• Centrally confirmed HER2+ breast carcinoma per 2018 American Society of Clinical Oncologists (ASCO) College of American Pathologists (CAP) guidelines.
• Have unresectable locally advanced or metastatic disease.
• If recurrent (after [neo]adjuvant therapy), must be at least 6 month treatment free from any trastuzumab or pertuzumab received for advanced HER2+ disease.
• Have received 4-8 cycles (21 day cycles) of previous treatment with trastuzumab, pertuzumab, and taxane as first-line therapy for advanced HER2+ breast cancer with no evidence of disease progression.
• Known hormone receptor status (per local guidelines; may be hormone receptor positive [HR+] or negative [HR-]).
• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 -CNS Inclusion.
•  Based on screening contrast brain magnetic resonance imaging (MRI), participants may have any of the following:
  • No evidence of brain metastases;
  • Untreated brain metastases which are asymptomatic and, if identified on prior brain imaging, without evidence of progression since starting first-line induction therapy with trastuzumab, pertuzumab, and taxane;
  • Previously treated brain metastases which are asymptomatic;
  • Brain metastases previously treated with local therapy must not have progressed since treatment.

• Prior treatment with any anti-HER2 and/or anti-epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor including pyrotinib, lapatinib, tucatinib, neratinib, and afatinib (except neratinib if given in extended adjuvant setting and ≥ 12 months have elapsed since last neratinib dose prior to start of study drug).
• Unable to undergo contrast MRI of the brain -

CNS Exclusion:

• Based on screening brain MRI and clinical assessment.
• Symptomatic brain metastasis.
• Progression of brain metastases since starting first line trastuzumab, pertuzumab, and taxane.
• Ongoing use of systemic corticosteroids at a total daily dose of > 2 mg of dexamethasone (or equivalent).
• Any untreated brain lesion in an anatomic site which may pose risk to participant.
• Known or suspected leptomeningeal disease (LMD).
• Poorly controlled (> 1/week) seizures, or other persistent neurologic symptoms.

Eligibility last updated 2/28/22. Questions regarding updates should be directed to the study team contact.

• Patients with life or limb threatening traumatic injury to an arterial vessel in the limb or torso, other than the heart, which requires replacement or reconstruction.
• Preoperative imaging or clinical examination indicates the damaged vessel has a defect length of ≤ 38cm and is appropriately size matched to the 6mm Human Acellular Vessel (HAV) per the judgment of the treating surgeon taking into account vasoconstriction and situational inflow and outflow considerations.
• Autologous vein graft is either not feasible in the judgment of the treating surgeon (e.g., because of lack of availability of suitable conduit, presence of severe venous insufficiency) or is not desirable because of the urgency of revascularization.
• Aged 18 to 85 years old, inclusive.
• Able to communicate meaningfully with investigative staff, and able to comply with entire study procedures. If the patient is unconscious, then information from a reliable witness indicates that the patient would normally be able to comply with study procedures.
• Patient or relative is able, willing and competent to give informed consent.
• Life expectancy of at least 1 year.

• Mangled Extremity Severity Score (MESS) of ≥ 7.
• Limb at high risk of amputation despite vascular reconstruction (e.g., because of crush injury).
• Catastrophic injuries that make survival unlikely (e.g., Abbreviated Injury Scale (AIS) > 5 or Injury Severity Score (ISS) > 60).
• HAV may not be used for coronary artery repair.
• Known pregnant women.
• Known medical condition which would preclude long term antiplatelet therapy after resolution of acute injuries.
• Any other condition which in the judgment of the investigator would preclude adequate evaluation of the safety and efficacy of the HAV.
• Previous exposure to HAV.
• Known participation in any investigational study within the last 30 days.
• Employees of the sponsor or patients who are employees or relatives of the investigator.

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

Inclusion Criteria
•Main Phase 0:

• Histologically (if prior biopsy) or radiologically diagnosed glioblastoma.
• Eligible for neurosurgical tumor resection.
• Patients must be at least 18 years old.
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1.
• Adequate organ function.
• Life expectancy ≥ 3 months at the start of treatment in the opinion of the investigator.

