• Adult patients (18 years or older) who have had a 10-second 12-lead ECG at Mayo Clinic and have a CHA2DS2-VASc ≥ 2 for men or CHA2DS2-VASc ≥3 for women.
• Adult patients who have AI-detected AF and are eligible for anticoagulation will be eligible for the first group of patients.
• Adult patients who do not have AI-detected AF but are similar to the first group in other aspects will be eligible as part of the second group of patients.

• Patients with diagnosed atrial fibrillation or atrial flutter, on anticoagulation or have another indication for anticoagulation (e.g., mechanical valve), missing DOB or sex in EHR, history of intracranial bleeding, history of end-stage kidney disease, or have an implantable cardiac monitoring device (pacemaker, debfibrillator, implanted loop recorded).
• Patients who are deemed by research personnel to have limitations that would prevent them from being able to provide informed consent, use the patch, or complete interviews will not be included.

• Adult patients, ≥ 18 years of age.
• Patients with histopathologic or molecular confirmation of either IDH-mutant diffuse astrocytoma or IDH-mutant anaplastic astrocytoma.
• Patients who will be proceeding to receive routine standard of care treatment (radiation with concurrent oral temozolomide) at Mayo Clinic, Rochester.

• Patients who have previously received any adjuvant therapy (radiation, chemotherapy, investigational) directed towards the glioma.
• Patients who have been previously treated with Gliadel wafers.

• Male or female at least 18 years of age at the time of giving informed consent.
• Participants currently receiving warfarin anticoagulation and who are able to receive warfarin with a target INR 2.0 to 3.0.
• Participants are able to take low-dose aspirin at a dose of 75 -100 mg daily or have a documented contraindication to aspirin use.
• Implantation of an On-X mechanical valve in the aortic position at least 3 months (90 days) ago.
• Female participants of childbearing potential, including those who are less than 2 years post-menopausal, must agree to, and comply with using a highly effective method of birth control (e.g., barrier contraceptives [condom or diaphragm with a spermicidal gel], hormonal contraceptives [implants, injectables, combination oral contraceptives, transdermal patches, or contraceptive rings], intrauterine devices or sexual abstinence) while partaking in this study. In addition, all women of childbearing potential must agree to continue to use birth control throughout the study until last study visit.
• Informed of the full nature and purpose of the study, including possible risks and side effects, given ample time and opportunity to read and understand this information, and sign and date the written informed consent before inclusion in the study.

• Mechanical valve in any position other than aortic valve.
• Any cardiac surgery in the three months (90 days) prior to enrollment.
• Need to be on aspirin >100 mg daily or a P2Y12 inhibitor (clopidogrel, ticagrelor, prasugrel, or ticlopidine).
• Known hypersensitivity or other contraindication to apixaban.
• On dialysis or a creatinine clearance < 25 mL/min.
• Ischemic stroke or intracranial hemorrhage within 3 months.
• Active pathological bleeding at the time of screening for enrollment.
• Active endocarditis at the time of screening for enrollment.
• Pregnant, plan to become pregnant, or are breast feeding.
• On concomitant combined strong P-gp and CYP3A4 inducers or inhibitors.
• History of non-compliance with recommended monthly INR testing.

• Solid organ transplant candidates (18 years or older) on deferred, active, or inactive transplant waiting lists.
• Nominated adult caregivers (18 years or older) of solid organ transplant patients listed for deceased donor solid organ transplantation.
• CG identified in the electronic medical record.

• Individuals unwilling to provide consent.
• Patients or CG unable to complete questionnaires or consents due to limited English proficiency.

• Patients with either an imaging diagnosis of HCC by CT or MRI (LI-RADS 5) confirmed by a board-certified abdominal radiologist, or with biopsy-proven HCC.
• Subjects who may undergo hepatic surgical resection, liver transplant, hepatic locoregional therapy (ablation, embolization, etc.) or systemic therapy.
• No prior treatment for index HCC lesion (surgical resection, liver transplant, hepatic locoregional therapy arm).
• For the systemic therapy arm, patients who have had unequivocal progression after prior LRT and/or those undergoing de novo systemic therapy in view of advanced HCC at diagnosis.
• Male or female with age greater than 18 years, with the capacity and willingness to provide a written informed consent.

• Subjects requiring emergent surgery for a ruptured/bleeding HCC.
• Bilirubin > 3.0 mg/dL, which is a contraindication for Gadoxetate, the MRI contrast agent (relevant to PET/MRI).
• Pregnant and/or breast-feeding subjects. A negative pregnancy test within 48 hours of the PET scan.
• Subjects with higher than the weight/size limitations of PET/MRI or PET/CT scanner.
• Subjects with contraindication to MRI (relevant to PET/MRI):
  • Subjects who have a heart pacemaker;
  • Subjects who have a metallic foreign body (metal sliver) in their eye, or who have an aneurysm clip in their brain;
  • Subjects who have implanted devices with magnets;
  • Subjects who have other implanted electronic devices;
  • Subjects who have deep brain stimulator;
  • Subjects who have vagal nerve stimulator;
  • Subjects with cochlear (ear) or auditory implants.

• Adults aged 18 to 80 years, inclusive.
• Diagnosed with celiac disease based on positive serology (eg, tissue transglutaminase IgA antibody and/or deamidated gliadin peptide IgG) and intestinal histology consistent with ≥ Marsh Type II or with evidence of villous atrophy.
• Has HLA-DQ2.5 genotype (HLA-DQA1*05 and HLA-DQB1*02) (homozygotes or heterozygotes).
• Has followed a GFD for > 12 months immediately prior to study entry.
• Negative for tTG and negative or weak positive for DGP-IgA/IgG during screening.
• Male or female, and using at least 2 acceptable birth control methods or who are sterile or postmenopausal.
• Capable of understanding and complying with protocol requirements.
• Patient understands and has signed the informed consent form.

• Refractory celiac disease.
• Selective IgA deficiency.
• Positive for HLA-DQ8 (DQA1*03, DQB1*0302).
• Previous treatment with tolerance-inducing therapies for celiac disease.
• Known wheat allergy.
• Part B only: History of hyperacute or prolonged symptoms following gluten exposure.
• Uncontrolled or significant medical conditions (including active infections or chronic hepatitis) which, in the opinion of the Investigator, preclude participation.
• History of dermatitis herpetiformis.
• Pregnant or breastfeeding.

