• A healthy control will be defined as an otherwise healthy person who does not have a medical condition that affects brain function or have problems with concentration, memory, balance, or coordination.
• Patients who have a suspected diagnosis of altered CSF dynamics including but not limited to normal pressure hydrocephalus will be referred to Dr. Cogswell by their care team to be included in the study. 
• Conditions of altered CSF dynamics include obstructive and non-obstructive hydrocephalus and may be associated with headaches and/or decreased cognitive function.
• Similarly, patient’s with impaired cognitive function including, but not limited to, Alzheimer’s disease will be referred to Dr. Cogswell by their care team to be included in the study.

• Subjects with non-MRI compatible devices.
• Subjects with required sedation.
• Women who may be pregnant.

• Patients with hypophosphatemia or suspected tumor induced osteomalacia (TIO) or suspected or confirmed X-linked hypophosphatemia (XLH).

• Patients with iron deficiency and chronic kidney disease as these patients might have elevations of FGF23.

• Age 18 years old and above.
• New diagnosis of CS of any of the three subtypes (pituitary, adrenal or ectopic CS) and MACS.
• Planning for a curative surgery.
• Ability to provide informed consent.

• Systemic supraphysiological GC for any reason within 1 month of enrollment, and for more than 2 weeks.
• Inability to provide informed consent.

• Age ≥ 18 years.
• Able to provide written consent.
• All patients must undergo p16 staining on biopsy for enrollment.
• All patients must undergo HPV16 family ISH and/or RNA on biopsy or surgical specimen, unless amount of tissue is too small to have conclusive HPV ISH testing done on it.
• Patients with < 70% of tumor cells positive for p16 will be considered p16 negative
• Patient has given permission to give his/her tumor/tissue/blood/saliva sample for research testing.
• Clinical diagnosis of oropharyngeal squamous cell carcinoma or clinical diagnosis of HPV negative oral cavity cancer, to be enrolled for subgroup 1D.
• Ability to complete questionnaire(s) by themselves or with assistance.
• Willingness and intent to return in person to enrolling institution for follow-up (during the Active Monitoring Phase of the study) for at least 2 of the standard follow-up time points for a total of 3 time-points including pre-treatment. A participant who does not return in person to Mayo Clinic Rochester for every standard of care post-treatment follow up will not be considered deviating from the protocol. 

• Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm. Patients enrolled in DART are eligible.
• Other active malignancy ≤ 5 years prior to registration.
• Exceptions:  Non-melanotic skin cancer, non-metastatic thyroid cancer, non-metastatic prostate cancer, carcinoma-in-situ of the cervix.
  • Note:  If there is a history or prior malignancy, they must not be receiving other specific treatment for their cancer.

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

• Male or female patients.
• Age ≥ 18 years old at screening.
• Able to provide written informed consent to participate in the trial prior to any trial related procedures are performed.
• Diagnosis of acromegaly by historical evidence of (persistent or recurrent) acromegaly.
• Treatment with a stable dose of octreotide LAR or lanreotide ATG for at least 3 months as monotherapy prior to screening.
• IGF-1 levels ≤ 1 x ULN at screening.
• Adequate liver, pancreatic, renal and bone marrow functions.
• Normal ECG.

• GH ≥ 2.5 μg/L at screening (cycle).
• Have received medical treatment for acromegaly with pasireotide (within 6 months prior to screening), pegvisomant (within 3 months prior to screening), dopamine agonists (within 3 months prior to screening) or other investigational agents (within 30 days or 5 half-lives prior to screening [whichever is longer].
• Patients who usually take octreotide LAR or lanreotide ATG less frequently than every 4 weeks (e.g., every 6 weeks or 8 weeks).
• Patients with compression of the optic chiasm causing any visual field defect for whom surgical intervention is indicated.
• Patients who have undergone major surgery/surgical therapy for any cause within 1 month from screening.
• Patients who have undergone pituitary surgery within 6 months prior to screening.
• Patients who have received prior pituitary irradiation.
• Patients with poorly controlled diabetes mellitus (hemoglobin A1c > 8.0%)

• Consenting individuals age 18 or older.
• Have received a lung transplant within the last 36 months at Mayo Clinic Rochester MN or Mayo Clinic Jacksonville FL.
• Have received or are receiving outpatient antifungal chemoprophylaxis. 

Exclusion Criteria: 

• Under the age of 18 years old.
• Multiple organ transplantations or re-transplantation.
• Requires language interpreter.

• requires home oxygen therapy or non-invasive ventilation (except nocturnal treatment of sleep apnea without supplemental oxygen);
• severely limits exercise tolerance to < 4 METs (e.g., patients unable to do light housework, walk flat at 4 miles/h or climb one flight of stairs);
• required previous lung surgery; or
• includes presence of severe pulmonary emphysema or bullae.

- Significant heart disease: cardiac conditions that limit exercise tolerance to < 4 METs

- Renal failure: peritoneal or hemodialysis requirement or preoperative creatinine ≥ 2 mg/dL

- Neuromuscular disease that impairs ability to ventilate without assistance

- Severe chronic liver disease (Child-Turcotte-Pugh Score > 9)

- Sepsis

- Malignancy or other irreversible condition for which 6-month mortality is estimated ≥ 20%

- Bone marrow transplant

• Ages 18 to 22 years old.

• Subjects outside the inclusion criteria age range.

• All adult patients with newly diagnosed or relapsed multple myeloma (MM) or amyloidosis (AL),
• Follow-up care received at Mayo Clinic.

