Aim 1

• All participants will be 50 years of age or older and younger than 85 years of age. 
• All participants will be stratified into those with or without gastroesophageal reflux disease (defined as symptoms of heartburn or acid regurgitation more than once a week, or taking proton pump inhibitors for more than 3 months, or those with the diagnosis of gastroesophageal reflux disease in the diagnostic index, or those with endoscopic evidence of esophagitis).
• Other risk factors considered would include:
  • Caucasian race;
  • History of ever smoking (current or prior history of smoking);
  • BMI greater than equal to 30;
  •  Family history of Barrett's esophagus or esophageal adenocarcinoma;
  •  Male sex.

• History of Barrett's esophagus or esophageal adenocarcinoma.
• Prior endoscopy in the last 10 years.
• Pregnant or lactating females.
• Patients who are unable to consent.
• Patients with current history of uninvestigated dysphagia
• History of eosinophilic esophagitis, achalasia.
• Patients on oral anticoagulation including Coumadin, Warfarin.
• Patients on antiplatelet agents including Clopidogrel (Visit 1), unless discontinued for three to five days prior to the sponge procedure (Visit 2 and 3).
• Patients on oral thrombin inhibitors including Dabigatran and oral factor X a inhibitors such as rivaroxaban, apixaban and edoxaban (Visit 1), unless discontinued for three to five days prior to the sponge procedure (Visit 2 and 3).
• Patients with history of known varices or cirrhosis.
• Patients with history of esophageal or gastric resection.
• Patients with congenital or acquired bleeding diatheses.
• Patients with a history of esophageal squamous dysplasia or esophageal squamous carcinoma.
• Identification of patients meeting inclusion and exclusion criteria was done using two institutional EMR search tools (i2b2 and ACE) using ICD and CPT codes listed below along with NLP for some terms.

Aim 2:

 Inclusion criteria:

1. Subjects with known BE (cases).

1. Patient between the ages 18 – 90.
2. Patients with a BE segment ≥ 1cm in maximal extent endoscopically.
3. Histology showing evidence of intestinal metaplasia with or without presence of dysplasia.
4. Undergoing clinically indicated endoscopy.

1. Subjects without known history of BE (controls).

1. Undergoing clinically indicated diagnostic endoscopy.

Exclusion criteria:

a. Subjects with known BE.

1. Patients with prior history of ablation (photodynamic therapy, radiofrequency ablation, cryotherapy, argon plasma coagulation). Patients with history of endoscopic mucosal resection alone will not be excluded.
2. Patients with history of esophageal or gastric resection. 

b. Subjects with or without known evidence of BE (on history or review of medical records).

1. Pregnant or lactating females.
2. Patients who are unable to consent.
3. Patients with current history of uninvestigated dysphagia (this does not apply to the brushings only portion of the study).
4. History of eosinophilic esophagitis, achalasia.
5. Patients on oral anticoagulation including Coumadin, Warfarin.
6. Patients on antiplatelet agents including Clopidogrel, unless discontinued for three to five days prior to the sponge procedure.
7. Patients on oral thrombin inhibitors including Dabigatran and oral factor X a inhibitors such as rivaroxaban, apixaban and edoxaban, unless discontinued for three to five days prior to the sponge procedure.
8. Patients with history of known varices or cirrhosis.
9. Patients with history of esophageal or gastric resection. 
10. Patients with congenital or acquired bleeding diatheses.
11. Patients with a history of esophageal squamous dysplasia.

Aim 3:

Inclusion and exclusion criteria will be those outlined under Aims 1 and 2.

Inclusion Criteria (for 0169 Completers Group): 

• Subject has completed 4 weeks of double blind treatment in Study 0169 (V6) and, in the opinion of the Investigator, could benefit from continued treatment with TD-9855. No minimum score of OHSA#1 is required to enter V1 of Study 0170. 
• Subject has a minimum of 80% study medication compliance in Study 0169.
• 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 an understanding that entry to Study 0170 may result in changes occurring in the subject’s current therapeutic regimen).
• The subject must be willing to continue on treatment regardless of the possibility of randomization to either TD-9855 or PBO during the randomized withdrawal phase and must continue to meet the inclusion criteria for the preceding study (Study 0169) with the exception that tilt-table test, ESC review and approval of eligibility are not required for entry into Study 0170.

Inclusion Criteria (For De Novo Group): 

• Subject is male or female and at least 30 years old;
• Subject must meet the diagnostic criteria of snOH, as demonstrated by a ≥ 20 mm Hg (systolic) or ≥10 mm Hg (diastolic) within 3 min of being tilted-up ≥ 60o from a supine position as determined by a tilt-table test;
• Subject must score at least a 4 on the OHSA#1 at V1. 
• For subjects with PD only: Subject has a diagnosis of PD according to the United Kingdom Parkinson's Disease Society (UKPDS) Brain Bank Criteria (1992). 
• For subjects with MSA only: Subject has a diagnosis of possible or probable MSA of the Parkinsonian subtype (MSA-P) or cerebellar subtype (MSA-C) according to The Gilman Criteria (2008). 
• For subjects with PAF only: Subject has impaired autonomic reflexes, as determined by absence of Phase IV BP overshoot after release of the Valsalva strain. 
• Subject has plasma Norepinephrine (NE) levels ≥ 100 pg/mL after being in seated position for 30 minutes.
• Subject is willing and able to provide signed and dated written informed consent to participate prior to initiation of any study related procedures.
• Subject is able to communicate well with the Investigator and understand clinic staff, understands the expectations of the study and is able to comply with the study procedures, requirements, and restrictions.

Exclusion Criteria (for 0169 Completers Group): 

• Subject may not be enrolled in another clinical trial (other than exiting Study 0169).
• Subject has 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. 
• Uncooperative attitude or reasonable likelihood of non-compliance with the protocol.
• Subject has a concurrent disease or condition that, in the opinion of the Investigator, would confound or interfere with study participation or evaluation of safety, tolerability, or pharmacokinetics of the study drug.