• Individuals aged 18 to 70 years, inclusive, at Screening.
• Clinical diagnosis of IBS-C or IBS-D according to Rome IV criteria at Screening.
• Body mass index (BMI) 18.0 to 40.0 kg/m2, inclusive at Screening.
• Understands the study procedures, is willing and able to comply with the study procedures, and is able to give informed consent.
• Negative test results for alcohol and selected drugs at Screening and Day 1.
• Negative hepatitis panel (including hepatitis B surface antigen [HBsAg] and hepatitis C virus antibody [anti-HCV]) and negative for human immunodeficiency virus (HIV) antibody screens at Screening.
• Subjects with recent (within 6 months of Screening) or ongoing alarm features (unexplained weight loss, nocturnal symptoms, blood mixed with stool) are to have had a diagnostic colonoscopy prior to Screening and after the onset of alarm features (for subjects with alarm features) to exclude non-IBS conditions per the Rome IV diagnostic algorithm for IBS.
• If treated with any of the following medications, dosing must be stable for 90 days prior to Screening and the subject must agree to maintain the same dose of  medication throughout the study:
  • Tricyclic antidepressants, tetracyclic antidepressants (e.g., mirtazapine), selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), or anticonvulsants (e.g., pregabalin or gabapentin) for conditions other than IBS pain;
  • Benzodiazepines or non-benzodiazepine hypnotics, administered at bedtime for conditions other than IBS pain.

• Pregnant or lactating.
• Structural or metabolic diseases/conditions that affect the gastrointestinal system.
• Diagnosis of IBS-M or unsubtyped IBS (IBS-U).
• Unable to withdraw the following medications that alter GI transit for 72 hours prior to baseline colonic transit assay through the duration of treatment period, with the exception of rescue medicine usage (bisacodyl and loperamide):
  • Stimulant laxatives, osmotic laxatives, magnesium or aluminum-containing antacids, over the counter fiber, stool softeners, probiotics, bismuth subsalicylate, prokinetics;
  • Antibiotics, anticholinergics, antidiarrheals, antiflatulence agents, antispasmodics, chloride channel activators, bile acid sequestrants, cholinomimetics, 5-HT3 antagonists, 5-HT4 agonists, guanylate cyclase C agonists, opioid agonists or antagonists, sodium-proton exchanger NHE3 inhibitors.
    • Note: Low stable doses of thyroid replacement, estrogen replacement, low dose aspirin for cardioprotection, and birth control pills or depot injections are permissible.
• Clinically relevant changes in dietary, lifestyle, or exercise regimen within 30 days prior to Screening and for the duration of the study that may confound efficacy assessments in the clinical judgment of the Investigator (or designee).
• Any colonic or major abdominal surgery (e.g., bariatric surgery [including gastric banding], cholecystectomy, stomach surgery, small-/large-bowel surgery, or abdominal large vessel surgery), except that in IBS-C subjects a history of cholecystectomy more than 6 months prior to Screening is allowed. Procedures such as appendectomy, hysterectomy, caesarean section, or polypectomy are allowed as long as they have occurred at least 3 months prior to Screening.
• History of colorectal cancer, inflammatory bowel disease, diverticulitis, ischemic colitis, microscopic colitis, bile acid diarrhea, or celiac disease.
• History of organic abnormalities of the GI tract, intestinal obstruction, stricture, toxic megacolon, GI perforation, or impaired intestinal circulation (e.g., aortoiliac disease).
• Other GI diseases such as peptic ulceration, GI bleeding, or GI inflammatory disease (e.g., esophagitis, gastritis, or duodenitis) within 6 months prior to Screening. The following conditions will not exclude a subject: acute gastritis that resolved without complication,
• and gastroesophageal reflux disease (GERD).
• Use of any of the following medications within 30 days prior to Screening and for the duration of the study:
  • Opioids;
  • The following are excluded if they are prescribed for IBS pain: tricyclic antidepressants, tetracyclic antidepressants (eg, mirtazapine), SSRIs, SNRIs, anticonvulsants (e.g., pregabalin or gabapentin);
  • Medical or recreational marijuana, tetrahydrocannabinol (THC), cannabidiol (CBD), synthetic cannabinoids, or other cannabis derivatives for any indication;
  • Benzodiazepines, or non-benzodiazepine hypnotics, unless administered at bedtime for conditions other than IBS pain.
• Use of cigarettes or any other nicotine-containing products within 30 days of Screening.
• Prior (within 15 days of Screening) or anticipated concomitant use of GI antibiotics.
• Ongoing treatment with GLP-1 or amylin analogues or agonists.
• Any elective major surgery planned or anticipated at any time during the study.
• History of pancreatitis of any etiology, cholecystitis, or symptomatic gallbladder stone disease within 6 months prior to Screening.
• Have received tube feeding, defined formula diets, or parenteral alimentation within 30 days prior to Screening.
• History of cerebrovascular disease (e.g., stroke, transient ischemic attacks), acute coronary syndrome, myocardial infarction, or unstable angina within 6 months prior to Screening.
• History or presence of:
  • Risk factors for Torsade de Pointes (eg, heart failure, cardiomyopathy, or family history of Long QT Syndrome);
  • Sick sinus syndrome, second or third-degree atrioventricular block, myocardial infarction, pulmonary congestion, symptomatic or significant cardiac arrhythmia, prolonged QT interval corrected by Fridericia's formula (QTcF) interval, or clinically significant conduction abnormalities.
• Clinically significant cardiac history or presence of ECG findings as judged by the Investigator or qualified designee at Screening or Day 1, including each criterion as listed below:
  • Abnormal sinus rhythm (heart rate < 40 or > 100 beats per minute [bpm]);
  • QTcF interval > 470 ms (If there is an abnormal result, ECGs are to be repeated 3 times to obtain a mean QTcF before excluding patient);
  • QRS interval ≥ 110 ms;
  • PR interval ≥ 220 ms.
• Uncontrolled hypertension with an abnormal supine blood pressure defined as a systolic blood pressure (SBP) ≥ 160 mm Hg or a diastolic blood pressure (DBP) ≥ 100 mm Hg, confirmed by at least 1 repeated measurement at Screening.
• Tachycardia defined as a resting heart rate ≥ 120 bpm or bradycardia defined as a resting heart rate of ≤ 40 bpm, confirmed by at least 1 repeated measurement at Screening.
• Hypotension with an abnormal supine blood pressure defined as SBP < 90 mm Hg or DBP < 60 mm Hg, confirmed by at least 1 repeated measurement at Screening.
• Orthostatic hypotension consisting of SBP decrease of ≥ 20 mm Hg or a DBP decrease of ≥ 10 mm Hg approximately 3 minutes after standing from a 5-minute supine position, confirmed by at least 1 repeated measurement at Screening.
• Hepatic dysfunction (history of cirrhosis or abnormal serum alanine aminotransferase [ALT] or aspartate transaminase [AST] > 3 × upper limit of normal [ULN]); total direct bilirubin > 2 × ULN, or alkaline phosphatase > 2 × ULN at Screening.
• Clinically significant renal insufficiency (i.e., serum creatinine > 2.5 mg/dL or estimated glomerular filtration rate [eGFR] ≤ 60 mL/min/1.73 m2) based on CKD-EPI equation at Screening.
• History of insulin-dependent diabetes mellitus.
• Significant history or clinical manifestation of any endocrine, allergic, dermatological, hepatic, renal, hematological, pulmonary, GI, neurological or psychiatric disorder, malignancy (with the exception of treated basal cell carcinomas), or any other condition as determined by the Investigator (or designee), that would prevent the individual from participating in the study due to risk to the scientific validity of study assessments or to personal well-being of the subject.
• History of severe head injury or history of seizures.
• Current suicidal ideation or history of suicide attempt or a hospitalization for a major psychiatric condition within 1 year prior to Screening.
• History of alcohol use disorder or substance use disorder within 2 years of Screening.
• Subjects who do not agree to use a highly effective method of contraception if the possibility of conception exists. Eligible male and female subjects must also agree not to participate in a conception process (ie, actively attempt to become pregnant or to impregnate, sperm donation, in vitro fertilization) during the study and for 30 days after the last dose of study treatment for female subjects and for 90 days after the last dose of study treatment for male subjects. Highly effective methods of contraception include the following:
  • Oral, implantable, transdermal or injectable contraceptives (starting ≥ 60 days before administration of study treatment) in combination with diaphragm with vaginal spermicide, cervical cap with vaginal spermicide, or male condom;
  • Standard intrauterine device (IUD; e.g., Copper T 380A IUD), intrauterine system (IUS; e.g., LNg 20 IUS
    •progesterone IUD), progesterone implant, or tubal sterilization (≥ 6 months after surgery) in combination with a female condom with spermicide, a diaphragm with vaginal spermicide, cervical cap with vaginal spermicide, or male condom;
  • Post vasectomy and male condom, partner using diaphragm with spermicide, cervical cap with spermicide, estrogen and progesterone oral contraceptives (“the pill”), estrogen and progesterone transdermal patch, vaginal ring, or progesterone
  • injection;
  • Complete sexual abstinence defined as refraining from heterosexual intercourse for the entire period of risk associated with study treatment. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the subject. If a subject who is abstinent at the time of signing the informed consent form (ICF) becomes sexually active they must agree to use contraception as described previously;
  • Females who are surgically sterile (defined as women with documentation of prior hysterectomy, bilateral salpingectomy, or bilateral oophorectomy) or postmenopausal (defined as: 12 consecutive months with no menses without an alternative medical cause) are not considered to be of childbearing potential; otherwise women are considered to be of childbearing potential;
  • Male study participant must agree to utilize medically acceptable methods of contraception as described above with female partners of childbearing potential.
• Use of any prescription medications/products or available over the counter (e.g., St John’s wort) which are known to chronically alter drug absorption or elimination processes and/or are known to induce or inhibit cytochrome P450 (CYP) 3A4/5 within 30 days or 5 half-lives (whichever is longer) prior to Screening.
• History of significant hypersensitivity, intolerance, or allergy to any drug compound, food, or other substance, unless approved by the Investigator or history of severe allergies (e.g., any history of anaphylaxis to medication[s] or allergens and/or asthma requiring hospitalization).
• Identified active infection and/or fever (defined as axillary or forehead temperature ≥ 37.4°C, oral temperature ≥ 37.7°C, or rectal or ear temperature ≥ 38.3°C) at Screening or Day 1.
• Blood donation or significant blood loss within 8 weeks prior to Screening.
• Plasma donation within 7 days prior to Screening.
• Participated in another clinical study (e.g., investigational drug or device study) within 30 days or 5 half-lives (whichever time period is longer) or 6 weeks for biologic therapies prior to Screening.
• Consumption of foods and beverages containing grapefruit or Seville oranges within 14 days prior to Day 1.