• Adult patients with any other plasma cell disorder or hematologic disorder/malignancy.

• Male or female subjects must be ≥ 18 years of age. 
• Subjects must have a diagnosis of Systemic Sclerosis as defined by the 2013 American College of Rheumatology criteria/EULAR criteria.
• Subjects must have a diagnosis or history of Raynaud's Phenomenon, self-reported or reported by a physician, with at least a 2-phase color change in finger(s) of pallor, cyanosis, and/or reactive hyperemia in response to cold exposure or emotion.
• Subjects must have a minimum of 10 symptomatic Raynaud's Phenomenon attacks, documented in the electronic patient-reported outcomes (ePRO) diary, occurring over at least 3 separate days of the 3- to 5-day eligibility period.
• Subjects must complete a minimum of 80% of the daily ePRO diary entry during the baseline period.
• Female subjects of childbearing potential and male subjects must agree to use contraception for the duration of the study. 
• Subjects must be willing and able to comply with the study requirements and give informed consent for participation in the study.

• Female subjects who are pregnant or breastfeeding.
• Subjects with systolic blood pressure < 85 mmHg.
• Subjects with an estimated glomerular filtration rate <15 mL/min/1.73 m^2 at screening as determined by the Modification of Diet in Renal Disease equation.
• Subjects with an alanine aminotransferase and/or aspartate aminotransferase value > 3 × the upper limit of normal at screening.
• Subjects who have a digital ulcer infection within 30 days of screening.
• Subjects with a history of cervical or digital sympathectomy, or botulism toxin injections in their hands [for RP or digital ulcers] within 90 days of screening. Subjects should not have a planned botulism toxin or sympathectomy during their participation in the study.
• Subjects with gangrene or digital amputation within 6 months of screening.
• Subjects with current intractable diarrhea or vomiting.
• Subjects with a risk of clinically significant bleeding events, including those with coagulation or platelet disorders at screening.
• Subjects with a history of major trauma or hemorrhage within 30 days of screening.
• Subjects with clinically significant chronic intermittent bleeding, such as active gastric antral vascular ectasia or active peptic ulcer disease, within 60 days of screening.
• Subjects who have had any cerebrovascular events (e.g., transient ischemic attack or stroke) within 6 months of screening.
• Subjects with a history of myocardial infarction or unstable angina within 6 months of screening. Subjects should not have a planned coronary procedure during their participation in the study.
• Subjects with acute or chronic congestive heart failure (New York Heart Association Class III [moderate] or Class IV [severe]) at screening.
• Subjects with a history of more than mild restrictive or congestive cardiomyopathy uncontrolled by medication or implanted device.
• Subjects with a history of life-threatening cardiac arrhythmias.
• Subjects with a history of hemodynamically significant aortic or mitral valve disease.
• Subjects with a history of known pulmonary hypertension, pulmonary arterial hypertension, or pulmonary veno-occlusive disease.
• Subjects with a history of significant restrictive lung disease, defined as forced vital capacity < 45% predicted and diffusing capacity of the lungs for carbon monoxide <40% predicted (uncorrected for hemoglobin).
• Subjects with scleroderma renal crisis within 6 months of screening. 
• Subjects with a concomitant life-threatening disease with a life expectancy < 12 months.
• Subjects who have a clinically significant disorder that, in the opinion of the Investigator, could contraindicate the administration of study drug, affect compliance, interfere with study evaluations, or confound the interpretation of study results.
• Subjects who have taken or are currently taking any parenteral, inhaled, or oral prostacyclin or prostacyclin receptor agonists (e.g., epoprostenol, treprostinil, iloprost, and selexipag) within 8 weeks of screening.
• Subjects who have initiated or had a dose change of any of the following within 2 weeks of screening: oral, topical, or intravenous (IV) vasodilators (e.g., calcium channel blockers, phosphodiesterase-5 (PDE5) inhibitors [e.g., sildenafil, tadalafil, or vardenafil], nitrates, and
• fluoxetine).
• Subjects with any history of acetaminophen intolerability (e.g., allergic reaction to acetaminophen).
• Subjects with any malignancy that requires treatment during the study period, that has required treatment within 1 year of screening (including excision of skin cancer) or that is currently not in remission.
• Subjects who have used any investigational medication or device for any indication within 30 days or 5 half-lives (whichever is longer) of screening.
•  
•  

Obese, insulin resistant men and women using the following criteria

• Age 50-75 years.
• BMI 28-38kg/m^2.
• Hip-to-waist ratio of > 0.85 in women and > 80cm and > 0.90 in men or > 94cm.
• Fasting glucose ≥ 100-140mg/dl.

Lean, insulin sensitive men and women

• Age 50-75 years.
• Hip-to-waist ratio of < 0.76 in women and 0.90 in men.
• Fasting glucose of < 100mg/dl. 

Lactate discorder group

• Invitation from PI.