Exclusion Criteria (For De Novo Group): 

• Subject has a known systemic illness known to produce autonomic neuropathy, including, but not limited to, amyloidosis and autoimmune neuropathies. Subject has diabetes mellitus and diagnosis of PAF. Subject with diabetes mellitus and either MSA or PD, will be evaluated on a case by case basis by the medical monitor and considered ineligible unless they meet all of the following criteria:
  • Well controlled type-2 DM in treatment with only oral medications and diet;
  • HgbA1C of ≤ 7.5% performed during screening or up to 12 weeks before screening;
  • No clinically evident peripheral neuropathy (e.g., normal sensory examination on peripheral extremities);
  • No known retinopathy (e.g., annual ophthalmic exam is sufficient);
  • No nephropathy (e.g., absence of albuminuria and GFR > 60).
• Subject has a known intolerance to other NRIs or serotonin norepinephrine reuptake inhibitors (SNRIs).
• Subject currently uses concomitant antihypertensive medication for the treatment of essential hypertension.
• Subject has used strong CYP1A2 inhibitors or inducers within 7 days or 5 half-lives, whichever is longer, prior to V1 or requires concomitant use until the follow-up visit.
• Subject has changed dose, frequency, or type of prescribed medication for orthostatic hypotension within 7 days prior to V1:
  • Midodrine and droxidopa (if applicable) must be tapered off at least 7 days prior to V1. 
• Subject has known or suspected alcohol or substance abuse within the past 12 months (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision [DSM-IV-TR®] definition of alcohol or substance abuse).
• Subject has a clinically unstable coronary artery disease or has had a major cardiovascular or neurological event in the past 6 months.
• Subject has used any monoamine oxidase inhibitor (MAO-I) within 14 days prior to V1.
• Subject has a history of untreated closed angle glaucoma, or treated closed angle glaucoma that, in the opinion of an ophthalmologist, might result in an increased risk to the subject.
• Subject has any significant uncontrolled cardiac arrhythmia.
• Subject has a Montreal Cognitive Assessment (MoCA) ≤ 23.
• Subject is unable or unwilling to complete all protocol specified procedures including questionnaires.
• Subject had a myocardial infarction in the past 6 months or has current unstable angina.
• Subject has known congestive heart failure (New York Heart Association [NYHA] Class 3 or 4).
• Subject has had any malignant disease, other than carcinoma in situ of the cervix or basal cell carcinoma, within the past 2 years prior to screening.
• Subject has a known gastrointestinal (GI) condition, which in the Investigator’s judgment, may affect the absorption of study medication (e.g., ulcerative colitis, gastric bypass).
• Subject has psychiatric, neurological, or behavioral disorders that may interfere with the ability of the subject to give informed consent or interfere with the conduct of the study.
• Subject is currently receiving any investigational drug or has received an investigational drug within 30 days of dosing. An investigational drug is defined as drug that is not approved by a regulatory agency (e.g., Food and Drug Administration [FDA]).
• Subject has a clinically significant abnormal laboratory finding(s) (e.g., alanine aminotransferase [ALT] or aspartate aminotransferase [AST] > 3.0 x upper limit of normal [ULN]; blood bilirubin [total] >1.5 x ULN; estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m^2 , or any abnormal laboratory value that could interfere with safety of the subject).
• Subject has demonstrated a history of lifetime suicidal ideation and/or suicidal behavior, as outlined by the C-SSRS (Baseline/Screening Version). Subject should be assessed by the rater for risk of suicide and the subject’s appropriateness for inclusion in the study.
• Subject has a concurrent disease or condition that, in the opinion of the Investigator, would confound or interfere with study participation or evaluation of safety, tolerability, or pharmacokinetics of the study drug.
• Subject has known hypersensitivity to TD-9855 (ampreloxetine hydrochloride), or any excipients in the formulation.
• Subject has:
  • confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) documented with coronavirus disease 2019 [COVID-19] positive test result; OR
  • is suspected of SARS-CoV-2 infection (clinical features without documented test results two weeks after resolution of symptoms and remains asymptomatic until Day 1); OR
  • has been in close contact with a person with known (or suspected) SARS-CoV-2 infection and remains asymptomatic until Day 1.
• At V3 (Week 4), following the initial 4-week OL treatment, subjects must demonstrate a reduction in OHSA#1 of at least 2 points compared to the baseline value, as determined in Study 0169 for subjects entering from Study 0169 and from V1 for de novo subjects, in order to continue in Study 0170.

• Age 18 to 70 years old.
• Chronic lumbar spine pain or other non-spine pain for ≥ 3 months duration.
• Scheduled for elective lumbar spine surgery or other non-spine surgery.
• Daily morphine equivalent dose between 50 mg and 200 mg.

• Cancer-related pain.
• Medical or surgical conditions that could be adversely impacted by opioid tapering or use of lofexidine including, but not exclusively limited to, cardiac disease, inflammatory bowel disease, renal or hepatic impairment, vascular disease, and history of anaphylaxis.  Patients may be excluded for other comorbid medical or surgical conditions based on the physician investigator’s discretion.
• History of schizophrenia or other chronic psychiatric disorder that could be adversely impacted by opioid tapering or use of lofexidine. Patients may be excluded for other comorbid mental health conditions based on the physician investigator’s discretion.
• Neurological condition that impair functioning in an ambulatory setting or could be adversely impacted by opioid tapering or use of lofexidine including, but not exclusively limited to, Parkinson’s disease, amyotrophic lateral sclerosis, or a dementing illness.  Patients may be excluded for other neurological conditions based on the physician investigator’s discretion.              
• Active substance abuse disorder.
• Inability to function in an ambulatory care setting due to severe deconditioning requiring use of supportive gait aids including a cane or walker.  Patients may be excluded for other functional problems based on the physician investigator’s discretion.      
• History of adverse effects attributed to opioid tapering or lofexidine use.
• Use of medications from drug classes known to have adverse interactions with lofexidine including, but not exclusively limited to, beta-blockers, calcium channel blockers, alpha 1 and 2 receptor antagonists, tricyclic antidepressants, benzodiazepines, and selective serotonin reuptake inhibitors.  Patients may be excluded for use of other medications based on the physician investigator’s and research pharmacy’s discretion.

• Diagnosis of large duct PSC.
• Liver biopsy at screening that is deemed acceptable for interpretation and demonstrates stage F0. 
• F3 fibrosis in the opinion of the central reader. 
• Individual has the following laboratory parameters at the screening visit, as determined by the central laboratory: 
  • Platelet count ≥ 150,000/mm^3; 
  • Estimated glomerular filtration rate (eGFR) ≥ 30 milliliter/minute (mL/min), as calculated by the Cockcroft-Gault equation;
  • ALT ≤ 8 x upper limit of the normal range (ULN);
  • Total bilirubin < 2 mg/dL, unless the individual is known to have Gilbert's syndrome or hemolytic anemia; 
  • International normalized ratio (INR) ≤ 1.4, unless due to therapeutic anticoagulation;
  • Negative anti-mitochondrial antibody.

Current or prior history of any of the following:

• Cirrhosis; 
• Liver transplantation; 
• Cholangiocarcinoma or hepatocellular carcinoma (HCC); 
• Ascending cholangitis within 30 days of screening; 
• Presence of a percutaneous drain or biliary stent;
• Other causes of liver disease; 
• Current or prior history of unstable cardiovascular disease;
• Current moderate to severely active inflammatory bowel disease (IBD).