• Age 15 and over (15+ will only occur in dental setting).
• English- or Spanish-speaking.
• Experiencing acute pain of less than 8 weeks duration at the time the opioid is prescribed.
• Received prescription for opioid analgesic at visit; opioids included in the study will be all FDA-approved enteral, transdermal, and transmucosal opioid analgesics including the most common: hydrocodone (except cough and anti-diarrheal medications), oxycodone, codeine (except cough medications), tramadol, morphine, hydromorphone.
  • We do not anticipate many opioid-naïve people receiving an opioid analgesic for acute pain will receive the following drugs, however, we will not exclude otherwise eligible patients who receive one of the following drugs: buprenorphine (as an analgesic), butorphanol, dihydrocodeine, fentanyl, meperidine, methadone (as an analgesic), oxymorphone, pentazocine, sufentanil, and tapentadol.
  • All of these opioids are included in any combinations with acetaminophen, aspirin, ibuprofen, naloxone, etc.
• Opioid naive (no use of prescribed opioids or illicit opioids, including medical or non-medical use, in the past 6 months) by self-report.
• Willing and able to give consent and participate in study.
• Able to access a mobile device (smartphone or tablet) with web access every day to complete study surveys.
• Willing to connect Fitbit to a device that can regularly link to Hugo for data transfer.
• Willing to use the health data sharing platform.
• Released/discharged to home after their visit.

• Pain thought to be caused by a systemic disease very likely to progress to chronic pain (e.g., sickle cell disease, fibromyalgia, lupus, multiple sclerosis, etc.).
• Cancer or end-of-life pain.
• Unable to give consent and be enrolled within 3 days of their visit.

We propose recruiting a total of 150 subjects with ages ranging from 18 to 99 including 3 groups: (1) mTBI+/RHI+: 50 patients with diagnosed mild traumatic brain injury (mTBI) and with the history of organized contact-sports; (2) mTBI-/RHI+: 50 age (by decades) /sex-matched participants that has a history of organized contact-sports but without diagnosed mTBI; (3) mTBI-/RHI-: 50 age (by decades)/sex-matched control participants with no history of organized contact-sports and no diagnosis of mTBI. It is not anticipated that these subjects will have mild cognitive impairment (MCI) from the TBI. MCI is a syndrome defined as a cognitive decline greater than expected for an individual’s age and education level but that does not interfere with activities of daily living.