Inclusion Criteria
•Main Phase Ia:

• Histologically demonstrated diagnosis of TP53 wild type glioblastoma harboring unmethylated MGMT promoters (Glioblastoma definition according to 2021 WHO Classification of CNS tumors; i.e., IDH-wild type only).
• Patient has undergone neurosurgical tumor resection and is eligible for standard radiotherapy.
• Formalin-fixed paraffin-embedded tumor blocks or representative H/E (haematoxylin/eosin) slides (preferably both) must be available for retrospective histopathological central review.
• Locally performed histopathological diagnosis will be accepted for entry into this trial.
• Patients must be at least 18 years old.
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1.
• Adequate organ function.
• Life expectancy ≥ 3 months at the start of treatment in the opinion of the investigator.

Exclusion Criteria
•Main Phase 0:

• Known TP53 mutant glioblastoma.
  • Note: testing is not mandatory for inclusion.
• Known IDH mutant grade IV astrocytoma.
  • Note: testing is not mandatory for inclusion.
• Patients with pacemakers or other metallic implants that can interfere with the magnetic field during MRI investigations.
• Inability to undergo contrast-enhanced MRI (GFR < 30 mL/min).

Exclusion Criteria
•Main Phase Ia:

• Patients who have received previous systemic therapy (with the exception of patients who participated in Phase 0) or radiotherapy for glioblastoma.
• Patients with pacemakers or other metallic implants that can interfere with the magnetic field during MRI investigations.
• Inability to undergo contrast-enhanced MRI (GFR < 30 mL/min).

Eligibility last updated 3/1/22. Questions regarding updates should be directed to the study team contact.

• Subject is older than 18 years of age.
• Symptomatic coronary artery disease (CAD) with greater than or equal to 90 days of persistent refractory angina pectoris classified as CCS Grade III or IV despite maximally tolerated guideline directed medical therapy.
• Must have attempted treatment with the maximally tolerated dose of at least three of the four (and preferably all four) approved classes of anti-anginal agents:
  • long-acting nitrates, calcium channel blockers (either a dihydropyridine or a non-dihydropyridine), beta blockers, and ranolazine. The regimen must be stable for greater than 2 months prior to enrollment, with no intent to change the medical regimen for at least 12 months after randomization.
• Subject has either no treatment options for revascularization by coronary artery bypass grafting or by percutaneous coronary intervention, or is otherwise unsuitable or high risk for revascularization.
• Evidence of either exercise or pharmacologically induced reversible ischemia severity by stress echo, nuclear study, PET, perfusion MRI, CT perfusion, FFRCT, FFR, iFR, or other non-hyperemic FDA approved tests in the distribution of the left coronary artery (LCA). Note: if the subject has evidence of ischemia in both the LCA and RCA distributions, the extent of ischemia must be greater in the LCA distribution.
• Functional limitation due to refractory angina as defined by a modified Bruce exercise tolerance test duration of greater than or equal to 2 minutes but less than or equal to 8 minutes:
  • Subject has ETT variability less than 20% between last two ETTs performed.
• Left ventricular ejection fraction (LVEF) greater than or equal to 30% within the 12-months prior to procedure (must be reassessed after any intervening myocardial infarction); the most recent LVEF assessment is used as the qualifying test.
• Subject is willing and able to sign informed consent.
• Subject is willing to comply with the specified follow-up evaluations.

