• uncomplicated pregnancy at gestational age >12 weeks
• pregnancy complicated by abnormal fetal heart rate or rhythm or risk of abnormal fetal heart rate or rhythm at gestational age >15 weeks
• uncomplicated pregnancy <12 weeks gestation
• pregnancy complicated by abnormal fetal heart rate or rhythm or risk of abnormal fetal heart rate or rhythm at gestational age <15 weeks

Aim 1 (Ultrasound (US) only):
• Adults at least 18 years
• Are able to provide written informed consent on their own behalf Aim 2 (US and MRI):
• Participation in the US study (Aim 1)
• Determined by presence of hypoechogenic or echolucent lipid-rich soft plaque during initial ultrasound imaging session
• Adults willing to participate over 5 years Aim 1 (US only)
• Women that are currently pregnant
• Inability to cooperate with the ultrasound study, in particular those unable to sit without gross movement for the duration the ultrasound study (estimated at 60-90 minutes)
• Open wounds or sores in the anterior neck
• History of cardiac disease, stroke or TIA
• History of statin medication
• History of hypertension medications Aim 2 (US and MRI):
• Women that are currently pregnant
• Inability to cooperate with the ultrasound study, in particular those unable to sit without gross movement for the duration the ultrasound study (estimated at 60-90 minutes)
• Patients that require intravenous (IV) conscious sedation for imaging are not eligible; patients requiring mild, oral anxiolytics for research imaging will be allowed to participate as long as:
• The participants has their own prescription for the medication;
• The informed consent process is conducted prior to the self-administration of this medication; and,
• The participant comes to the research visit with a driver
• Contraindications to MR
• Unable to lie in the MRI scanner for 45-60 minutes
• Patients with a contraindication to gadolinium based contrast agents, including allergy or impaired renal function (per University of Wisconsin Health Guidelines)

• 40-75 years of age (inclusive)
• Free of chronic disease
• Comprehension of the protocol as indicated by an ability to respond to questions about the study after reading the consent form.
• Able to use and be contacted by telephone.
• Able to speak, read, and understand English, and complete a questionnaire in English
• Independently mobile
• Pregnancy
• Heart disease (history, abnormal ECG, abnormal stress ECG)
• Cerebrovascular disease (history)
• Cancer (history)
• Chronic respiratory disease (history, forced expiratory volume at one second/forced vital capacity [FEV1/FVC] < 70, FEV1 < 80% predicted)
• Chronic liver disease (history, alanine transaminase [ALT] > 52 IU/L)
• Diabetes (history, HbA1C ≥ 6.5, fasting blood glucose≥126 mg/dl, oral glucose tolerance test [OGTT] ≥ 200 mg/dl at 2 hrs)
• Impaired kidney function (eGFR ,45 mL/min)
• B12 lab values outside of normal range (<193 or >982 pg/mL)
• Alzheimer's (history)
• Chronic kidney disease (history, abnormal blood kidney panel including serum creatinine > 1.4)
• Problems with bleeding, on medication that prolongs bleeding time (if subject cannot safely stop prior to biopsy)
• Those on glucose lowering drugs
• Those planning to have imaging that requires intravenous contrast dye (within 6 weeks) or are on any of the following medications since they are contraindicated with the use of metformin: Dofetilide, Lamotrigine, Pegvisomant, Somatropin, Trimethoprim, Trospium, Gatifloxacin, Cephalexin, Cimetidine, Dalfampridine
• Tobacco use
• Allergies to lidocaine or metformin

