Subjects will be recruited from approved  FMT (Fecal Microbiota Transplant) donors at Mayo Clinic Rochester campus.  All donors to the FMT program will be asked to take part in this study.  

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.

• At least 22 years old and no older than 75 years old at the time of enrollment.
• Non-progressive cervical spinal cord injury from C2-C8 inclusive.
• American Spinal Injury Association (ASIA) Impairment Scale (AIS) classification B, C, or D.
• Indicated for upper extremity training procedures by subject's treating physician or a physical therapist.
• Baseline GRASSP-Prehension score ≥ 10 or GRASSP-Strength score ≥ 30.
• Minimum 12 months post-injury.
• Titration of baclofen to 10 mg or less at night.
• On stable spasticity and pain medications for at least 4 weeks prior to enrollment.
• Capable of providing informed consent.

• Has uncontrolled cardiopulmonary disease or cardiac symptoms as determined by the Investigator.
• Has any unstable or significant medical condition that is likely to interfere with study procedures or likely to confound study endpoint evaluations like severe neuropathic pain, depression, mood disorders or other cognitive disorders.
• Has been diagnosed with autonomic dysreflexia that is severe, unstable, and uncontrolled.
• Requires ventilator support.
• Has an autoimmune etiology of spinal cord dysfunction/injury.
• Previously diagnosed as having transverse myelitis.
• History of additional neurologic disease such as stroke, multiple sclerosis, traumatic brain injury, etc.
• Peripheral neuropathy (diabetic polyneuropathy, entrapment neuropathy, etc.).
• Spasms that limit the ability of the subjects to participate in the study training as determined by the Investigator.
• Received Botulinum toxin injections in their upper extremity, neck or hand within 6 months prior to enrollment.
• Has painful musculoskeletal dysfunction unrelated to SCI, unhealed fracture, contracture, pressure sore, or urinary tract infection at time of enrollment.
• Breakdown in skin area that will come into contact with electrodes.
• Presence of syringomyelia as confirmed by an MRI.
• Currently undergoing treatment for cancer or has been in remission for less than 2 years.
• Received stem cell treatment within the past two years prior to enrollment.
• Has any active implanted medical device.
• Pregnant, planning to become pregnant or currently breastfeeding.
• Concurrent participation in another drug or device trial that may interfere with this study.
• Has undergone a prior course of NESS therapy directed at UE improvement.
• In the opinion of the investigators, the study is not safe or appropriate for the participant.

• ≥ 18 years of age.
• Presence of an external traumatic event that results in a spinal cord injury, including surgical procedures, radiation, and medical complications.
• Temporary or permanent loss of sensory and/or motor function as a result of the traumatic event.
• Admission to the database within one year of injury.
• If patient is discharged as Minimal Deficit or Recovered, they must be hospitalized in the system for at least one week before discharge.
• Discharge from the system as:
  • Having completed inpatient acute rehabilitation;
  • Achieving a neurologic status of normal or minimal deficit;
  • Deceased.
• Reside in the geographic catchment area of the system (greater Minnesota, Iowa, North Dakota, South Dakota, and western Wisconsin) at the time of the injury. Patients may be injured outside of the catchment area.
• A US citizen or non-US citizen who is expected to stay in the catchment area.

• Completion of an organized rehabilitation program prior to the admission to the system.
• Patients who are discharged as deceased.

• Subject must have one of the clinical indications before device implant in adherence with Medicare, ACC/AHA/HRS/ESC single chamber pacing guidelines including:
  • Chronic and/or permanent atrial fibrillation with 2° or 3° AV or bifascicular bundle branch block (BBB block), including slow ventricular rates (with or without medication) associated with atrial fibrillation; or
  • Normal sinus rhythm with 2° or 3° AV or BBB block and a low level of physical activity or short expected lifespan (but at least one year); or
  • Sinus bradycardia with infrequent pauses or unexplained syncope with EP findings; and
  • Subject is ≥ 18 years of age; and
  • Subject has a life expectancy of at least one year; and
  • *Subject is not enrolled in another clinical investigation; and
  • Subject is willing to comply with clinical investigation procedures and agrees to return for all required follow-up visits, tests, and exams; and
  • Subject has been informed of the nature of the study, agrees to its provisions and has provided a signed written informed consent, approved by the IRB/EC; and
  • Subject is not pregnant and does not plan to get pregnant during the course of the study.

• Subject has known pacemaker syndrome, has retrograde VA conduction, or suffers a drop in arterial blood pressure with the onset of ventricular pacing; or
• Subject is allergic or hypersensitive to < 1 mg of dexamethasone sodium phosphate (DSP);
• Subject has a mechanical tricuspid valve prosthesis; or
• Subject has a pre-existing endocardial pacing or defibrillation leads; or
• Subject has current implantation of either conventional or subcutaneous implantable cardioverter defibrillator (ICD) or cardiac resynchronization therapy (CRT) device; or
• Subject has an implanted vena cava filter; or
• Subject has evidence of thrombosis in one of the veins used for access during the procedure; or
• *Subject had recent cardiovascular or peripheral vascular surgery within 30 days of enrollment; or
• Subject has an implanted leadless cardiac pacemaker; or 
• *Recent cardiovascular or peripheral vascular surgery within 30 days of enrollment is defined as the following:
  • Percutaneous valvular correction ≤ 30 days;
  • Femoral or abdominal vascular procedure involving incisional access ≤ 30 days;
  • Peripheral arterial endovascular procedure or surgery ≤ 30 days;Cardiac surgery ≤ 72 hrs with ongoing complications, ongoing mediastinal drainage, or re-do sternotomy attributed to bleeding ≤ 30 days;
  • Tricuspid valve replacement or annuloplasty ≤ 30 days;
  • Any endovascular procedure with specified complication ≤ 30 days;
  • Femoral access site-vascular complication including hematoma requiring transfusion, surgical intervention or prolongation of hospitalization, arterio-venous fistula, pseudoaneurysm or tear;
  • New pericardial effusion more than trivial/mild, or requiring percutaneous/surgical drainage.
  • Acute deep venous thrombosis.

Eligibility last updated 8/19/21. Questions regarding updates should be directed to the study team contact.

