• Adults, age ≥ 40 years.
• Severe, symptomatic primary mitral regurgitation identified by Doppler transthoracic echocardiogram:
  • Heart team (cardiologist and cardiac surgeon) agree that patient would be eligible for TMVR with MitraClip.
  • TMVR procedure will be performed in the cardiac catheterization laboratory for hemodynamic data recording.

• None.

• Medical indication for examination under anesthesia and OCT/OCTA imaging, including an ocular oncology or retinal disorder, such as retinoblastoma.
• Control images will be obtained from patients with an indication for OCT/OCTA imaging who are able to cooperate for images in the office.

• Patients who do not have a medical indication for OCT/OCTA imaging.

• Patients over the age of 18 years old.

• Children.

General

• Referring diagnosis of an FTLD clinical syndrome (see below) or a member of a family with a strong medical history of an FTLD syndrome.
• Age 18 years of age or greater (preferably at least 30 because symptoms rarely develop before then).
• Have a reliable study partner who can provide general information about behavior and feelings/emotions, and an independent evaluation of functioning.
• Must, in the opinion of the site investigator, be able to complete a majority of study procedures.

Longitudinal Arm

• All longitudinal arm participants must speak English or Spanish (consents will be translated) as a primary language. Many of the clinical and neuropsychological scales required for ALLFTD are unvalidated in languages other than English or Spanish, rendering the data unusable for cross-sectional comparisons.

Familial FTLD Participants:

• Members of families in whom at least one member has a known disease-associated mutation in one of the major genes that cause f-FTLD: MAPT, GRN, C9orf72 (or other rare genes) OR an autosomal dominant family history of a FTLD syndrome (without a known gene) verified by medical record review or well-documented family history including family members with a medical history consistent with FTLD or a related disorder.
• Participants will be enrolled based on membership in these families and not individual genotype status, and knowledge of personal genotype status (in families with known mutations) is not required for participation.
• Each center will evaluate the eligibility of candidates prior to enrollment through a phone interviewing process, or via direct contact with the center or laboratory including establishing symptom severity (this may be conducted by phone interview for screening purposes). All familial enrollees will be made aware that they are being enrolled because of family history and/or because of a known mutation in the family; no participant has to be aware of their own genetic status to participate.
• Familial participants may be asymptomatic or symptomatic; all assessments are the same regardless of the presence or absence of symptoms. Because genetically-mediated FTLD syndromes may manifest in heterogeneous and diverse ways, participants do not have to meet research criteria for a known FTLD syndrome to be included.

Sporadic FTLD Participants:

• Sporadic participants should be symptomatic with no known family history or genetic mutation to indicate f-FTLD. All sporadic participants must have an FTLD syndrome as a referring diagnosis; those determined by ALLFTD clinicians to have non-FTLD diagnoses will be excluded from longitudinal visits, but their baseline visit will be included in comparative datasets. For inclusion in the longitudinal follow-up, participants should meet research criteria for one of the following FTLD syndromes:

  • Progressive Supranuclear Palsy: Inclusion criteria for progressive supranuclear palsy are based upon the 2017 Movement Disorders Society Consensus Criteria (full criteria can be found in the Manual of Procedures).29 These criteria for probable or possible PSP of either typical (Richardson’s) or variant syndromes are defined based on criteria plus 2 or 3 features below:
    • Core Features:
      • History of postural instability;
      • Ocular motor deficits  (supranuclear gaze palsy);
      • Akinesia;
      • Cognitive dysfunction and/or a speech/language disorder.
  • Semantic variant Primary Progressive Aphasia (svPPA): The core features of svPPA include:
    • a language disorder characterized by progressive, fluent, empty spontaneous speech, and semantic paraphasias;
    • selective impairment of semantic memory causing anomia, impaired spoken and written single word comprehension, and an impoverished fund of general information;
    • relative sparing of syntax and phonology; and
    • normal visuospatial abilities. 
  • Corticobasal Syndrome (CBS). Inclusion criteria for CBS are based on the probable or possible CBD criteria by Armstrong et al.30
    • for probable CBS: insidious onset after age 50, at least a 12 month history of symptoms: Asymmetric presentation of at least 2 of the following: limb rigidity or akinesia, limb dystonia, limb myoclonus, plus 2 of: orobuccal or limb apraxia, alien limb phenomenon, cortical sensory loss;
    • insidious onset with no minimum age; at least one year history of at least one of: limb rigidity or akinesia, limb dystonia, limb myoclonus, plus 2 of: orobuccal or limb apraxia, alien limb phenomenon, cortical sensory loss. Symptoms may be symmetric.
  • Behavioral variant Frontotemporal dementia (bvFTD). Inclusion criteria for bvFTD are based on consensus criteria. The primary features are early decline in regulation of personal and social and interpersonal conduct, emotional blunting, and loss of insight. Specifically, early presentation (first six months) must be characterized by at least five of the following: loss of insight, disinhibition, restlessness, distractibility, emotional lability, reduced empathy or unconcern for others, lack of foresight and planning, impulsivity, social withdrawal, apathy or lack of spontaneity, poor self-care, reduced verbal output, verbal stereotypies or echolalia, perseveration, overeating or excessive fluid intake, and sexual hyperactivity.
  • Nonfluent variant Primary Progressive Aphasia (nfvPPA) subtype: The primary clinical features in nfvPPA are non-fluent spontaneous speech with agrammatism, phonemic paraphasias, and anomia. Other features include problems with speech initiation, and finding and sequencing of articulatory movements. Comprehension is relatively well preserved, although difficulty following syntactically complex commands may be present.
  • Frontotemporal Dementia with Amyotrophic Lateral Sclerosis (FTD/ALS): A diagnosis of FTD-ALS relies on meeting diagnostic criteria for possible bvFTD or PPA plus clear evidence of ALS on physical examination, such as weakness, muscle atrophy, fasciculations, and elevated reflexes as described in the El Escorial diagnostic criteria for ALS, but not necessarily meeting probable ALS criteria. EMG is not required for diagnosis