• Coronary artery disease or heart failure. 
• Participation in a structured exercise program > 2 days per week.
• A known medical condition that in the judgment of the investigator might interfere with the completion of the protocol such as the following examples:
  • Inpatient psychiatric treatment in the past 6 months;
  • Presence of a known adrenal disorder;
  • Abnormal liver function test results (Transaminase > 2 times the upper limit of normal); testing required for subjects taking medications known to affect liver function or with diseases known to affect liver function;
  • Abnormal renal function test results (calculated GFR < 45 mL/min/1.73m^2); testing required for subjects with diabetes duration of greater than 5 years post onset of puberty.
  • Active gastroparesis;
  • If on antihypertensive, thyroid, anti-depressant or lipid lowering medication, lack of stability on the medication for the past 2 months prior to enrollment in the study;
  • Uncontrolled thyroid disease; (TSH undetectable or > 10 mlU/L); testing required within three months prior to admission for subjects with a goiter, positive antibodies, or who are on thyroid hormone replacement, and within one year otherwise;
  • Abuse of alcohol or recreational drugs;
  • Infectious process not anticipated to resolve prior to study procedures (e.g., meningitis, pneumonia, osteomyelitis);
  • Uncontrolled arterial hypertension (Resting diastolic blood pressure > 90 mmHg and/or systolic blood pressure > 160 mmHg) at the time of screening;
  • Oral steroids;
  • A recent injury to body or limb, muscular disorder, use of any medication, any carcinogenic disease, or other significant medical disorder if that injury, medication or disease in the judgment of the investigator will affect the completion of the protocol.
• Restrictions on Use of Other Drugs or Treatments:
  • Medications that may impact study end points such as mitochondrial biology; e.g.. beta blockers;
  • Anti-hyperglycemic drugs including metformin;
  • Any other medication that the investigator believes is a contraindication to the subject’s participation.

Eligibility last updated 5/4/22. Questions regarding updates should be directed to the study team contact.

• Healthy subjects: apparently normal health with suspected eGFR >90 (will be confirmed at baseline testing), willing and able to participate in complete study duration.
• Patients with renal impairment: eGFR reported in the EMR within the last 60 days 15-59 mL/min/1.73 m­­­2 with diagnosis of chronic kidney disease.

• Healthy subjects:  
  • weigh less than 110 lbs;
  • known kidney dysfunction;
  • hypertension;
  • diabetes;
  • pregnant;
  • breast-feeding mother;
  • intolerance to biotin, currently taking or have taken biotin or biotin-containing;
  • supplements within the last 30 days.
• Patients with renal impairment: weigh less than 110 lbs, patients on dialysis, pregnant, breast-feeding.
• mother, intolerance to biotin, currently taking or have taken biotin or biotin-containing supplements within the last 30 days.

• Subject is ≥ 18 years of age at the time of signing the informed consent form (ICF).
• Subject must understand and voluntarily sign an ICF prior to any study-related assessments/procedures being conducted.
• Subject is willing and able to adhere to the study visit schedule and other protocol requirements.
• Subject has an Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1 or 2.
• Females of childbearing potential (FCBP) must:
  • Have 2 negative pregnancy tests as verified by the Investigator prior to starting study therapy. She must agree to ongoing pregnancy testing during the course of the study, and after end of study treatment. This applies even if the subject practices true abstinence* from heterosexual contact;
  • Either commit to true abstinence* from heterosexual contact (which must be reviewed on a monthly basis and source documented) or agree to use, and be able to comply with two reliable forms of contraception as defined in the Pregnancy Prevention Plan (PPP) without interruption, 28 days prior to starting CC-92480, during the study treatment (including during dose interruptions), and for 28 days after the last dose of CC-92480, 7 months after the last dose of BTZ (for Cohorts A, D and G), 90 days after the last dose of DARA (for Cohorts B and E), 6 months after the last dose of CFZ or ELO (for Cohorts C and F and Cohorts H and J), or 5 months after the last dose of ISA (for Cohorts I and K), whichever is later.
• Note: A female of childbearing potential (FCBP) is a female who:
  • has achieved menarche at some point; and
  • has not undergone a hysterectomy or bilateral oophorectomy; or
  • has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (ie, has had menses at any time in the preceding 24 consecutive months).
• Male subjects must:
  • Practice true abstinence* (which must be reviewed on a monthly basis) or agree to use of a condom during sexual contact with a pregnant female or a female of childbearing potential while participating in the study (even during dose interruptions) and for at least 3 months following study treatment discontinuation, even if he has undergone a successful vasectomy.

* True abstinence is acceptable when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and coitus interruptus (withdrawal) are not acceptable methods of contraception.

• Males must agree to refrain from donating sperm or semen while on study treatment, and for at least 3 months following last dose of study treatment. Females must refrain from egg cell (ova) donation while on study treatment, and for 28 days after the last dose of CC-92480.
• All subjects must agree to refrain from donating blood while on study treatment and for 28 days after the last dose of study treatment.
• All male and female subjects must follow all requirements defined in the PPP. 