• Male or female.
• 18 to 80 years of age, inclusive.
• Lack of cortisol suppression (> 1.8 μg/dL serum cortisol with adequate dexamethasone levels) on either 1-mg overnight or 2-mg 48-hour DST during Screening.
• Suppressed or low (≤15 pg/mL) early-morning ACTH levels on at least 2 occasions during Screening.
• A radiologically confirmed benign adrenal lesion (single adenoma, multiple adenomas, hyperplasia [≥ 3 times the size of the normal adrenal gland]) within 3 years prior to screening
• Has at least 1 of the following at Baseline:
  • DM (fasting plasma glucose ≥ 126 mg/dL and/or 2-hour oGTT plasma glucose ≥ 200  mg/dL at 2 hours, or HbA1c ≥ 6.5%), or IGT (plasma glucose ≥ 140 mg/dL and < 200 mg/dL on a 2-hour oGTT) (American Diabetes Association 2020);
  • Systolic hypertension (mean SBP ≥ 130 to ≤ 170 mm Hg) based on 24-hour ABPM (Parati et al. 2014).
• If receiving medical treatment for DM/IGT or hypertension,there has been no increase in medication dosage for at least 4 weeks prior to Baseline assessment.
• For women of childbearing potential, has a negative serum pregnancy test at Screening and negative urine pregnancy test at Baseline.

• Has severe, uncontrolled hypertension (mean SBP > 170 mm Hg or mean DBP > 110 mm Hg at Screening), based on 24-hour ABPM.
• Has poorly controlled DM (HbA1c > 12% at Screening).
• Has DM Type 1. 
• Has abnormal liver test results (total bilirubin >1.5 × ULN or elevated alanine aminotransferase or aspartate aminotransferase > 3 × ULN at Baseline).
• Has severe renal insufficiency (glomerular filtration rate ≤ 29 mL/min at Baseline).
• Has uncontrolled, clinically significant hypothyroidism or hyperthyroidism.
• Has prolonged QT interval corrected for heart rate using Fridericia’s equation (QTcF) (> 450 ms for men and > 470 ms for women) with normal QRS interval (500 ms with wide QRS interval (≥ 120 ms).
• Has persistent atrial fibrillation.
• Has used or plans to use any treatments for Cushing syndrome within 12 weeks prior to Screening and throughout the study, including mifepristone, metyrapone, osilodrostat, ketoconazole, fluconazole, or any investigational drug for treatment of Cushing syndrome.
• Patients who require inhaled glucocorticoids and have no alternative option if their condition deteriorates during the study.
• Has adrenocortical carcinoma.
• Has pseudo-Cushing syndrome. Patients with known or suspected pseudo-Cushing syndrome based on medical history (such as patients with severe obesity, major depression, or a history of alcoholism) should undergo a dexamethasone-CRH/DDAVP stimulation test (Yanovski et al.1993, Giraldi et al. 2007, Yanovski et al. 1998) to rule-in or rule-out this possibility.
• Has a history of cyclic Cushing syndrome with fluctuating clinical manifestations.
• Has autonomous cosecretion of aldosterone.
• Has plans for adrenalectomy or nodulectomy during the study, including follow-up.
• Has taken any non-Cushing syndrome investigational drug within 4 weeks prior to Baseline, or within less than 5 times the drug’s half-life, whichever is longer.
• Ongoing use of antidiabetic, antihypertensive, antidepressant or lipid-lowering medications that are highly dependent on CYP3A for clearance and that cannot undergo dose modification upon coadministration with strong CYP3A inhibitors.
• Ongoing use of any strong CYP3A4 inducer or any other prohibited medications.
• Is pregnant or lactating.
• Is a female patient of childbearing potential who cannot use a highly effective method of contraception (including all women < 50 years old, women whose surgical sterilization was performed < 6 months ago, and women who have had a menstrual period in the last 2 years).
• Has an acute or unstable medical problem that could be aggravated by treatment with the investigational study drug.
• Has a history of severe reaction to the study drug, to a similar class of drug, or to the study drug’s excipient.
• In the Investigator’s opinion, should not participate in the study or may not be capable of following the study schedule.
• Has known HIV, hepatitis B, or hepatitis C infection and is taking medication for treatment of HIV, hepatitis B, or hepatitis C infection.
• Has used mitotane prior to Baseline.

Eligibility last updated 2/16/22. Questions regarding updates should be directed to the study team contact.

PRE-REGISTRATION

• Histologically confirmed glioblastoma (World Health Organization [WHO] grade IV) presenting at first or second recurrence including secondary glioblastoma.
• Presence of measurable disease, as defined by a bidimensionally measurable lesion on magnetic resonance imaging (MRI) with a minimum diameter of 10 mm in both dimensions, prior to resection or biopsy of recurrent tumor.
• Tissue available from surgical resection or biopsy of recurrent tumor ≤ 14 days prior to pre-registration, or planned surgery or biopsy of recurrent tumor ≤ 14 days after pre-registration.
• Does not require > 4 mg dexamethasone beyond the perioperative period defined as the time ≤ 2 weeks after surgical procedure.
• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.
• Able to undergo brain MRI with contrast.
• Absolute neutrophil count ≥ 1500/mm^3.
• Platelet count ≥ 100,000/mm^3.
• Total bilirubin ≤ 1.5 x upper limit of normal (ULN).
• If Gilbert syndrome, then total bilirubin ≤  3 x ULN.
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.0 x ULN.
• Creatinine ≤ 1.5 x ULN OR creatinine clearance (CrCl) ≥ 50 mL/min (if using the Cockcroft-Gault formula).

REGISTRATION

• Tissue obtained from biopsy or resection at first or second recurrence exhibits TMB ≥ 20 on FoundationOne CDx testing.

• No active autoimmune disease or history of autoimmune disease.
• These include but are not limited to patients with a history of immune related neurologic disease, multiple sclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome, myasthenia gravis; systemic autoimmune disease such as systemic lupus erythematosus (SLE), connective tissue diseases, scleroderma, inflammatory bowel disease (IBD), Crohn's, ulcerative colitis, hepatitis; and patients with a history of toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, or phospholipid syndrome should be excluded because of the risk of recurrence or exacerbation of disease.
• Patients with vitiligo, endocrine deficiencies including thyroiditis managed with replacement hormones including physiologic corticosteroids are eligible.
• Patients with rheumatoid arthritis and other arthropathies, Sjogren's syndrome and psoriasis controlled with topical medication and patients with positive serology, such as antinuclear antibodies (ANA), anti-thyroid antibodies should be evaluated for the presence of target organ involvement and potential need for systemic treatment but should otherwise be eligible.
• No prior treatment with checkpoint blockade therapies (anti-CTLA4, anti-PD1/PD-L1) or bevacizumab.

