• 18 years of age or older
•  ST-elevation MI
• Non-ST elevation MI

• None

• BMI 18 – 35  Kg/M2
•  Fifteen patients with normal glucose tolerance and fifteen with impaired fasting glucose
• Participants will be in good health
• Stable weight
• Not engaged in regular vigorous exercise
• No history of diabetes or of prior therapy with antidiabetic medication
• No history of chronic disease
• No prior abdominal surgery other than cholecystectomy or appendectomy

• Subjects < 20 years of age or > 65 years of age

Inclusion Criteria

• Male or female
• Has hepatic masses
• Age 18 or greater
• Body mass index (BMI) below 35

Exclusion Criteria

• Unreliable ultrasound images due to conditions such as fatty liver or poor ultrasound imaging window
• Adults lacking capacity to consent
• Vulnerable subjects such as prisoners

Inclusion Criteria

• Study subjects with the glomerular diseases

• An informed consent or waiver
• Patient has experienced an acute ischemic stroke
• Treatment within 8 hours of stroke onset

• Concurrent participation in a randomized study

Inclusion Criteria

• Willing to sign the informed consent
• Male and non-pregnant female subjects ages 50
  •90 at the time of surgery
• Require a primary reverse total shoulder arthroplasty
• Have the diagnosis of cuff-tear arthropathy (CTA), massive irreparable rotator cuff tear (MRCT) or osteoarthritis (OA) with marked posterior subluxation or bone loss

Exclusion Criteria

• Inability to comply with follow-up requirements
• Have inflammatory arthritis
• Have proximal humerus fractures
• Have sequels of trauma
• Are immunologically compromised
• Have an active or suspected latent infection in or about the shoulder
• Need to add a tendon transfer
• Need a structural humeral bone graft
• Are pregnant

• >18 years old
• Undergoing a POEM or laparoscopic modified heller myotomy and anti-reflux procedures
• Esophagus diameter less <8 cm on barium swallow test

• Pregnant
• Diverticular disease of the esophagus
• Barrett's esophagus
• Extensive abdominal adhesions
• <50% predicted FEV1 on pulmonary function testing
• Cardiac ejection fraction <25%
• Esophageal stricture from prior myotomy
• Sigmoidization of the esophagus
• More than one prior balloon dilation (>3 cm) or any prior dilation of 3 cm

• Age 18-80 years old.
• Gender: both males and females.
• Target disease: Moderate OA of the knee.
• Persistent symptoms, despite standard NSAID.
• Absence of clinically significant abnormal values for the following:
  • Complete blood count;
  • Prothrombin Time, Activated partial thromboplastin time;
  • Blood chemistry (Glucose, Na, K, Cl, CO2, BUN, creatinine, Ca, PO4, magnesium, uric acid);
  • Liver function tests (amylase, total bilirubin, alkaline phosphate, GGT, AST, ALT, total protein, albumin).
• Able and willing to return to the Mayo Clinic for follow-up visits, as required by this study.
• Able undergo MRI of the knee.
• Subjects should be able to give appropriate consent.
• Potential subjects should have failed a three-month trial of a minimum of two conservative therapies before being considered for this trial. These conservative therapies include: activity modification, weight loss, physical therapy, and anti-inflammatory or injection therapy.

• Pregnant, or currently breast-feeding.
• Ongoing infectious disease including HIV, HTLV, hepatitis, syphilis or tuberculosis positive.
• Individuals who have OA as part of another syndrome (e.g. Ehler’s Danlos, Stickler syndrome, etc.).
• Systemic, rheumatic or inflammatory disease of the knee or chondrocalcinosis, hemochromatosis, inflammatory arthritis, arthropathy of the knee associated with juxta-articular Paget's disease of the femur or tibia, ochronosis, hemophilic arthropathy, infectious arthritis, Charcot's knee joint, villonodular synovitis, and synovial chondromatosis.
• Clinically significant cardiovascular, renal, hepatic, endocrine disease, diabetes, cancer, autoimmune diseases; a serious infection or major operation within 30 days of enrollment; a history of untreated psychiatric disease or recent history of alcoholism or drug addiction.
• Currently taking immunosuppressant medications.
• Anticipated major surgery during the study period.
• Individuals involved in another interventional protocol, or have been treated under one within the last 3 months.
• Intra-articular therapy in the index knee within the previous 3 months.
• Surgery to the target knee within 6 months prior to screening.
• Surgery to other weight bearing joints if it will interfere with knee assessments.
• Prior articular transplant procedures.
• Orthopedic hardware or implantable devices anywhere in the body, other than dental.
• Prior reconstruction surgery to the target knee within 12 months.
• X-ray findings of acute fractures.
• Known severe loss of bone density, and/or severe bone or joint deformity in the target knee.
• Significant target knee infection or overlying skin disorder/infection within the previous 6 months prior to study enrollment.
• Require cane or other assistive device for walking.
• Symptomatic OA of the hips, spine or ankle if it would interfere with the evaluation of the target knee.
• History of documented nerve damage in the affected limb, or vascular insufficiency.
• Condition requiring use of systemic steroids.
• Coagulation disorder.
• Patients with unstable knees.
• Temperature above 99.5° F.
• Identification as a member of a vulnerable population.
• BMI greater than 40.
• History of allergy to local anesthetics.
• Currently taking anti-rheumatic disease medication (including methotrexate or other antimetabolites) within the 3 months prior to entry in the study.
• Any illness or condition which, in the investigators’ judgement will interfere with the patient’s ability to comply with the protocol, compromise patient safety, or interfere with the interpretation of the study results.