• Subject has any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study.
• Subject has any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study.
• Subject has any condition that confounds the ability to interpret data from the study.
• Subject has any of the following laboratory abnormalities:
  • Absolute neutrophil count (ANC) < 1,000/µL (for Phase 1 without growth factor support for ≥ 7 days [≥ 14 days for pegfilgrastim]);
  • Platelet count: < 75,000/µL (it is not permissible to transfuse a subject to reach this level);
  • Hemoglobin < 8 g/dL (< 4.9 mmol/L);
  • Creatinine clearance (CrCl) < 45 mL/min (< 30 mL/min for Cohort G);
  • Corrected serum calcium > 13.5 mg/dL (> 3.4 mmol/L);
  • Serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2.5 x ULN;
  • Serum total bilirubin > 1.5 x ULN or > 3.0 mg/dL for subjects with documented Gilbert’s syndrome;
  • Prothrombin time (PT)/international normalized ration (INR) > 1.5 x ULN or partial thromboplastin time (PTT) > 1.5 x ULN, (for subjects not receiving therapeutic anticoagulation).
• Note: Subjects receiving therapy for a thromboembolic event that occurred > 3 months prior to enrollment are eligible as long as they are on a stable regimen of anticoagulation with warfarin, low-molecular weight heparin or other approved therapeutic anticoagulation regimen.
• Subject has peripheral neuropathy ≥ Grade 2.
• Subject with gastrointestinal disease that may significantly alter the absorption of CC92480. 7. Subject has prior history of malignancies, other than MM, unless the subject has been free of the disease for ≥ 5 years with the exception of the following non-invasive malignancies:
  • Basal cell carcinoma of the skin;
  • Squamous cell carcinoma of the skin;
  • Carcinoma in situ of the cervix;
  • Carcinoma in situ of the breast;
  • Incidental histologic finding of prostate cancer (T1a or T1b using the TNM [tumor, nodes, metastasis] clinical staging system) or prostate cancer that is curative.
• Subject has plasma cell leukemia, Waldenstrom’s macroglobulinemia, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes) or clinically significant amyloidosis. 
• Subject with known central nervous system (CNS) involvement with myeloma.
• Subject has received immunosuppressive medication within the last 14 days of initiating study treatment. The following are exceptions to this criterion:
  • Intranasal, inhaled, topical or local corticosteroid injections (e.g., intra-articular injection);
  • Systemic corticosteroids at doses that do not exceed 10 mg/day of prednisone or the equivalent;
  • Steroids as premedication for hypersensitivity reactions (e.g., computed tomography [CT] scan premedication).
• Subject has impaired cardiac function or clinically significant cardiac disease, including any of the following:
  • Left ventricular ejection fraction (LVEF) < 45% as determined by echocardiogram (ECHO) or multigated acquisition (MUGA) scan at Screening;
  • Complete left bundle branch, bifascicular block or other clinically significant abnormal electrocardiogram (ECG) finding at Screening;
  • A prolongation of QT interval on Screening ECG as defined by repeated demonstration of a QTc interval > 470 milliseconds (msec) using Fridericia’s QT correction formula; a history of or current risk factors for Torsades de Pointe (e.g., heart failure, hypokalemia, or a family history of Long QT Syndrome); and concurrent administration of medications that prolong the QT/QTc interval;
  • Congestive heart failure (New York Heart Association Class III or IV);
  • Myocardial infarction within 12 months prior to starting study treatment.
  • Unstable or poorly controlled angina pectoris, including the Prinzmetal variant of angina pectoris;
  • History of severe coronary artery disease, severe uncontrolled ventricular arrhythmias, sick sinus syndrome, pericardial disease or electrocardiographic evidence of acute ischemia or Grade 3 conduction system abnormalities unless subject has a pacemaker. 
• Uncontrolled hypertension or uncontrolled diabetes within 14 days prior to enrollment. 
• Concurrent administration of strong CYP3A modulators; concurrent administration of proton-pump inhibitors (e.g., omeprazole, esomeprazole, lansoprazole, pantoprazole) ≤ 2 weeks prior to starting CC-92480.
• Subject is a female who is pregnant, nursing or breastfeeding, or who intends to become pregnant during the participation in the study.
• Subject is positive for human immunodeficiency virus (HIV), chronic or active hepatitis B, or active hepatitis A or C.
• Subject has a history of anaphylaxis or hypersensitivity to thalidomide, lenalidomide, pomalidomide, BTZ (for Cohorts A, D and G), DARA (for Cohorts B and E), CFZ (for Cohorts C and F), ELO (for Cohorts H and J), ISA (for Cohorts I and K), or dexamethasone.
• Subject has known or suspected hypersensitivity to the excipients contained in the formulation of CC-92480, BTZ (for Cohorts A, D and G), DARA (for Cohorts B and E), CFZ (for Cohorts C and F), ELO (for Cohorts H and J), ISA (for Cohorts I and K), or dexamethasone.
• Contraindications to the standard treatment regimens, per local prescribing information. 
• Subject is unable or unwilling to undergo protocol required thromboembolism prophylaxis.

• Adult volunteers (18 years of age and older).

• Patient is unable to provide informed consent.
• Patient has pre-existing respiratory condition.

• Patients ≥ 18 years old.
• Patients undergoing flexible laryngoscopy.

• Patients with neurological disorders potentially impacting gag or cough reflex.
• Patients who havenever received dental care.
• Patients unable to complete the surveys provided.
• Patients with head and neck cancer and post radiation.
• Patients with a history of extensive tracheal and/or laryngeal surgeries.
• Patients under 18 years old.
• Patients who cannot consent for themselves
• Patients who have undergone flexible laryngoscopy previously on the same day as the study

• Females and males aged from ≥ 1 year to < 18 years old.
• Confirmed diagnosis of Chronic Immune Thrombocytopenia (ITP) according to American Society of Hematology (ASH) 2011 guidelines.
• Platelets count < 30x10^9/L at the Baseline Visit.
• Voluntarily given written informed consent (provided by patient's parent or legal guardian) and assent (provided by patient [if age-appropriate per IRB (Institutional Review Board) requirements]).
• Females of childbearing potential have been using at least 1 acceptable form of birth control for a minimum of 30 days (or a minimum of 3 months for hormonal contraceptives) prior to the Screening visit, and must agree to use at least 1 acceptable method of contraception for 30 days after the last dose of PANZYGA. Acceptable methods of birth control for this study include: intrauterine device (IUD), hormonal contraception, male or female condom, spermicide gel, diaphragm, sponge, or cervical cap. Abstinence is not considered an acceptable method of birth control.
• Parent or legal guardian must agree and be willing to assist the participant attend study visits, and to follow all protocol requirements and instructions of the study doctor.