Inclusion criteria: Participants must meet all of the following criteria to be included in this study: 1. Male or female, age 55 to 80 years inclusive at the time of informed consent, with a plasma biomarker result that is predictive of intermediate or elevated brain amyloid at Screening or known before Screening to have elevated or intermediate amyloid according to previous PET, cerebrospinal fluid (CSF), or plasma testing • Those 55 to 64 must have 1 of the following additional risk factors, given the relatively low rates of amyloid positivity less than (<) 65 years, before screening:
• First degree relative diagnosed with dementia onset before age 75, or
• Known to possess at least 1 apolipoprotein E4 variant (APOE4) allele, or
• Known before screening to have elevated brain amyloid according to previous plasma biomarker results, PET imaging, or CSF testing 2. Global Clinical Dementia Rating (CDR) score of 0 at screening 3. Mini Mental State Examination score greater than or equal to (>=) 27 (with educational adjustments) at screening. 4. Wechsler Memory Scale-Revised Logical Memory subscale II (WMS-R LM II) score at screening of >=6 5. A45 Trial: Elevated brain amyloid pathology by amyloid PET: defined as approximately greater than (>) 40 Centiloids on screening scan A3 Trial: Intermediate levels of brain amyloid pathology by amyloid PET: defined as approximately 20 to 40 Centiloids on screening scan 6. Has a study partner that is willing to participate as a source of information and has approximately weekly contact with the participant (contact can be in-person, via telephone or electronic communication). The study partner must have sufficient contact such that the investigator feels the study partner can provide meaningful information about the participant's daily function 7. Provide written (or electronic, if allowed per country-specific regulations) informed consent 8. Willing and able to comply with all aspects of the protocol For extension phase : 1. Completed the Core Study, or meet the following progression criteria during the Core Study:
• Two consecutive CDR visits with Global Scores > zero when measured at least 6 months apart within the Core Study
• The principal investigator's confirmation that the participant has clinically declined consistent progression to EAD 2. Must continue to have a study partner who is willing and able to provide follow-up information on the participant throughout the course of the Extension Phase. The study partner must provide separate written informed consent for the Extension Phase. Study partners must continue to have sufficient contact such that the investigator feels the study partner can provide meaningful information about the participant's daily functions 3. Provide written informed consent for the Extension Phase. If a participant lacks capacity to consent in the investigator's opinion, the participant's assent should be obtained, if required and in accordance with local laws, regulations, and customs, plus the written informed consent of a legal representative (capacity to consent and the definition of a legal representative should be determined in accordance with applicable local laws and regulations). In countries where local laws, regulations, and customs do not permit participants who lack capacity to consent to participate in this study (example, Spain), they will not be enrolled 4. Willing and able to comply with all aspects of the protocol Exclusion criteria: Participants who meet any of the following criteria will be excluded from this study: 1. Females who are breastfeeding or pregnant at screening or baseline 2. Females of childbearing potential who: • Within 28 days before study entry, did not use a highly effective method of contraception For sites outside of Europe, it is permissible that if a highly effective method of contraception is not appropriate or acceptable to the participant, then the participant must agree to use a medically acceptable method of contraception 3. History of transient ischemic attacks (TIA), stroke, or seizures within 12 months of screening 4. Current or history within the past 2 years of psychiatric diagnosis or symptoms that, in the opinion of the investigator, could interfere with study procedures 5. Contraindications to 3 Tesla magnetic resonance imaging (MRI) scanning, including cardiac pacemaker/defibrillator, ferromagnetic metal implants (example, in-skull and cardiac devices other than those approved as safe for use in MRI scanners), or exhibit other significant pathological findings on brain MRI at Screening 6. Hypersensitivity to any monoclonal antibody treatment 7. Any immunological disease which is not adequately controlled, or which requires treatment with immunoglobulins, systemic monoclonal antibodies (or derivatives of monoclonal antibodies), systemic immunosuppressants, or plasmapheresis during the study 8. Bleeding disorder that is not under adequate control (including a platelet count <50,000 or international normalized ratio [INR] >1.5) at screening 9. Results of laboratory tests conducted during screening that are outside the following limits:
• Thyroid stimulating hormone (TSH) above normal range
• Abnormally low (below lower limit of normal [LLN]) serum vitamin B12 levels for the testing laboratory (if participant is taking vitamin B12 injections, level should be at or above the LLN for the testing laboratory). A low vitamin B12 is exclusionary, unless the required follow-up labs (homocysteine and methylmalonic acid [MMA]) indicate that it is not physiologically significant 10. Known to be human immunodeficiency virus (HIV) positive 11. Any other clinically significant abnormalities that in the opinion of the investigator require further investigation or treatment or may interfere with study procedures or safety 12. Malignant neoplasms within 3 years of screening (except for basal or squamous cell carcinoma in situ of the skin, or localized prostate cancer in male participants with treatment cycles completed at least 6 months before screening). Participants who had malignant neoplasms but who have had at least 3 years of documented uninterrupted remission before screening need not be excluded 13. Answer "yes" to Columbia-Suicide Severity Rating Scale (C-SSRS) suicidal ideation Type 4 or 5, or any suicidal behavior assessment within 6 months before screening, at screening, or at baseline, or has been hospitalized or treated for suicidal behavior in the past 5 years before screening 14. Known or suspected history of drug or alcohol abuse or dependence within 2 years before screening or a positive urine drug test at screening. Participants who test positive for benzodiazepines, opioids, or tetrahydrocannabinol (THC) in urine drug testing need not be excluded unless in the clinical opinion of the investigator this is due to potential drug abuse 15. Taking prohibited medications 16. Participation in a clinical study involving:
• Any anti-amyloid plaque lowering immunotherapy (example, therapeutic monoclonal antibody or active anti-amyloid vaccine) at any time, unless it can be documented that the participant was randomized to placebo or never received study drug
• Any immunoglobulin therapy, or vaccine within 6 months before Screening, unless it can be documented that the participant was randomized to placebo or never received study drug
• Lecanemab
• Any new chemical entities or investigational drug for AD within 6 months before randomization unless it can be documented that the participant received only placebo
• Any other investigational medication or device study in the 8 weeks or 5 half-lives (whichever is longer) of the medication before randomization unless it can be documented that the participant was in a placebo treatment arm 17. Planned surgery during the pre-randomization phase or within 3 months of randomization, which requires general anesthesia For extension phase: 1. Discontinued from the Core Study or from study treatment 2. Under study drug interruption due to ARIA or other AE at the time of transition to the extension phase