• Age ≥ 18 years.
• Women with an initial pathologically confirmed diagnosis of stage I-III, hormone receptor positive, HER2-neu negative, invasive breast cancer within 18 months prior to enrollment.
• Women who have undergone neo-adjuvant chemotherapy who have no residual invasive disease post-surgery are eligible based on an initial pathologically confirmed diagnosis.
• Hormone receptor positive is defined as estrogen receptor (ER) and/or progesterone receptor (PR) of > 1%.
• HER2-neu negative is defined as 0-1+ by immunohistochemical (IHC) analysis, or non-amplified by fluorescence in situ hybridization (FISH) analysis.
• Patients must have received cancer-directed surgery, and/or completed all other adjuvant therapy, except reconstruction.
• Patients must have initiated an endocrine therapy drug within the 6 months prior to registration, OR have received a prescription with stated intent to initiate within 6 weeks after registration.
• No history of previous cancer as follows:
  • Invasive or non-invasive breast cancer at any time.
  • Non-breast cancer, within the past 5 years, excluding non-melanoma skin cancer.
• Patients must be willing to use a smart phone for study activities.
• Patient is NOT to be deemed ineligible during the recruitment process if they do not have a smart phone.
• If a participant does not own a smart phone or has limited data or texting capabilities or their smart phone cannot support the Alliance electronic patient reported outcomes (ePRO) survey application (app), a smart phone and service can be provided to the participant at no cost through the Ohio State University (OSU) partnership with Verizon Wireless for the duration of the study activities.
• The CRP is ONLY to discuss this option with those patients who self-identify a phone-related barrier to participation, including: lack of a smart phone, insufficient phone plan (minutes/text/data), or a smart phone incompatible with the Alliance ePRO app.
• For OSU provided phones, charges will be paid by the grant through the intervention period. At the end of the 12-month intervention period, patients will be responsible for paying monthly fees, if continued service is desired. The physical phones will belong to the patients at the end of their study activities.
• Patients must be willing to use a Pillsy medication event monitoring system for the duration of study participation.
• In order to complete the mandatory patient-completed measures, participants must be able to speak and read English.

• Age ≥ 18 years.
• Radiologically presumed or histologically proven, newly diagnosed or recurrent, hepatocellular carcinoma.
• Clinical Stage T0-T4N0M0 (AJCC 8th edition).
• One to three discrete Liver Reporting and Data System—5  (LIRADS-5) lesions that can be encompassed within a single radiation treatment plan.
• Patients treated with external beam radiation as a bridge to transplant are allowed.
• Minimum single lesion size ≥ 1cm, Maximum cumulative diameter ≤ 15cm
• Vascular involvement (including portal vein, inferior vena cava (IVC) and/or hepatic vein) is allowed
• Target lesion must be amenable to a SBRT regimen utilizing proton beam therapy (i.e., SBPT).
• Prior local liver treatment including surgery, percutaneous ablation, transarterial bland or chemoembolization (TACE), or Y-90 radioembolization is allowed if         completed at least 6 weeks prior to treatment start date.       
• ECOG Performance Status (PS) 0 to 2. 
• Life expectance ≥ 3 months based on medical comorbidities, tumor extent and other clinical factors as determined by treating physician.
• Child Pugh Score of A or B7
• All blood work within 45 days of study entry with laboratory values to maintain adequate bone marrow function as below:
  • Absolute neutrophil count (ANC) ≥ 1000 cells/mm^3;
  • Patelets (Plt) ≥ 30,000 cells/mm^3 (the use of transfusion or other intervention to achieve the minimum platelet level is allowed);
  • Hemoglobin (Hgb) ≥ 8.0 g/dL (the use of transfusion or other intervention to achieve the minimum hemoglobin level is allowed);
  • Total bilirubin < 2 mg/dL.
• Able to and provides IRB approved study specific written informed consent.
• Willing to return to enrolling institution for follow-up (during the active monitoring phase of the study).
• Enrollment on a second independent protocol is allowed if the second  protocol does intervention will not significantly results of the current protocol as determined by the study investigators. 

• Medical contraindication to receipt of radiotherapy.
• Severe active co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens.
• Uncontrolled concurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements or providing informed consent.
• Active systemic lupus or scleroderma.
• Women of childbearing potential who are sexually active and not willing/able to use medically acceptable forms of contraception.
• Prior receipt of external beam radiation to the current active disease site or if additional radiotherapy to the current site would be unsafe as determined by the treating radiation oncologist.
• More than 3 LIRADS-5 lesions or disease extent. 
• Tumor extension into common or main branch biliary duct or adjacent organs including stomach, small or large bowel. 
• Extrahepatic metastases or lymph node involvement.
• History of other malignancies (except for in situ cancers treated only by local excision and basal cell and squamous cell carcinomas of the skin) within 1 year prior to study entry.
• Patient is unable to undergo intravenous contrast enhanced liver imaging (either CT or MRI) based on clinical imaging protocols established at the treating institution.

• 18 years of age or older at time of consent.
• Diagnosed with Fibromyalgia.
• Not pregnant by subject self-report at time of consent.
• Have the ability to provide informed consent.
• Have the ability to complete all aspects of this trial.
• Have access to a  iPhone, iPad, Android device.
• Has no contraindicating comorbid health condition as determined by the clinical investigators.

• Used or been enrolled in any treatments for fibromyalgia, or pain  within the past 30 days.
• Used an investigational drug within the past 30 days.
• Currently (within the past 3 weeks) been practicing mindfulness training on a weekly/regular basis.
• Currently (within the past 3 weeks) been undergoing an additional program (e.g., CAM) to improve quality of life.
• Currently (within 3 weeks) been enrolled in another clinical or research program (e.g., CAM) which intervenes on the patients’ QOL, or stress.
• An unstable medical or mental health condition as determined by the physician investigator.

• 18 years of age or older.
• Community members in the catchment area.

• Under the age of 18.

KEY ELIGIBILITY CRITERIA

Eligibility last updated 9/28/22. Questions regarding updates should be directed to the study team contact.

• Age ≥ 18 years.
• Women with an initial pathologically confirmed diagnosis of stage I-III, hormone receptor positive, HER2-neu negative, invasive breast cancer within 18 months prior to enrollment.
• Women who have undergone neo-adjuvant chemotherapy who have no residual invasive disease post-surgery are eligible based on an initial pathologically confirmed diagnosis.
• Hormone receptor positive is defined as estrogen receptor (ER) and/or progesterone receptor (PR) of > 1%.
• HER2-neu negative is defined as 0-1+ by immunohistochemical (IHC) analysis, or non-amplified by fluorescence in situ hybridization (FISH) analysis.
• Patients must have received cancer-directed surgery, and/or completed all other adjuvant therapy, except reconstruction.
• Patients must have initiated an endocrine therapy drug within the 6 months prior to registration, OR have received a prescription with stated intent to initiate within 6 weeks after registration.
• No history of previous cancer as follows:
  • Invasive or non-invasive breast cancer at any time.
  • Non-breast cancer, within the past 5 years, excluding non-melanoma skin cancer.
• Patients must be willing to use a smart phone for study activities.
• Patient is NOT to be deemed ineligible during the recruitment process if they do not have a smart phone.
• If a participant does not own a smart phone or has limited data or texting capabilities or their smart phone cannot support the Alliance electronic patient reported outcomes (ePRO) survey application (app), a smart phone and service can be provided to the participant at no cost through the Ohio State University (OSU) partnership with Verizon Wireless for the duration of the study activities.
• The CRP is ONLY to discuss this option with those patients who self-identify a phone-related barrier to participation, including: lack of a smart phone, insufficient phone plan (minutes/text/data), or a smart phone incompatible with the Alliance ePRO app.
• For OSU provided phones, charges will be paid by the grant through the intervention period. At the end of the 12-month intervention period, patients will be responsible for paying monthly fees, if continued service is desired. The physical phones will belong to the patients at the end of their study activities.
• Patients must be willing to use a Pillsy medication event monitoring system for the duration of study participation.
• In order to complete the mandatory patient-completed measures, participants must be able to speak and read English.