• Recent (within 30 days prior to enrollment) troponin or CKMB positive acute coronary syndrome (NSTEMI or STEMI).
• Recent successful revascularization by CABG or PCI within six months prior to enrollment.
• Recent unsuccessful PCI (e.g., no relief from symptoms, failed attempt to open a chronic total occlusion) within 30 days prior to enrollment.
• The predominant manifestation of angina is dyspnea .
• Has extra-coronary contributory causes of angina; e.g., untreated hyperthyroidism, anemia (hgb < 10 g/dL), uncontrolled hypertension (systolic blood pressure > 160 mmHg or diastolic blood pressure > 100 mmHg despite medications), atrial fibrillation with rapid ventricular response (consistently >100 bpm despite medications) or other tachyarrhythmia, severe aortic stenosis, hypertrophic cardiomyopathy with left ventricular outflow tract obstruction or asymmetric septal hypertrophy (concentric left ventricular hypertrophy is not an exclusion criterion), etc.
• NYHA Class III or IV heart failure (HF), decompensated HF or hospitalization due to HF during the 90 days prior to enrollment.
• Life threatening rhythm disorders or any rhythm disorders that would require future placement of an internal defibrillator and/or pacemaker.
• Severe chronic obstructive pulmonary disease (COPD) as indicated by a forced expiratory volume in one second (FEV1) that is less than 55% of the predicted value, or need for home daytime oxygen or oral steroids.
• Severe valvular heart disease (any valve).
• Moderate or severe RV dysfunction by echocardiography.
• Pacemaker electrode/lead is present in the coronary sinus.
• A Class I indication is present for an implantable defibrillator or cardiac resynchronization therapy according to ACCF/AHA/HRS guidelines.
• Recent implantation of a new pacemaker or defibrillator lead with electrode in the right atrium within 90 days of enrollment.
• Chronic severe renal failure (estimated eGFR less than 30 mL/min/1.73m2 by the MDRD formula) or subjects on chronic dialysis.
• Known allergy to stainless steel or nickel.
• Any clinical condition that might interfere with the trial protocol or the subject's ability to be compliant with the trial protocol (e.g., active alcohol or drug abuse, dementia, magnetic resonances imaging (MRI) planned within 8 weeks of randomization, etc.).
• Currently enrolled in another investigational device or drug trial that has not reached its primary endpoint or that might clinically interfere with the current trial endpoints or procedures.
• Pregnant or planning pregnancy within the next 12 months (women of reproductive potential must have a negative pregnancy test within 7 days of the randomization procedure).
• Subject is part of a vulnerable population who, in the judgment of the investigator, is unable to give Informed Consent for reasons of incapacity, immaturity, adverse personal circumstances or lack of autonomy. This may include individuals with mental disability, persons in nursing homes, children, impoverished persons, persons in emergency situations, homeless persons, nomads, refugees, and those incapable of giving informed consent. Vulnerable populations also may include members of a group with a hierarchical structure such as university students, subordinate hospital and laboratory personnel, employees of the Sponsor, members of the armed forces, and persons kept in detention.
• Inability to tolerate dual antiplatelet therapy for 6 months if not on a chronic oral anticoagulant, or inability to tolerate a P2Y12 inhibitor for at least 6 months if on a chronic oral anticoagulant.
• Comorbidities limiting life expectancy to less than one year.

Eligibility last updated 4/15/22. Questions regarding updates should be directed to the study team contact.

• Adult postmenopausal women, aged 45-60 years.
• Menopause symptoms (hot flashes/night sweats) rated moderate or greater or total MRS score ≥ 14.

• Current use of hormone therapy.

Eligibility last updated 3/10/22. Questions regarding updates should be directed to the study team contact.

• Age 18+.
• Capable of consenting.
• Actively being monitored on Philips inpatient telemetry.

• Under the age of 18.
• Unable to consent.
• Pregnant patients.

Eligibility last updated 4/21/22. Questions regarding updates should be directed to the study team contact.

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

Eligibility last updated 10/18/22. Questions regarding updates should be directed to the study team contact.

• Age ≥ 18 years.
• Stage 3 acute kidney injury according to the KDIGO criteria.
• Started or intending to start CKRT for volume management.
• Attending intensivist or nephrologist intending to remove fluid using CKRT for at least 48 hours.

• Respiratory distress due to pulmonary edema or fluid overload.
• Massive volume infusion (i.e., > 200 mL/h for > 6 hours of continuous infusion).
• No intention to remove fluid as determined by attending intensivist or nephrologist.
• Attending intensivist or nephrologist believes that the protocol will not be followed.
• Continuous fluid removal for > 24 hours prior to study enrollment.
• Actual or estimated premorbid body weight > 120 kilograms.
• Patients treated with intermittent hemodialysis during the current admission.
• Patients on chronic outpatient hemodialysis. 
• Patients with history of, or current admission for kidney transplantation.
• Do not resuscitate, intubate, or comfort measures only orders (i.e., DNR/DNI/CMO).
• Moribund not expected to survive > 24 hours.
• Confirmed pregnancy.
• Patients treated with extracorporeal membrane oxygenation (ECMO), ventricular assist device (VAD), or intra-aortic balloon pump (IABP).
• Organ donors with neurological determination of death (i.e., brain dead donors).
• Drug overdose requiring CKRT.
• Enrollment in a concurrent interventional clinical trial with direct impact on fluid balance (e.g., > 500 mL study drug administration).