• Thrombocytopenia secondary to other diseases (such as Acquired Immunodeficiency Syndrome [AIDS] or systemic lupus erythematosus [SLE]), drug-related thrombocytopenia, or congenital thrombocytopenia.
• Administration of intravenous immunoglobulin (IGIV) or anti-D immunoglobulin within 3 weeks before enrollment.
• Administration of thrombopoietin receptor agonists when the dose has NOT been stable within 3 weeks before enrollment and a dosage change is planned before Day 32.
• Administration of oral immunosuppressants when the dose has NOT been stable during the preceding 2 months (2 weeks for long-term corticosteroid therapy) and a dosage change is planned before Day 32.
  • Note: topical agents and inhaled corticosteroid therapy use is permitted.
• Administration of long-term anti-prolific agents or attenuated androgen therapy when the dose has NOT been stable during the preceding 2 months and a dosage change is planned before Day 32.
• Non-responsive to previous treatment with IGIV or anti-D immunoglobulin.
• Evidence of an active major bleeding episode at Screening.
• Splenectomy in the previous 4 weeks or planned splenectomy throughout the study period.
• Evans syndrome (experiencing active disease with 2 out of 3 of the following: autoimmune thrombocytopenia, autoimmune hemolytic anemia, and/or autoimmune neutropenia).
• Known or suspected human immunodeficiency virus (HIV), hepatitis B virus (HBV), and/or hepatitis C virus (HCV) infections.
• Emergency surgery in the previous 4 weeks.
• Severe liver and/or kidney disease (alanine aminotransferase [ALT] >3 x upper limit of normal (ULN), aspartate aminotransferase [AST] > 3 x upper limit of normal (ULN), and/or creatinine > 120 µmol/L).
• History of severe hypersensitivity to blood or plasma derived products, or any component of the PANZYGA.
• Known immunoglobulin A (IgA) deficiency and antibodies against IgA. History of, or suspected alcohol or drug abuse in the previous year.
• Females who are pregnant or nursing.
• Unable or unwilling to comply with the study protocol.
• Receipt of any other investigational medicinal product within 3 months before study entry.
• Risk factors* for thromboembolic events in whom the risks outweigh the potential benefit of PANZYGA treatment.
• Any other condition(s), that in the Investigator's opinion, make it undesirable for the patient to participate in the study or may interfere with protocol compliance.

*Risk factors include, but are not limited to:

• obesity, advanced age, hypertension, diabetes, a history of atherosclerosis/vascular disease or thrombotic events, hyperlipidemia, multiple cardiovascular risk factors, acquired or inherited thrombophilic disorders, prolonged periods of immobilization, severe hypovolemia, central venous catheterization, active malignancy and/or known or suspected hyperviscosity.

• Subjects scheduled to elective and/or urgent median sternotomy for cardiac surgery, who are preoperative hemodynamically stable. 
• Males and females. 
• Subjects of age 18 years and older. 
• Subjects with both Diabetes Mellitus AND BMI ≥ 30 OR Diabetes Mellitus/BMI ≥ 30 AND at least one of the following: 
  • Current/Previous smoking history ≥ 30 pack year;
  • Chronic Obstructive Pulmonary Disease (COPD).
• Female of childbearing potential should have a negative serum pregnancy test prior to index procedure.
  • Note: All female of childbearing potential must agree to use a highly effective method of contraception (such as double barrier, oral or parenteral hormonal, intrauterine device and spermicide) consistently and correctly for the duration of the study. 
• Subject is willing and able to provide a signed Informed Consent Form and is willing and able to comply with study's procedures including follow-up visits.

• Subjects undergoing partial sternotomy. 
• Subjects with any preoperative active significant infection. 
• Subjects that received oral or IV doxycycline during the last 4 weeks prior to screening. 
• Subjects with sensitivity to doxycycline and/or to tetracycline family of drugs and/or other study drug ingredients. 
• Subjects with known allergies to more than 3 substances (an allergy questionnaire will be filled during the screening process). 
• Subjects with history of allergic/hypersensitivity reaction to any substance having required hospitalization and/or treatment with intra-venous steroids/epinephrine or in the opinion of the investigator the patient is at high risk of developing severe allergic/hypersensitivity reactions. 
• Subjects with uncontrolled Asthma (GINA III-IV). 
• Subjects with chronic urticaria. 
• Immunocompromised subjects from any reason, at screening. 
• Subjects with renal failure requiring dialysis. 
• Subjects scheduled to major organ transplantation and/or to other significant concomitant surgical procedure. 
• Subjects scheduled for mechanical assist device. 
• Subjects scheduled to be treated with preventive negative pressure devices.
• Subjects undergone Cerebro-Vascular Accident (CVA)/Transient Ischemic Attack (TIA) within the past 3 months prior to randomization. 
• Subjects that have undergone previously, any cardiac surgery through sternotomy. 
• Subjects with active or previous malignancy in the chest area. 
• Any subject with active malignancy or with malignancy that has not been in complete remission for at least 5 years. Subjects who have had carcinoma in situ of the cervix, squamous cell carcinoma of the skin and basal cell carcinoma of the skin, are eligible. 
• Pregnant or breast-feeding women or women of childbearing age not protected by an effective contraceptive method of birth control (such as double barrier, oral or parenteral hormonal, intrauterine device and spermicide). 
• Subjects enrolled in any intervention study with an investigational medicinal product and/or received any investigational medicinal product within 30 days or 5½ half-lives of the product prior to enrollment (whichever is longer). 
• In the opinion of investigator, subject is not eligible to participate in the study and/or to comply with protocol requirements (e.g., due to a cognitive, medical condition or residency distanced from site that may jeopardize Follow-Up visits attendance etc.).