• Patients must have relapsed and/or refractory myeloma and be experiencing disease relapse.
• Patients must have measurable disease by International Myeloma Working Group (IMWG) criteria (any of the following):
  • Serum M-protein ≥ 0.5 g/dL or for IgA myeloma, an elevated IgA level by quantitative IgA nephelometry;
  • Urine M-protein ≥ 200 mg in a 24-hour collection; 
  • Serum free light chain level ≥ 10 mg/dL with an abnormal free light chain ratio;
  • Measurable plasmacytoma by cross sectional imaging (computed tomography [CT], magnetic resonance imaging [MRI] or [18F]-fluorodeoxyglucose positron emission tomography with CT [FDG PET/CT]); 
  • 20% or more light chain restricted, clonal plasma cells in the bone marrow.
• At least two prior lines of therapy and all patients should have at least been exposed to a proteasome inhibitor (PI), an immunomodulatory drug (IMiD), and an anti-CD38 antibody.
• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 (Karnofsky >= 60%).
• Leukocytes ≥ 3,000/mcL.
• Absolute neutrophil count ≥ 1,000 cells/mm3 without growth factors (within 14 days of enrollment). 
• Hemoglobin ≥ 8 g/dL (within 14 days of enrollment)
• Platelets ≥ 50,000 cells/mm3 (≥ 30,000 cells/mm3 if bone marrow plasma cells ≥ 50% at enrollment).
• Total bilirubin ≤ 1.5 x upper limit of normal (ULN).
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) ≤ 3 x institutional ULN.
• Creatinine ≤ institutional ULN OR glomerular filtration rate (GFR) ≥ 40 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal.
• Willingness to undergo interim bone marrow biopsy/aspiration for clinical purposes.
• Negative pregnancy test done ≤ 7 days prior to registration, for women of childbearing potential only. 
  • The effects of CB-839 HCl on the developing human fetus are unknown. For this reason and because carfilzomib caused embryo-fetal toxicity in pregnant rabbits at doses lower than the recommended dose, women of child-bearing potential and men must agree to use two effective methods of contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and 4 months after completion of CB-839 HCl, carfilzomib, and dexamethasone administration. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of CB-839 HCl, carfilzomib, and dexamethasone administration.
• Ability to understand and the willingness to sign a written informed consent document.

• Patients who are refractory or intolerant to carfilzomib (prior carfilzomib exposure accepted).
• Patients who have received recent prior chemotherapy with:
  • alkylators (e.g., melphalan, cyclophosphamide) and anthracyclines ≤ 14 days prior to registration;
  • high dose corticosteroids and immunomodulatory drugs (thalidomide or lenalidomide) ≤ 7 days prior to registration; or
  • monoclonal antibodies ≤ 14 days prior to registration.
• Patients who have not recovered from AEs due to prior anti-cancer therapy (i.e., have residual toxicities > grade 1 except peripheral neuropathy).
• Patients who are receiving any other investigational agents.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to CB-839 HCl (telaglenastat), carfilzomib, or dexamethasone.
• Patients with uncontrolled intercurrent illness.
• Any of the following: 
  • Pregnant women or women of reproductive ability who are unwilling to use two effective methods of contraception from the time of signing the informed consent form through 4 months after the last dose of study drug, nursing women, and men who are unwilling to use birth control while taking the drug and for 4 months after stopping treatment;
  • Pregnant women are excluded from this study because carfilzomib is a PI with the potential for abortifacient effects. Because there is an unknown but potential risk for AEs in nursing infants secondary to treatment of the mother with CB-839 HCl (telaglenastat), carfilzomib, and dexamethasone, breastfeeding should be discontinued if the mother is treated with this drug combination.
• Adverse cardiac history (unstable angina, myocardial infarction less than 4 months, New York Heart Association [NYHA] class III or IV congestive heart failure [CHF], ejection fraction [EF] <40%, uncontrolled arrhythmias).
• Concomitant high dose corticosteroids other than what is part of treatment protocol (concurrent use of corticosteroids).
  • EXCEPTION: Patients may be on chronic steroids (maximum dose 10 mg/day prednisone equivalent) if they are being given for disorders other than myeloma; e.g., adrenal insufficiency, rheumatoid arthritis, etc.
• Central nervous system (CNS) involvement.
• Patients with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other AEs.
• Concurrent amyloid light-chain (AL) amyloidosis.
• No history of other active malignancies, including myelodysplastic syndromes (MDS), within the past 3 years with the following exceptions:
  • Adequately treated in situ carcinoma of the cervix uteri or the breast;
  • Basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin;
  • Prostate cancer Gleason grade 6 or lower AND with stable Prostate Specific Antigen (PSA) levels not receiving any current therapy; or
  • Previous malignancy with no current evidence of disease, and which was confined and surgically resected (or treated with other modalities) with curative intent and unlikely to impact survival during the duration of the study.
• Patient has ≥ grade 3 peripheral neuropathy or grade 2 with pain on clinical examination during the screening period.
• Major surgery within 14 days before study registration.
• On concurrent treatment with an HIV protease inhibitor. HIV protease inhibitors can affect the unfolded protein response in myeloma cells as well as the activity of PIs.
• Any serious medical or psychiatric illness that could, in the investigator’s opinion, potentially interfere with the completion of treatment according to this protocol.
• Known GI disease or GI procedure that could interfere with the oral absorption or tolerance of CB-839 HCl (telaglenastat) including difficulty swallowing, refractory vomiting, gastric resection or bypass, or duodenal/jejunal resection.