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

• At least 18 years of age, at the time of signing the informed consent. 
• Signs and symptoms of CDI including diarrhea such that in the Investigator's opinion CDI antimicrobial therapy is required. Diarrhea is defined as a change in bowel habits, with ≥ 3 Unformed Bowel Movements (UBMs) (5, 6 or 7 on the Bristol Stool Chart) in the 24 hours prior to randomization. 
• The presence of either toxin A and/or B of C. difficile in the stool determined by a positive free toxin test, produced within 72 hours prior to randomization. 
• Male or Female
  •Male must agree to use contraception as detailed in the protocol during the treatment period and for at least 5 days after study treatment and refrain from donating sperm during this period.
• Female patient is eligible to participate if she is not pregnant, not breastfeeding, and either:
• Not a woman of childbearing potential (WOCBP). A WOCBP who agrees to follow the contraceptive guidance per protocol during the treatment period and for at least 5 days after study treatment. 
• Documented signed informed consent and any authorizations required by local law (e.g., Protected Health Information [PHI]).

• More than one prior episode of CDI in the previous 3 months or more than 3 episodes in the past 12 months.
• A history of chronic diarrheal disease including inflammatory bowel disease (Crohn's disease or ulcerative colitis). 
• Positive diagnostic test for other gastro intestinal (GI) pathogens within 2 weeks of randomization. 
• Major gastrointestinal (GI) surgery (e.g., significant bowel resection) within 3 months of randomization (except appendectomy). Presence of a colostomy or ileostomy or likely requirement of an ostomy during the study. 
• Life threatening or fulminant CDI with evidence of hypotension, septic shock, peritoneal signs or absence of bowel sounds, or toxic megacolon. 
• Current history of significantly compromised immune system:
  • HIV positive with a CD4<200 cells/mm3 within 6 months of randomization;
  • Severe neutropenia with neutrophil count < 500 cells/mL;
  • Concurrent immunosuppressive therapy for recent (within previous 6 months) or anticipated solid organ transplant or bone marrow transplant;
  • Concurrent chemotherapy, radiotherapy or biologic for active malignancy. Or active malignancy with ablative chemotherapy within the past 3 months or anticipated during the study;
  • More than one day (24 hours) of dosing of antimicrobial treatment active against CDI for the current episode of CDI prior to randomization;
  • Prior or current use of anti-toxin antibodies including bezlotoxumab;
  • Unable to discontinue products used to affect bowel movement or disease progression;
  • Involved in a clinical trial and received an IMP for indications other than CDI within 1 month or five half-lives (whichever is longer) or within 3 months if the IMP was for CDI;
  • Received an investigational vaccine against C.difficile;
  • Patients that the Investigator feels are inappropriate for the study for any other reason; e.g., have any conditions that would make the patient unsuitable for inclusion, patients not likely to complete the study for whatever reason, known hypersensitivity or intolerance to study IMPs, patients unwilling or unable to comply with protocol requirements.

• Documented diagnosis of UC at least 12 weeks prior to screening.
• Active UC with an an adapted Mayo score of 5 to 9 points, endoscopic subscore of ≥ 2. 
• Demonstrated an inadequate response, loss of response, or intolerance to at lease one of the following treatments including, 5-aminosalicylic acids (ASAs), corticosteroids, immunosuppressants, anti-tumor necrosis factor (TNF)-α agents, integrin inhibitor.

• Participant with current diagnosis of Crohn's disease (CD) or diagnosis of indeterminate colitis (IC), ischemic colitis, pseudomembranous colitis.
• Current evidence of fulminant colitis, abdominal abscess, toxic megacolon, or bowel perforation. 
• History or evidence of any extensive colonic resection, subtotal or total colectomy, with or without presence of a stoma or ileoanal pouch.

Inclusion Criteria (Group A and B):

• Patient with either GM1 gangliosidosis, GM2 gangliosidoses (Tay-Sachs, Sandhoff, AB Variant), or GD2.
• Diagnosis confirmed by either biochemical (enzyme activity) or genetic testing, or both.
• Date of birth on or after 1 January 2000.
• Onset of the first neurological symptom within the first 24 months of age.
• Informed consent of parent or legal guardian as required by local law.

• Any diversion from the above Inclusion Criteria.

• Will utilize the Mayo Clinic Biobank to identify randomly- selected individuals encompassing the age span of 25-65 years old.
• No history of diabetes.
• Reside within a 100 mile radius of Mayo Clinic, Rochester, MN.
• Individuals who have expressed interest in participating in research will then be contacted and invited to participate in the study.

• Age < 25 or > 65 years old (to avoid studying subjects who could have latent type 1 diabetes or the effects of age extremes in subjects with normal or impaired fasting glucose).
• HbA1c ≥ 6.5%.
• Use of glucose-lowering agents.
• For female subjects, positive pregnancy test at the time of enrollment or study.
• History of prior upper abdominal surgery such as adjustable gastric banding, pyloroplasty and vagotomy.
• Active systemic illness or malignancy.
• Symptomatic macrovascular or microvascular disease.
• Hormone therapy >0.625 mg premarin daily.

• Up to 60 weight-stable, non-diabetic subjects from Biobank participants at Mayo Clinic, Rochester will be recruited.
• Potentially eligible subjects who express a desire to be contacted by the research team will be invited to meet with the PI and / or another member of the study team.
• Interested subjects will come to the Clinical Research Trials Unit for a screening visit.

• Age < 25 or > 65 years old (to avoid studying subjects who could have latent type 1 diabetes, or the effects of age extremes in subjects with normal or impaired fasting glucose).
• HbA1c ≥ 6.5%.
• Use of glucose-lowering agents.
• For female subjects: positive pregnancy test at the time of enrollment or study.
• History of prior upper abdominal surgery such as adjustable gastric banding, pyloroplasty and vagotomy.
• Active systemic illness or malignancy.
• Symptomatic macrovascular or microvascular disease.
• Hormone therapy >0.625 mg premarin daily.

• Female patients age 18 years and greater.
• Willing and able to give informed consent.
• Mastectomy with immediate reconstruction using tissue expander or direct to implant.

• Antibiotic use within 14 days of operation.
• Prior history of breast implant placement.
• Male patients.
• Vulnerable subjects (prisoners, institutionalized individuals).
• Non-English speaking patients without adequate interpreter assistance.