Eligibility last updated 3/9/22. Questions regarding updates should be directed to the study team contact.

Eligibility last updated 7/19/22. Questions regarding updates should be directed to the study team contact.

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

Eligibility last updated 12/6/22. Questions regarding updates should be directed to the study team contact.

• Premenopausal women, ages 18-50 years old.
• Uterine fibroid group (n≈20): These participants will have had a previous or current diagnosis of UF determined by ultrasound, hysteroscopy, or MRI, confirmed with medical documentation within one year of recruitment.
• Control (non-fibroid) group (n≈20): These participants will not have evidence of UF (confirmed by imaging) at the time of study participation.

• History or evidence of:
  • hepatic, renal, or hematological disease;
  • peripheral vascular disease;
  • stroke/neurovascular disease;
  • diabetes;
  • dyslipoproteinemia;
  • hypertension (> 130/80 mmHg brachial cuff pressure); 
  • lung disease;
  • arthritis affecting ability to exercise; or
  • a body mass index > 30 kg/m^2. 
• Participants also will be excluded if taking antihypertensive medication or medication that alters autonomic or vascular function (e.g., tricyclic antidepressants, alpha-blockers, beta-blockers, etc.). 
• Participants will be non-smokers. 
• Subjects must have a negative pregnancy test in order to participate in the study. 
• Participants who are breastfeeding will be excluded.
• Women who have undergone hysterectomy will be excluded.

Eligibility last updated 3/7/22. Questions regarding updates should be directed to the study team contact.

Eligibility last updated 3/31/22. Questions regarding updates should be directed to the study team contact.

• Practicing physicians, nurses and allied health staff that participate in surgery process.   

• Physicians, Nurses and allied health staff that do not have time to participate in the study.

Eligibility last updated 3/8/22. Questions regarding updates should be directed to the study team contact.

• Age ≥ 60 years old at time of consent.
• Concurrent enrollment in the Mayo Clinic Study of Aging (MCSA, IRB 14-004401):
  • Note: Participants may be but are not required to be concurrently enrolled in Brain Amyloid Imaging with Pittsburgh Compound B in Normal Aging, Mild Cognitive Impairment and Dementia (PiB, IRB 08-005553).  
•  Normal or mildly impaired cognition with CDR ≤ 1.0.

• History of dementia or major neurological condition (i.e., non-lacunar stroke, TBI, epilepsy, tumor, CNS infection, demyelinating disease, neurodegenerative disease), severe autonomic failure (pure autonomic failure or autonomic neuropathy), major psychiatric disease (i.e., alcohol/drug abuse and schizophrenia), 
• Current treatment of OSA. Diagnosed but untreated OSA is acceptable.
• Use of short-acting nitrates within 3 hours of the sleep study.
• Use of selective α1-adrenergic receptor antagonists, for example, tamsulosin (Flomax®), doxazosin (Cardura®), prazosin (Minipress®), and terazosin (Hytrin®) and nonselective α1 and α2 blockers (pentholamine and phenoxybenzamine).
• Finger deformity that precludes adequate sensor application.
• Placement of a permanent pacemaker.
• Persistent atrial fibrillation or other sustained non-sinus cardiac arrhythmias.
• Severe peripheral vascular disease (e.g., status post stent or by-pass surgery in one of the limbs, faint/absent pulses).
• Status post bilateral cervical or thoracic sympathectomy.
• Acute lung or heart disease (e.g., decompensated COPD or heart failure).

Eligibility last updated 9/21/22. Questions regarding updates should be directed to the study team contact.

• Patient 18 years or older with breast cancer and biopsy-proven malignant involvement of an axillary lymph node.
• Surgical management will be determined by Dr. Mara Piltin, who will decide if preoperative I-125 seed localization of the positive node is necessary or if she will retrieve the positive node with intraoperative ultrasound guidance. During surgery, the targeted node, its associated biopsy markers, I-125 seed if placed, and twinkling marker will be resected. The position of the marker in the lymph node or proximity to the node will be noted from the surgical and pathology documentation.
• Surgery will be performed by Dr. Mara Piltin.
• Patients must be able to understand the study procedures and comply with them for the entire length of the study.
• No contraception is necessary or required.