Group 1 recruitment mTBI+/RHI+:

Residents of Olmsted County, Minnesota who were diagnosed with mTBI will be identified by using the medical-records linkage system of the Rochester Epidemiology Project (REP) between 2017 and 2020. The REP indexes all medical information of individuals residing and receiving care in Olmsted County, Minnesota. Individuals will be identified if they had a diagnostic code in the medical records suggestive of a potential head injury (Table 1),then the medical records will be reviewed for the dates of the specific codes and determined whether a mTBI occurred based on the Mayo Classification System for TBI severity (Definite, Probable, and Possible). By this definition, a “Definite” TBI had to have at least one of the following: loss of conscious of ≥30 minutes, post-traumatic anterograde amnesia of ≥24 hours, intracerebral hematoma, subdural hematoma, epidural hematoma, cerebral contusion, hemorrhagic contusion, penetrating TBI (dura penetrated) or subarachnoid hemorrhage; a “Probable” TBI had to have at least one of the following: loss of consciousness of momentary to <30 minutes, post-traumatic anterograde amnesia of momentary to <24 hours, or depressed, basilar, or linear skull fracture; a “Possible” TBI had to have at least two of the following: blurred vision, confusion (mental state changes), dazed, dizziness, focal neurologic symptoms, headache, or nausea.

If the “Probably” or “Possible” TBI criteria apply to the trauma event, the event will be considered as a mTBI.

The participation of organized contact-sport will be self-reported. Potential participants will be approached with the phone script and/or the letter. If the patient expresses willingness to participate, we will send him/her the follow-up letter or email with a tentative study visit date according to his/her preference. The consent form will be enclosed with the letter/email for his/her review. The questionnaire about the history of contact-sports play will also be enclosed.

Table 1- Codes for traumatic brain injury-related emergency department visits and hospitalizations as recommended by Center for Disease Control and Prevention

Description

ICD-9-CM Codes

Concussion

850

Cerebral laceration and contusion

851

Intracranial injury of other and unspecified nature

854

Injury to optic nerve and pathways

950.1-950.3

Head injury, unspecified

959.01

Inclusion Criteria for Group 1 (mTBI+/RHI+):

1. A history of “Possible” or “Probably” TBI as defined above.
2. A history of participating in at least one organized contact-sport (e.g., football, hockey, soccer, rugby, lacrosse, martial art, etc.) featuring officiated competition.
3. Able to understand the goal of the project and give informed consent/assent;
4. Age ≥18 years;

Exclusion Criteria for Group 1 (mTBI+/RHI+):

1. A history of “Definite” TBI as defined above.
2. A history of chronic neurological disease;
3. Pregnancy or breastfeeding;
4. Inability to provide consent.

Group 2 and Group 3 recruitment:

Recruitment of these paid, groups 2 and 3 participants will be conducted (1) through established Mayo Clinic Rochester research study advertisements, and (2) through Mayo Clinic Study of Aging (MCSA) that provides a list of Olmsted County, MN residents who enrolled in MCSA, from whom matched control will be drawn. The participation of organized contact-sport will be self-reported.

Inclusion Criteria for Group 2 (mTBI-/RHI+):

1. A history of participating in at least one organized contact-sport (e.g., football, hockey, soccer, rugby, lacrosse, martial art, etc.) featuring officiated competition.
2. No history of “Definite”, “Possible” or “Probably” TBI as defined above.
3. Able to understand the goal of the project and give informed consent/assent;
4. Age ≥18 years;

Exclusion Criteria for Group 2 (mTBI-/RHI+):

1. A history of chronic neurological disease;
2. Pregnancy or breastfeeding;
3. Inability to provide consent.

Inclusion Criteria for Group 3 (mTBI-/RHI-):

1. No history of participating in any organized contact-sport (e.g., football, hockey, soccer, rugby, lacrosse, martial art, etc.) featuring officiated competition.
2. No history of “Definite”, “Possible” or “Probably” TBI as defined above.
3. Able to understand the goal of the project and give informed consent/assent;
4. Age ≥18 years;

Exclusion Criteria for Group 3 (mTBI-/RHI-):

1. A history of chronic neurological disease;
2. Pregnancy or breastfeeding;
3. Inability to provide consent.

The 3 groups will be age- (by decades) and sex-matched. We will start by recruiting the 3 groups together for the efficiency of data collection. During the recruitment process, if we notice a certain age range or sex is lacking, we will focus on targeting this particular age group or sex group to ensure the maximum matching. For example, if we particularly looking for 18-25-year-old male volunteers with no history of contact-sports participation in group 3, we will have a 2nd advertisement focusing on this particular age group and/or sex group.

Remuneration of $75 will be provided for each participant. If the participant were asked to return for additional imaging, remuneration of $75 will be provided for each visit.

All subjects will be carefully screened by MRI personnel to be certain that they do not have any contraindication to an MRI exam such as foreign bodies in the brain or eye or an incompatible device such as a cardiac pacemaker. This safety screening is part of the routine clinical practice and is performed before any subject is permitted to enter the scanning room. The patients and parents will be given the option of withdrawing from the study at any point in the project without jeopardizing their medical care at Mayo Clinic. Patients requiring sedation to complete the MRI will be excluded from the study.

Pregnant or nursing women are not eligible to participate in this study.  If the participant wishes to participate with the study she will be asked about her pregnancy status.  If she thinks she may be pregnant or if she is unsure of her pregnancy status, she will be offered a no-charge urine pregnancy test before proceeding with any study visit imaging.

We will attempt to recruit an equal number of men and women, but the final proportions will be dependent upon the available subjects in the disease group. Although we will make every effort to include minority subjects, most of the subjects enrolled in Rochester will be of Caucasian background which is a reflection of the regional demographics.

If there is a question on whether or not the subject has the capacity to provide informed consent, the investigator or a member of the study team will assess the patient by reviewing questions regarding the study such as:

1. Can you tell me the purpose of this study?
2. Do you have to be in this study?
3. Can you tell me what will happen if you agree to take part in this study?
4. What will happen to you if you choose not to be in the study?

If it is determined that the subject does not have the capacity to provide informed consent, the subject will then be excluded from the study.

The investigator or coordinator will meet with the potential participants in a private consult room to review and discuss the details of the study using the informed consent document as a guide. The discussion will include all of the elements of informed consent. Potential participants will be given an opportunity to ask questions and we be provided a copy of the informed consent document.