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

• Severe nausea or vomiting, which may preclude study assessments.
• Use of medications that, in the opinion of the investigator have the potential, to alter GI motility (e.g., narcotics, medications with significant anticholinergic effects, prokinetic agents) and which cannot be discontinued for 4 half-lives prior to the imaging studies.
• Clinical evidence of significant cardiovascular, respiratory, renal, hepatic, gastrointestinal, hematological, neurological, psychiatric or other disease that may interfere with the objectives of the study.  A history of inflammatory bowel disease (e.g, Crohn’s disease or ulcerative colitis).  However, participants with microscopic or collagenous colitis will be eligible to participate.
• Prior gastric or major intestinal (i.e., resection of > 50 cm) or colonic surgery (i.e., hemi or subtotal colectomy).  Appendectomy, cholecystectomy, tubal ligation,  hysterectomy, herniorrhaphy, and limited colonic resection are permissible.
• Participants who are allergic to eggs or decline to consume milk.
• History of radiation therapy to the abdomen.
• Anxiety or depression as assessed by the Hospital Anxiety and Depression Questionnaire 11.
• Contraindications for MR imaging: i.e. pacemakers, aneurysm clips, cochlear implants.*
• Pregnant women, breast-feeding women, prisoners and institutionalized individuals.*
• Treatment with GLP-1 agonists and amlyin which cause vagal blockade and may affect central processing of pain.
• Positive tissue transglutaminase antibodies (TTG).
• Poor peripheral venous access, if central venous access is not available.
• Any other condition or prior therapy that, in the opinion of the investigator, would make the patient unsuitable for the study.

• Newly diagnosed GVHD that meets criteria for Minnesota standard risk.
• Ann Arbor 1 GVHD by biomarkers.
• GVHD not previously treated systemically (topical therapies and non-absorbed steroids are allowed).
• Any donor type, HLA-match, conditioning regimen is acceptable.
• Age 12 years and up (children < 18 years must also weigh 50 kg or more).
• Patients must be engrafted post-transplant (ANC > 500/μL and platelet count > 20,000). Use of growth factor supplementation to maintain neutrophil count is allowed. 
• Direct bilirubin must be < 2 mg/dL unless the elevation is known to be due to Gilbert syndrome within 3 days prior to enrollment. 
• ALT/SGPT and AST/SGOT must be < 5 x the upper limit of the normal range within 3 days prior to enrollment. 
• Signed and dated written informed consent obtained from patient or legal representative.

• Patients currently being treated with any JAK inhibitor including ruxolitinib. 
• Relapsed, progressing, or persistent malignancy requiring withdrawal of systemic immune suppression.
• Patients with uncontrolled infection (i.e., progressive symptoms related to infection despite treatment or persistently positive microbiological cultures despite treatment or any other evidence of severe sepsis).
• Severe organ dysfunction including requirement for dialysis, mechanical ventilation or oxygen supplementation exceeding 40% FiO2 within 7 days of enrollment. 
• Creatinine clearance or estimated glomerular filtration rate < 30 ml/min as calculated by institutional practice (e.g., Cockcroft-Gault equation, CKD-EPI equation, etc.).
• A clinical presentation resembling de novo chronic GVHD or overlap syndrome developing before or present at the time of enrollment .
• Patients receiving corticosteroids >10 mg/day prednisone (or other steroid equivalent) for any indication within 7 days before the onset of acute GVHD except for adrenal insufficiency or premedication for transfusions/IV meds.
• Patients who are pregnant. 
• Patients receiving investigational agents within 30 days of enrollment. However, the Principal Investigator (PI) may approve prior use of an investigational agent if the agent is not expected to interfere with the safety or the efficacy of itacitinib.
• History of allergic reaction to itacitinib or any JAK inhibitor.

• Patients admitted with encephalopathy concerning for non-convulsive seizures or NCSE who can also undergo conventional multi-lead EEG monitoring.
• ≥ 18 years of age.

• Patients who have dermatologic contraindication to the adhesive by which the portable EEG device is attached.
• < 18 years of age.

Inclusion Criteria - Part A and B:

• Weakness attributable to ALS and documented SOD1 mutation at Screening Visit 2. 
• A forced vital capacity (FVC) ≥50% of predicted value as adjusted for sex, age, and height (from the sitting position). Participants with stable FVC <50% but ≥45%, whose FVC has not declined by more than 5% in the last 6 months may be considered for inclusion, at the discretion of the Investigator. 
• If taking riluzole, participant must be on a stable dose for ≥30 days prior to Day 1 and expected to remain at that dose until the final study visit.
• Medically able to undergo the study procedures, and to adhere to the visit schedule at the time of study entry, as determined by the Investigator.

Exclusion Criteria - Part A and B:

• History of or positive test result for human immunodeficiency virus. 
• History of, or positive test result at Screening, for hepatitis C virus antibody.
• Current hepatitis B infection (defined as positive for hepatitis B surface antigen [HBsAg] and/or hepatitis B core antibody [HBcAb]). Participants with immunity to hepatitis B from previous natural infection (defined as negative HBsAg, positive hepatitis B surface antibody immunoglobulin G, and positive HBcAb) or vaccination (defined as positive anti-HBs) are eligible to participate in the study. 
• Treatment with another investigational drug, biological agent, or device within 1 month or 5 half-lives of study agent, whichever is longer. Specifically, no prior treatment with small interfering ribonucleic acid, stem cell therapy, or gene therapy is allowed. 
• Current enrollment in any other interventional study.
• Current or recent (within 1 month) use, or anticipated need, in the opinion of the Investigator, of copper (II) (diacetyl-bis (N4-methylthiosemicarbazone)) or pyrimethamine.
• Current or anticipated need, in the opinion of the Investigator, of a diaphragm pacing system (DPS) during the study period.

Inclusion Criteria
•Part C:

• Weakness attributable to ALS and confirmed SOD1 mutation at Screening Visit.
• If taking riluzole, participant must be on a stable dose for ≥ 30 days prior to Day 1 and expected to remain at that dose until the final study visit. 
• If taking edaravone, participant must have initiated edaravone ≥ 60 days (2 treatment cycles) prior to Day 1 and expected to remain at that dose until the final study visit, unless the Investigator determines that edaravone should be discontinued for medical reasons, in which case it may not be restarted during the study. Edaravone may not be administered on dosing days of this study. 
• Medically able to undergo the study procedures and to adhere to the visit schedule at the time of study entry, as determined by the Investigator.