• Current drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements.
• Inability or unwillingness of individual or legal guardian/representative to give written informed consent.
• Current or past participation within a specified timeframe in another clinical trial, as warranted by the administration of this intervention.

• Southeast Minnesota (SEMN, covering MCR and MCHS vicinities), Southwest Wisconsin (SWWI, covering MCR and MCHS vicinities), Florida (covering Jacksonville FL region) and Arizona (covering Scottsdale AZ region) residents (residency established at least one year prior to consent).
• Aged 18- 64 years at the time of consenting.
• Those who have primary care physician at Mayo Clinic and had at least one visit to one of Mayo Clinic sites within 3 years prior to the study index date.
• Those who authorize use of their medical record for research (MN only).
• Those who provide written consent to participate in the study.

• Subjects without authorization for use of medical records for research.
• Those who do not reside in catchment areas served by MCR/MCHS, MCF, and MCA.
• Those who receive primary care at a non-Mayo medical facility.
• Those who develop ARI after October 1st, 2022, if consent is done between October 1st, 2022, and November 30th, 2022.
• Those who refuse swab test.
• Those who cannot ambulate or those who are bedridden.
• Those with known cognitive impairment.
• Those who reside out of their resident counties > 2 weeks during winter season (Oct-April) and/or >4 weeks during summer season (May-Sep).

Aim 1-3 Patient Participants

• Age ≥ 50 years old;
• Estimated length of stay ≥ 24 hours in ICU; and
• Are not admitted for acute alcohol intoxication, drug (prescribed or illicit) overdose or withdrawal.

Aim 3 Nurse Clinician Participants

• Age ≥ 18 years old;
• Employed by Mayo Clinic;
• Assigned to care for study patient for > 4 hours.

Aim 3 Care Partner Participants

• Age ≥ 18 years old;
• Proxy decision maker for patient participant;
• Willing to complete survey (verbal consent).

Aim 1-3 Patient Participants

• Admitted for acute alcohol intoxication, drug (prescribed or illicit) overdose or withdrawal;
• Admitted for acute neuronal injury;
• Unable to communicate with research team due to sensory deficits (aphasic, blind, deaf); or
• Language (does not speak English).

Aim 3 Nurse Clinician Participants

• Not assigned to study patient.

Aim 3 Care Partner Participants

• Did not visit patient in ICU during study period;
• Already listed above in previous protocol version, was not copied/mentioned here.

Eligibility last updated 12/1/22. Questions regarding updates should be directed to the study team contact.

• Ability to understand and provide written informed consent.
• Age ≥ 50 years and ≤ 80 years.
• Current or former smoker.
• ≥ 20 pack-years (pack years = number of packs per day × number of years smoked).
• An initial or annual lung cancer screening chest CT..

• Evidence of any cancer (including prior lung cancer) other than non-melanoma skin cancer or carcinoma in situ (transitional cell carcinoma in situ and bladder carcinoma in situ are exclusionary) within 2 years prior to enrollment
• Prior systemic therapy, definitive therapy, radiation, or surgical resection for any cancer diagnosis within 2 years prior to enrollment (with the exception of surgery for nonmelanoma skin cancer and biopsies).
• Any history of hematologic malignancies or myelodysplasia.
• Any history of organ tissue transplantation.
• Any history of blood product transfusion within 120 days prior to enrollment.
• Current pregnancy.
• Any condition that in the opinion of the Investigator should preclude the participant’s participation in the study.

Eligibility last updated 8/2922. Questions regarding updates should be directed to the study team contact.

• Healthy male or female participants.
• Between the ages of 18 and 89.
• Must have had experience as a pilot or passenger in an unpressurized general aviation aircraft at altitudes above 8,000 feet and have not experienced any serious adverse effects from this experience (such as serious vertigo, loss of consciousness, any cardiac or respiratory dysfunction, or any other illness requiring medical treatment). 
• Participants need to be able to complete cognitive tests.
• Must be fluent in English.

• Patients < 18 years of age or > 89 years of age.
• Pregnant women.
• Unable to read and speak English.
• History of Cardiac disease, Pulmonary disease, Cerebrovascular disease, Neurological disease, Vertigo, or Syncope.
• Any documented incidences of Serious Adverse effects from General Aviation.