• ≥ 18 years of age.
• Female patients with confirmed IBD diagnoses who are pregnant and taking immunosuppressants and/or biologic therapy.

• Pregnant female patients younger than 18 years of age.
• Confirmed multiple gestation.

Eligibility last updated 10/18/21. Questions regarding updates should be directed to the study team contact.

• Age ≥ 18 years old.
• Capable of giving consent.
• Established diagnosis of Multiple Sclerosis according to McDonald Criteria (2018). Patients may be diagnosed with any of the conventional phases of MS, primary progressive, relapsing remitting, secondary progressive etc.
• Willing to participate in a 7T MRI examination within a few days of their clinical 3T or 1.5T examination.

• Age < 18 years old.
• Any metallic implant, device implant, ventriculoperitoneal shunt, cardiac valve, pacemaker which would constitute a contraindication to 7T imaging.
• Previous craniotomy.
• Permanent facial makeup (for brain scanning).
• Suffer from claustrophobia.
• Pregnancy.
• Fever / elevated temperature.

Inclusion Criteria

• Men and women, ≥ 70 years of age.
• New or established patients in the primary care practice.
• Willing to provide consent to participate in the study and to use personal health information to ascertain endpoints from the CMS Medicare Claims Database and to access data from health records.
• Health insurance by Medicare Parts A & B (Medicare Fee-for-service).

• Oral anticoagulation (OAC) for any indication at the time of enrollment.
• History of atrial fibrillation (AF) or atrial flutter (AFL) as documented in the patient’s current medical problem list.
• Any condition the investigator considers a contraindication to OAC; e.g., bleeding that required medical attention or severe renal impairment.
• Any condition the investigator considers will prevent compliance with study instructions.
• Implanted cardiac devices (pacemakers, implantable cardiac defibrillators, or cardiac resynchronization therapy, and implantable loop recorders).
• History of allergy to adhesive.
• Patient is not able to wear the Zio®XT monitor or not able to apply the monitor by herself/himself or with the help of a caregiver

• Males and females, age ≥ 18 years.
• Patients with tumors of the head and neck, thorax, abdomen, pelvis, and extremities.
• Histological confirmation of oncologic diagnosis.
• Completed oncologic imaging (per discretion of treating physician).
• ECOG Performance Status 0-3.
• Ability to complete questionnaire(s) by themselves or with assistance.
• Willing to return to enrolling institution for follow-up (during the Active Monitoring Phase of the study).
• Provide informed written consent.

• Any of the following because this study involves an agent that has known genotoxic, mutagenic and teratogenic effects:
  • Pregnant women;
  • Nursing women;
  • Women of childbearing potential who are unwilling to employ adequate contraception.
• Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens.
• Immunocompromised patients and patients known to be HIV positive and currently receiving antiretroviral therapy.  NOTE:  Patients known to be HIV positive, but without clinical evidence of an immunocompromised state, are eligible for this trial.
• Uncontrolled inter-current illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.

• Age ≥ 22 years old.
• A clinician-diagnosed NYHA I-IV heart failure.
• LVEF ≤ 40% on most recent cardiac imaging.
• Ability to read, speak and understand English.
• Access to a telephone for interviews or ability to meet study staff in person for an interview.
• Ability and willingness to participate in all study related activities.
• Provide informed written or verbal consent based on site IRB requirements.

• Clinically significant cognitive or memory impairment in the opinion of research staff (e.g., patient has trouble holding a conversation, patient exhibits signs of disorientation).
• Currently hospitalized.
• Individuals who have left ventricular assist device (LVAD) or are planning to have surgery to implant an LVAD within 2 weeks of screening.
• Individuals who have received a cardiac transplant at any time prior to screening.

• Subjects must be 18 years of age or older on the day of screening.
• Subjects with heart failure or history of heart failure.
• Subjects with ischemic or non-ischemic cardiomyopathy.
• Subjects with an ejection fraction ≤ 40%, measured within the last 6 months from screening for the study.

• Subjects with implanted left ventricular assist device.
• Subjects with pacemaker dependency.
• Subjects currently hospitalized.
• Subjects in atrial fibrillation on their last ECG or having irregularly irregular pulse.

• Age 0 to 9 months at the time of surgery.
• Undergoing a planned congenital cardiac surgery at Mayo Clinic.
• All races, ethnicities, and sexes are eligible.

• Age 9 months or older at the time of surgery.
• Patients undergoing a cardiac surgery that will not include the standard remove and disposal of thymus tissue.
• Subjects whose parents/guardians are unwilling or unable to give consent.

• Age ≥ 18 years old.
• Suspected Suspected acute infection (respiratory, urinary, abdominal, skin & soft-tissue), and at least one of the symptoms; OR
• Suspected sepsis of any cause as defined by a blood culture order by the treating physician, and at least two of the symptoms:
  • Heart rate: > 90 beats/ minute;
  • Temperature: > 38C or < 36C;
  • Respiratory Rate: > 20 breaths / minutes or PaO2 of < 60 mmHg or SpO2 < 90%;
  • Systolic blood pressure: < 100 mmHg;
  • Altered mental status: Per clinical exam.
• Able to provide informed consent, or consent by legally authorized representative.

• Patient-reported treatment with systemic antibiotics, systemic antiviral agents (antiviral treatment for HIV infection and hepatitis B and hepatitis C do not represent exclusion criteria), or systemic antifungal agents within the past 7 days prior to the emergency department study visit:
  • Participants will not be excluded for the use of topical antibiotics, topical antiviral or topical antifungal agents;
  • Participants will not be excluded for the use of peri-operative (prophylactic) antibiotics;
  • Participants will not be excluded for the use of a single dose of antibiotics during the present ED visit (<6h before blood draw).
• Patients receiving palliative or hospice care, or those receiving limited interventional care.
• Prisoners, mentally disabled, or unable to give consent. Should the patient not be able to provide informed consent the legally authorized representative can provide the consent on behalf of the patient.
• Patients receiving experimental therapy or already enrolled in an interventional clinical trial in which a subject receives some type of intervention, which can include but is not limited to investigational drugs, medical devices, or vaccines:
  • Subjects that are enrolled in non-interventional or observational clinical trials will be allowed to participate in this clinical trial.
• Patients previously enrolled in the present clinical trial.