Exclusion Criteria - Part C:

• History of or positive test result for human immunodeficiency virus. 
• History of, or positive test result at Screening, for hepatitis C virus antibody.
• Current hepatitis B infection (defined as positive for HBsAg and/or anti-HBc). participants with immunity to hepatitis B from previous natural infection (defined as negative HBsAg, positive IgM anti-HBc, and positive anti-HBc) or vaccination (defined as positive anti-HBs) are eligible to participate in the study. 
• Treatment with another investigational drug (including investigational drugs for ALS through compassionate use programs), biological agent, or device within 1 month or 5 half-lives of study agent, whichever is longer. Specifically, no prior treatment with small interfering RNA, stem cell therapy, or gene therapy is allowed. 
• Current enrollment in any other interventional study. 
• Current or recent (within 1 month) use, or anticipated need, in the opinion of the Investigator, of copper (II) (diacetyl-bis(N4-methylthiosemicarbazone)) or pyrimethamine. 
• Current or anticipated need, in the opinion of the Investigator, of a DPS during the study period.
  • NOTE: Other protocol defined Inclusion/ Exclusion criteria may apply.

• Infants born at or after 37 weeks gestational age at Methodist hospital in the level 1 nursery, who currently live in Olmsted County, and will receive primary care within Employee Community Health (ECH).
• Infants born to mothers age 18 or older.
• For multi-gestation births, only the first born child is eligible.
• A score of > 3 on the Infant Unhealthy Growth Factor assessment.
• Families who require interpreter services are eligible for the study as OCPHS Family Home Visiting utilizes interpreters and there are interpreters available in the nursery.

• Those not meeting the inclusion criteria.
• Families with grandparent(s) as primary caregivers or if infant has been determined in nursery to be going to foster care or CPS.
• Families who have previously qualified for and participated in on-going home visits over a period of months to years or who have recently accepted OCPH home visits to be scheduled in the near future and anticipated to span over months to years.

• Male or female subjects.
• 2 to < 17 years of age.
• Having confirmed or possible CIDP.

• Absence of CIDP symptoms.
• History or family history of inherited neuropathy.
• Diagnosed developmental delay or regression.
• History of thrombotic episode.
• Known or suspected hypersensitivity to Privigen.
• Known allergic or other severe reactions to blood products.
• Female subject of childbearing potential either not using or not willing to use a medically reliable method of contraception or not sexually abstinent during the study.
• Pregnant or breastfeeding mother.

• Men and women, aged 18-55 years old.

• Patients with safety contraindications to MRI scanning at 3T. 
• Patients unable to adequately perform the fMRI task due to physical, neurological, or cognitive disability. 
• Patients that demonstrate 3 mm or greater translational head motion during scanning of the fMRI rhyming task data sets. 
• Pregnant women.
• Patients that have implanted medical devices or other safety contraindications for a 7T or 3T MRI exam.

• Only participants who completed the parent PVDOMICS study will be approached for the L-PVDOMICS Study.  This includes all participants:
  • PH, comparators and controls with a minimum 6 months post-enrollment in PVDOMICS. 
• See the parent PVDOMICS protocol for full details of inclusion/exclusion criteria.
• Any PH, comparators or control participant previously enrolled in the parent PVDOMICS protocol with a minimum of six months post-enrollment.
• Dialysis dependent renal function since the parent study acceptable.

Participant Level 1

• Previously received a heart and/or lung transplant
• In the clinician’s opinion, too ill to perform L-PVDOMICS testing even if limited testing.
• Participants who withdrew from the parent PVDOMICS study.
• Pregnant or nursing.
• Concurrent participation in any pulmonary hypertensioninvestigational drug study or other blinded placebo-controlled drug clinical trial.

Participant Level 2:  

• Transplant other than heart or lung.
• Participants who withdrew from the parent PVDOMICS study.

Participant Level 3:  

• Participants who withdrew from the parent PVDOMICS study.

• Diagnosis of diabetes mellitus; existing appointment with participating clinician.

• Do not speak English.
• Severe vision/hearing impairments.
• Unable to give informed consent for any reason.

• Patients ≥ 18 years of age.
• Cirrhosis of the liver defined by histological and/or clinical, endoscopic, laboratory and radiological criteria. 
• Refractory or recurrent ascites primarily managed with periodic therapeutic paracentesis. Patients must have a minimum of 2 therapeutic paracenteses in the 30 Days prior to enrollment.
• Not a candidate for (e.g., refused, contraindicated) Transjugular intrahepatic portosystemic shunt (TIPS) or previously implanted TIPS is permanently obstructed or non-functioning.
• Screened for esophageal varices and on optimal management. Absence of contraindications to prophylactic antibiotic use from time of pump implant.
• Life expectancy of at least 6 months following pump implant (approximately 10 months from enrollment).
• Capable of giving written informed consent, willing to comply with study procedures including the 3-month pre-implant observation period and ability to operate and charge the device. 
• Women of childbearing age should use adequate contraceptives. Reassessed at time of implant procedure (Pivotal Cohort Only): 
• Has required a minimum of 5 therapeutic paracenteses in the 3-month observation period prior to pump implant.

• Renal failure defined as serum creatinine higher than or equal to 1.5 mg/dL.
• More than one episode of spontaneous bacterial peritonitis over the previous 6 months.
• Recurrent urinary infections as per standard criteria, defined as 2 or more episodes over the last 6 months.
• Evidence of loculated ascites, as per imaging.
• Hepatocellular carcinoma, exceeding Milan criteria or for which RF ablation is anticipated.
• Pregnant females or females anticipating pregnancy during study period.
• Patients currently enrolled in another interventional clinical study that has not reached the primary endpoint assessment point, or (for pivotal cohort) patients who have previously had an alfapump implanted.
• Immuno-modulatory treatment (including azathioprine, methotrexate, anti-TNF therapies) used within last 4 months (corticosteroids at stable dose over the last 4 months but < 15 mg/day, or in tapering doses are allowed).
• Known or suspected hepatic or extra hepatic malignancy (other than skin cancer and in-situ cancers), unless adequately treated or in complete remission for ≥ 3 years.
• History of bladder cancer.
• BM I > 40 presenting a risk for technical difficulties for surgery or catheter implantation.
• Contraindications to general anesthesia.
• Comorbid condition or other reason (example hypertension) that may preclude stopping diuretics after enrollment.
• MELD-Na Score > 18.
• Budd Chiari syndrome (Pivotal cohort only).
• Clostridium difficile infection within the past year.  Assessed or re-assessed at time of pump implant: 
• Acute gastrointestinal hemorrhage requiring transfusions over the previous 42 days.
• Condition that prevents continued cessation of diuretic use.
• Patient condition does not allow the implant procedure to be performed within the limits of acceptable risk (e.g., cardiovascular comorbidities).
• Hepatocellular carcinoma exceeding Milan criteria or for which RF ablation is anticipated.
• ICU admission since enrollment.
• INR ≥ 2.0.
• Platelet count of < 50,000 /μL at the time of implantation, unless the platelet count is ≥ 30,000 / μL and bleeding risk can be satisfactorily addressed with means such as platelet infusion during the implant procedure and/or thrombopoietin receptor agonists.
• Bacterial peritonitis within 4 weeks of implant procedure (this includes peritonitis diagnosed at the time of intervention).
  • Note: at the time of final eligibility (just prior to implantation) the subject will not be allowed to move forward with the procedure if he/she has experienced an episode of SBP within four weeks of the implant procedure date.
• Bacterascites within 4 weeks of implant procedure (this includes bacterascites diagnosed at the time of intervention).
  • Note: at the time of final eligibility (just prior to implantation) the subject will not be allowed to move forward with the procedure if he/she has experienced an episode of bacterascites within four weeks of the implant procedure date.
• Serum sodium < 125 mmol/L.
• Urinary infection within the last 2 weeks.
• Obstructive uropathy, residual urinary volume exceeding 100 ml, or any bladder anomaly which might contraindicate implantation of the device.
• Evidence of renal failure, defined as serum creatinine higher than or equal to 1.5 mg/dL, in the preceding 30 days.
• Evidence of loculated ascites, as per imaging.
• Pregnant females or females anticipating pregnancy during study period.