Biofluid-Focused Arm

• Participants enrolled in the biofluid arm may be either f-FTLD or s-FTLD.
• All general inclusion criteria apply.
• Participants should meet research criteria (as specified above) for any FTLD syndrome or meet familial FTLD inclusion criteria.
• Because the biofluid arm participants do not undergo the same detailed clinical and functional assessments required for the longitudinal arm, participants may be included regardless of primary language, as long as an appropriately translated consent is available.

Exclusion criteria are evaluated at the site investigator’s discretion; if the site investigator believes that the participant’s symptoms are due to FTLD despite the presence of an exclusionary condition, the investigator may overrule the exclusion.

• Known presence of a structural brain lesion (e.g. tumor, cortical infarct) that could reasonably explain symptoms in a symptomatic participant.
• Known presence of an Alzheimer’s disease causing mutation in PSEN1, PSEN2 or APP; or biomarker evidence for Alzheimer’s disease as a cause of the clinical syndrome.
• A previous history of Korsakoff encephalopathy, severe alcohol dependence (within 5 years of onset of dementia), frequent alcohol or other substance intoxication, or other neurological disorder.
• Evidence through history or laboratory testing of uncorrected B12 deficiency (B12 < 95% of local laboratory’s normal value), unregulated hypothyroidism (TSH >150% of normal), HIV positive, renal failure (creatinine > 2), liver failure (ALT or AST > two times normal), respiratory failure that requires supplemental oxygen, large confluent white matter lesions, significant systemic medical illnesses such as deteriorating cardiovascular disease.
• Current medication likely to affect CNS functions in the opinion of the site PI.
• In the site investigator’s opinion, the participant cannot complete sufficient key study procedures. The participant may be enrolled into the biofluid-focused arm if they can tolerate a blood draw and short clinical exam, but must be able to complete at least 75% of study procedures for enrollment into the longitudinal arm.

• 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.

• Critically ill patients with either ARF on mechanical ventilation or requiring vasopressors or both  admitted to the ICU and expected ICU stay > 48 hours.

• Patients with a history of dementia.
• Patients with intellectual disability.
• Patients who have attempted suicide.
• Patients with psychotic disorders such as schizophrenia, acute alcohol/substance intoxication or withdrawal.
• Patients with severe metabolic encephalopathy.
• Patients with any form of cognitive impairment significant enough to preclude patient from completing study questionnaires.
• Patients on comfort care.
• Patients not expected to survive the hospital stay.
• Non-English speaking patients.

• All subjects, 1 month to 17 years old.
• Subjects with a diagnosis or history of unilateral or bilateral retinoblastoma.

• Su bjects less than 31 days old or 18 years of age and older.

• Age > 18 years old.
• ECOG performance status (PS) 0, 1 or 2.
• Clinical and radiographic evidence suggesting a diagnosis of a diffuse glioma, or a prior diagnosis of a diffuse glioma.
• Diffuse gliomas include diffuse astrocytoma, anaplastic astrocytoma, glioblastoma, oligodendroglioma and anaplastic oligodendroglioma.
• Planned neurosurgical procedure for purposes of biopsy or resection of suspected or previously diagnosed brain tumor as part of routine clinical care.
• Willing to undergo neurosurgical resection or biopsy at Mayo Clinic (Rochester, MN).
• Ability to understand and the willingness to sign a written informed consent document.

• Vulnerable populations:
  • Pregnant women;
  • Prisoners;
  • Mentally handicapped.
• Patients who are not appropriate candidates for surgery due to current or past medical history or uncontrolled concurrent illness.