Pregnant Women- Pregnant women who meet all of the following criteria are eligible for enrollment as study participants: 1. Age 18 years or older 2. Able to understand the oral and written instructions associated with study visits and procedures and provide informed consent 3. Pregnant at any stage 4. Planning to give birth at a study-site designated center 5. Agrees to enroll offspring into the study at birth 6. In the case of multiple gestation, agrees to enroll only one child who will be selected by randomized birth order Biological Fathers- Biological fathers who meet all of the following criteria are eligible for enrollment as study participants: 1. Age 18 years or older 2. Able to understand the oral and written instructions associated with study visits and procedures and provide informed consent Pregnant Women- Pregnant women who meet any of these criteria are not eligible for enrollment: 1. Inability or unwillingness to comply with study protocol 2. Serious pregnancy complication (in the judgement of the investigator) prior to enrollment 3. Fetus has a major chromosomal anomaly 4. Plans to move and would not be available for in-person visits at a study site 5. Plans to give up her child for adoption at birth 6. Pregnancy is the result of an egg donation Infants- Infants who meet any of these criteria are not eligible for enrollment: 1. Delivered earlier than 34 weeks of gestation 2. Sibling already enrolled 3. Born with a significant birth defect or medical condition, and in the judgment of the investigators, participation is not in the infant's best interest Biological Father- 1. Biological fathers who are unable or unwilling to comply with the study protocol as it pertains to the biological father's participation are not eligible for enrollment ----Note Regarding Legal Guardians who are not the Biological Parents: 1. At screening for enrollment of either the mother or the child, if the biological mother intends to give the infant up for adoption, neither the mother nor the child are eligible for enrollment 2. If the biological mother gives up legal guardianship of the child during the child's follow-up period, the child may remain enrolled as long as the new legal guardian:
• Agrees to meet the child's study requirements, and
• Provides written informed consent for the child's continued participation. 3. Throughout the protocol where it refers to the mother, father, or parent answering questionnaires about the child or collecting samples from the child and the child's primary home, the legal guardian who provides consent for the child's participation may complete those procedures