Inclusion Criteria

• Age 1 to 30 years
• Clinically planned, elective surgical Ebstein repair
• Individuals able to undergo bone marrow aspirate according to clinical consultation with Hematology (cell treatment group only)
• Individuals able to undergo preoperative MRI or CT examination
• Individual and/or parent willing and able to give informed consent and willing to commit to completion of follow-up

Exclusion Criteria

• Individuals requiring cavopulmonary shunt at the time of surgical Ebstein repair; planned preoperatively or required intraoperatively
• Individuals with, or reasonably expected to have, complications during surgical Ebstein repair or during post-operative recovery
• Individual has not completed or will not be completing all pre-procedure work-up within 30 days of surgical Ebstein repair as listed in section 6 of this protocol AND lack of pre-procedure work-up documented as a safety concern by a site investigator
• Other clinical concerns as documented by a site investigator that could reasonably increase the risk of complications during or after surgical Ebstein repair
• Individual whose cells have been determined, by the sponsor, to not be acceptable for release to the investigational site or individual whose cells have been compromised after cells released to investigational site (cell treatment group only)
• Individuals who require surgery on pulmonary, mitral, or aortic valve
• Individuals with pulmonary atresia or atrioventricular discordance with ventriculoarterial discordance

• Neonates delivered at <32 weeks gestation and weighing <1500 grams who have been diagnosed with moderate to severe bronchopulmonary dysplasia
• Neonates who have received supplemental oxygen for ≥28 days and by 36 weeks postmenstrual age still require up to 30% supplemental oxygen (moderate) or ≥30% supplemental oxygen or positive pressure support (severe)
• Neonates who have isolated congenital heart disease or if they are receiving caffeine for treatment of apnea of prematurity

• Neonates that have suspected or documented chromosomal anomalies or complex congenital anomalies consistent with a suspected or confirmed genetic syndrome

Inclusion Criteria

• Adults ≥ 18 years
• Appointment for lung screening assessment

Exclusion Criteria

• Major barriers to providing informed consent (i.e. dementia, severe hearing or visual impairment)

Inclusion Criteria 

• Male or female
• Age 40-70 years 
• Females of childbearing potential
  • Must have a negative pregnancy test prior to receiving the study drug 
  • Agree to use adequate contraception (hormonal or barrier method or abstinence) from the time of screening to a period of 1 year following completion of the drug treatment cycle
  • Are defined as premenopausal and not surgically sterilized, or post-menopausal for fewer than 2 years
  • A urine pregnancy test will be performed prior to the administration of the study drug to confirm negative results
    • If the urine pregnancy test is positive, the study drug will not be administered 
    • Will be confirmed by a serum pregnancy test performed at a central clinical laboratory
  • Females becoming pregnant during the study will continue to be monitored for the duration of the study or completion of the pregnancy, whichever is longer
    • Monitoring will include perinatal and neonatal outcome
    • Any SAEs associated with pregnancy will be recorded
  • Females in the multiple-dose cohorts (M50 and M100) who become pregnant during the treatment cycle will not receive their remaining injections
• Chronic (> 3 months), unilaterally symptomatic, primary femorotibial knee osteoarthritis
• Radiographic medial and/or lateral femorotibial knee OA at least Kellgren-Lawrence grade 2 accompanied by definite joint space narrowing as agreed upon by two study co-investigators 
• Previous 6 week or longer trial of one of the following conservative treatments
  • Activity modification
  • Weight loss
  • Physical therapy
  • Anti-inflammatory medications or injection therapy (e.g. cortisone, hyaluronic acid/viscosupplement)
• Able to routinely walk without assistance (e.g. cane, walker) 
• Clinically stable target knee 
• No surgery planned in the target knee for at least 12 months following the last injection 
• Completed general physical evaluation with primary care provider within 12 months of enrollment 
• Fully understanding of the requirements of the study and willingness to comply with the treatment plan, including
  • Fat harvesting
  • Laboratory tests
  • Diagnostic imaging
  • Repeated knee injections/aspirations
  • Arthroscopic examination 
  • Follow-up visits and assessments 
• Can provide written informed consent and complete HIPAA documentation after the nature of the study is fully explained and prior to any study-related procedure