• Clinical diagnosis of type 1 diabetes.
• Age ≥ 65 years old.
• T1D Duration of at least 1 year.
• HbA1c < 10.0% from point of care or local lab at time of screening visit.
• Insulin regimen involves basal/bolus insulin via insulin pump or multiple daily injections.
• Most recent GFR ≥ 30 ml/min/m2 from local lab within the past 6 months.
• Willingness to use a rapid acting insulin compatible with the Tandem t:slim X2 pump (currently aspart and lispro; other rapid acting insulins likely to be approved for pump use prior to study initiation such as Fiasp).
• Familiarity with and willingness to use a carbohydrate ratio for meal boluses.
• Willing to use study devices and automated insulin delivery features.
• Participant is independently managing his/her diabetes with respect to insulin administration and glucose monitoring (may include assistance from spouse or other caregiver)
• Participant understands the study protocol, agrees to comply with it and is able to successfully pass the consent understanding assessment with no more than 2 attempts. 
• Participant comprehends written and spoken English.
• At least 240 hours of CGM readings available during the end of run-in assessment.
• At least 1.5% of time with CGM glucose levels < 70 mg/dL prior to SAP initiation.

• Use of PLGS technology or HCL insulin delivery in the past 3 months.
• History of 1 or more Diabetic Ketoacidosis episodes in the previous 6 months.
• Clinical diagnosis by a primary care provider, neurologist or psychiatrist of dementia, in the investigator’s opinion a suspected severe cognitive impairment such that it would preclude ability to understand the study or use devices, or ascore of 13 or less on the Montreal Cognitive Assessment (mild cognitive impairment is not an exclusion)
• A condition, which in the opinion of the investigator or designee, would put the participant or study at risk, including severe vision or hearing impairment and any contraindication to the use of any of the study devices per FDA labeling.  
• Known adhesive allergy or skin reaction during the run-in pre-randomization phase or previous difficulty with pump and CGM insertions that would preclude participation in the randomized trial.
• Concurrent use of any non-insulin glucose-lowering agent other than metformin (including GLP-1 agonists, Symlin, DPP-4 inhibitors, SGLT-2 inhibitors, sulfonylureas).
• Stage 4 or 5 renal disease.
• The presence of a significant medical or psychiatric condition or use of a medication that in the judgment of the investigator may affect completion of any aspect of the protocol, or is likely to be associated with life expectancy of < 1 year.

• Age 18 or older.
• Able to read, understand, and give written informed consent.
• Receiving or have received care at the Mayo Clinic Rheumatology outpatient clinic in Rochester.
• Patients meeting the 2006 Sydney Classification Criteria for Definite APS.
• Patients who have not had clinical events that fulfill the Sydney criteria, but have a positive antiphospholipid antibody laboratory test.

• Patients not meeting the case definitions listed above will be ineligible.

• Fuchs Endothelial Corneal Dystrophy (FECD): Presence of central or paracentral corneal guttae with or without corneal edema. (Controls will not have any guttae).
• Any age (expected range will be 40-90 years).
• Any sex or race.
• Subjects who have previously undergone uncomplicated cataract surgery (to eliminate the confounding effect of cataract on vision) at least 2 months prior to enrollment.

• Any ocular disease that is known to affect vision (e.g., cataract, macula/retinal disease, amblyopia, etc.).
• Previous corneal transplantation in both eyes.

• At minimum, 4 years of age at Visit 1.
• Previously molecularly and/or enzymatically-confirmed PMM2-CDG Affected with ataxia evidenced by Mini International Cooperative Ataxia Rating Scale (Mini-ICARS) score > 0 at baseline.
• Parent or legal guardian available to provide consent on behalf of minor subjects or adult subjects who are unable to give informed consent due to developmental disabilities. Willingness of subject or legal guardian to provide consent.
• If female and > 10 years old, willing to practice abstinence or using an effective contraceptive regimen that is constituted by two acceptable effective methods of contraception, including a barrier method such as a condom or occlusive cap (diaphragm or cervical/vault cap) with spermicidal foam/gel/film/cream/suppository and an established non-barrier method such as oral, injected, or implanted hormonal methods, an intrauterine device, (IUD), or intrauterine system for the entire duration of the treatment period and for at least 28 days after receiving the last study drug dose. Sterilized or infertile subjects (defined as having undergone surgical sterilization, ie, bilateral tubectomy, hysterectomy and bilateral ovariectomy or as being postmenopausal, defined as at least 12 months of amenorrhea prior to enrollment) will be exempted from the requirements to use contraception in this study.

• Hepatic impairment defined as AST/ALT > 5 x ULN in the last 12 months.
• Renal impairment defined as serum creatinine 1.5-1.9 x ULN for age OR ≥ 26.5 umol/l increase from ULN for age.
• Hypersensitivity to acetazolamide.
• Hypersensitivity to any of the components of the placebo.
• History of treatment with experimental drug within 28 days of Visit 1.
• Currently taking Mecamylamine, Sodium Phosphates, Salicylates, Mefloquine, Methenamine and other Carbonic Anhydrase Inhibitors.
• Participation in another therapeutic trial
  •the subject will not be permitted to participate in any other drug trial during the blinded phase and during the 28 days prior to Visit 1.
• Pregnant (positive urine beta-HCG test) or nursing (by history) women.

• A participant in the Diabetes Control and Complications Trial (DCCT)(N01-DK-6-2204-A).

• Completion of Study 0170 and, in the opinion of the Investigator, would benefit from long-term treatment with TD-9855.
• The subject must be able to understand the nature of the study and must provide written informed consent prior to the conduct of any study procedures (including any changes occurring in the subject’s current therapeutic regimen).
• The subject must be willing to continue on treatment and must continue to meet all the inclusion criteria for the preceding study (Study 0170) except, a score of > 4 in OHSA#1.

• Subjects may not be enrolled in another clinical trial, with the exception of purely observational studies, which are allowed.
• Psychiatric, neurological, or behavioral disorders that may interfere with the ability of subjects to give informed consent or interfere with the conduct of the study.
• Medical, laboratory, or surgical issues deemed by the Investigator to be clinically significant. 
• Hypersensitivity to TD-9855 or the formulation excipients.

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

Eligibility last updated 5/16/23. Questions regarding updates should be directed to the study team contact.

• Males or females 60 years of age or older.
• Meet the requirements for one of the four groups (CU A−, CU A+, MCI A+, AD A+).
• Neurologic evaluation procedures with testing in the MCSA or ADRC or Mayo Clinic Behavioral Neurology Practice. Must have had or plan to have at least 2 testing sessions.
• All participants must complete an amyloid PiB PET scan and MRI brain scan within approximately 6 months prior to the ER176 PET/CT scan.
• Capacity to sign consent or have a legally authorized representative to sign the consent.

