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Key
Concepts
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Virtually all-human diseases result from the interaction
of genetic susceptibility and modifiable environmental factors,
broadly defined to include infectious, chemical, physical,
nutritional, and behavioral factors.
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Slight variations in genetic makeup called Single Nucleotide
Polymorphisms (SNPs—pronounced "snips") are
associated with almost all diseases.
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Genetic variations themselves do not cause disease but rather
influence a person’s susceptibility to specific environmental
factors that increase disease risk.
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Genovations™ offers a unique line of Predictive Genomic
Diagnostic Profiles. Each profile focuses on a carefully
selected set of SNPs associated with a particular disease
or physiologic imbalance (e.g. cardiovascular, bone metabolism,
detoxification, immune surveillance, etc.).
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Though many SNPs can be related to a particular disease
or function, not all are clinically useful. To assure clinical
value, Genovations™ profiles assess only SNPS that
meet four critical requirements:
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Relevant- The activity of individual proteins and enzymes
can be simultaneously coded by tens or hundreds of SNPs.
Genovations™ SNPs are carefully selected based
on their direct influence over specific biochemical
imbalances which create known symptom clusters or diseases.
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Prevalent- Genovations™ SNPs carry clinically significant
population prevalence. These are relatively common genetic
predispositions associated with extremely prevalent
conditions.
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Modifiable-. Genovations™ profiles focus on genetic
variations whose expression is influenced by environmental
factors. Each profile contains intervention options
based on the patient’s genomic pattern. Commentary
provides specific risk reduction strategies, including
dietary, nutritional, lifestyle, and pharmaceutical
interventions.
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Measurable- For each SNP, Genovations™ profiles
provide recommendations for follow-up functional laboratory
testing. These functional assessments evaluate and monitor
phenotypic expression of genetic tendency, functional
integrity, and metabolic reserve.
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Genovations™ profiles can be applied to three broad
areas of clinical relevance.
I.
Genomic Testing for Challenging/Refractory Cases- for chronic
diseases that arise from multifactorial etiologies
II. Familial Association Testing- for identifying inherited
risks within families
III. Predictive Genomic Testing- for more precise, proactive
health risk screening
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How will genomics transform medicine? |
Introduction
to Clinical Genomics
The concept of "biochemical individuality" was first
proposed by Roger Williams in 1956 to explain variability in
disease susceptibility, nutrient needs, and drug responsiveness
among otherwise seemingly healthy people. It is only in the
wake of the ongoing genomic revolution, however, that predictive
genetic testing has become available to allow us to assess true
biochemical individuality. For the first time, physicians can
gauge with increasing precision who is more likely to develop
specific diseases, who will respond favorably (or react adversely)
to a particular drug or supplement therapy, and finally, which
nutrients are optimal for a particular individual’s health
and well-being.
Genetics is the scientific study of heredity, one gene at a
time. Genomics is the study of genomes, or the totality of the
DNA of a single species. While genetics studies the laws of
inheritance in an isolated and linear fashion, Genomics attempts
to look at all our genes together as a flexible, dynamic system
over time, interacting with and influencing our biochemical
pathways and physiology.
The Human Genome Project is the mapping and sequencing of the
entire human genome. The first draft of the entire human genome
was published in April 2001, almost exactly one hundred years
after the rediscovery of Mendel’s "Laws of Heredity."
The human genome consists of slightly more than 3 billion nucleotides
(give or take a hundred million) and it codes for every protein
and every enzyme made by the human body. Some 30,000 to 40,0000
thousand genes are thought to exist in the human genome, yet
we know the function of slightly less than half of those genes.
As primary care practitioners, we stand at a critical crossroads
where increases in availability of DNA-based testing and demand
by patients for genetic information and advice necessitate our
need to become both genetically literate and genomically competent.
The power to read and understand the genetic code of individuals
will prove to be every bit as great an advance in clinical diagnostics
as when Robert Hooke’s breakthroughs with the microscope
enabled him to discover that living organisms were made up of
"cells."
New methods of investigating the genome are now being aimed
at better understanding the multifactorial etiology of the most
prevalent and debilitating health conditions that humans face—opening
up the potential for astounding clinical applications.
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What is the function of DNA? |
 How
Genes Work
Deoxyribonucleic acid (DNA) is the chemical inside the nucleus
of a cell that holds the genetic instructions to create living
organisms. DNA has three known functions:
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DNA replicates itself
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DNA codes for RNA which in turn codes for proteins (the
primary building blocks of the cell, the tissues, and the
body)
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DNA regulates gene expression, allowing for
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Cell growth
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Cell differentiation
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Cell replication
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Programmed cell death
The
structure of DNA is complementary. It is built from deoxyribose
(a sugar), phosphate groups and four nucleotides or bases: adenine,
cytosine, guanine, and thymine (mercifully abbreviated to A,
C, G, and T). Adenine can only bind with thymine, and cytosine
can only bind with guanine, producing the complementary structure.