• Patients who receive a Hepatic Artery Infusion Pump at Mayo Clinic Rochester for localized unresectable liver metastases from colorectal cancer.
• Age ≥ 18 years old.
• Written consent.

• Age < 18 years old.
• Absence of written consent.
• Systemic disease.
• Pregnancy.

• Male or female.
• Between > 18-80 years of age.
• Able and willing to give informed consent 
• Subjects with a suspected glioblastoma tumor on pre-operative brain imaging scans.
• Subjects that are scheduled, or will be scheduled within 4 weeks, for surgical resection or biopsy per standard clinical tumor care.
• Karnofsky Performance Score > 70.
• Able to communicate sensations during the Exablate BBBD procedure.

• Tumor originating from the deep midline, thalamus, midbrain, cerebellum or brainstem.
• Multifocal tumors.
• MRI or clinical findings of:
  • Active or chronic infection(s) or inflammatory processes;
  • Acute or chronic hemorrhages, specifically any lobar microbleeds, and no siderosis, amyloid angiopathy, or macro-hemorrhages;
  • Intracranial thrombosis, vascular malformation, cerebral aneurysm or vasculitis.
• MR non-compatible metallic implants in the skull or the brain or the presence of unknown MR unsafe devices.
• Significant cardiac disease or unstable hemodynamic status:
  • Documented myocardial infarction within six months of enrollment;
  • Unstable angina on medication;
  • Unstable or worsening congestive heart failure;
  • Left ventricular ejection fraction below the lower limit of normal;
  • History of a hemodynamically unstable cardiac arrhythmia;
  • Cardiac pacemaker;
  • History of hypersensitivity to Perflutren lipid microsphere or its components; e.g., polyethylene glycol.
• Uncontrolled hypertension (systolic > 180 and diastolic BP > 120 on medication).
• Unable to discontinue use of anti-coagulant/antiplatelet therapy as per local standard.
• History of a liver disease, bleeding disorder, coagulopathy or a history of spontaneous hemorrhage or evidence of increased risk of bleeding.
• Abnormal coagulation profile (Platelets < 80,000), PT (> 14) or PTT (> 36), and INR > 1.3.
• Known cerebral or systemic vasculopathy.
• Significant depression and at potential risk of suicide.
• Known sensitivity/allergy to gadolinium or DEFINITY®.
•  Active seizures despite medication treatment (defined as > 1 seizure per week) which could be worsened by disruption of the blood brain barrier.
• Active drug or alcohol disorder which have a higher risk for seizures, infection and/or poor executive functioning.
• Positive HIV status, which can lead to increased entry of HIV into the brain parenchyma leading to HIV encephalitis.
• Potential blood-borne infections which can lead to increased entry to brain parenchyma leading to meningitis or brain abscess.
• Any contraindications to MRI scanning, including:
  • Large subjects not fitting comfortably into the scanner;
  • Difficulty lying supine and still for up to 3 hours in the MRI unit or claustrophobia.
• Impaired renal function with estimated glomerular filtration rate < 30 mL/min/1.73m^2.
• Severe Respiratory Illness: chronic pulmonary disorders; e.g.,severe emphysema, pulmonary vasculitis, or other causes of reduced pulmonary vascular cross-sectional area, subjects with a history of severe drug allergies, asthma or hay fever, and multiple allergies where the benefit/risk of administering Definity® is considered unfavorable by the study physicians in relation to the product labeling for Definity®.
• Currently in a clinical trial involving an investigational product or non-approved use of a drug or device.
• Pregnancy or lactation.

• 18 years or older with a clinician diagnosis of bipolar disorder (any bipolar disorder type including bipolar I disorder, bipolar II disorder, cyclothymic disorder, and unspecified bipolar and related disorder).
• Ability to consent to participation in research. 
• Patients (n=10) will be recruited from those currently receiving treatment in the included clinics in the Mayo Clinic (Collaborating Institution). 
• Additionally, stakeholder partners at the Depression and Bipolar Support Alliance will publicize our research study and identify 10-15 individuals with bipolar disorder currently receiving treatment to participate.

