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Flashcards in Precision Med Deck (29):
1

Types of Oral Samples

Whole Saliva (stimulated/unstimulated)
> Stimulated - spit into a tube after chewing non flavored gum to stimulae salivation from mainly the parotid glands
> Unstimulated - is pretty much just drooling and comes from parotid and sub mandibular

Duct Saliva - from salivary ducts

Gingival Crevicular Fluid - Not a lot of it - taken from a paper point and only end up with 1 micrometer (closely related to blood - more so than saliva)

Mucosal Transudate - Moist and slimy texture of cheeks; mixture of saliva and vascular fluid from small capillaries (take in substances or out from the blood)

Buccal Swabs for DNA testing

Plaque - toxins can reside in dental plaque (fun fact)

Volatiles - volatile molecules present in for example, with cancer or other systemic diseases

2

Transmission/Diagnostics

- HIV (though proven its not in saliva although a series of proteins in saliva are anti HIV active - one identified and they made a drug out (DMDT-1 protein) HIV in hypotonic solution, it will lyse RBCs AND the virus

-Strep Throat

- Flu

- Herpes

- Zika

3

Why develop oral/salivary diagnostic tests?

-Non-invasive
- Safe
- User friendly
- Cost effective
-Field studies
-Home testing
-Special populations

4

Widely used Oral Tests

HIV
Herpes
Candidiasis
HPV
Kaposi's sacroma
Mononucleosis (EBV)
Flu
Strep throat

5

Preventing HIV

-Education
-Behavior
- Vaccine
- Microbicides
- Test and Treat
- PrepExposure Prophylaxis (PrEP)

6

PrepExposure Prophylaxis (PrEP)

Oral anti-retroviral provided 70-90% protection

- approved for high risk MSM populations
- long-active vaginal rings and injectable products being developed

7

HIV rapid testing

- Currently excellent screening tests available for antibodies to HIV-1 and HIV-2
- test results in 20 minutes
- positive test results require a confirmatory test
- ideally want a combined screening and confirmatory test

8

Rapid Screening + Confirmatory Test

- Ideally, want to detect:
1. anti- HIV antibodies
2. HIV antigen
3. HIV RNA
- Combine screening test with a confirmatory test
- narrow the seroconversion window
- less stress on subject with immediate access to care/treatment

9

4th Generation HIV Test

- Measures antibodies to HIV and p24, a viral antigen
- First FDA approved test was the Abbotts Architect HIV Ag/ Ab
- Decreases the seroconversion window to ~12 days
- important because individuals are 10-20 times more infectious during the early infection

10

Dealing with the HIV pandemic

- Theurapeutics - HAART
- Vaccines/microbicides/ PrEP
- Treatment of opportunistic infections
- Identification of reservoirs
- Behavior modification
- Natural Defenses: Exposed uninfected elite controllers long term non-progressors

11

Target Analytes

HIV- antigen or antibody plus RNA
Malaria - DNA
Zika - Antibody plus RNA

12

Point of Care (POC) HIv Diagnosis

- Current POC tests are screening which detect antibodies to HIV but require a confirmatory test which takes days-weeks

- goal is to create a combined screening and confirmatory test using blood or saliva with results in less than 1 hours
- confirmatory tests use PCR or isothermal amplication (LAMP)

13

Diagnosis of Malaria

- currently tests rely on blood smears
-time consuming and requires trained personnel
- existing POC tests for antigen are insensitive and signal persists
- POC "Test and Treat" using blood/saliva to detect P. falciparium/P vivax followed by treating all positives

14

Zika Overview

-A member of the flavivirus genus
- First isolated from a monkey in 1946 in the Zika forest in Uganda
- Generally infection is asymptomatic
- Transmitted by mosquitos and sexual transmission (virus persists in semen)
- Zika disappears from blood in 7-10 days
- Persists longer in saliva and urine

15

Saliva

• Facilitates physiologic functions of:
- tasting and swallowing food
- antibacterial and antiviral protection of oral
structures
- tissue lubrication

• Contains enzyme, hormones, antibodies, cytokines, antimicrobial, and other biomarkers