• 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).

Inclusion Criteria
•ES and PNES Cohorts:

• Aged 18-59 years old, inclusive.
• Undergoing clinically indicated evaluation in the Mayo Clinic’s EMU.
• Able to provide Informed Consent OR are accompanied by a LAR who can provide informed consent on their behalf.

Exclusion Criteria
•ES and PNES Cohorts:

• Age 17 or under or age 60 or over.
• Unable to provide Informed Consent, AND are not accompanied by a LAR who can provide informed consent on their behalf.
  • Note that individuals who are normally able to provide consent on their own behalf but suffer from an altered mental status after a seizure may not be provide informed consent in this post-ictal state.
• Prisoners.
• Individuals known to have any of the following conditions:
  • Systemic or metastatic cancers;
  • Brain tumors;
  • HIV or AIDS;
  • Acute or chronic central nervous infections;
  • Lennox-Gastaut Syndrome;
  • Genetic epilepsy syndromes (including but not limited to Dravet’s Syndrome and Tuberous Sclerosis Complex);
  • Central nervous system or systemic inflammatory autoimmune disorders (including but not limited to SLE, multiple sclerosis, and vasculitis).
• Individuals with intracranial recording EEG electrodes.
• Individuals who have undergone brain surgery for any reason within the past 6 months incliuding any type of invasive EEG monitoring.

Inclusion Criteria
•Control Subjects:

• Aged 18-59 years old, inclusive.
• Able to provide Informed Consent.

Exclusion Criteria
•Control Subjects:

• Age 17 or under or age 60 or over.
• Unable to provide Informed Consent (an LAR is not permitted to provide Informed Consent on a Control Subject’s behalf).
• Prisoners.
• Individuals known to have any of the following conditions:
  • Systemic or metastatic cancers;
  • Brain tumors;
  • HIV or AIDS;
  • Acute or chronic central nervous infections;
  • Lennox-Gastaut Syndrome;
  • Genetic epilepsy syndromes (including but not limited to Dravet’s Syndrome and Tuberous Sclerosis Complex);
  • Central nervous system or systemic inflammatory autoimmune disorders (including but not limited to SLE, multiple sclerosis, and vasculitis).
• A history of either seizures or suspected seizures of any type (a single instance of febrile seizure prior to age 2 is allowed).
• Treatment with an anti-seizure medication, for any reason, within two months prior to providing a blood sample.
• Individuals who have undergone brain surgery for any reason within the past 6 months including any type of invasive EEG monitoring.

• Subjects with a history of heart failure scheduled for LVAD placement within 3 weeks (21 days), but at least 5 days of RMT prior to surgery.

• Inability to perform the respiratory muscle training (RMT) or more emergent LVAD placement not allowing time for pre- surgical training (less than 5 days).

• Patients 18 years of age or older.
• Healthy volunteers
  and patients referred for evaluation of possible arterial disease.

• Patients less than 18 years of age. 
• Patients that are unable have standard non-invasive arterial air plethysmography evaluation.

• Patients with a compound heterozygous ARG141HIS + PHE119LEU PMM2-CDG mutation.
• Patients with the haplogroup H, J and K mtDNA

• Patients with CDG mutations other than ARG141HIS + PHE119LEU PMM2-CDG.

• 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.

• Adults age 18 years or older.
• Olmsted County residents at the time of survey.

• Pediatric population (age < 18 years old).
• Unwilling to participate or unable to consent.
• Known liver disease other than NAFLD at the time of survey.
• Pregnant women.

• Clinical and radiographic evidence of a brain tumor.
  • This includes gliomas, ependymomas and medulloblastomas or low grade glioma or gliosis. The pathology will be confirmed after the sample is obtained during the surgery.
• Tissue sample of the suspected lesion(s) is to be obtained by means of elective surgery as part of clinical management.

• Emergency surgery.

• 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.

• Male and female, up to 17 years of age.
• Weight over 3 kilograms.
• Children undergoing major orthopedic surgery which includes spine surgery, hip and femur reconstruction and osteotomy and lower extremity osteotomies.
• Children undergoing routine postoperative hemoglobin monitoring.

• Weight under 3 kilograms.
• Minor surgeries.
• Children not undergoing routine postoperative hemoglobin monitoring.
• Children who do not have exposed fingers or toes because of injuries, wound dressings or congenital anomalies.

• Planned endomyocardial biopsy post-cardiac transplant.
• Suitable anatomy for coronary sinus sampling and successful retrieval of coronary sinus blood.
• Ability to provide informed consent and consent for the study.

• Multiorgan transplant aside from heart-kidney.
• Refusal of study participation.
• Unsuccessful endomyocardial biopsy.