The 3-dimensonal structure of DNA is like a ladder that has
been twisted around its vertical axis: the deoxyribose and phosphate
form the ‘rails’ of the ladder, while pairs of A &
T and C & G form the ‘rungs’. The advantage of
the complementary structure is simply that the DNA ‘ladder’
can split with each half binding to complementary nucleotides
in order to make two perfect copies of the original DNA.
This is no small feat. If all the DNA in a single human cell
were unraveled and stretched out into a straight line, it would
measure about 2 meters (6 feet). Given the 100 trillion or so
cells in your body, if all the DNA in all your cells were stretched
out in a straight line, it would reach to the sun and back…
a thousand times.
Genes are those sections of the DNA that code for ribonucleic
acid, or RNA. The complementary binding of nucleotides to one
another allows DNA to code precisely. RNA delivers DNA's genetic
message to the cell cytoplasm, where proteins are made. RNA
is structurally similar to DNA except:
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RNA is single stranded;
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RNA uses the nucleotide uracil (U) in the place of thymine;
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RNA’s 3-nucleotide codons (think of them as "3-letter
words") code directly for specific amino acids, allowing
for the synthesis of proteins in ribosomes.
The
Genome Structure
"Imagine the genome is a book.
There are twenty-three chapters, called CHROMOSOMES.
Each chapter contains several thousand stories, called
GENES.
Each story is made up of paragraphs, called EXONS, which
are interrupted by advertisements called INTRONS.
Each paragraph is made up of words, called CODONS.
Each word is written in letters called BASES.
There are 1 billion words in the book which makes it longer
than… 800 Bibles."
–Matt Ridley. Genome: an Autobiography of a Species
in 23 Chapters. New York: Perennial, 1999.
Mendelian Inheritance |
Heredity
is dependent on the genes found within the entire genome. The
average gene is about 3,000 nucleotides long, but this can vary
considerably. Surprisingly, only about 3% of the human genome
is actually used by and for human physiology.
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How are traits inherited? |
The Laws of Heredity are few; their implications for life are
vast. The simplest genetic characteristics are those whose presence
depends on the genotype at a single locus; i.e., one gene controls
the expression of one characteristic. Such characters are known
as Mendelian, after their original discoverer, the Austrian
botanist Gregor Mendel. Over 10,000 Mendelian characters have
been identified in humans. In sum, Mendel’s Laws of Heredity
state that:
I. Each physical characteristic corresponds to a single gene
II. Genes come in pairs
III. Only one gene of the pair is passed on to the next generation
by each parent
IV. It is equally probable that either gene will be passed on
V. Some characteristics are "dominant" while others
are "recessive."
A trait (character) is dominant if it is expressed in the heterozygote
(only one of the chromosome pair carries the gene) and recessive
if it is only expressed in a homozygote (both chromosomes carry
the gene). Dominant and recessive are properties of traits,
not of genes themselves.
These pedigree patterns are not always as evident in humans
as in the pea plants that Mendel originally studied to define
these concepts. This is due to a number of confounding factors,
chief among them being incomplete penetrance. The penetrance
of a character is the probability that a person with the genotype
will manifest the dominant character. Other confounders include
delayed onset of late-age genetic disorders, multi-gene effects,
and variable expression of genes (different features of a single
genetic syndrome will appear in similarly affected individuals).
In addition, spontaneous mutations can occur where no pedigree
association exists.
Mendelian inheritance patterns were the first evidence to unlock
the mysteries of heredity. While 10,000 traits are known to
be Mendelian, at least as many traits are non-Mendelian. Height,
intelligence, personality, and a thousand more characteristics
of creatures are multifactorial – controlled by the interaction
of numerous genes, each independently assorted. Furthermore,
the same confounders for simple Mendelian inheritance (incomplete
penetrance, environmental influences, spontaneous mutations)
also occur in characteristics determined by multiple genes—but
their effects are exponentially multiplied.
Still, the Laws of Heredity have taught us much. They form the
basis from which we can begin to understand dynamic interactions
between genes within the genome and between the genome and the
environment.
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Which SNPs are clinically important? |
Clinical Genomics
A polymorphism is a variation in the DNA genetic code that occurs
in a subset of individuals. Polymorphic variation conveys greater
or less susceptibility toward specific diseases by improving
or impairing physiological function. The most common type of
polymorphism is known as a single nucleotide polymorphism (SNP)
in which, as we have said, a single nucleotide in a gene is
changed.