Exclusion Criteria

• Pregnant or nursing, or planning on becoming pregnant during the study period 
• Congenital or acquired malformation of the target knee resulting in significant deformity or leading to problems with the study treatment or analysis of the results 
• Significant malalignment on full length, standing radiographs 
• Orthopedic hardware or implantable devices anywhere in the body, other than dental 
• Surgery on the index knee within 1 year of study enrollment 
• Injections of any into the index knee within 3 months prior to study enrollment 
• Locking, catching, give-away or another major mechanical symptoms of the target knee
• Symptomatic patellofemoral arthritis or chondromalacia in the index knee
• History of intra-articular infection in the index knee 
• History of superficial infection in the index knee within 6 months of study enrollment, or evidence of current superficial infection affecting the index knee 
• History of falls requiring medical attention, or gait instability 
• Clinically significant abnormal hematology (complete blood count with differential), blood chemistry, or urinalysis screening laboratory results, including aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), bilirubin, creatinine, and CRP 
• Body mass index (BMI) > 40 kg/m2 
• Taking anticoagulant medications (e.g. warfarin, heparin) or clopidogrel (Plavix)
• Taking herbal therapies or supplements within 4 weeks of enrollment or unwilling to avoid use of herbal therapies or supplements until at least 30 days following completion of the study drug treatment cycle (includes, but not limited to chondroitin sulfate, diacerein, n-glucosamine, piascledine, and capsaicin) 
• Taking non-steroidal anti-inflammatory medications (e.g. COX-2 inhibitors) without a stable dosing regimen for at least 4 weeks before baseline evaluation, or anticipating not remaining on a stable dose until at least 30 days following completion of the study drug treatment cycle
• Use of electrotherapy or acupuncture for OA, unless there is a stable regimen for at least 4 weeks before baseline assessment
• Taking anti-rheumatic disease medication (including methotrexate or other antimetabolites) within 3 months prior to study enrollment 
• On chronic, immunosuppressive transplant therapy or having a chronic, immunosuppressive state, including use of systemic steroids/corticosteroids 
• Current tobacco product use, including nicotine patch or other nicotine products
• Systemic inflammatory, rheumatological or connective tissue disorder including but not limited to rheumatoid arthritis, systemic sclerosis, system lupus erythematosus, and Ehlers-Danlos Syndrome 
• Rheumatological or inflammatory disease of the knee or chondrocalcinosis/calcium pyrophosphate disease (CPPD), hemochromatosis, inflammatory arthritis, arthropathy of the knee associated with juxta-articular Paget's disease of the femur or tibia, ochronosis, hemophilic arthropathy, infectious arthritis, Charcot's knee joint, villonodular synovitis, and synovial chondromatosis 
• Ongoing infectious disease, including but not limited to tuberculosis, HIV, hepatitis, and syphilis
• Clinically significant cardiovascular (e.g. history of myocardial infarction, congestive heart failure or uncontrolled hypertension > 90 mmHg diastolic and/or 180 mmHg systolic), neurologic (e.g. stroke, TIA) renal, hepatic, orthopedic (e.g. surgery on other weight bearing joints that will interfere with study, osteoporosis, acute lower body fractures), or endocrine disease (e.g. diabetes) 
• Vascular or neurological disorder affecting the either lower limb 
• History of cancer/malignancy with the exception of adequately treated basal cell or squamous cell carcinoma of the skin not associated with the target knee
• History of blood dyscrasia, including but not limited to anemia, thrombocytopenia, and monoclonal gammopathy 
• Participation in a study of an experimental drug or medical device within 3 months of study enrollment 
• Known allergy to local anesthetics or other components of the study drug 
• Any contraindication to MRI scan according to MRI guidelines, or unwillingness to undergo MRI procedures 
• History of or current evidence of alcohol or drug abuse or dependence, recreational use of illicit drug or prescription medications, or have use of medical marijuana within 30 days of study entry 
• Any illness or condition which, in the investigators' judgement will interfere with the patient's ability to comply with the protocol, compromise patient safety, or interfere with the interpretation of the study results

• Healthy, active individuals, both control subjects and individuals that are candidates for ACL reconstruction due to recent primary tearing of the ACL

• Lower extremity injury/surgery in past 6 months other than ACL injury
• Neurological disorders
• Paralysis
• Neuromuscular disease
• Cardiovascular disease
• Exercise-induced injury
• Asthma
• Pregnancy

Inclusion Criteria

• Subjects who have received a primary unilateral total knee arthroplasty for a diagnosis of osteoarthritis.
• Manipulation under anesthesia scheduled 4-12 weeks postoperatively.
• Subjects if they are on any NSAIDs prior to MUA.

Exclusion Criteria

• Intolerance to NSAIDs.
• Renal dysfunction.
• Age < 18 or > 90 years.
• Primary diagnosis of rheumatoid arthritis.
• Patients with a Glomerular Filtration Rate (GFR) <60 as the cut off for Chronic Kidney Disease (CKD) (stage 3 CKD).

Inclusion Criteria

• Clinical diagnosis of Eosinophilic Esophagitis
• Age 18-65
• Has clinically indicated endoscopy/ biopsies for Eosinophilic Esophagitis
• Healthy volunteers
   of age and sex matched controls from a biobank

Exclusion Criteria

• Prior history of abdominal surgeries (except appendectomy and cholecystectomy)
• Known diagnosis of inflammatory bowel disease, microscopic colitis, celiac disease, atopic dermatitis, active asthma or other inflammatory conditions
• Antibiotic use within the past 4 weeks (they can be enrolled after a four week washout period and subsequent use during the 6 month study duration does not exclude them)
• Bowel preparation for colonoscopy within the past week
• Vulnerable adults
• Age ≥ 66

Inclusion criteria:

• ≥ 18 years old
• Scheduled to undergo Foregut surgery at Mayo Clinic Rochester which includes surgery for gastroesophageal reflux disease, hiatal hernias, and paraesophageal hernias

• Individuals of 18 year of age and older undergoing thoracentesis or pleural catheter insertion (inpatient and outpatient)

• Samples obtained from a chest tube not implanted at the time of sample collection
• Not enough fluid for analysis
• Lack of research authorization on file

Inclusion criteria                                        Asymptomatic controls              IBS patients

Age (yr)                                                           18-75                                       18-75

Gender (F:M)                                                   10:1                                         10:1

BDQ
•IBS symptoms                                     -ve by Rome III criteria          +ve by Rome III criteria

Hospital Anxiety/Depression score                 <8                                            No restrictions

Abdominal surgery (except appy or choly)     None                                        None

GI medications                                                None past 6 months               None past 48h

Exclusion criteria

In all patients diagnosed with IBS, we apply rigorous standards to exclude clinically-relevant inflammation. Patients with known bleeding diathesis will be excluded, given the need for sigmoid mucosal biopsies.  Anyone with a known allergy to Midazolam and Fentanyl for Aim 2 in protocol and named medications.

•  age >18
• Healthy control volunteers
• Patients with Multiple Sclerosis (Relapsing remitting multiple sclerosis and progressive multiple sclerosis)

Exclusion criteria:

Patients with anxiety or claustrophobia

• 18 years or older
• Diagnosis of chronic low back pain (> 3 months duration)
• May have a current prescription for at-home exercises for chronic low back pain

• Patients with a high likelihood of being lost to follow-up or contact
• Patients with an inability to provide good data or follow commands
• Patients with an inability to do mild exercise
• Patients with a history of spine surgery that included instrumentation or hardware
• Patients who are taking opioid medication chronically without reasonable reduction in pain

• Written informed consent by parent(s)/legal guardian(s) for the pediatric patient must be obtained before any study-specific assessment is performed.