• Among participants recruited from the Mayo Clinic, individuals who are not intending to return to care in that system.
• No exclusion criteria apply to participants recruited from the Depression and Bipolar Support Alliance.

• Participant must be ≥ 18 years of age, at the time of signing the informed consent.
• Participants who are ≥ 40 kg at Screening Visit 1.
• Participants who have a documented diagnosis of HES prior to Visit 2. HES diagnosis is based on:
  • blood eosinophilia of > 1500 eosinophils/µL on at least 2 occasions at ≥ 1-month interval, without a discernible non-haematological secondary cause; and
  • signs or symptoms of organ involvement and/or dysfunction that can be directly related to eosinophilia.
• Flare history: A history of 2 or more HES flares within the past 12 months prior to Visit 1. Historical HES flares are defined as documented HES-related worsening of clinical symptoms or blood eosinophil counts requiring an addition or escalation in OCS or cytotoxic/immunosuppressive therapy. At least one HES flare within the past 12 months must not be related to a decrease in HES therapy during the 4 weeks prior to the flare.
• A female participant is eligible to participate if she is not pregnant or breastfeeding, and one of the following conditions applies:
  • Is a woman of non-childbearing potential (WONCBP); OR
  • Is a woman of childbearing potential (WOCBP) and using a contraceptive method that is highly effective, with a failure rate of <1%, from at least 14 days prior to the first dose of study intervention until at least 30 weeks after the last administered dose of study intervention. The Investigator should evaluate the potential for contraceptive method failure (e.g., non-compliance, recently initiated) in relationship to the first dose of study intervention;
  • A WOCBP must have a negative highly sensitive serum pregnancy test at Screening Visit 1 and a negative highly sensitive urine pregnancy test within 24 hours before the first dose of study intervention. If a urine test cannot be confirmed as negative (e.g., an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive. Additional requirements for pregnancy testing during and after study intervention;
  • Contraceptive use by women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies;
  • The Investigator should evaluate the potential for contraceptive method failure (e.g., non-compliance, recently initiated in relationship to the first dose of study intervention;
  • The Investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy.
• Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.
• In France, a participant will be eligible for inclusion in this study only if either affiliated to or a beneficiary of a social security category.

• HES disease manifestations which in the opinion of the Investigator may put the participant at unacceptable risk from study participation or confound interpretation of efficacy or safety data. Specific consideration should be given to the participant’s ability to comply with protocol requirements, including the list of prohibited therapies; exclusion criteria no. 14
  •16.
• Participants with chronic or ongoing active infections requiring systemic treatment.
• Participants with a pre-existing parasitic infestation within 6 months prior to Visit 1.
• Participants with a known immunodeficiency (e.g., Human Immunodeficiency Virus [HIV]), other than that explained by the use of OCS or other therapy taken for HES.
• Participants with a history of or current lymphoma.
• Participants with current malignancy or previous history of cancer in remission for less than 5 years prior to Visit 1. Participants that had localized carcinoma (i.e., basal or squamous cell) of the skin which was resected for cure will not be excluded.
• Participants with a haematologic malignancy with hypereosinophilia in which HES is not the primary diagnosis; e.g., chronic myeloid leukaemia, myelodysplastic syndrome, chronic eosinophilic leukaemia-not otherwise specified.
• Cirrhosis or current unstable liver or biliary disease per Investigator assessment defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia, oesophageal or gastric varices, persistent jaundice.
  • NOTE: Stable non-cirrhotic chronic liver disease (including Gilbert’s syndrome, asymptomatic gallstones, and chronic stable hepatitis B or C) are acceptable if participant otherwise meets entry criteria.
• Participants who have severe or clinically significant cardiovascular disease uncontrolled with standard treatment.
• Participants with current diagnosis of vasculitis. Participants with high clinical suspicion of vasculitis at Screening will be evaluated and current vasculitis must be excluded prior to randomization.
• Eosinophilia of unknown significance: Hypereosinophila with no clinical symptoms and/or proof of organ dysfunction.
• Clinical diagnosis of EGPA.
• Participants that, according to the Investigator's medical judgment, are likely to have active COVID-19 infection should be excluded.
• Participants with known COVID-19 positive contacts within the past 14 days must be excluded for at least 14 days following the exposure during which the participant must remain symptom-free.
• Participants who have known, pre-existing, clinically significant endocrine, autoimmune, metabolic, neurological, renal, gastrointestinal, hepatic, haematological, respiratory, cardiac or any other system abnormalities that are not associated with HES and are uncontrolled with standard treatment.
• Participants with an allergy/ intolerance to a monoclonal antibody or biologic, or any of the excipients of the investigational product.
• Monoclonal antibodies (mAbs) targeting IL-5/5R: Participants who have a previous documented failure with anti-IL-5/5R therapy.
• Participants who have received mAb within 30 days or 5 half-lives, whichever is longer, prior to Visit 1. If a participant has been treated with and responsive to biologics for HES, the participant should not stop the treatment for study eligibility purpose.
• Non-oral systemic corticosteroids: Participants who have received intravenous, intramuscular, or subcutaneous corticosteroids within 4-weeks prior to Visit 2.
• Participants who have received treatment with an investigational agent within 30 days or 5 drug half-lives whichever is longer, prior to Visit 1. The term “investigational” applies to any drug not approved for sale in the country in which it is being used or investigational formulations of marketed products.
• Participants who are currently participating in any other interventional clinical study.
  • Note: Any COVID-19 vaccine approved by local government is permitted. Experimental COVID-19 vaccines are not permitted.
• Participants who test positive for the FIP1L1-PDGFRα fusion gene. Blood sampling is required for all participants at Screening (Visit 1) for this test unless the documented result is available.
• ECG Assessment: QTcF ≥ 450 msec or QTcF ≥ 480 msec for participants with Bundle Branch Block at Screening Visit 1.
• Participants who are not responsive to OCS based on clinical response or blood eosinophil counts in the opinion of the Investigator.
• A history (or suspected history) of alcohol misuse or substance abuse within 2 years prior to Visit 1.
• Participants who are pregnant or breastfeeding.
• Participants must not be randomized if they plan to become pregnant during the time of study participation.
• Participants who have known evidence of lack of adherence to controller medications and/or ability to follow physician’s recommendations.