• Age greater than 18 years or older.

• Age < 18 years.
• Having received any investigational drug or device within 30 days prior to entry into the study.
• Clinically unstable patients (e.g. systolic blood pressure < 90 mmHg, ongoing requirement for vasopressors or mechanical circulatory support, or mechanical ventilation).
• Hospitalization within three months prior to study for hemodialysis or an ongoing requirement for hemodialysis or ultrafiltration.
• Prior organ transplantation or being on a waiting list for organ transplantation.
• Presence of cardiac conditions such as clinically significant cardiac valve stenosis, hypertrophic cardiomyopathy, restrictive cardiomyopathy, constrictive pericarditis, or primary arterial pulmonary hypertension (Group 1 PAH).
• History of blood pressure > 190/115 mmHg or unexplained syncope within the past 3 months.
• Symptomatic carotid artery disease, known critical carotid stenosis, or stroke within the past 3 months.
• Clinically significant intrinsic renal disease (eGFR <15 ml/min/1.72m2), renal artery stenosis, or history of fibromuscular dysplasia of the renal arteries.
• Baseline hemoglobin < 8.5 g/dl, aspartate aminotransferase (AST) or alanine aminotransferase (ALT) that is five times or more the upper limit of normal or bilirubin three times or more the upper limit of normal.
• History of alcohol abuse within the past 6 months.
• Women who are pregnant, or breast-feeding.

Inclusion Criteria

• A patient with at least one soft-tissue liver lesion ≤ 5 cm undergoing MWA using the NEUWAVE Microwave Ablation System. Note: A patient cannot have more than three lesions ablated during the procedure.
• Intent to use Ablation Confirmation software (any AC software version permitted) during the ablation procedure.
• Written informed consent to voluntarily participate in the study, follow CT scan schedule, and authorize the transfer of his/her data to the Sponsor.
• Patients ≥ 22 years old.
• Performance status 0-2 (Eastern Cooperative Oncology Group classification [ECOG]).
• Class A or B functional hepatic reserve based on the Child-Pugh score.
• Lesion must be visualized by non-contrast enhanced CT scan -or- the patient must tolerate contrast and meet institutional guidelines for contrast use based on glomerular filtration rate (GFR).

• Active bacterial infection or fungal infection on the day of the ablation.
• Patients with implantable pacemakers or other electronic implants.
• Platelet count < 50,000/mm^3  
• Patients with uncorrectable coagulopathy at the time of ablation.
• Currently breastfeeding or pregnant (latter confirmed by serum pregnancy test).
• Physical or psychological condition which would impair study participation.
• ASA (American Society of Anesthesiologists) score of ≥ 4.
• Use of hydrodissection.
• Systemic administration (intravenous or oral) of steroids, including herbal supplements that contain steroids, within 30 days prior to the study ablation procedure.
• Systemic Chemotherapy or radiation therapy for the liver, within 30 days prior to the study ablation procedure.
• INR > 1.85.
• Patient has participated in an investigational clinical study within 30 days of the screening visit for this study.
• Patient judged unsuitable for study participation by the performing physician for any other reason.

Eligibility last updated 9/7/21. Questions regarding updates should be directed to the study team contact.

• Age 18-55 years old.
• BMI 21.0 – 32.0 kg/m^2.

• BMI > 32.0 kg/m^2.
• For the 20 participants who are involved in training - participation in structured exercise (>2 times per week for 30 minutes or longer).
• For the 10 participants in the aerobic arm
  •do not participate in structured exercise > 5 times per week.
• For all participants
  •cardiovascular, metabolic (type 2 diabetes, fasting plasma glucose at or above 110 mg/dL and untreated hypo- or hyperthyroidism) or renal disease, orthopedic problems that would keep them from being able to perform leg extensions; medications that are known to have an impact on mitochondrial function: 
  • Corticosteroids, opiates, benzodiazepines, tricyclic antidepressants, beta blockers, sulfonylureas, insulin, anticoagulants, barbiturates, insulin sensitizers, fibrates (PPAR gamma agonist), smoking, pregnancy. 
  •  

Participants must be adults with the ability to provide cosent

• Male or female between 6 months through 36 months of age at the time of informed consent as clinical diagnosis of IS, confirmed by video-electroencephalogram (EEG) analysis, and hypsarrhythmia on EEG at screening according to the Burden of Amplitudes and Epileptiform Discharges (BASED) scale score.
• As assessed by the investigator has no or partial response to at least 2 out of the 3 therapies of adrenocorticotrophic hormone (ACTH), vigabatrin, and glucocorticoids (i.e. prednisolone), or has no or partial response to at least 1 out of the 3 therapies of ACTH, vigabatrin, and glucocorticoids and is contraindicated to and/or refused by the patient’s legal representative(s) for treatment with one or both other 2 therapies.
• Patient has general good health (defined as the absence of any clinically relevant abnormalities as determined by the investigator) based on physical and neurological examinations, medical history, normal renal function and electrocardiogram (ECG), and clinical laboratory values completed during the Screening Period visit (Visit 1).