• Males and females, ≥ 18 years of age. 
• Subjects with postsurgical chronic HP, or auto-immune, genetic, or idiopathic HP for at least 26 weeks. Diagnosis of HP is established based on historic hypocalcemia in the setting of inappropriately low serum PTH levels.
• Requirement for doses of SoC (e.g., calcitriol, alfacalcidol, calcium supplements) at or above a minimum threshold:
  • For countries other than Japan: requirement for a dose of calcitriol ≥ 0.5 μg/day, or alfacalcidol ≥ 1.0 μg/day and (elemental) calcium ≥ 800 mg/day (e.g., calcium citrate, calcium carbonate etc.) for at least 12 weeks prior to Screening. In addition, the dose of calcitriol, or alfacalcidol, or calcium should be stable for at least 5 weeks prior to Screening;
  • For Japan: requirement for a dose of calcitriol ≥ 1.0 μg/day, or alfacalcidol ≥ 2.0 μg/day for at least 12 weeks prior to Screening. In addition, the dose of calcitriol or alfacalcidol should be stable for at least 5 weeks prior to Screening. In Japan only (due to local practice and dietary patterns), there is no requirement to exceed a minimum dose of calcium supplements.
• Optimization of supplements prior to randomization to achieve the target serum levels of:
  • 25(OH) vitamin D levels of 20-80 ng/mL (49-200 nmol/L); and
  • Magnesium level in the normal range, or just below the normal range; and
  • Albumin-adjusted or ionized sCa level in the normal range, or *just below the normal range; i.e.:
    • Albumin-adjusted sCa 7.8-10.6 mg/dL (or 1.95-2.64 mmol/L);
    • Ionized sCa 4.40-5.29 mg/dL (or 1.10-1.32 mmol/L) *Just below the normal range implies the numerical range of 7.8-8.2 mg/dL (or 1.95-2.06 mmol/L) for albumin-adjusted sCa and the numerical range of 4.40-4.636 mg/dL (or 1.10-1.159 mmol/L) for ionized sCa.
• The subject demonstrates a 24-hour uCa excretion of ≥ 125 mg/24h (on a sample collected within 52 weeks prior to Screening or during the Screening Period).
  • Note: Although 24-hour urine samples prior to Screening may be done on or off thiazide therapy, thiazide therapy is prohibited during the trial; and the 24-hour urine collection scheduled prior to Visit 1 must be done while off thiazides for at least 4 weeks prior to collection.
• BMI 17- 40 kg/m^2 at Screening.
• If ≤ 25 years of age, radiological evidence of epiphyseal closure based on X-ray of nondominant wrist and hand.
• Thyroid-stimulating hormone (TSH) within normal laboratory limits within the 6 weeks prior to Visit 1; if on suppressive therapy for a history of thyroid cancer, TSH level must be ≥ 0.2 mIU/mL.
• If treated with thyroid hormone replacement therapy, the dose must have been stable for at least 5 weeks prior to Screening.
• eGFR ≥ 30 mL/min/1.73 m^2 during Screening.
• Able to perform daily subcutaneous self-injections of study drug (or have a designee to perform injections) via a pre-filled injection pen.
• Able and willing to provide written and signed informed consent in accordance with GCP.
• For France only: The subject is obligated to be affiliated with, or beneficiary of a social security system or assimilated.

• Impaired responsiveness to PTH (pseudohypoparathyroidism) which is characterized as PTH-resistance, with elevated PTH levels in the setting of hypocalcemia.
• Any disease that might affect calcium metabolism or calcium-phosphate homeostasis or PTH levels other than HP, such as:
  • active hyperthyroidism;
  • Paget disease of bone;
  • severe hypomagnesemia;
  • type 1 diabetes mellitus or poorly controlled type 2 diabetes mellitus (HbA1C > 9%;
  • documented HbA1C result drawn within 12 weeks prior to Screening is acceptable);
  • severe and chronic liver, or renal disease;
  • Cushing syndrome;
  • multiple myeloma;
  • active pancreatitis;
  • malnutrition; rickets;
  • recent prolonged immobility; active malignancy (other than low-risk well differentiated thyroid cancer or basal cell skin cancer); active hyperparathyroidism;
  • parathyroid carcinoma within 5 years prior to Screening;
  • acromegaly; or
  • multiple endocrine neoplasia types 1 and 2 3. High risk thyroid cancer within 2 years, requiring suppression of TSH < 0.2 mIU/mL.
• Use of loop diuretics, phosphate binders (other than calcium supplements), digoxin, lithium, methotrexate, biotin > 30 μg/day, or systemic corticosteroids (other than as replacement therapy).
• Use of thiazide diuretic within 4 weeks prior to the 24-hour urine collection scheduled to occur within 1 week prior to Visit 1.
• Use of PTH-like drugs (whether commercially available or through participation in an investigational trial), including PTH(1-84), PTH(1-34), or other N-terminal fragments or analogs of PTH or PTH-related protein, within 4 weeks prior to Screening.
• Use of other drugs known to influence calcium and bone metabolism, such as calcitonin, fluoride tablets (> 0.5 mg/day), strontium, or cinacalcet hydrochloride, within 12 weeks prior to Screening.
• Use of osteoporosis therapies known to influence calcium and bone metabolism; i.e., bisphosphonate (oral or intravenous [IV]), denosumab, raloxifene, or romosozumab therapies within 2 years prior to Screening.
• Non-hypocalcemic seizure disorder with a history of a seizure within 26 weeks prior to Screening.
  • Note: History of seizures that occur in the setting of hypocalcemia is not exclusionary.
• Increased risk for osteosarcoma, such as those with Paget's disease of bone or unexplained elevations of alkaline phosphatase, hereditary disorders predisposing to osteosarcoma, or with a prior history of substantial external beam or implant radiation therapy involving the skeleton.
• Pregnant or lactating women. 
  • Note: Acceptable highly effective contraception (see Appendix 1) is required for sexually active women of childbearing potential during the trial and for 2 weeks after the last dose of study drug, and pregnancy testing will be performed throughout the trial. Sexually active women of childbearing potential who are unwilling to use acceptable highly effective contraception are excluded from the trial.
• Male who has a female partner who intends to become pregnant or is of childbearing potential and is unwilling to use adequate contraceptive methods during the trial.
  • Note: Male subjects must use a condom, or his female partner of childbearing potential must use an effective form of contraception from the beginning of screening to the last trial visit.
• Diagnosed drug or alcohol dependence within 3 years prior to Screening.
• Disease processes that adversely affect gastrointestinal absorption, including but not limited to short bowel syndrome, significant small bowel resection, gastric bypass, tropical sprue, active celiac disease, active ulcerative colitis, active Crohn's disease, gastroparesis and AIRE gene mutations with malabsorption.
• Chronic or severe cardiac disease within 26 weeks prior to Screening including but not limited to congestive heart failure, myocardial infarction, severe or uncontrolled arrhythmias, bradycardia (resting heart rate < 48 beats/minute, unless chronic and asymptomatic), symptomatic hypotension or systolic BP < 80 mm Hg or diastolic < 40 mm Hg or poorly controlled hypertension (systolic BP > 165 mm Hg or diastolic > 95 mm Hg). In the absence of a prior history of hypertension, an isolated BP > 165/95 in the setting of white coat hypertension/anxiety may not be exclusionary and a measurement can be repeated prior to randomization.
• Cerebrovascular accident within 5 years prior to Screening.
• Within 26 weeks prior to Screening: acute colic due to nephrolithiasis, or acute gout. Subjects with asymptomatic renal stones are permitted.
• Participation in any other interventional trial in which receipt of investigational drug or device occurred within 8 weeks (or within 5.5 times the half-life of the investigational drug (whichever comes first) prior to Screening.
• Any disease or condition that, in the opinion of the investigator, may require treatment or make the subject unlikely to fully complete the trial, or any condition that presents undue risk from the investigational product or procedures, including treated malignancies that are likely to recur within the approximate 3.5-year duration of the trial.
• Known allergy or sensitivity to PTH or any of the excipients [metacresol, mannitol, succinic acid, NaOH/(HCl)].
• Likely to be non-compliant with respect to trial conduct.
• Any other reason that in the opinion of the investigator would prevent the subject from completing participation or following the trial schedule.