Eligibility last updated 11/10/21.  Questions regarding updates should be directed to the study team contact.

• Consumers of Mayo Clinic GeneGuide who have previously indicated a willingness to be contacted regarding future research AND who have received a positive result for variants in the BCHE gene (associated with pseudocholinesterase deficiency) and CACNA1S and RYR1 genes (associated with malignant hyperthermia).

• Not a consumer.
• Has not consented to be contacted.
• Has not received a relevant genetic result.

• At least 18 years of age.
• Able to speak, read and understand English.
• Able to provide informed consent (i.e., no impairments or barriers).
• Owns a suitable iOS or Android device and demonstrates average control and basic understanding of using a smartphone
• At least 12 weeks gestation.
• Pregnancy documented as low risk

• Any observed cranial or cardiac anomalies on formal ultrasound.
• Multifetal gestation.
• Maternal history of defibrillation.
• Maternal history of electro-surgery.
• Patients with external electrical stimulators, cardiac pacemakers or requiring use of MRI or other high frequency medical equipment.
• Clinical judgment that determines that the pregnancy is at high risk for complications requiring outpatient or inpatient monitoring for clinical care.
• Any of the following high risk factors would disqualify the mother for the study:
  • Abnormal fetal anatomy;
  • Chronic hypertension, including severe hypertension (>160/110);
  • Possible ectopic pregnancy or pregnancy of unknown location;
  • Multi-fetal pregnancy;
  • Hypertensive disorders (chronic hypertension, gestational diabetes, preeclampsia);
  • Prior PE/DVT/stroke;
  • Anticoagulation during prior pregnancy (e.g., antiphospholipid antibody syndrome);
  • Prosthetic heart valve (non-bio);
  • Pulmonary hypertension;
  • Mothers currently taking Immunosuppressants, Prednisone > 10mg per day);
  • Women with mental health disorders (including eating disorders, severe depression, on antipsychotics);
  • Recurrent pregnancy loss (> 2 losses);
  • Current maternal malignancy;
  • Prior myocardial infarction/cardiomyopathy;
  • Bio-prosthetic heart valves;
  • Marfan syndrome;
  • Active liver disease (e.g., hepatitis);
  • Congenital heart disease;
  • Coagulopathies including thrombophilias and bleeding disorders;
  • Pre-existing diabetes;
  • Genetic disease/CF testing/anomalies in prior child;
  • Incompetent cervix (prior cerclage);
  • Isoimmunization (Rh, Kell, etc.);
  • History of transplant or currently on Dialysis;
  • Prior 2nd or 3rd trimester loss;
  • Human Immunodeficiency Virus (HIV);
  • Inflammatory bowel disease;
  • Asthma and currently on steroid to control disease;
  • History of preterm delivery < 37 weeks;
  • BMI > 40 (class 3 obesity).

• Men and women of age 65 years and older at the time of enrollment.
• Eligible to receive Fluzone.
• Female subjects must be past menopause and not pregnant.
• No history of anaphylactic reaction to gelatin, neomycin, or other vaccine component.
• Must not have had the flu vaccine within the past 90 days.
• Medically stable with no exacerbations or changes in medication regimen for chronic diseases in the past 3 months and no hospitalizations in the past 6 months.
• Must be able to read/write English in order to provide informed consent and comply with study procedures.
• Expected to be available for the duration of the study.

Study candidates who meet any of the following criteria within 28 days prior to entolimod administration will not be eligible for participation in this study:

• Receipt of any other vaccines within the past 30 days prior to enrollment.
• Acute illness within the last 30 days.
• History of hypersensitivity to the flu vaccine or its components (including gelatin, formaldehyde, octoxinol, thimerosal, and chicken protein).
• History of Guillain Barré syndrome (GBS).
• History of bleeding disorders.
• Medical contraindication to treatment with vaccine as indicated by a history of autoimmune disease, immune deficiency, or hypersensitivity to other vaccines.
• Unstable major cardiovascular, renal, endocrine, immunological or hepatic disorder.

Systolic blood pressure (SBP) < 110 mmHg or orthostatic hypotension [> 20 mmHg fall in SBP or > 10 mmHg fall in diastolic blood pressure (DBP) with standing] at the time of screening.

• Evidence of an ongoing systemic bacterial, fungal, or viral infection (including upper respiratory tract infections) (within 14 days prior to entolimod administration).
  • Note: Subjects with localized fungal infections of skin or nails are eligible.
• Clinical signs of febrile illness (temperature >99.5°F).
• Baseline vital signs with ³ Grade 2 abnormalities.
• Significant cardiovascular disease (e.g., myocardial infarction, arterial thromboembolism, cerebrovascular thromboembolism, venous thromboembolism) within 6 months prior to study drug administration; symptomatic dysrhythmias or unstable dysrhythmias requiring medical therapy; angina requiring therapy; symptomatic peripheral vascular disease; New York Heart Association Class 3 or 4 congestive heart failure; or uncontrolled Grade ≥ 3 hypertension (diastolic blood pressure ≥ 100 mmHg or systolic blood pressure ≥ 160 mmHg) despite antihypertensive therapy.
• Significant screening ECG abnormalities, including unstable cardiac arrhythmia requiring medication, atrial fibrillation, 2nd-degree atrioventricular (AV) block type II, 3rd degree AV block, or Grade ≥ 2 bradycardia (within 14 days prior to entolimod administration).
• Inadequate hepatic function (within 14 days prior to entolimod administration):
  • Serum alanine aminotransferase (ALT) ³3 × upper limit of normal (ULN) (Grade ³1);
  • Serum aspartate aminotransferase (AST) ³3 × ULN (Grade ³1);
  • Serum alkaline phosphatase (ALP) ³5 × ULN (Grade ³2);
  • Serum bilirubin ³1.5 × ULN (Grade ³ 1).
• Positive antiviral serology:
  • Positive hepatitis C virus (HCV) antibody or positive HCV ribonucleic acid (RNA) by quantitative PCR;
  • Positive hepatitis B surface antigen (HBsAg) and negative hepatitis B core (HBc) antibody or undetectable hepatitis B (HBV)deoxyribonucleic acid (DNA) by quantitative polymerase chain reaction (PCR) testing;
  • Positive human immunodeficiency virus (HIV) antibody.
• Use of medication that might interact with the flu vaccine including (but not limited to) specifically: aminopyrine, phenytoin sodium, theophylline, and warfarin sodium.
• Any ongoing treatment with immunosuppressive or immune-stimulant therapy;
• Ongoing use of systemic corticosteroids.
• Blood or blood products given within the three months prior to vaccination and two months after vaccination;
• Current and/or expected receipt of chemotherapy, radiation therapy or any other cytotoxic or immunosuppressive therapy [i.e., more than 10 mg of prednisone given daily or on alternative days for 2 weeks or more in the past 3 months].
• Receipt of another investigational pharmaceutical product within 60 days of treatment.
• Diagnosis of Parkinson’s Disease, previous stroke, or significant cognitive impairment (defined as MMSE < 20).
• Other concerns that in the opinion of the PI would preclude a subject from participating in study procedures or from completing the study.

