immediately; theoretically, CYP3A induction with tazemetostat use may result in the loss of efficacy in hormonal contraceptives, thus a barrier method of contraception must be used in addition to hormonal contraceptives due to the potential drug-drug interaction with tazemetostat.
• The patient or a legally authorized representative must provide study-specific informed consent and authorization permitting release of personal health information prior to study entry.
• Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial.

• Prior treatment with an investigational EZH2 inhibitor.
• Patients who are unable to swallow pills or absorb orally administered medication.
• A prior history of myeloid malignancies, including myelodysplastic syndrome (MDS).
• Abnormalities known to be associated with MDS (e.g., del 5q, chr 7 abn) and myeloproliferative neoplasms (MPN) (e.g., JAK2 V617F) observed in cytogenetic testing and deoxyribonucleic acid (DNA) sequencing.
• A prior history of T-cell lymphoblastic lymphoma (T-LBL)/T-cell acute lymphoblastic leukemia (T-ALL).
• Severe, active co-morbidity per the treating investigator's discretion.
• Pregnant or lactating patients.
• Known human immunodeficiency virus (HIV) positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with tazemetostat; in addition, treatments involved in this protocol may be immunosuppressive, increasing the risk of lethal infections in this patient population.
• Treatment with strong inhibitors or inducers of CYP3A within 14 days of registration and during the study treatment.