• ≥ 18 years of age.
• Able to give informed consent; patients will be invited to consent via the portal.
• Have a US mailing address.  

• Current or previous within 2 months infection to SARS-CoV-2.
• No compatible smartphone to connect and run the AliveCor system (https://store.alivecor.com/products/kardiamobile).

• Ages 1 to 17 years.
• Diagnosed with positive HHT causing. mutations or based on Curacao criteria.

• Acute respiratory distress.
• Unstable cardiovascular status.
• Pneumothorax, hemoptysis.
• Pulmonary edema.
• Pulmonary emboli.
• Fractured ribs or other chest trauma.
• Recent bronchoscopy.
• Lung transplantation.

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

Eligibility last updated 3/22/23. Questions regarding updates should be directed to the study team contact.

• Male or female, age 55 to 80 years, inclusive, at the time of informed consent:
  • Those 55 to 64 must have 1 of the following additional risk factors, given the relatively low rates of amyloid positivity of amyloid positivity < 65 years:
    • First degree relative diagnosed with dementia onset before age 80; or
    • Known to possess at least 1 apolipoprotein є4 variant (APOE4) allele; or
    • Known before screening to have elevated brain amyloid according to previous PET or CSF testing. Individuals with historical amyloid PET scans with Aβi (e.g., from preclinical AD studies such as A4 or EARLY) are eligible to be screened provided the subject did not participate in any clinical studies involving antiamyloid therapies subsequent to the PET assessment.
• Global CDR score of 0 at Screening.
• Mini Mental State Examination (MMSE) score ≥ 27 (with educational adjustments) at Screening.
• Wechsler Memory Scale-Revised Logical Memory subscale II (WMS-R LM II) score at Screening of ≥ 6.

A45 Trial:

Elevated brain amyloid pathology by amyloid PET: Elevated amyloid is defined as approximately > 40 centiloids on Screening scan.

A3 Trial:

• Intermediate levels of brain amyloid pathology by amyloid PET: Intermediate amyloid is defined as approximately 20 to 40 centiloids on Screening scan.
• Has a study partner that is willing to participate as a source of information and has approximately weekly contact with the participant (contact can be in-person, via telephone or electronic communication). The study partner must have sufficient contact such that the investigator feels the study partner can provide meaningful information about the subject’s daily function.
• Provide written informed consent.
• Willing and able to comply with all aspects of the protocol.

• Females who are breastfeeding or pregnant at Screening or Baseline (as documented by a positive beta-human chorionic gonadotropin [β-hCG] or human chorionic gonadotropin [hCG] test witha minimum sensitivity of 25 IU/L or equivalent units of β-hCG [or hCG]). For women of childbearing potential, a separate baseline assessment is required if a negative Screening pregnancy test was obtained more than 72 hours before the first dose of study drug.
• Females of childbearing potential who:
  • Within 28 days before study entry, did not use a highly effective method of contraception,which includes any of the following:
    • total abstinence (if it is their preferred and usual lifestyle);
    • an intrauterine device or intrauterine hormone-releasing system;
    • a contraceptive implant o an oral contraceptive (with additional barrier method) (Subject must be on a stable dose of the same oral contraceptive product for at least 28 days before dosing and throughout the study and for 28 days after study drug discontinuation);
    • have a vasectomized partner with confirmed azoospermia.
  • Do not agree to use a highly effective method of contraception (as described above) throughoutthe entire study period and for 28 days after study drug discontinuation For sites outside of the EU, it is permissible that if a highly effective method of contraception is not appropriate or acceptable to the subject, then the subject must agree to use a medically acceptable method of contraception; i.e., double-barrier methods of contraception such as latex or synthetic condom plus diaphragm or cervical/vault cap with spermicide.
    • NOTE: All females will be considered to be of childbearing potential unless they are postmenopausal (amenorrheic for at least 12 consecutive months, in the appropriate age range, and without other known or suspected cause) or have been sterilized surgically (ie, bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, all with surgery at least 1 month before dosing).
• History of transient ischemic attacks (TIA), stroke, or seizures within 12 months of Screening.
• Current or history within the past 2 years of psychiatric diagnosis or symptoms (eg, hallucinations, major depression, or delusions) that, in the opinion of the investigator, could interfere with study procedures.
• Contraindications to MRI scanning, including cardiac pacemaker/defibrillator, ferromagnetic metal implants (e.g., in-skull and cardiac devices other than those approved as safe for use in MRIscanners), or exhibit other significant pathological findings on brain MRI at Screening, including but not limited to: more than 4 microhemorrhages (defined as 10 mm or less at the greatest diameter); a singlemacrohemorrhage greater than 10 mm at greatest diameter; an area of superficial siderosis; evidence of vasogenic edema; evidence of cerebral contusion, encephalomalacia, aneurysms, vascular malformations that are at high risk for hemorrhage, or infective lesions; evidence of multiple lacunar infarcts (that in the opinion of the investigator, may impact cognition) or stroke involving a major vascular territory, severe small vessel, or severe diffuse white matter disease; space occupying lesions; or brain tumors (however, lesions diagnosed as meningiomas or arachnoid cysts and less than 1 cm at their greatest diameter need not beexclusionary).
• Hypersensitivity to any monoclonal antibodytreatment.
• Any immunological disease which is not adequately controlled, or which requires treatment with immunoglobulins, systemic monoclonal antibodies (or derivatives of monoclonal antibodies), systemic immunosuppressants, or plasmapheresis during the study.
• Bleeding disorder that is not under adequate control (including a platelet count 1.5) at Screening.
• Results of laboratory tests conducted during Screening that are outside the following limits:
  • Thyroid stimulating hormone (TSH) above normal range. Other tests of thyroid function with results outside the normal range should only be exclusionary if they are considered clinically significant by the investigator. This applies to all subjects whether or not they are taking thyroid supplements
  • Abnormally low (below lower limit of normal [LLN]) serum vitamin B12 levels for the testing laboratory (if subject is taking vitamin B12 injections, level should be at or above the LLN for the testing laboratory). A low vitamin B12 is exclusionary, unless the required follow-up labs (homocysteine and methylmalonic acid [MMA]) indicate that it is not physiologically significant.
• Known to be human immunodeficiency virus (HIV) positive.
• Any other clinically significant abnormalities that in the opinion of the investigator require further investigation or treatment or may interfere with study procedures or safety, such as:
  • Physical examination or vital signs at Screening; 
  • Laboratory tests or ECG at Screening;
  • Other medical conditions (e.g., cardiac, respiratory, gastrointestinal, psychiatric, renal disease), which are not adequately and stably controlled;
  • Severe visual or hearing impairment that would prevent the subject from performing psychometric tests accurately.
• Malignant neoplasms within 3 years of Screening (except for basal or squamous cell carcinoma in situ of the skin, or localized prostate cancer in male subjects with treatment cycles completed at least 6 months before Screening). Subjects who had malignant neoplasms but who have had at least 3 years of documented uninterrupted remission before Screening need not be excluded.
• Answer “yes” to Columbia-Suicide Severity Rating Scale (C-SSRS) suicidal ideation Type 4 or 5, or any suicidal behavior assessment within 6 months before Screening, at Screening, or at Baseline, or has been hospitalized or treated for suicidal behavior in the past 5 years before Screening.
• Known or suspected history of drug or alcohol abuse or dependence within 2 years before Screening or a positive urine drug test at Screening. Subjects who test positive for benzodiazepines, opioids, or tetrahydrocannabinol (THC) in urine drug testing need not be excluded unless in the clinical opinion of the investigator this is due to potential drug abuse.
• Taking prohibited medications. 
• Participation in a clinical study involving:
  • Any therapeutic monoclonal antibody, protein derived from a monoclonal antibody, immunoglobulin therapy, or vaccine within 6 months before Screening (anti-amyloid therapies within 1 year before Screening), unless it can be documented that the subject was randomized to placebo or never received study drug;
  • BAN2401;
  • Any new chemical entities or investigational drug for AD within 6 months before Screening unless it can be documented that the subject received only placebo;
  • Any other investigational medication or device study in the 8 weeks or 5 half-lives (whichever is longer) of the medication before randomization unless it can be documented that the subject was in a placebo treatment arm.
• Planned surgery during the Pre-randomization Phase or within 3 months of Randomization, which requires general anesthesia.