• Age 18 (or age of legal consent, whichever is older) to 85 years, inclusive.
• Documented diagnosis of ATTR amyloidosis with cardiomyopathy, classified as either hereditary ATTR amyloidosis with cardiomyopathy or wild-type ATTR amyloidosis with cardiomyopathy:
  • Hereditary ATTR amyloidosis with cardiomyopathy diagnosed based on meeting all of the following criteria:
    • TTR pathogenic mutation consistent with hATTR;
    • Evidence of cardiac involvement by echocardiography with an end-diastolic interventricular septal wall thickness >12 mm (based on central echocardiogram reading at screening);
    • Amyloid deposits in cardiac or noncardiac tissue (eg, fat pad aspirate, salivary gland, median nerve connective sheath) confirmed by Congo Red (or equivalent) staining OR technetium (99mTc) scintigraphy (99mTc-3,3-diphosphono-1,2- propanodicarboxylic acid [DPD-Tc] or 99mTc-pyrophosphate [PYP-Tc]) with Grade 2 or 3 cardiac uptake, if monoclonal gammopathy of undetermined significance (MGUS) has been excluded;
    • If MGUS, confirm TTR protein in tissue with immunohistochemistry (IHC) or mass spectrometry.
  • Wild-type ATTR amyloidosis with cardiomyopathy diagnosed based on meeting all of the following criteria:
    • Absence of pathogenic TTR mutation;
    • Evidence of cardiac involvement by echocardiography with an end-diastolic interventricular septal wall thickness >12mm (based on central echocardiogram reading at screening);
    • Amyloid deposits in cardiac tissue with TTR precursor identification by IHC, mass spectrometry, OR technetium (99mTc) scintigraphy (99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid [DPD-Tc] or 99mTc-pyrophosphate [PYP-Tc]) with Grade 2 or 3 cardiac uptake, if MGUS has been excluded;
    • If MGUS, confirm TTR protein in cardiac tissue with IHC or mass spectrometry.
• Medical history of heart failure with at least 1 prior hospitalization for heart failure, or current clinical evidence (signs and symptoms of heart failure).
• Clinically stable with no cardiovascular related hospitalizations within 6 weeks of study start.
• Has never taken tafamidis before (tafamidis naïve) or currently on tafamidis for ≥ 6 months with evidence of disease progression while on tafamidis treatment.
• Able to complete ≥ 150 m on the 6-minute walk test.
• Screening N-terminal pro B-type natriuretic peptide (NT-proBNP), a blood marker of heart failure severity, > 300 ng/L and < 8500 ng/L.
• Patient is able to understand and is willing and able to comply with the study requirements and to provide written informed consent; and patient agrees to sign the medical records release form for collection of vital status.

• Has known primary amyloidosis (AL) or leptomeningeal amyloidosis.
• NYHA Class III AND ATTR amyloidosis disease Stage 3 (defined as both NT-proBNP >3000 ng/L and estimated glomerular filtration rate [eGFR] <45 ml/min/1.73 m^2).[Gillmore 2018]
• NYHA Class IV at the Screening visit.
• Has a polyneuropathy disability (PND) Score IIIa, IIIb, or IV (requires cane or stick to walk, or is wheelchair bound) at the Screening visit.
• Has any of the following laboratory parameter assessments at screening:
  • Aspartate transaminase (AST) or alanine transaminase (ALT) levels ˃2.0 × the upper limit of normal (ULN);
  • Total bilirubin ˃ULN. Patients with elevated total bilirubin that is secondary to documented Gilbert’s syndrome are eligible if total bilirubin <2 × ULN
  • International normalized ratio (INR) ˃1.5 (unless patient is on anticoagulant therapy, in which case excluded if INR ˃3.5).
• Has eGFR <30 mL/min/1.73 m^2 (using the modification of diet in renal disease [MDRD] formula).
• Has known human immunodeficiency virus infection; or evidence of current or chronic hepatitis C virus or hepatitis B virus infection.
• Tafamidis naïve patients (at baseline) for whom the Investigator actively plans or anticipates commencing treatment with tafamidis during the 12-month double-blind period, taking into consideration clinical status, patient preference and/or commercial availability of tafamidis.
• Is currently taking diflunisal; if previously on this agent, must have at least a 6-month wash-out prior to dosing (Day 1).
• Is currently taking doxycycline, or tauroursodeoxycholic acid; if previously on any of these agents, must have completed a 30-day wash-out prior to dosing (Day 1).
• Received prior TTR-lowering treatment or participated in a gene therapy trial for hATTR amyloidosis.
• Current or future participation in another investigational device or drug study, scheduled to occur during this study, or has received an investigational agent or device within 30 days (or 5 half-lives of the investigational drug, whichever is longer) prior to dosing (Day 1). In the case of investigational TTR stabilizer drugs, washout for 6 months prior to dosing (Day 1) is required; this does not apply to patients who are on tafamidis at baseline.
• Requires treatment with calcium channel blockers (e.g., verapamil, diltiazem) or digitalis.
• Other non-TTR cardiomyopathy, hypertensive cardiomyopathy, cardiomyopathy due to valvular heart disease, or cardiomyopathy due to ischemic heart disease (e.g., prior myocardial infarction with documented history of cardiac enzymes and electrocardiogram [ECG] changes).
• Has non-amyloid disease affecting exercise testing (e.g., severe chronic obstructive pulmonary disease, severe arthritis, or peripheral vascular disease affecting ambulation).
• Recent or planned orthopedic procedure during the double-blind period (e.g., lower extremity or back surgery) that could impact 6-MWT.
• Unstable congestive heart failure (CHF) (eg, no adjustment of diuretics at time of screening required to achieve optimal treatment of CHF).
• Had acute coronary syndrome or unstable angina within the past 3 months.
• Has history of sustained ventricular tachycardia or aborted ventricular fibrillation.
• Has history of atrioventricular nodal or sinoatrial nodal dysfunction for which a pacemaker is indicated but will not be placed.
• Has persistent elevation of systolic (˃180 mmHg) and diastolic (˃100 mmHg) blood pressure that is considered uncontrolled by physician.
• Has untreated hypo- or hyperthyroidism.
• Prior or planned heart, liver, or other organ transplant.
• Had a malignancy within 5 years, except for basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix that has been successfully treated.
• Has other medical conditions or comorbidities which, in the opinion of the Investigator, would interfere with study compliance or data interpretation.
• Is not willing to comply with the contraceptive requirements during the study period.
• Female patient is pregnant or breast-feeding.
• Has a known history of alcohol abuse within the past 2 years or daily heavy alcohol consumption (for females, more than 14 units of alcohol per week; for males, more than 21 units of alcohol per week [unit: 1 glass of wine [125 mL] = 1 measure of spirits = ½ pint of beer]);
• History of illicit drug abuse within the past 5 years that in the opinion of the Investigator would interfere with compliance with study procedures or follow-up visits.