• Participants unable to lie down without moving for 20 minutes.
• Women who are pregnant or cannot stop breast feeding for 24 hours.
• Actively taking daily anti-inflammatory medications (NSAIDs, corticosteroids, etc.) except for a small control group. Anti-inflammatory creams, eye drops, and nasal sprays are not exclusions.
• Generalized inflammatory condition and treatment with immunosuppressive, corticoid/glucocorticoid, steroidal or non-steroidal anti-inflammatory medication within 2 weeks of scanning (only acute medication use as an exclusion so as to limit medication interaction but preserve possible chronic systemic inflammation interaction).
• Standard safety exclusionary criteria for MRI such as metallic foreign bodies, pacemaker, etc., since the quantitative PET data analysis is based on anatomic criteria that are established uniquely for each subject by registration to his/her MRI.

Eligibility last updated 8/20/21. Questions regarding updates should be directed to the study team contact.

• Age 18 years or greater.
• Eastern Cooperative Oncology Group (ECOG) performance status ≤1.
• Confirmed diagnosis of active MM by IMWG diagnostic criteria (Rajkumar, 2014).
• Patients must have myeloma that is response-evaluable according to the 2016 IMWG response criteria.
• Measurable disease is defined as 1 or more of the following:
  • Serum M-protein ≥ 1 g/dL;
  • Urine M-protein ≥ 200 mg/24-hour; and/or
  • FLC assay with involved FLC level ≥ 10 mg/dL with an abnormal serum FLC ratio:
    • A patient with Immunoglobulin A (IgA) myeloma but without measurable M-protein may be enrolled if quantitative IgA levels are ≥ 400 mg/dL and can be followed longitudinally;
    • A patient with non-secretory MM may be considered for enrollment after discussion with the sponsor that includes the feasibility of an individualized plan for response assessment.
• Patients with MM who have exhausted all therapeutic options that are expected to provide meaningful clinical benefit, either through disease relapse, treatment refractory disease, or intolerance of the therapy, and including either:
  • Progression on or after at least 3 lines of therapy, or intolerance of therapy, including a proteasome inhibitor, an IMiD, and an anti-CD38 antibody; OR
  • Progression on or after an anti-CD38 antibody and having disease that is "double refractory" to a proteasome inhibitor and an IMiD, or intolerance of therapy. The anti-CD38 antibody may have been administered alone or in combination with another agent such as a proteasome inhibitor. Refractory disease is defined as lack of response or relapse within 60 days of last treatment.
• Adequate hematologic function as measured by:
  • Platelet count > 50 x 10^9/L. A patient may not have received a platelet transfusion within 7 days to meet this platelet eligibility requirement;
  • ANC > 1.0 x 10^9/L. A patient may not have received granulocyte colony stimulating factor (G-CSF) within 2 days to meet this absolute neutrophil count eligibility requirement;
  • Hemoglobin > 8.0 g/dL.
• Adequate hepatic function, defined as:
  • Total bilirubin ≤ 1.5 x ULN;
  • Transaminase (ALT, AST) ≤ 2.5 x ULN;
  • Alkaline phosphatase ≤ 2.5 x ULN.
    • Patients with Gilbert syndrome do not need to meet this total bilirubin requirement provided that the total bilirubin is unchanged from the baseline value.
  • Serum creatinine clearance by Cockcroft-Gault >30 mL/min.
    • A patient with a creatinine clearance by Cockcroft-Gault who does not meet eligibility criteria may be considered for enrollment if a measured creatinine clearance (based on 24-hour urine collection or other reliable method) is >30 mL/min.
• If previously treated with CAR T therapy or any gene therapy products, patients must have recovered from the toxicities of this therapy.
• Life expectancy of at least 6 months.
• Willing and able to comply with clinic visits and study-related procedures, including serial bone marrow evaluations according to the protocol schedule.
  • A bone marrow aspirate and biopsy, or other tissue infiltrated with malignant plasma cells, must be provided at screening for evaluation of BCMA levels in malignant cells, but demonstration of BCMA levels will not be required for enrollment.
• Provide informed consent signed by the study patient.
• Able to understand and complete study-related questionnaires.

• Diagnosis of plasma cell leukemia, amyloid light-chain amyloidosis, Waldenström macroglobulinemia (lymphoplasmacytic lymphoma), or POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes).
• Patients with known MM brain lesions or meningeal involvement.
• History of neurodegenerative condition or CNS movement disorder, or patients with a history of seizure within 12 months before study enrollment are excluded
• Cardiac ejection fraction <40% by echocardiogram or multi-gated acquisition scan (multi-gated acquisition scan [MUGA])
• Continuous systemic corticosteroid treatment with >10 mg per day of prednisone or anti-inflammatory equivalent within 72 hours of start of study drug.
• Vaccination within 28 days before first study drug administration with a vector that has replicative potential.
• Treatment with any systemic standard or investigational anti-myeloma therapy within 5 half-lives or within 28 days before first administration of study drug, whichever is shorter.
• Prior treatment with any anti-BCMA antibody (including antibody-drug conjugate or bispecific antibody) or BCMA-directed CAR T therapy.
• Any infection requiring hospitalization or treatment with IV anti-infectives within 2 weeks of first administration of study drug.
  • A patient being screened for R5459-ONC-1888 who has documented or suspected ongoing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection should not be enrolled in the study.
  • A patient being screened for R5459-ONC-1888 who had documented or suspected SARS-CoV-2 may be enrolled per the investigator’s medical judgment if the patient has:
    • Recovered from COVID-19 (ie, all COVID-19-related symptoms and major clinical findings that can potentially affect the safety of the patient have resolved), and:
    • It is advisable that 2 repeat COVID-19 polymerase chain reaction (PCR) tests, or equivalent test depending on regional recommendations, be conducted to confirm that the patient is negative for SAVS-CoV-2.
    • If COVID-19 PCR testing is not feasible, it is advised that at least 3 months have transpired since the initial diagnosis.
• Uncontrolled infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV) infection; or other uncontrolled infection.
  • Patients with HIV who have controlled infection (undetectable viral load and CD4 count above 350 cells/microliter either spontaneously or on a stable antiviral regimen) are permitted.
  • Patients with hepatitis B (Hepatitis B Surface Antigen Test positive [HepBsAg+]) who have controlled infection (serum HBV DNA polymerase chain reaction [PCR] that is below the limit of detection AND receiving anti-viral therapy for hepatitis B) are permitted.
  • Patients who are HCV antibody-positive (HCV Ab+) who have controlled infection (undetectable HCV RNA by PCR either spontaneously or in response to a successful prior course of anti-HCV therapy) are permitted.
• Has known allergy or hypersensitivity to components of REGN5459.
• Known hypersensitivity to both allopurinol and rasburicase.
• History of allogeneic stem cell transplantation at any time, or autologous stem cell transplantation within 12 weeks of the start of study treatment.
• Member of the clinical site study team or his/her immediate family, unless prior approval granted by the sponsor.
• Women of childbearing potential (WOCBP) with a positive serum beta-human chorionic gonadotropin (β-hCG) pregnancy test are ineligible for this study.
• Patients who are committed to an institution by an order issued either by the judicial or the administrative authorities.
• Pregnant or breastfeeding women.
• Women of childbearing potential* and men** who are unwilling to practice highly effective contraception before the initial dose/start of the first treatment, during the study, and for at least 6 months after the last dose.
  • Highly effective contraceptive measures for women include:
    • stable use of combined (estrogen and progestogen containing) hormonal contraception (oral, intravaginal, transdermal) or progestogen-only hormonal contraception (oral, injectable, implantable) associated with inhibition of ovulation initiated 2 or more menstrual cycles before screening 
    • intrauterine device (IUD); intrauterine hormone-releasing system (IUS)
    • bilateral tubal ligation
    • vasectomized partner (provided that the male vasectomized partner is the sole sexual partner of the study participant and that the partner has obtained medical assessment of surgical success for the procedure)
    • and/or sexual abstinence†, ‡.
• Women of childbearing potential are defined as women who are fertile following menarche until becoming post-menopausal, unless permanently sterile. Permanent sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy.
• A post-menopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient to determine the occurrence of a post-menopausal state. The above definitions are according to Clinical Trial Facilitation Group (CTFG) guidance.