• Patient considered by the investigator, for any reason (including, but not limited to, the risks described as precautions and warnings in the current version of the investigator’s brochure for investigational product) to be an unsuitable candidate to receive the investigational product.
• Patient has known or suspected allergy to the investigational product or apple juice.
• Patient has clinically significant renal impairment, defined as creatinine > mg/dL or blood urea nitrogen > 2 × upper limit of normal (ULN); clinically significant liver dysfunction, defined as total bilirubin ≥ 2 × ULN, or aspartate aminotransferase or alanine aminotransferase ≥ 3 × ULN; has clinically significant abnormal laboratory values; the investigator may deem the patient eligible if he/she judges the laboratory values to be not clinically significant.
• Patient has an ongoing or known history of human immunodeficiency virus infection, or chronic hepatitis B or C.
• Patient has a clinically significant abnormality on ECG that, in the opinion of the investigator, increases the safety risks of participating in the study.
• Patient has a neurodegenerative disorder as the underlying cause of IS.
• Patient has a known history of aspiration pneumonia within the past year.
• Patient has previously participated in another clinical study of the investigational product or received any investigational drug or device or investigational therapy within 30 days of study entry.
• Patient has received therapy with felbamate, cannabinoids, ketogenic diet or vagus nerve stimulation within 14 days of screening.
• Patient has received therapy with a medication known to be a CYP3A4 substrate and whose PK has been shown to be impacted in the presence of a CYP3A4 inhibitor within 14 days impacted in the presence of a CYP3A4 inhibitor within 14 days of screening.
• Patient has not remained at stables doses of all drugs used for treating epileptic seizures for at least 14 days prior to screening (except for rescue medications used for acute treatment of breakthrough seizures which are not known to be CYP3A4 substrates and whose PK has not been shown to be impacted in the presence of a CYP3A4 inhibitorist of CYP3A4 substrates]).
• Patient has a lethal or potentially lethal condition other than infantile spasms, with a significant risk of death before 18 months of age such as non-ketotic hyperglycinemia.
• Patient has an underlying metabolic disease associated with glucose intolerance (e.g., glucose transporter deficiencies).
• Patient has a body weight below 5 kg.

• Male and female subjects between the ages of 18 and 70 years, inclusive.
• Diagnosis of Crohn's disease localized in the ileum and/or colon, with active mucosal inflammation and visible lesion(s), documented by centrally read ileocolonoscopy and a Simple Endoscopic Score for Crohn's Disease (SES-CD) ≥ 6 (≥ 4 for isolated ileal disease). 
• Subjects who do not have an optimal response (daily stool frequency > 3 and pain score > 1) to their current ongoing treatment of biologics (e.g., first anti-tumor necrosis factor-alpha [TNF-α] monoclonal antibody), immunosuppressants, low-dose steroids, or 5-aminosalicylic acid (5-ASA) formulations.
• Subjects who are on stable Crohn's disease medications for at least 4 weeks. 
• Subjects with a CDAI score between 180 and 450 points, inclusive.
• Subjects who are willing and able to follow the trial protocol and have signed informed consent.

• Females who are breast-feeding and/or who have a positive pregnancy test result prior to receiving IMP. 
• Sexually active males or WOCBP who do not agree to practice 2 different methods of birth control or remain abstinent during the trial and for 30 days after the last dose of IMP. If employing birth control, 2 of the following precautions must be used: vasectomy, tubal ligation, vaginal diaphragm, intrauterine device, birth control pill, birth control implant, birth control depot injection, condom with spermicide, or sponge with spermicide. 
• Subjects taking any nonsteroidal anti-inflammatory drugs that cannot be stopped or replaced.
• Use of prednisone or prednisolone > 30 mg/day or budesonide > 9 mg/day within 4 weeks prior to screening; or intravenous steroids within 4 weeks prior to screening.
• Subjects taking blood thinners. 
• Subjects with bowel stenosis > 5 mm, fistula, or stoma; or with 2 or more bowel resections. 
• Subjects with a history of upper gastrointestinal involvement of Crohn's disease or perianal Crohn's disease. 
• Subjects with prior surgery that removed the ileocecal valve or resections that led to short bowel syndrome. 
• Subjects with known existing aortic aneurysm, or who are at risk for an aortic aneurysm, such as subjects with peripheral atherosclerotic vascular diseases, uncontrolled hypertension, certain genetic conditions such as Marfan syndrome and Ehlers-Danlos syndrome, and elderly subjects (over the age of 70). 
• Subjects with known or suspected (family history, unexplained syncope) long QT syndrome or QTcF > 470 msec for females or > 450 msec for males at baseline. 
• Subjects with inadequate organ function, as follows:
  • Serum creatinine > 1.5 x the upper limit of normal (ULN);
  • Aspartate aminotransferase or alanine aminotransferase levels > 1.5 x ULN;
  • Total bilirubin > 1.5 x ULN; Elevated unconjugated bilirubin related to Gilbert's syndrome is allowed.
• Use of antibiotics (e.g., metronidazole, rifaximin, tinidazole, ciprofloxacin, clarithromycin) within 15 days prior to screening or for greater than 2 months within the past year. A short course (maximum of 5 days) of antibiotics will be permitted during the trial, as needed, for indications other than Crohn's disease. 
• Known hypersensitivity to quinolones or other significant adverse reaction to quinolones. 
• Conditions or circumstances that could prevent completion of the trial according to the judgment of the investigator, including an uncontrolled comorbidity, heart condition, or dysfunction of any other organ; peripheral neuropathy; known arrhythmias, atrial fibrillation, or paroxysmal tachycardia; history of myasthenia gravis; history of drug or alcohol abuse, mental illness, or noncompliance with treatments or visits; or known immune-deficiency. 
• HIV infection, viral hepatitis, prior organ transplant, or malignant disease that is not in remission for at least 3 years, with the exception of basal cell carcinoma. 
• Subjects who have used any investigational drug within 2 months prior to screening. 
• Blood donation in the last 2 months. 
• Use of inhibitors of UGT1A1 and UGT1A9 (e.g., Silybin, diclofenac, mycophenolic acid, efavirenz, regorafenib) and BCRP (eg, Estrone, 17β-estradiol, flavonoids, herb extracts, gefitinib, imatinib, tamoxifen, novobiocin, nelfinavir, ritonavir, dipyridamole, fumitremorgin C, Ko143, cyclosporine, curcumin, eltrombopag, omeprazole, ivermectin). 
• Subjects with a history of treatment failure with 2 or more biologics. 
• Subjects with risk factors for tendon rupture (i.e., psoriasis, ankylosing spondylitis, competitive athletes, renal failure, diabetes mellitus) or who have a history of tendon rupture and/or ongoing tendinopathy.
• Subjects with systolic blood pressure > 150 mmHg or diastolic blood pressure > 90 mmHg.
• Subjects taking quinidine, procainamide, disopyramide, encainide, flecainide, sotalol, amiodarone, ibutilide, dronedarone, or propafenone.