Inclusion Criteria for Aim 1:
• : Adults (>18 years) with no known liver pathology
• Obese volunteers: Adults (>18 years), no known liver pathology, body mass index (BMI) ≥ 35
• Patients: Adults (>18 years) with known cirrhosis and known Gastroesophageal varices Exclusion Criteria for Aim 1:
• contraindications to MRI
• hypersensitivity reactions to both contrast agents
• patients with recent treatment for varices with embolization, TIPS, or other endovascular treatment
• patients with active GEV bleeding; known occlusive thrombus in portal vein, splenic vein, or superior mesenteric vein.
• patients with large HCC with known PC involvement. Inclusion criteria for Aim 2-4:
• Adults (>18 years) with known cirrhosis scheduled for EGD to assess for GEV. Exclusion Criteria for Aim 2-4:
• Contraindications to MRI
• Recent treatment (< 1 year) for varices
• recent (< 1 year) GEV bleeding
• Known occlusive thrombus in portal vein; splenic vein, or superior mesenteric vein
• Large hepatocellular carcinoma (HCC) with known PV involvement
• hypersensitivity reactions to both contrast agents

1. Willing to provide informed consent. 2. Willing to comply with all study procedures and be available for the duration of the study. 3. Ability to take oral medication. 4. At least 18 years of age. 5. Leukoplakia study groups: 1. Leukoplakia due to hyperkeratosis with dysplasia: biopsy-confirmed diagnosis of hyperkeratosis with dysplasia. 2. Leukoplakia due to hyperkeratosis with no dysplasia: biopsy-confirmed diagnosis of hyperkeratosis with no dysplasia. 6. Control group: Laryngoscopy showing no evidence of vocal fold mucosal disease. 1. History of malignant vocal fold mucosal pathology. 2. History of metabolic or liver disorder. 3. History of anorexia or bulimia. 4. Pregnant, lactating, or planning on becoming pregnant during the study period. 5. History of >4.5 kg weight loss in the past 90 days. 6. Medical or other inability to complete an 8 hour fast. 7. Acute respiratory or gastrointestinal illness. 8. Currently incarcerated. 9. Impaired decision-making capacity. 10. No or limited English speaking ability; illiterate or low-literacy ability. 11. Profound visual or hearing impairment that limits written or verbal communication. 12. Status relationship with a member of the study team. 13. Not suitable for study participation due to other reasons at the discretion of the investigators.