Genovations™ panels assess genetic polymorphisms, deletions,
and allelic variances- not expressive Mendelian traits. That
is, the phenotypic expression (trait) of each SNP we test does
not depend upon the dominant or recessive nature of the trait.
Rather, the potential strength of expression of a SNP often
depends upon whether it resides upon one chromosome (heterozygote
positive) or both chromosomes (homozygote positive), as well
as the environment to which it is exposed. (See the detailed
interpretation of a Genovations™ Profile results on page
XX.)
Currently, a consortium of private companies and governmental
agencies has set for itself the task of identifying and cataloguing
as many SNPs as possible and as quickly as possible in order
to keep this intellectual property within in the public domain
(since genetic variations are patentable under U.S. law). Their
goal is to identify 100,000 SNPs in the human genome by the
end of 2002.
SNP analysis may be critical for the complete understanding
of complex human diseases since certain genotypes (forms of
a gene) will be consistently associated with the development
of particular diseases – both acute and chronic. Aberrant
genes produce aberrant proteins and enzymes. By identifying
the genetic aberrations, we may come to a more complete understanding
of the molecular basis of diseases, from which novel therapeutics
may arise.
To this end, it has become increasingly important to identify
SNPs in individuals that confer greater risk or protection in
developing chronic diseases. Those SNPs that are most important
clinically are the SNPs that are relevant to the development
of common chronic diseases, that are prevalent to a reasonably
high degree in the general population, whose physiological effects
are modifiable using diet, nutritional intervention, lifestyle
changes and specific pharmacological intervention, and whose
phenotypic expression is measurable by laboratory analysis.
In other words, clinically important SNPs must be relevant,
prevalent, modifiable, and measurable.
Genovations™ predictive genomic testing is currently available
for numerous chronic diseases, including cardiovascular disease,
osteoporosis, detoxification impairments, and immunological
defects associated with gut associated lymphoid tissue (GALT)
and chronic inflammatory conditions. In each of these areas,
functional laboratory testing also exists which allows the practitioner
to assess the dynamic integrity and metabolic reserve of associated
physiological systems. The combination of genomic SNP analysis
and functional laboratory testing thus provides a novel, effective,
and comprehensive method for assessing genetic risk, phenotype
expression, and physiological function.
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Who can benefit from genomic testing? |
A natural consideration at this point is: "Which patients
would benefit most from predictive genomic diagnostics?"
Currently, three broad areas of clinical genomics are rapidly
advancing. These focus on genomic testing for:
I. Challenging/Refractory Cases- for patients with chronic diseases
characterized by multifactorial etiologies
II. Familial Association Testing- for patients with a family
history of a specific chronic disease who want to identify their
inherited risks
III. Predictive Genomic Testing- for proactive patients who
desire earlier, more precise health risk screening
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I. Genomic Testing for Challenging/Refractory Cases
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What causes disease and chronic illness? |
The treatment of challenging conditions (e.g. chronic fatigue
syndrome, irritable bowel syndrome, fibromyalgia, premenstrual
syndrome, etc.) requires immense diagnostic prowess and clinical
expertise. What were once viewed as a "symptom clusters"
of unknown origin are now understood to be the result of the
failure of primary metabolic or physiologic mechanisms. Patients
with chronic conditions who have been refractory to traditionally
effective treatment are excellent candidates for Genovations™
panels.
Virtually all-human diseases result from the interaction of
genetic susceptibility factors and modifiable environmental
factors, broadly defined to include infectious, chemical, physical,
nutritional, and behavioral factors.
While SNPs are also known to play a role in the development
of many chronic diseases, genetic variations themselves do not
cause disease. Rather, SNPs influence a person’s susceptibility
to environmental factors. By examining conditions like heart
disease, allergies, chromic fatigue, and osteoporosis, we can
demonstrate how genetic testing for SNPs can play an enormous
adjunctive role in developing targeted interventions for these
common clinical conditions.
SNPs that influence important biochemical pathways can alter
critical health-supporting functions. Consider the body’s
detoxification capacity and its ability to maintain proper immune
surveillance. Multiple variations in the genes that code for
cytochrome p-450 enzymes, as well as glutathione-s-transferase
and N-acetyl transferase, have been identified and are known
to play important roles in adverse drug reactions, drug resistance,
as well as the development of complex syndromes like multiple
chemical sensitivity and cancer. This potential may be modulated
by the body’s burden of oxidative stress.