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

Eligibility last updated 10/6/22. Questions regarding updates should be directed to the study team contact.

Registration
•Inclusion Criteria

• Age ≥ 18 years
• Women with a diagnosis of breast cancer who are being treated with curative intent, with the one exception being women who are receiving CDK4/6 inhibitors (these patients being allowed to have more advanced disease).
• Provide written informed consent.
• Ability to complete questionnaire(s) by themselves or with assistance.
• Filling into one of the 5 groups discussed in section 5.0 (understanding that groups will close once they complete their accrual goals of 30 patients.
• Willingness to complete questionnaires every 3 months.
• Ability to complete the first questionnaire within 2 weeks of therapy initiation (for the four arms that are receiving adjuvant hormonal therapy).

Registration
•Exclusion Criteria

• Verbal baseline alopecia ≥ 2 on an 11 point scale (from none=0 to severe=10).   The question to use for this item is: Please rate your hair thinning or loss on a scale from 0 to 10, with 0 being no hair loss and 10 being complete hair loss.
• Planned receipt of chemotherapy or another cancer-directed therapy concurrently (e.g., everolimus, etc.; note that a CDK4/6 inhibitor is allowed within cohort 3).
• Prior use of endocrine therapy for breast cancer.
• Receipt of chemotherapy over the previous 6 months.

Eligibility last updated 7/18/22. Questions regarding updates should be directed to the study team contact.

• Adult male and female, age from 18 years old.
• Having signs and symptoms of HFpEF. HFpEF (EF ≥ 40%, PCWP at rest ≥15 mm Hg).
• With 1, 2, 3 grades or indeterminate degree of DD (ACC/AHA stages C and D HF).

• Reduced Ejection Fraction (EF ≤ 39%), mitral valve prosthesis, mitral stenosis.

Eligibility last updated 9/16/22. Questions regarding updates should be directed to the study team contact.

• Scheduled for a MR guided biopsy or ablation.
• Male, 45 years of age or older.
• One, two, or three tumor suspicious regions identified on multiparametric MRI.
• Tolerance for anesthesia/sedation.
• Ability to give informed consent.

• Presence of any condition (e.g., metal implant, shrapnel) not compatible with MRI.
• History of other primary non-skin malignancy within previous three years.