* A consent or assent may also be required for some patients depending upon their age and local requirement.

• Male or female, inpatient or outpatient, 1 month (≥ 44 weeks post-conception for pre-term infants) to < 18 years of age.
• Chronic heart failure resulting from left ventricular systolic dysfunction, and receiving chronic HF therapy (if not newly diagnosed).
• NYHA classification II-IV (older children: 6 to less than 18 year old) or Ross HF classification II-IV (younger children: less than 6 year old) any time prior to screening.
  • Note: Age Group 1 patients may be NYHA class I at time of screening if there is a prior history of NYHA class II-IV. Age Group 2 patients must be Ross class II or higher at time of randomization.
• Systemic left ventricular ejection fraction (EF) ≤ 45% or fractional shortening ≤ 22.5% (assessed by echocardiogram, MRI, MUGA or left ventricular angiogram within 1 month before patient begins Part 2).
  • Note: The study will target enrollment of approximately 80% patients with a systemic left ventricular ejection fraction (EF) ≤ 40% or fractional shortening ≤ 20% for Part 2 only.
• Biventricular physiology with systemic left ventricle.
• For Part 1 PK/PD, patients must be treated with an ACEI or ARB prior to screening. For Part 1 PK/PD, patients in Group 1 and 2 must be currently treated with a daily dose equivalent of at least enalapril 0.2 mg/kg prior to the LCZ696 3.1 mg/kg single dose assessment. For Part 1 PK/PD, patients in Group 3 must be currently treated with a daily dose equivalent of at least enalapril 0.1 mg/kg prior to the LCZ696 1.6 mg/kg single dose assessment.
• HF etiologies include: Congenital Cardiac Malformation with systemic ventricular systolic dysfunction; Idiopathic Cardiomyopathy; Familial/Inherited and/or Genetic Cardiomyopathy; History of Myocarditis; Neuromuscular Disorder; Inborn Error of Metabolism; Mitochondrial Disorder; Acquired (Chemotherapy, Iatrogenic, Infection, Rheumatic, Nutritional); Ischemic (e.g., Kawasaki Disease, post-operative); Left ventricular noncompaction

*Assessments of HF (e.g. ECHO) in patients that are done according to current local institutional/hospital standard protocol or that are part of routine clinical care can be used to support patient screening and may have taken place before signing informed consent. An informed consent must be obtained from a patient once they become 18 years old during the study.

• Patients with single ventricle or systemic right ventricle.
• Patients listed for heart transplantation as United Network for Organ Sharing (UNOS) Status 1A or hospitalized waiting for transplant while on inotropes or with ventricular assist device at time of entry into the study.
• Sustained or symptomatic dysrhythmias uncontrolled with drug or device therapy.
• For Part 2 only, patients that have had cardiovascular surgery or percutaneous intervention to palliate or correct congenital cardiovascular malformations within 3 months of the screening visit. Patients anticipated to undergo corrective heart surgery during the 12 months after entry into Part 2.
• Patients with unoperated obstructive or severe regurgitant valvular (aortic, pulmonary, or tricuspid) disease, or significant systemic ventricular outflow obstruction or aortic arch obstruction.
• Patients with restrictive or hypertrophic cardiomyopathy.
• For Part 2 only, active myocarditis (diagnosed with presumed or acute myocarditis within 3 months of enrollment).
• Symptomatic hypotension or blood pressures (BPs) below the calculated 5th percentile systolic BP (SBP) for age at screening visit.
• Renal vascular hypertension (including renal artery stenosis).
• Severe pulmonary hypertension (defined by pulmonary vascular resistance (PVR) index > 6 Wood units-m2 ) unresponsive to vasodilator agents (such as oxygen, nitroprusside or nitric oxide).
  • Note: measurement of PVR is not a requirement for study eligibility.
  • History or current clinical evidence of moderate-to severe obstructive pulmonary disease or reactive airway diseases (e.g., asthma).
  • Serum potassium > 5.3 mmol/L at Visit 1 or at Visit 301.
  • Patients with significant renal (eGFR calculated using the modified Schwartz formula < 30% mean GFR for age; hepatic (serum aspartate aminotransferase or alanine aminotransferase > 3 times upper limit of normal); gastrointestinal or biliary disorders (that could impair absorption, metabolism, or excretion of orally administered medications).
  • Concurrent terminal illness or other severe disease (e.g., acute lymphocytic leukemia) or other significant laboratory values that, in the opinion of the Investigator, precludes study participation or survival.
  • Patients with a history of angioedema.
  • Patients with allergy or hypersensitivity to ACEI or ARB.
  • Patients who have parents or legal guardians who do not give consent or allow the child to give assent, or inability of the patient or the parents/legal guardians to follow instructions or comply with follow-up procedures.
  • Pregnant or nursing (lactating) women.
  • Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing of investigational drug and for 7 days after study drug discontinuation. Highly effective contraception methods include:
    • Total abstinence (when this is in line with the preferred and usual lifestyle of the subject and if acceptable by the local regulation);
    • Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception;
    • Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy or tubal ligation at least six weeks before taking investigational drug. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment;
    • Male sterilization (at least 6 months prior to screening). For female subjects on the study, the vasectomized male partner should be the sole partner for that subject;
    • Use of oral, (estrogen and progesterone), injected or implanted hormonal methods of contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS), or other forms of hormonal contraception that have comparable efficacy (failure rate < 1%); for example, hormone vaginal ring or transdermal hormone contraception;
    • In case of use of oral contraception women should have been stable on the same pill for a minimum of 3 months before taking investigational drug.
• Use of other investigational drugs within 5 half-lives or within 30 days of enrollment, whichever is shorter.
• History of hypersensitivity to any of the study drugs or its excipients or to drugs of similar chemical classes.
• Any major solid organ transplant recipient.
• History of malignancy of any organ system, treated or untreated, within the past year with a life expectancy less than 1 year.
• Any advanced severe or unstable disease that may interfere with the primary or secondary study outcome evaluations or put the patient at special risk.
• Any other medical conditions that may put the patient at risk or influence study results in the Investigator’s opinion, or that the Investigator deems unsuitable for the study.
• Patient breastfed by a mother taking ACEI.