Inclusion Criteria:

• English s.peaking
• Willing and able to communicate and participate.
• ≥ 18 Years of Age.
• Admitted to one of the ICUs described in the Setting section.
• ICU admission > 24 hours.
• CAM-ICU negative (delirium absent), RASS 0 (calm and cooperative) as documented by the patient-care nurse during the most recent documented assessment that calendar day.

• Non-English speaking.
• Not willing to communicate or participate.
• < 18 years of age.
• CAM-ICU positive (delirium present) or RASS other than 0 (Not calm and cooperative) as documented by the patient-care nurse during the most recent documented assessment that calendar day.
• Not admitted to one of the ICUs described in the Setting section.
• ICU admission < 24 hours.
• Documented as a threatening/verbal abuse.
• Documented cognition or communication problems (i.e., admission for treatment of active substance abuse/withdrawal, codependence, Traumatic Brain Injury,  developmental delay, Alzheimer’s disease, dementia).
• Prisoners.

• Able and willing to provide informed consent.
• Postmenopausal women (FSH > 20 IU/L).
• Aged 50-80 years old.
• Lean control subjects:  BMI < 25, Hemoglobin A1c <or= 5.9%
• Obese, non-diabetic subjects:  BMI ≥ 30, Hemoglobin A1c <or= 5.9%
• Obese, T2DM subjects:  BMI ≥ 30, Hemoglobin A1c > 6.5% (for at least the past 5 years).

• Clinical significant abnormality in any of the screening laboratory studies (see below).
• Presence of (documented clinical diagnosis of any of the following):
  • Significant liver or renal disease;
  • Malignancy (including myeloma);
  • Malabsorption (as defined by clinical diagnosis);
  • Hypoparathyroidism (as defined by clinical diagnosis);
  • Hyperparathyroidism (as defined by clinical diagnosis);
  • Acromegaly;
  • Cushing’s syndrome;
  • Hypopituitarism;
  • Severe chronic obstructive pulmonary disease;
  • History of cardiac failure;
  • Bleeding disorders or current use of therapeutic doses of anticoagulants other than aspirin.
• Undergoing treatment with any medications that affect bone turnover, including the following:
  • corticosteroids > 3 months at any time (inhaled steroids acceptable unless used year-round);
  • anticonvulsant therapy for seizures (carbamazepine or phenytoin within the previous year);
  • pharmacological doses of:
    • thiazolidinediones;
    • thyroid hormone (causing decline of thyroid stimulating hormone below normal);
    • Bisphosphonates (within the past 3 years);
    • denosumab, estrogen therapy or treatment with a selective estrogen receptor modulator, or teriparatide (within the past year).
  • Any history of fracture prior to screening.

• Adolescent patients between 12 and 18 years old, inclusive.
• Patients being evaluated at the Pediatric Diagnostic Referral Clinic for symptoms of suspected orthostatic intolerance (OI), postural orthostatic tachycardia syndrome (POTS), or autonomic dysfunction or already carry diagnosis of OI, POTS, or autonomic dysfunction. Identified with pre-appointment triaging to have any of the following symptoms: dizziness, lightheadedness, fainting, heart racing, shortness of breath, vision changes, fatigue, exercise intolerance, and chest pain when standing.

• Age not within 12-18 years old.
• Lack of assent from child to participate/wear actigraph.

Patients or adult caregivers with severe cognitive disabilities; patients or adult caregivers who otherwise meet study criteria but do not fall within above inclusion criteria.

• Adult subjects undergoing MR imaging for radiation therapy planning.