• Middle-age adults free of overt chronic disease
• Willing to provide informed consent
• Willing to comply with all study procedures and be available for the duration of the study
• Able to use and be contacted by telephone
• Ability to take oral medication
• Not planning to change diet or physical activity status
• Adequate organ function as indicated by standard laboratory tests: hematology (complete blood count), and clinical chemistry
• Males must agree to avoid impregnation of women during and for four weeks after completing study visits through use of an acceptable method of contraception
• Heart disease (history, abnormal ECG)
• Cerebrovascular disease (history)
• Cancer or less than 5 years in remission (history)
• Chronic respiratory disease (history, FEV1/FVC < 70, FEV1 < 80% predicted)
• Chronic liver disease (history, abnormal blood liver panel, ALT >104 IU/L, AST >80 IU/L)
• Diabetes (history, HbA1C ≥ 6.5, fasting blood glucose≥126 mg/dl, OGTT ≥ 200 mg/dl at 2 hrs.)
• Alzheimer's (history)
• Chronic kidney disease (history, abnormal blood kidney panel including serum creatinine>1.4, eGFR≤60 ml/min/1.73m2)
• Problems with bleeding, on medication that prolongs bleeding time (if subject cannot safely stop prior to biopsy)
• Taking azathioprine (Imuran), cyclosporine (Gengraf, Neoral, Sandimmune), dexamethasone (Decadron, Dexpak), methotrexate (Rheumatrex, Trexall), prednisolone (Orapred, Pediapred, Prelone), prednisone (Sterapred), sirolimus (Rapamune), and tacrolimus (Prograf) or other medications proposed to lower the immune system
• Taking strong or moderate CYP3A4 and/or P-glycoprotein (PgP) inhibitors such as ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole, amprenavir, fosamprenavir, aprepitant, erythromycin, fluconazole, verapamil, diltiazem
• Taking strong CYP3A4 activators such as phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital
• Subjects who are not willing to restrict the use of grapefruit, grapefruit juice, cannabidiol (CBD) and other foods/substances that are known to inhibit cytochrome P450 and PgP activity and may increase everolimus exposures and should be avoided during treatment
• Subjects who are not willing to restrict the use of St. John's Wort (Hypericum perforatum) because it may decrease everolimus exposure unpredictably.
• Subjects who are not willing to avoid blood donations 8 weeks prior to the first visit and 8 weeks after the last visit
• Low white-blood cell count (<4,000 cell/µL)
• History of stomatitis or ulcers in the mouth
• Those on glucose lowering drugs
• Participating in intensive exercise training program (high to moderate intensity exercise greater than 150 minutes per week) or planning to start new exercise program during study period
• Tobacco use
• Allergies to lidocaine, sirolimus, or everolimus
• Subjects currently enrolled in other clinical trials. Subjects may be eligible after a washout period that will be reviewed on a case-by-case basis.
• Individuals with limited English proficiency
• Subjects who are planning to have elective surgery 12 weeks prior to or during the intervention

Neonate
• Delivered at ≥ 35 weeks of gestation
• <12 hours of age
• Inpatient at Meriter Hospital, Inc. NICU or Newborn Nursery or AFCH PICU or NICU
• Diagnosed as at risk for CoA Neonate
• Major congenital anomalies of the kidney
• Attending physician's discretion to not place sensors due to clinical concerns
• In the researcher's medical opinion, there is a significant likelihood that the neonate would not survive the first 3 days of life Primary Caregiver
• Able to understand and the willing to sign a written informed consent document
• Willing to comply with all study procedures and be available for the duration of the study
• Birth parent (i.e., the parent who gave birth to the baby) who is the primary caregiver of a neonate who is eligible to participate in study
• Agrees to enroll neonate into study
• Aged 15 years or older
• Pregnant mother with a baby diagnosed prenatally as at risk for CoA will be eligible for the study. They must also meet the following criteria:
• Require an "arch watch care plan" as a results of prenatal ultrasonography findings
• Agree to enroll offspring into the study at birth Primary Caregiver
• Subject is unable to provide informed consent, including subjects who are in foster care and subjects within state custody
• Pregnant woman who does not plan to maintain custody of the child after birth, such as instances of adoption or surrogacy Newborn Nursery Nursing Staff:
• All Newborn Nursery nursing staff at Meriter Hospital, Inc.'s Newborn Nursery are eligible to participate

1. Participant and/or parent guardian must be able to understand and provide informed consent 2. Children ages 4-12 years of age 3. Cohort 1: Family is self-identified as Plain community member 4. Cohort 2: Madison-area children with parental report of doctor-diagnosed asthma 5. Cohort 3: Madison-area children with no history of asthma by parental report 6. Cohort 4: Madison-area children who have an active respiratory illness 1. Inability or unwillingness of a participant to give written informed consent or comply with study protocol 2. Chronic sinusitis (frequent sinus infections) 3. Plans to move out of the area before completing the study 4. Past or current medical problems or findings from physical examination or laboratory testing that are not listed above, which, in the opinion of the investigator, may pose additional risks from participation in the study, may interfere with the participant's ability to comply with study requirements or that may impact the quality or interpretation of the data obtained from the study 5. Enrolled family member