Inclusion Criteria

• Have a Body Mass Index (BMI) between 20-25 (healthy control) or 35 and above (obese)
• Adults aged 18-65

Exclusion Criteria

• Known diagnosis of inflammatory bowel disease, microscopic colitis, celiac disease or other inflammatory conditions or diabetes mellitus
• Antibiotic use within the past 4 weeks (they can be enrolled after a four week washout period and subsequent use during the 6 month study duration does not exclude them)
• Bowel preparation for colonoscopy within the past week
• Significant bowel surgery other than hysterectomy or appendectomy
• Pregnancy or plans to become pregnant within the study time frame
• Any other disease(s), condition(s) or habit(s) that would interfere with completion of study, or in the judgment of the investigator would potentially interfere with compliance to this study or would adversely affect study outcomes
• Age < 18 or vulnerable adults

Inclusion Criteria                                           

• > 18 and < 65 years of age
• Recruited from the Mayo Clinic bariatric surgery clinic
• Meets one of the National Institute of Health’s criteria for bariatric surgery
  • Body mass index (BMI) > 40 kg/m2 
  • BMI > 35 kg/m2 with significant weight-related comorbidities
• Is not on chronic antibiotic therapy        
• Does not have active systemic illness

Exclusion Criteria

• Type 1 or 2 diabetes due to the known pre-existing changes in the gut microbiome in this population
• Has had exposure to probiotics, prebiotics or antibiotics in the preceding 4 weeks
• Has an allergy to antibiotics precluding the use of standard peri-operative antibiotics cefazolin and metronidazole

• Individuals ages 18-65
• Scheduled to receive a hearing test   
• Able to give informed consent                      

• Patients < 18 years or >65 years
• Specialized populations (adult developmentally delay, cognitive decline, etc.)
• Patients using implantable hearing devices (ex. cochlear implant, osseointegrated devices, etc.)
•  Patients that have had ear surgery (or planned) within the month
• Patients with sudden changes (or fluctuating) hearing (bilateral or unilateral)
• Patients with ear drainage and/or ear pain noted (bilateral or unilateral)                  
• Vulnerable populations (ex. prisoners, severe mentally illness etc.)

Inclusion Criteria

• Adult male and female, 18-35 years of age;

• Able to understand the study, and having understood, provide written informed consent in English

• Subject must be in general good health as determined by medical history, physical exam and by physician investigator

• If female and of child bearing potential, have a negative pregnancy test prior (within 48 hours) to participating in the study.

• Subject is unable or unwilling to participate in all aspects of the study.

• Females who are pregnant

• Significant medical history including neurological disease, learning disability or cognitive dysfunction, pulmonary disease, or cardiovascular disease

• Adult patients with an imaging diagnosis of a vascular anomaly and vascular anomaly associated pain (Pain score of 4 or higher on a scale of 0–10 for the question, “Please rate your pain by circling the one number that best describes your worst pain over the past 24 hours”) referred for clinically indicated MRI-guided percutaneous laser ablation or cryoablation using FDA approved ablation devices who consent to study participation.

• Adult patients with an imaging diagnosis of a vascular anomaly and vascular anomaly associated pain (Pain score of 3 or less on a scale of 0–10 for the question, “Please rate your pain by circling the one number that best describes your worst pain over the past 24 hours”) referred for clinically indicated MRI-guided percutaneous laser ablation or cryoablation using FDA approved ablation devices who consent to study participation.

• Adults 18 years of age and older
• Healthy subjects without known cardiovascular disease, thyroid disease or documented mental health illness
• Subjects who are not on any medications
• Subjects with no prior history of regular amphetamine use, and non-prescription stimulants
• Nonsmokers

• Subjects with known cardiovascular disease, thyroid disease
• Subjects with history of psychotic disorders/mental health illness, including but not limited to anxiety, depression, bipolar disorder; history of substance abuse or dependence
• Subjects currently taking medications
• Prior history of regular amphetamine use, or non-prescription stimulants
• Smokers
• Pregnant subjects
• Known lactose intolerance (due to presence of lactose in the prepared medication)
• Family history of sudden cardiac death

Inclusion Criteria

• Has suspected or confirmed myofascial trigger points in the upper trapezius
• Age 18 or greater

Exclusion Criteria 

• Has deep seated MTrPs not accessible to ultrasound evaluation
• Adults lacking capacity to consent
• Vulnerable subjects such as prisoners

• Hypertension defined as 140 mmHg ≤ systolic BP ≤ 180 mmHg or  90 mmHg ≤ diastolic BP ≤ 100 mmHg despite anti-hypertensive medical therapy
• Metabolic Syndrome defined as the presence of any two of the following traits:
  • Abdominal obesity, defined as a waist circumference in men ≥102 cm (40 in) and in women ≥88 cm (35 in)
  • Serum triglycerides ≥150 mg/dL (1.7 mmol/L)
  • Serum HDL cholesterol <40 mg/dL (1 mmol/L) in men and <50 mg/dL (1.3 mmol/L) in women or drug treatment for low HDL cholesterol
  • Fasting plasma glucose ≥100 mg/dL (5.6 mmol/L) or drug treatment for elevated blood glucose
• Between the ages of 18 and 75 years
• Use of antihypertensive medications at a stable dose for 30 days preceding screening visit.
• Use of statins or ezetimibe or combinations on stable dose for 60 days preceding screening visit.
•  Fish oil, omega 3 or other medications prescribed for lipid levels which are not mentioned in these instructions:
  • They can be taken according to the usual regimen