• N/A

• N/A

•  Any pediatric patient between the ages of 7 to 17 years old.
• First permanent molars must be in occlusion (first permanent molars should be in occlusion to exclude ambiguity of their position).
• All patients must complete a baseline PSG study.
• Patients of any race, gender, ethnicity and sex.
• Patients with and without adenoid/tonsils will be included.

• Patients with previous expansion or other orthodontic treatment.
• Patients with craniofacial syndromes or craniosynostosis forms.
• Patients with nasal abnormalities such as polyps, etc.
• Patients with first permanent molars not in occlusion.

• Adults, age > 18 years old.
• Subjects with wet and dry macular degeneration.
   
• Note:  Patients with all levels of cognitive ability will be enrolled.

• Patients who do not speak English.

• Patients diagnosed with congenital disorders of glycosylation based on genetic confirmatory testing.

• Patients without congenital disorders of glycosylation.

• Adults aged 18 and over.
• Confirmed C. difficile infection based on positive C. difficile toxin PCR testing and clinical evidence of diarrhea.

• Known active pregnancy.
• Prior diagnosis of C. difficile infection within 2 months of this diagnosis.
• Other known active gastrointestinal infectious process.
• Vulnerable adults.
• Any other disease(s), condition(s) or habit(s) that would interfere with completion of study, or in the judgment of the investigator would potentially interfere with compliance to this study or would adversely affect study outcomes.

• Adults, aged 18 and over.
• Confirmed C. difficile infection based on positive C. difficile toxin PCR testing and clinical evidence of diarrhea.

• Known pregnancy.
• Prior diagnosis of C. difficile infection within 2 months prior to this diagnosis.
• Other known active gastrointestinal infectious process.
• Known diagnosis of inflammatory bowel disease, microscopic colitis, celiac disease or other inflammatory conditions.
• Vulnerable adults.
• Any other disease(s), condition(s) or habit(s) that would interfere with completion of study, or in the judgment of the investigator would potentially interfere with compliance to this study or would adversely affect study outcomes.

Eligibility last updated 9/29/21. Questions regarding updates should be directed to the study team contact.

Inclusion Criteria - CDI patients:

• Adults aged 18 and over
• Confirmed C. difficile infection based on positive C. difficile toxin PCR testing and clinical evidence of diarrhea who are currently undergoing treatment or have completed treatment within the last 6 months

Exclusion Criteria - CDI patients:

• Known active pregnancy.
• Other known active gastrointestinal infectious process.
• Vulnerable adults.
• Any other disease(s), condition(s) or habit(s) that would interfere with completion of study, or in the judgment of the investigator would potentially interfere with compliance to this study or would adversely affect study outcomes.

Patient Inclusion Criteria - Control Population:

• Adults aged 18 and over.
• Undergoing clinically indicated colonoscopy for colon cancer screening or colon polyp surveillance purposes in the absence of active GI symptoms.

Patient Exclusion Criteria
•Control Population:

• Known active pregnancy.
• Prior diagnosis of CDI.
• Other known active gastrointestinal infectious process.
• Vulnerable adults.
• Any other disease(s), condition(s) or habit(s) that would interfere with completion of study, or in the judgment of the investigator would potentially interfere with compliance to this study or would adversely affect study outcomes.

• Adult patients meeting criteria for cardiogenic shock during the study period of August 1, 2019 to July 31, 2022.
• Cardiogenic shock criteria defined as:
  • Systolic blood pressure < 90 mm Hg or mean arterial blood pressure 30 mm Hg below baseline for at least 30 minutes despite volume resuscitation and/or vasoactive therapy; and
  • Evidence of end-organ hypoperfusion (altered mental status, oliguria with urine output <30 mL/hour, cool extremities, lactate >2.0 mmol/L); or
  • Pulmonary edema.
• The etiology of cardiogenic shock can be categorized into one of the following subtypes:
  • Ischemic (acute myocardial infarction, ischemic cardiomyopathy), myocardial (end-stage heart failure, myocarditis), post-cardiotomy, cardiac tamponade, pulmonary thromboembolus.
• Subjects requiring mechanical circulatory support for one of the CS subtypes listed above.
• Age ≥ 18 years old.
• Consent for study participation has been obtained.

• Lack of consent for study participation.
• Shock due to causes other than cardiogenic shock (e.g., sepsis, serious ventricular arrhythmias not due to myocardial ischemia or heart failure, neurogenic, anaphylactic, hemorrhagic/hypovolemic).
• Shock with unwitnessed out of hospital cardiac arrest.
• Severe non-cardiac morbidity with expected survival of < 6 months (e.g., malignancy, end-stage liver disease, severe chronic lung disease, severe CNS morbidity).
• Admission occurring outside the study period.
• Refusal of active treatment.