• Male or female, 12 years of age or older.
• Have undergone an allo-HSCT from any donor source using bone marrow, peripheral blood stem cells, or cord blood for hematologic malignancies. Recipients of nonmyeloablative and myeloablative conditioning regimens are eligible.
• Clinically suspected all grades acute or chronic GVHD as per Minnesota-Center for International Blood and Marrow Transplant Research (MN-CIBMTR) criteria, that is refractory or intolerant to corticosteroids, occurring after allo-HSCT with any conditioning regimen and any anti-GVHD prophylactic program. Clinical suspicion of GVHD by the treating physician is also sufficient. 
• Evidence of myeloid engraftment (e.g., absolute neutrophil count ≥ 1.0 × 10^9/L for 3 consecutive days if ablative therapy was previously used). Use of growth factor supplementation is allowed. 
• Evidence of platelet engraftment (i.e., platelets ≥ 20 × 10^9/L). 
• Eastern Cooperative Oncology Group (ECOG) performance status 0 to 3. 
• Be willing to avoid pregnancy or fathering children based on 1 of the following criteria: 
  • Women of non-childbearing potential (i.e., surgically sterile with a hysterectomy and/or bilateral oophorectomy OR ≥ 12 months of amenorrhea);
  • Woman of childbearing potential who has a negative serum pregnancy test at screening and who agrees to take appropriate precautions to avoid pregnancy (with at least 99% certainty) from screening through safety follow-up. Permitted methods that are at least 99% effective in preventing pregnancy should be communicated to the patient and their understanding confirmed;
  • Man who agrees to take appropriate precautions to avoid fathering children (with at least 99% certainty) from screening through safety follow-up. Permitted methods that are at least 99% effective in preventing pregnancy should be communicated to the patient and their understanding confirmed.
• Able to provide written informed consent and/or assent from the patient, parent, or guardian.

• Eligible for an existing and actively enrolling Incyte sponsored clinical trial for ruxolitinib for the treatment of GVHD. 
• Patients or legal guardians unable to review and sign informed consent form.
• Females who are pregnant or breastfeeding, and males and females who cannot comply with requirements to avoid fathering a child or becoming pregnant. 
• Patients with inadequate liver function (alanine aminotransferase above 4 × upper limit of normal (ULN) or direct bilirubin 4 × ULN and the laboratory abnormalities are considered to be due to underlying liver dysfunction) unless attributed to GVHD. 
• Patients with end stage renal function (creatinine clearance (CrCl) < 15 mL/min or glomerular filtration rate < 15 mL/min), regardless of whether hemodialysis is required. 
• Any underlying or current medical or psychiatric condition that, in the opinion of the treating physician, would place the patient at an unacceptable risk if he or she were to participate in the program. 
• Previous allergic reactions to Janus kinase (JAK) inhibitors or excipients. 
• Patients who are currently taking any anticancer therapy (e.g., chemotherapy, radiation therapy, surgery, immunotherapy, biologic therapy, hormonal therapy, or tumor embolization). 
• Patients taking any secondary GVHD therapy due to insufficient response/progression on program treatment including, but not limited to, ibrutinib, filgotinib, and other off-label medications.
• Concomitant use of any JAK inhibitor.
• Initiating therapy with any investigational medication. 
• Presence of an active uncontrolled infection. An active uncontrolled infection is defined as hemodynamic instability attributable to sepsis or new symptoms, worsening physical signs, or radiographic findings attributable to infection. Persisting fever without signs or symptoms will not be interpreted as an active uncontrolled infection. 
• Known HIV infection. 
• Active hepatitis B virus (HBV) or hepatitis C virus infection that requires treatment or at risk for HBV reactivation. At risk for HBV reactivation is defined as hepatitis B surface antigen positive or anti-hepatitis B core antibody positive. Previous test results obtained as part of standard of care before allo-HSCT that confirm a patient is immune and not at risk for reactivation (i.e., hepatitis B surface antigen negative, surface antibody positive) may be used for purposes of eligibility.

• Patients that are undergoing endoscopy with duodenal or small bowel biopsies

• Patients that are not undergoing endoscopy with duodenal or small bowel biopsies

Inclusion Criteria:  

• Women age ≥ 18 years.
• Biopsy-proven high-grade endometrial cancer.
• Biopsy histology is Grade 3 endometrioid, serous, clear cell, poorly differentiated, or undifferentiated.
• Scheduled to undergo hysterectomy at Mayo Clinic.
• Willing to complete pre-op blood sample and follow-up serial blood samples post-operatively.
• Willing and able to provide signed informed consent.

Exclusion Criteria: 

• Biopsy histology is Grade 1 or Grade 2 endometrioid.
• Change in planned surgical procedure such that hysterectomy is not performed at Mayo Clinic.
• Pre-op blood sample is not obtained.
• Tumor quantity or cell viability expected to not be sufficient for the study analyses.

• All eligible Junior A hockey players (ages 16-21).
• Medically cleared for hockey when enrolled (21 is the USA Hockey Program age limit).

• Players not medically cleared.
• Players who are restricted from hockey.
• Players who decline.

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

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

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

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