• Participants from an existing IRB approved protocol (#18-008476, #14-004401, #712-98)

• Unable to complete study activities.
• Unable to read and speak English.

• Diagnosis of intrahepatic cholangiocarcinoma.
• High-quality cross-sectional imaging by computerized tomography (CT) or magnetic resonant imaging (MRI) performed within 6 weeks prior to enrollment and showed a resectable, but high-risk, IHCCA confined to the liver, bile duct, and /or regional lymph nodes. Tumors will be considered high-risk if the high-quality, contrast-enhanced CT and/or MRI +/- positron emission tomography (PET) scan showed (must meet at least one of the criteria below):
  • T-stage ≥ Ib (Ib – IV);
  • Solitary lesion > 5 cm;
  • Multifocal tumors or satellite lesions present confined to the same lobe of the liver as the dominant lesion but still technically resectable;
  • Presence of major vascular invasion but still technically resectable;
  • Suspicious or involved regional lymph nodes (N1).
• No distant extrahepatic disease (M0).
• Adults ≥ 18 years of age.
• Able to give informed consent.
• Able to adhere to study visit schedule and other protocol requirements.
• ECOG performance status of 0-1.
• Adequate bone marrow reserves as evidenced by:
  • ANC ≥ 1,500 cells/μl; and
  • Platelet count ≥100,000 cells/μl; and
  • Hemoglobin ≥ 9 g/dL.
• Adequate hepatic function as evidenced by:
  • Serum total bilirubin ≤ 1.5 x ULN; and
  • AST and ALT ≤ 2.5 x ULN; and
  • Albumin ≥ 3 g/dl.
• Adequate renal function as evidenced by:
  • Ccreatinine ≤ 1.5 x ULN.
• Male, or a non-pregnant and non-lactating female.
• Women of child-bearing potential (defined as a sexually mature woman who:
  • has not undergone hysterectomy [the surgical removal of the uterus] or bilateral oophorectomy [the surgical removal of both ovaries]; or 
  • has not been naturally postmenopausal for at least 24 consecutive months [i.e., has had menses at any time during the preceding 24 consecutive months]) must commit to true abstinence from heterosexual contact, or agree to use, and be able to comply with, effective contraception without interruption for 28 days prior to starting gemcitabine/cisplatin/nab- paclitaxel (including dose interruptions) until treatment with gemcitabine/cisplatin/nab-paclitaxel is complete.
• Male subjects must practice true abstinence or agree to use a condom during sexual contact with a female of childbearing potential or a pregnant female while on treatment (including during dose interruptions) with gemcitabine/cisplatin/nab-paclitaxel and for 6 months followinggemcitabine/cisplatin/nab- paclitaxel discontinuation, even if he has undergone a successful vasectomy.

• < 18 years of age.
• Peripheral neuropathy of grade 2 or greater by Common Terminology Criteria for Adverse Events (CTCAE) 4.0. In CTCAE version 4.0, grade 2 sensory neuropathy is defined as “moderate symptoms; limiting instrumental activities of daily living (ADLs).”
• Concurrent severe and/or uncontrolled medical conditions which could compromise participation in the study such as unstable angina, myocardial infarction within 6 months, unstable symptomatic arrhythmia, symptomatic congestive heart failure, uncontrolled diabetes, serious active, uncontrolled infection after inadequate biliary drainage if tumor obstructing bile duct, or psychiatric illness/social situations.
• Pregnancy (positive pregnancy test) or lactation.
• Known CNS disease, except for treated brain metastasis.Treated brain metastases are defined as having no evidence of progression or hemorrhage after treatment and no ongoing requirement for dexamethasone, as ascertained by clinical examination and brain imaging (MRI or CT) during the screening period. Anticonvulsants (stable dose) are allowed.Treatment for brain metastases may include whole brain radiotherapy (WBRT), radiosurgery (RS; Gamma Knife, LINAC, or equivalent) or a combination as deemed appropriate by the treating physician.Patients with CNS metastases treated by neurosurgical resection or brain biopsy performed within 3 months prior to Day 1 will be excluded.
• Previous (within the past 5 years) or concurrent presence of other cancer, except non-melanoma skin cancer and in situ carcinomas.
• History of allergy or hypersensitivity to any of the study drugs.
• Current abuse of alcohol or illicit drugs.
• Inability or unwillingness to sign the informed consent form.