**Highly effective contraceptive measures for men include condoms or sexual abstinence, unless vasectomized (which has been medically assessed for surgical success) †, ‡.

†Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient.

‡Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and lactational amenorrhea method (LAM) are not acceptable methods of contraception. Female condom and male condom should not be used together.

• Another malignancy in the past 5 years, except for non-melanoma skin cancer that has undergone potentially curative therapy or in situ cervical carcinoma, or any other tumor that has been deemed to be effectively treated with definitive local control and with curative intent.

• Age ≥ 18 years old.
• Neuropathic pain of the upper limb ≥ 3 months following brachial plexus avulsion injury.
• Patients must be planned to undergo trial of high-frequency spinal cord stimulation for the treatment of chronic neuropathic pain due to brachial plexus avulsion injury.

• Pregnant at the time of consideration for trial and/or implant per patient report.
• Active substance use disorder of any kind.
• Active tobacco use.
• Use of moderate or high dose opioid medication (oral morphine equivalents >100 mg daily).
• Active, untreated major psychiatric disorder that might interfere with subject’s ability to participate.
• Involvement in active litigation related to injury per patient report.
• Patient has not undergone conservative medical management for at least 3 months (including physical and/or occupational therapy and at least one trial of neuropathic pain medication).

• Age > 18 years old.
• Outpatient.
• Able to give informed consent determined by MMSE ≥ 25 (those under this will be excluded and no LAR will be required).
• In the opinion of the PI, able to be compliant with clinic follow-up over time.
• Cirrhosis diagnosed by any one or more of the following:
  • Liver biopsy;
  • History of or current decompensation.
    • Ascites on diuretics, requiring TIPS or large volume paracentesis.
    • Prior overt HE.
    • Variceal bleeding.
    • Liver-lung syndromes (hepato-pulmonary syndrome, portopulmonary hypertension, hepatic hydrothorax).
    • Jaundice (serum bilirubin > 5mg/dl).
    • Hepato-renal syndrome or stage 2 AKI:
      • In a patient with chronic liver disease.
    • Fibroscan > 14.6 kPa.
    • Platelet count < 150,000 and AST/ALT ratio > 1.
• Able and willing to provide samples.

Specific additional inclusion criteria for the three subgroups:

• Patients without prior decompensation.
• No history of overt HE on therapy, variceal bleeding being eradicated/on BB, HRS, ascites on current diuretics.
• Control of underlying disease etiology should be at least 3 months prior.
  • SVR for HCV;
  • HBV suppression.
• Patients with prior /current decompensation without history of prior HE.
  • No history of prior overt HE (defined as grade 2 or higher HE per West-Haven criteria requiring hospitalization, initiation or change of therapy).
  • History of any of the other decompensating events as above.
  • Control of underlying disease etiology should be at least 3 months prior:
    • Alcohol abstinence.
    • SVR for HCV.
    • HBV suppression.
• Patients with prior/current decompensation with history of prior HE.
  • History of prior overt HE (defined as grade 2 or higher HE per West-Haven criteria requiring hospitalization, initiation or change of therapy), OR
  • Currently on therapy for HE, OR
  • Ascites especially refractory ascites.
  • With or without other prior variceal bleeding.
  • Control of underlying disease etiology should be at least 3 months prior:
    • Alcohol abstinence;
    • SVR for HCV;
    • HBV suppression.

• Unclear diagnosis of cirrhosis.
• Unable to provide informed consent, follow-up or provide samples
• On hospice..
• Acute Alcoholic hepatitis.
• Active malignancy other than HCC.
• HCC outside Milan criteria.
• End-stage organ disease in other organs:
  • On dialysis;
  • On home oxygen;
  • Systolic CHF with EF< 40%.
• Inpatient status.
• Prior bariatric surgery.
• Prior bone marrow or solid organ transplant.
• HIV infection.

• Age ≥ 18 years.
• Available for testing performed in Rochester, MN.
• Willing to undergo both an echocardiogram with RTMPE and CMR.
• Study subject providing consent.

• Adults < 18 years.
• BMI <30 kg/m^2.
• Hypertension.
• Diabetes Mellitus.
• Stroke.
• Cardiomyopathy or structural heart disease.
• Known coronary artery disease or history of myocardial infarction.
• Contraindication to echo enhancement agent or gadolinium administration such as an allergy.
• Renal GFR < 50 mL/mL.
• Females who are pregnant.
• Subject unwilling to consent.

• Neonates with myelomeningocele who are cared for at a study center NICU are eligible to participate after myelomeningocele repair.

• Born at < 30 weeks gestation.
• Congenital anomalies that would predispose to sleep-disordered breathing (e.g., micrognathia).
• Confirmed or suspected genetic syndromes that alter developmental outcomes.