16

Periodontal Disease

• Most common cause of tooth loss in the world
• More than 50% of Americans are affected
• Associated with such systemic diseases such as DIABETES, CARDIOVASCULAR DISEASES, OSTEOPOROSIS, ARTHRITIS, ALZHEIMER'S DISEASE, GASTRIC CANCER

17

Periodontal Disease Progression

1) Genetic predisposition
2) Infection
3) Inflammation with tissue degradation
4) Clinical findings of peridontal pockets and alveolar bone loss

18

Personalized Medicine

• Salivary diagnostics is a rapidly evolving discipline with conflicting data and challenges of statistical sensitivity and specificity

• As research is translated into clinical application, clinicians will use this technology to provide patients with personalized care

19

Microbiome - Initiator Biomarkers

• Bacterial initiators for Periodontal Disease Progression include:
- the "RED COMPLEX" pathogens:
> Treponema denticola
> Porphyromonas gingivalis
> Tannerella forsythia

• Other pathogens able to predict PDP:
- Fusobacterium nucleatum
- Campylobacter rectus
- Prevotella intermedia

20

Host-Response Inflammatory Mediators/Tissue Degradation Enzymes

• IL-1B
• MMP-8
• MMP-9
• ALT (alanine aminotransferase)

21

Tissue Degradation Enzyme/Microbiome Study

• 18 month longitudinal study
• P. Gingivalis and P. Intermedia – likely to predict loss of attachment and loss of bone
• Combination of ALT and P. gingivalis – most likely to predict loss of attachment

22

Microbiome/Host-Response Inflammatory
Mediators/Tissue Degradation Enzymes Study

• 100 patients followed for 12 months
• 6 months disease monitoring phase: OHI & prophy
• SRP intervention to test group
• 6 months recovery phase post-SRP
• During recovery phase, they found:
o Decreased MMP-8, MMP-9, IL-1B
o Decreased all bacterial pathogens

23

Goal of Biomarker Research

• Find a combination, a panel/signature, of biomarkers that can predict periodontal tissue destruction prior to the destruction occurring
• This panel would be used by clinicians to guide them in choosing an intervention that is both timely and appropriate in magnitude

24

Signature Metric Study

• Cross-sectional study aimed at finding a metric of active periodontal disease

• Looked at a “signature” of P, gingivalis, IL-1B, and MMP-8 to see if there was a correlation between this signature and traditional measures of
periodontal disease

• Found that this signature was strongly associated with periodontal disease

• This was only done on Scandinavian patients

25

British Study (2017)

Longitudinal study of 77 British patients

Looked at a signature of two host responder degradation enzymes (MMP-8 and elastase) and one red complex bacterial produced enzyme (sialidase) and the red complex microbiome

26

Salivary Diagnostics Conclusions

• ONE biomarker does NOT diagnose periodontal disease

• PANELS of biomarkers needed to predict PDP

• DIFFERENT biomarker signatures connote different periodontal disease
o Examples of different disease signatures:
(A) MMP-9, IL-1B, P. gingivalis
(B) MMP-9, IL-1B, P. gingivalis, diabetes
(C) MMP-9, IL-1B, P. gingivalis, diabetes, smoker

27

What to do about personalized medicine?

• Conduct pre-test counseling to educate patients about gene penetrance, biomarker sensitivity and specificity, obligations to relatives, privacy and confidentiality
• Provide patients with informed consents explaining these concepts
• With informed consent, provide post-test counseling on the findings, like carrier status, that would affect reproductive decision-making
• With informed consent, provide post-test counseling on findings that would motivate actionable changes in behavior

28

AXIN2 Gene

• SNP of this gene is linked to tooth agenesis

• It is also linked to breast, ovarian, and colorectal cancer

• Ex: see a patient missing both maxillary lateral incisors
o Congenitally missing and had implants placed
o Patient has 1 sister and 1 brother and 1 daughter
o How much information about cancer risk should the dentist share with the patient about the AXIN2 gene? What about the siblings and child? What is your ethical/legal obligation?

29

Orr-Shelton Model of Resolving Clinical Ethical Dilemmas

• Gather demographic data (name, DOB, etc.)
• Formulating ethics question (capture ethical dilemma in question form)
• Assessment (of clinical and ethical situation)
• Discussion (identify ethical principles relevant and apply them to the dilemma)
• Recommendations (provide coherent path for moving forward and identify boundaries for appropriate clinical action)