Exclusion Criteria

Subjects who met any of the following criteria will be excluded from the study:

• Known hypersensitivity or allergy to MANP or its components, carperitide, other natriuretic peptides, or related compounds;
• Subjects with orthostatic hypotension at the screening visit, defined as a decrease in systolic BP of >20 mmHg or a decrease in diastolic BP of >10 mmHg within three minutes of standing when compared with blood pressure from the sitting position.
• Subjects with a systolic BP >180 mmHg or a diastolic BP >100 mmHg
• Women of child-bearing potential
• The presence of abnormal laboratory values at screening visit considered clinically significant by the Investigator. Specifically they will be excluded if  a) Serum sodium of < 135 mEq/dL or > 145 mEq/dL; b) Serum potassium of < 3.5 mEq/dL or > 5.1 mEq/dL
• Subjects whose body weight has changed more than 3% in the last 3 months
• Having received any investigational drug or device within 30 days prior to entry into the study;
• A history (within the last 2 years) of alcohol risky use (defined as more than 14 standard drinks per week on average or more than 4 drinks on any day for men under age 65 
  •defined as more than 7 standard drinks per week on average or more than 3 drinks on any day for women and adults 65 years and older);
• A history of  illicit drug use, psychiatric  illness that might impair the participation to the study, physical dependence to any opioid, or any history of substance abuse or addiction;
• A history of difficulty with donating blood or donated blood or blood products within 45 days prior to enrollment;
• Clinically significant new illness in the 1 month before screening in the opinion of the Investigator  
• Any disease or condition (medical or surgical) which, in the opinion of the investigator, might compromise the hematologic, cardiovascular, pulmonary, renal, gastrointestinal, hepatic, or central nervous system; or other conditions that may interfere with the absorption, distribution, metabolism or excretion of study drug, or would place the subject at increased risk.
• History of severe allergies;
• History of coronary artery disease or cerebrovascular disease or syncope;
• History of epilepsy or other seizure disorder;
• History of organ transplantation;
• Malignancy within 5 years of the screening visit with the exception of basal cell and squamous cell skin carcinoma
• Clinically significant intrinsic renal disease, renal artery stenosis, or history of fibromuscular dysplasia of the renal arteries;
• Consumption of a phosphodiesterase-5 inhibitor (sildenafil, vardenafil, or tadalafil) within 72 hours of receiving MANP.
• Episodic or chronic use of nitrates (Isordil, nitroglycerine), MAO inhibitors, antipsychotics, antiarrhythmics, psychostimulants, systemic corticosteroids, cholestyramine and cholestipol reisins, fibrates, nicotinic acid, cyclosporin, rifampin or other highly potent PgP inhibitors.
• Nonsteroidal anti-inflammatory drugs including Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors) are NOT allowed within 48 hours before the screening visit
• Aspirin:
  • Chronic/Daily use for cardiac prophylaxis only. Not to exceed 325mg daily
• Herbal remedies:
  • Chronic/daily and episodic use is NOT allowed throughout the study
• Vitamin and mineral replacements:
  • Stable dose for 60 days preceding screening visit
• Thyroid medication may be used if stable regimen is established and subject has history of controlled thyroid disease. Dose expected to remain constant throughout the study.
• Inhaled, topical and nasal corticosteroid preparations are NOT allowed within 48 hours before the screening visit
• Oral or inhaled sympathomimetics (β-agonists) bronchodilators and over the counter cold/decongestant products that contain a β-agonist are NOT allowed within 48 hours before the screening visit
• Potassium supplements:
  • Chronic/daily use is allowed if at a stable dose for at least 14 days before the screening visit
• Any disease or condition (medical or surgical) which, in the opinion of the investigator, might compromise the hematologic, cardiovascular, pulmonary, renal, gastrointestinal, hepatic, or central nervous system; or other conditions that may interfere with the absorption, distribution, metabolism or excretion of study drug, or would place the subject at increased risk.
• Subjects who smoke or have any history of tobacco product use more recently than 6 months prior to the enrollment into the study