Key
• Participants who reside in areas with endemic Lyme disease and who lead lifestyles that put them at increased risk for Lyme disease. For example, this could include, but not be limited to:
• Individuals who work in B burgdorferi-infected/tick-infested areas, especially those with occupations that may be associated with higher risk of exposure, such as landscaping, forestry, and wildlife and parks management.
• Individuals who pursue recreational activities such as hiking, camping, fishing, hunting, jogging, or gardening in such areas.
• Individuals who live on land plots with tree lines and come into contact with these trees regularly.
• Individuals who have dogs that regularly are outdoors and frequently return with attached ticks.
• Individuals who participate in activities in areas with tall grass, smaller wooded areas beside forests, open fields, lakesides, and riversides. Key
• Any female participants that are pregnant (or have a positive urine pregnancy test) or are breastfeeding.
• Any diagnosis of Lyme disease within the past 3 months.
• Any history of Lyme carditis, neuroborreliosis, or arthritis, or other disseminated Lyme disease regardless of when diagnosed.
• Known tick bite within the past 4 weeks.
• Newly developed or unstable underlying conditions that may interfere with the assessment of Lyme disease, including but not limited to chronic arthralgia/arthritis, second/third-degree AV heart block, chronic pain syndromes, and chronic skin conditions that reduce the ability to detect cutaneous manifestations of Lyme disease.
• Any unstable autoimmune condition with a manifestation (eg, arthritic and neurologic) that may interfere with the assessment of Lyme disease.
• Chronic systemic doxycycline or minocycline or other tetracycline class drug use for acne or any other chronic suppressive antibiotics used to treat other conditions.

• Ability to understand and the willingness to sign a written informed consent document
• Individuals with no health concerns that might affect the outcome of the study
• Age 18-75 years of age
• Ability to tolerate a simulated MRI brain scanning session
• In the opinion of the investigator, capable and willing to grant written informed consent and cooperate with study procedures and requirements
• High-affinity TSPO-binding genotype. Mixed (high/low) binding-affinity genotype may be included at PIs discretion
• For participants with severe asthma:
• Physician diagnosis of asthma for at least six months prior to screening (can be determined at the discretion of an asthma/allergy physician member of the study team)
• Severe asthmatics must meet the ATS definition of severe asthma and/or be currently receiving a GINA 5 therapy (or greater), which may include ongoing use of currently approved biologic immunomodulators
• Current smoker (defined as more than 0.5 pack per week for the past 6 months and any smoking within two weeks of study procedures) or has a smoking history exceeding 5 pack years within the last 10 years
• Currently receiving immunotherapy
• Use of psychotropic medication that might affect function of neurocircuitry implicated in our hypotheses (at the discretion of the PI/Co-I)
• Inability to hold medications detailed in the medication hold schedule
• Needle phobia or claustrophobia
• Major health problems such as autoimmune disease, history of carotid stenosis, heart disease, uncontrolled hypertension, or lung diseases other than asthma, history of significant arrhythmias, and any of the following in the last 6 months: stroke/TIA, myocardial infarction, stent placement, or acute coronary syndrome. The listed health problems are definitively exclusionary, but decisions regarding major health problems not listed will be based upon the judgment of the investigator
• Use of biologic medication that might affect signaling pathways under investigation (at the discretion of the PI/Co-I)
• Pre-existing chronic infectious disease
• Scheduled use of non-selective beta-blockers prior to each study visit.
• Use of an investigational drug within 30 days of entering the study. This criterion will be reviewed on a case by case basis by the PI/Co-I to determine appropriate washout period. Appropriate wash out period may be greater than 30 days depending on the half-life of the investigational drug. Participants may be eligible for study participation after completing the washout period designated by the PI or Co-I (physician only).
• Any MRI incompatibility as determined by most current MRI screening form
• History of a diagnosed bipolar disorder, schizophrenia, or schizoaffective disorder
• History of serious head trauma or seizure disorder (can be included at the discretion of the PI or Co-I)
• Unable, in the judgement of the investigator, to comply with directions and/or tolerate the procedures required for participation in this study
• Pregnant or breast-feeding or has a planned pregnancy during the course of the study
• Any other medical condition or disease that would impact participant safety or data integrity in the opinion of the PI/CO-I