• Mayo Clinic patients.
• At least 18 years of age.
• Proficient in the English language.

• Inability to read (or lack of a support person to read to them) and lack of capacity to provide informed consent (and therefore lack of capacity to provide independent feedback on questionnaires, etc.).

• Patients coming to Mayo Clinic’s Genetic Heart Rhythm Clinic for evaluation or follow-up for their GHD.  
• Patients 18 years and older.

• Patient inability or unwillingness to participate in the study.
• Patients 17 years and under.

• Age ≥ 18 years.
• Cirrhosis or chronic liver disease (defined as FIB-4 > 1.45 or other non-invasive markers that show > F3 fibrosis on outpatient values).
• Admitted for non-elective reasons.
• Able to consent or have a legal representative who can consent.

• Individuals < 18 years of age.
• Acute liver failure.
• Unable to consent.
• Admitted electively.
• Life expectancy < 48 hours.
• Prisoners.
• HCC without loco-regional control for > 6 months or patients on systemic therapy for Hepatocellular Carcinoma (HCC) currently.
• COVID-19 diagnosis confirmed during the current admission.
• Post-TIPS if TIPS is > 6 months prior.
• Known recent MI (< 6 months) or stroke with residual defects.

• Males and females over the age of 18 years.
• Patients with either suspected or confirmed Barrett's-associated high grade dysplasia (HGD) or intramucosal cancer (IMC) presenting for endoscopy possibly requiring EMR.
• Ability to provide written, informed consent.
• Females must be willing to take a pregnancy test if still capable of bearing a child.

• Patients on anticoagulation undergoing high risk procedures in accordance to ASGE guideline for the management of antithrombotic agents for endoscopic procedures (2009)*.
• Patients with esophageal varices that preclude biopsies.
• Presence of an esophageal mass/cancer that precludes full distention of the balloon from the Nvision balloon guide sheath.
• Patients with esophageal strictures that would prevent adequate expansion of the balloon from the Nvision guide sheath.
• Patients with known inflammatory disease, esophageal tears or ulcers, which prohibit full distention of the balloon from the Nvision balloon guide sheath.
• Patients with known eosinophilic esophagitis.
• Patients who are pregnant.
• Patients with a history of hemostasis disorders.*
  • Patients on anticoagulation undergoing low risk procedures are not excluded.

* Hemostasis disorders will include, but will not be limited to: patients with hemophilia or other congenitally acquired clotting factor deficiencies, patients with cirrhosis with coagulopathy, patients known to have thrombocytopenia (< 100,000 plt/ul) and individuals with von Willebrand's disease or other known platelet malfunction disorders.

• Autosomal Dominant Polycystic Kidney Disease (ADPKD) (based on Ravine et al. criteria).
• Class 1 A-E according to imaging classification.
• Male and female subjects, 15- 40 years of age.
• Estimated GFR > 70 mL/min/1.73 m^2 (CKD-EPI).
• Ability to provide written, informed consent.

• Class 2 according to imaging classification.
• Concomitant systemic disease affecting the kidney.
• Diabetes mellitus.
• Predicted urine protein excretion in > 1 g/24 hrs.
• Use of antioxidants; i.e., vitamins, Nrf2 activators.
• Abnormal urinalysis.

Eligibility last updated 10/13/21. Questions regarding updates should be directed to the study team contact.

• Males and females, 18-65 years of age.
• Moderate to Severe medically refractory inflammatory ulcerative colitis:
  • as defined by a an Adapted Mayo Score of 5 to 9 points;
  • including an endoscopic sub-score of 2 or 3.
• Concurrent therapies with corticosteroids, 5-ASA drugs, thiopurines, MTX, antibiotics, anti-TNF, and anti-integrin therapy are permitted.
• To meet the definition of refractory UC, all patients must have failed at least 2 standard FDA approved medications for the treatment of UC:
  • Current standard therapy includes 5-ASA products, thiopurines, anti-TNF therapy, ustekinumab, vedolizumab, and tofacitinib (i.e., all FDA approved therapies for UC);
  • Refractory and failure to response is defined as continued symptoms despite 12 weeks of therapy at FDA approved doses by product necessitating change in medical strategy or referral for colectomy.
• All patients should have undergone a colonoscopy in last 12 months to rule out malignant or premalignant condition.
• Female subjects that are of child bearing potential must to agree to use effective contraception method(s) for the duration of the study.
• Hemoglobin must be greater than 8.
• INR must be less than 1.5.
• Ability to comply with protocol.
• Competent and able to provide written informed consent..

• Inability to give informed consent.
• Clinically significant medical conditions within the six months before administration of MSC; e.g., myocardial infarction, active angina, congestive heart failure or other conditions that would, in the opinion of the investigators, compromise the safety of the patient.
• Specific exclusions: Known history of hepatitis B, C, or HIV.
• Patients that have had a partial colectomy.
• Patients that have underlying vasculitis or have been diagnosed with an underlying condition that predisposes to developing blood clots.
• History of cancer including melanoma (with the exception of localized skin cancers).
• Investigational drug within thirty (30) days of baseline.
• History of clinically significant auto-immunity (other than UC) or any previous example of fat-directed autoimmunity:
  • Please note that auto-immunity is defined as a systemic immune mediated disease for which the antigen is known or unknown. Autoimmune diseases other than UC are excluded. Extraintestinal manifestations of UC (specifically joint inflammation, eye inflammation, PSC, skin manifestations; i.e., pyoderma gangrenosum, erythema nodosum) will be allowable.
• Allergic to local anesthetics.
• Pregnant patients or trying to become pregnant or breast feeding.
• Neoplasia of the colon and preoperative biopsy.
• C. Difficile infection within 30 days of study injection.
• Diagnosis of indeterminate colitis or suspicion of CD.
• Subjects with fulminant colitis, toxic megacolon, with ostomy, or ileoanal pouch.
• History or demonstration of pathology related to adipose tissue
• Any other indication determined by the PI to be counter indicated for participation on this trial.

• Mayo Clinic patients with positive COVID-19 test who agreed to follow up through video visit by Mayo COVID-19 Virtual Clinic providers.

• Non Mayo Clinic patients.
• Patients with negative COVID-19 result

• Adults, ≥ 18 years of age.
• Member of the community in a leadership or representative position.

• Individuals 18 years of age.