• Male or female ≥ 16 and ≤ 75 years of age at Baseline.
  • Adolescent subjects at the age of 16 and 17 years old will be enrolled if approved by the country or regulatory/health authority. If these approvals have not been granted, only subjects ≥ 18 years old will be enrolled.
  • Adolescent subjects at the age of 16 and 17 years old must weigh ≥ 40 kg and meet the definition of Tanner Stage 5 at the screening visit.
• Diagnosis of ulcerative colitis for 90 days or greater prior to Baseline, confirmed by colonoscopy during the Screening Period, with exclusion of current infection, colonic dysplasia and/or malignancy. Appropriate documentation of biopsy results consistent with the diagnosis of UC, in the assessment of the Investigator, must be available.
• Active ulcerative colitis with an Adapted Mayo score of 5 to 9 points and endoscopic sub score of 2 to 3 (confirmed by central reader).
• Demonstrated an inadequate response to, loss of response to, or intolerance to at least one of the following treatments including, oral aminosalicylates, corticosteroids, immunosuppressants and/or biologic therapies, in the opinion of the investigator as defined below:
  • Note: An inadequate response, loss of response, or intolerance to Oral Aminosalicylates will NOT count towards eligibility for the following countries:
    • Austria, Czechia, Finland, Ireland, Italy, Latvia, Lithuania, Norway, Poland, Portugal, Spain, Sweden and United Kingdom.
  • Oral aminosalicylates (e.g., mesalamine, sulfasalazine, olsalazine, balsalazide):
    • Signs and symptoms of persistently active disease, in the opinion of the investigator, during a current or prior course of at least 4 weeks of treatment with 2.4 g/day mesalamine, 4 g/day sulfasalazine, 1 g/day olsalazine, or 6.75 g/day balsalazide.
  • Corticosteroids:
    • Signs and symptoms of persistently active disease despite a history of at least one induction regimen that included a dose equivalent to prednisone ≥ 40 mg/day orally for at least 3 weeks or intravenously for 1 week, OR
    • Unable to taper corticosteroids to below a dose equivalent to prednisone 10 mg daily orally without recurrent active disease, OR
    • Signs and symptoms of persistently active disease during or after a course of at least 4 weeks of treatment with 9 mg/day budesonide or 5 mg/day beclomethasone, OR
    • Unable to taper oral budesonide to at or below 6 mg/day without recurrent active disease, OR
    • History of intolerance to corticosteroids (including, but not limited to Cushing's syndrome, osteopenia/osteoporosis, hyperglycemia, insomnia, infection).
  • Immunosuppressants:
    • Signs and symptoms of persistently active disease despite a history of at least one 90 day regimen of oral azathioprine (≥ 1.5 mg/kg/day; for subjects in Japan, China, and Taiwan only: ≥ 1.0 mg/kg/day), 6-MP (≥ 1 mg/kg/day; [for subjects in Japan, China, and Taiwan only: ≥ 0.6 mg/kg/day, rounded to the nearest available tablet of half tablet formulation] or a documented 6-TGN level of 230 –450 pmol/8 × 108 RBC or higher on the current dosing regimen), injectable MTX (≥ 15 mg/week subcutaneous [SC] or intramuscular), or tacrolimus (for subjects in Japan and Taiwan only: documented trough level of 5 –10 ng/mL); OR
    • History of intolerance to at least one immunosuppressant (including, but not limited to nausea/vomiting, abdominal pain, pancreatitis, liver enzyme abnormalities, lymphopenia, infection).
      • Note: Oral MTX use is allowed during the study, however prior or current use of oral MTX is not sufficient for inclusion into the study unless these subjects were previously treated with aminosalicylates, corticosteroids or immunosuppressants (azathioprine or 6-MP) and have inadequate response to, loss of response to or intolerance to the therapy as defined above.
  • Biologic Agents for UC:
    • Signs and symptoms of persistently active disease despite a history of any of the following:
      • at least one 6-week induction regimen of infliximab (≥ 5 mg/kg IV at 0, 2, and 6 weeks);
      • at least one 4-week induction regimen of adalimumab (one 160 mg subcutaneous (SC) dose followed by one 80 mg SC dose [or one 80 mg SC dose, in countries where this dosing regimen is allowed] followed by one 40 mg SC dose at least 2 weeks apart);
      • at least one 2-week induction regimen of golimumab (one 200 mg SC dose followed by one 100 mg SC dose at least 2 weeks apart);
      • at least one 6-week induction regimen of vedolizumab (300 mg IV at 0, 2 and 6 weeks); OR
    • Recurrence of symptoms during scheduled maintenance dosing following prior clinical benefit (discontinuation despite clinical benefit does not qualify); OR
    • History of intolerance to at least one biologic agent (including, but not limited to infusion-related reaction, demyelination, congestive heart failure, infection).
      • Note: Non-bio-IR subjects who have received a prior biologic for up to 1 year may be enrolled, however, subjects must have discontinued the biologic for reasons other than inadequate response or intolerance (e.g., change of insurance, well controlled disease), and must meet the criteria for inadequate response, loss of response or intolerance to aminosalicylates, corticorsteroids and/or immunosuppressants as defined above.
• Female subjects of childbearing potential must have a negative serum pregnancy test at the Screening Visit and a negative urine pregnancy test at the Baseline Visit prior to study drug dosing.
  • Note: subjects with borderline serum pregnancy test at Screening must have a serum pregnancy test ≥ 3 days later to document continued lack of positive result.
  • For subjects in Ireland, a repeat serum pregnancy test ≥ 3 days later that is still borderline will result in screen failure.
  • If female, subject must meet the contraception criteria.
• Subject is judged to be in otherwise good health as determined by the Investigator based upon the results of medical history, laboratory profile, physical examination and a 12-lead electrocardiogram (ECG) performed during Screening.
• Subject must be able and willing to give written informed consent and to comply with the requirements of this study protocol. In Japan, if the subject is < 20 years old, a subject's parent or legal guardian must be willing to give written informed consent.

• Subject with current diagnosis of Crohn's disease (CD) or diagnosis of indeterminate colitis (IC).
• Current diagnosis of fulminant colitis and/or toxic megacolon.
• Subject with disease limited to the rectum (ulcerative proctitis) during the screening endoscopy.
• History of colectomy (total or subtotal) with ileoanal pouch, Kock pouch, or ileostomy for UC or is planning bowel surgery.
• Received treatment with rectal aminosalicylates or corticosteroids, other enemas/suppositories (other than required for endoscopy), within 14 days prior to the Screening endoscopy and during the remainder of the Screening Period.
• Received cyclosporine, tacrolimus, mycophenolate mofetil or thalidomide within 30 days prior to Baseline.
• Subjects who received azathioprine or 6-mercaptopurine within 10 days of Baseline.
• Received intravenous corticosteroids within 14 days prior to Screening or during the Screening Period.
• Subject on MTX or oral aminosalicylates who:
  • has not been on the current course of MTX for at least 42 days prior to Baseline, and has not been on stable doses for at least 28 days prior to Baseline;
  • has not been on stable doses of oral aminosalicylates for at least 14 days prior to Baseline;
  • has discontinued use of aminosalicylates within 14 days of Baseline.
• Subject on treatment with corticosteroids who meet the following:
  • Oral corticosteroid dose > 30 mg/day (prednisone or equivalent) or has not been on the current course for at least 14 days prior to baseline and on a stable dose for at least 7 days prior to Baseline;
  • Oral budesonide dose > 9 mg/day or has not been on the current course for at least 14 days prior to Baseline and on a stable dose for at least 7 days prior to Baseline;
  • Oral beclomethasone dose > 5 mg/day or has not been on the current course for at least 14 days prior to baseline and on a stable dose for at least 7 days prior to Baseline.
  • Subject has been taking both oral budesonide (or oral beclomethasone) and oral prednisone (or equivalent) simultaneously, with the exception of topical or inhalers within 14 days prior to Screening or during the Screening Period.
• Subject has active TB or meets TB exclusionary parameters.
• Subject who received fecal microbial transplantation within 30 days prior to Baseline.
• Subject on UC-related antibiotics who has not been on stable doses for at least 14 days prior to Baseline or has discontinued these medications within 14 days of Baseline.
• Subjects who received any of the following biologic therapy:
  • infliximab, certolizumab, adalimumab, golimumab, vedolizumab, natalizumab, within 8 weeks prior to Baseline; OR
  • ustekinumab within 12 weeks prior to Baseline.
  • Note: If there is proper documentation of undetectable drug level measured by a commercially available assay for any of the approved biologics above, there is no minimum washout prior to Baseline.
• Subject with previous exposure to JAK inhibitor (e.g., tofacitinib, baricitinib, filgotinib, upadacitinib).
• Subject who received non-steroidal anti-inflammatory drugs (NSAIDs) (except topical NSAIDs and the use of low dose aspirin for cardiovascular [CV] protection) within 7 days prior to Baseline.
• Subject received traditional Chinese medicine within 30 days prior to baseline.
• Subject received live vaccine(s) within 30 days (8 weeks for Japan) prior to Baseline, or who is expected to need live vaccination during study participation including at least 30 days (8 weeks for Japan) after the last dose of study drug.
• Systemic use of known strong cytochrome P450 (CYP)3A inhibitors or strong CYP3A inducers during the Screening Period and through the end of the study.
• Subject currently receiving total parenteral nutrition (TPN) or plan to receive TPN at any time during study treatment.
• Subject who received any investigational agent or procedure within 30 days or 5 half-lives prior to Baseline, whichever is longer or is currently enrolled in an interventional study.
• Subject with positive C. difficile toxin stool assay during Screening.
• Infection(s) requiring treatment with intravenous anti-infectives within 30 days prior to the Baseline Visit or oral/intramuscular anti-infectives within 14 days prior to the Baseline Visit.
• Chronic recurring infection and/or active viral infection that, based on the investigator's clinical assessment, makes the subject an unsuitable candidate for the study.
• Subject has current or past history of recurrent or disseminated (even a single episode) herpes zoster.
• Subject has current or past history of disseminated (even a single episode) herpes simplex.
• Subject has HBV, HCV, or human immunodeficiency virus (HIV) infection defined as:
  • HBV: hepatitis B surface antigen (HBs Ag) positive (+) or detected sensitivity on the HBV deoxyribonucleic acid (DNA) polymerase chain reaction (PCR) qualitative test for subjects who are hepatitis B core antibody (HBc Ab) positive (+) subjects (and for Hepatitis B surface antibody positive (+) subjects where mandated by local requirements);
  • HCV: HCV ribonucleic acid (RNA) detectable in any subject with anti-HCV antibody (HCV Ab);
  • HIV: confirmed positive anti-HIV antibody (HIV Ab).
• Prior or current gastrointestinal (GI) dysplasia, other than completely removed lowgrade dysplastic lesion in any biopsy performed during or before the Screening endoscopy.
• History of any malignancy, except for successfully treated nonmelanoma skin cancer (NMSC) or localized carcinoma in situ of the cervix.
• History of gastrointestinal (GI) perforation (other than appendicitis or penetrating injury), diverticulitis or significantly increased risk of GI perforation per investigator's judgment.
• Screening laboratory and other analyses show any of the following abnormal results:
  • Serum Aspartate Transaminase (AST) or Alanine Transaminase (ALT) > 2 × upper limit of normal (ULN);
  • Estimated glomerular filtration rate (eGFR) by simplified 4-variable Modification of Diet in Renal Disease (MDRD) formula < 30 mL/min/1.73 m^2;
  • Total White Blood Cell (WBC) count < 2,500/μL;
  • Absolute neutrophil count (ANC) < 1,200/μL;
  • Platelet count < 100,000/μL;
  • Absolute lymphocytes count < 750/μL;
  • Hemoglobin < 9 g/dL.
• Female subject who is pregnant, breastfeeding or considering becoming pregnant during the study or within 30 days after the last dose of study drug, or has positive pregnancy test at Screening (serum) or Baseline (urine).
• History of an allergic reaction or significant sensitivity to constituents of the study drug (and its excipients) and/or other products in the same.
• History of clinically significant (per investigator's judgment) drug or alcohol abuse in the last 6 months.
• Subject who previously received stem cell transplantation.
• Subject has been a previous recipient of an organ transplant which requires continued immunosuppression.
• For Japan subjects only: positive result of beta-D-glucan or two consecutive indeterminate results of beta-D-glucan (screening for Pneumocystis jiroveci infection).
• Received cytoapheresis treatment (GCAP, LCAP etc.) within 60 days prior to Baseline.
• For Japan subjects only: received ATM treatment (antibiotic combination therapy with amoxicillin, tetracycline and metronidazole) during the Screening Period.
• Recent (within past 6 months) cerebrovascular accident, myocardial infarction, coronary stenting or Moderate to severe congestive heart failure (New York Heart Association class III or IV).
• Conditions that could interfere with drug absorption including but not limited to short bowel syndrome (e.g., history of gastric bypass surgery).
• History of clinically significant medical condition or any other reason which, in the opinion of the investigator, would interfere with the subject's participation in this study, would make the subject an unsuitable candidate to receive study drug, or would put the subject at risk by participating in the protocol.