Alterations
in immune parameters can be identified through SNPs that affect
the production of interleukins and TNF-a. Genetic up-regulation
of the production of these cytokines can lead to a TH-2 dominant
state with increased incidence and severity of chronic inflammatory
disorders such as irritable bowel disease and allergies.
The phenotypic expression of SNPs can frequently be modified
through targeted dietary and lifestyle choices, clinical nutrition,
and judicious pharmacological intervention. Alternative biochemical
pathways can also be supported to minimize the phenotypic impact
of defective enzyme systems. Furthermore, functional laboratory
testing is available to monitor the phenotypic modifications
in physiology elicited by these interventions.
A person’s genetic predisposition will never change. What
can be altered is the environmental, biochemical, and phy
siological
factors that influence the expression of those genes.
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Why test patients with a family history of disease? |
II.
Familial Association Testing
Patients with a "family history" of chronic illnesses
like heart disease, osteoporosis, chronic fatigue, or inflammatory
disorders are particularly good candidates for Genovations™
predictive genomic diagnostics. The specter of genetic determinism
looms large in the public consciousness – most people are
convinced that our genes are our fate. Nothing could be further
from the truth. In fact, phenotypic expression of genomic determinants
is largely modifiable. It is becoming increasingly evident that
who we are as individuals is a function of both our genetic
make up and the environment to which we subject our genes.
In many cases, the genetic variations we inherit are neither
inherently "good" nor "bad", but depend
upon the environmental context in which they occur. A familial
genetic variation which causes blood to clot excessively, for
example, may help protect the body in times of hemorrhage, but
may increase the risk of life-threatening thromboses as a person
ages. A genetic variation that protects the body in times of
starvation by allowing it to conserve more energy (fat), may
increase the risk of obesity, heart disease, and diabetes when
it is chronically exposed to a modern Western lifestyle and
diet. Testing specific genetic factors in patients with a family
history of a chronic illness, then, allows us as practitioners
to determine which environmental contexts may pose the most
severe risk for these patients.
Consider the following analogy. It would be very difficult for
patients to win at poker if they were never allowed to see what
cards they had been dealt. They would have no way of knowing
which cards to keep or which cards to discard. Similarly, until
patients understand their genetic strengths and weaknesses (and
gain your counsel relative to prevention/therapeutic strategies),
they won’t know how to play the genetic ‘hand’
life has dealt them. Without that information, there will be
no clear way of knowing if clinical interventions are addressing
their most important individual risks and needs.
From another perspective, a patient’s genes come from their
parents, are shared (to a high degree) with their siblings,
and are passed on to their children. Thus, an individual’s
genetic polymorphisms are likely to be shared by other family
members as well. In that sense, all genetic tests are, by definition,
familial. For this reason, patients with positive SNPs may choose
to share this information with immediate relatives (parents,
siblings, and children) to encourage proactive genomic testing.
By identifying SNPs years before a disease has a chance to develop,
family members can take steps to potentially modify their expression
and minimize their health impact.
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How can testing improve preventive therapy? |
III.
Predictive Genomic Testing
We do not inherit a disease state per se. Rather, we inherit
a set of susceptibility factors to environmental influences
that modify the risk of developing a disease.
Genetic susceptibility factors help explain why individuals
are affected differently by the same environmental factors.
For example, some health conscious individuals with "acceptable"
cholesterol levels suffer myocardial infarction at age 40. Other
individuals seem immune to heart disease in spite of years of
smoking, poor diet, and obesity. Genetic variations account
for, at least in part, this difference in response to similar
environmental factors.
Many patients are choosing to become more proactive about their
health. Why? Again, because, in large part, diet, nutrition,
and lifestyle factors can exert a strong influence on how, or
even if, a gene will express itself. Knowing about increased
risk (and specific risk reduction strategies)—and knowing
about them as early as possible—is the first step towards
an effective primary prevention program.
Through carefully targeted dietary, nutritional, and lifestyle
changes, as well as pharmacological therapies, it is often possible
to modify the expression of genes and to overcome genetic limitations
of biochemical pathways. Predictive genomic testing allows us
to be smarter clinicians, ones who can offer our patients more
effective, customized therapeutics with fewer unwanted side
effects. Furthermore, these therapeutic gains are clearly measurable
through follow-up functional laboratory testing.
The genomic revolution is happening now. Medicine will never
be the same. A new era of truly individualized medicine is rapidly
becoming a clinical reality for practitioners and their patients.
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What are the risks and benefits? |
A Few Considerations
Bioethics
In every new paradigm shift in medicine, ethical issues arise,
as they should. Genomic testing is no exception. Ethical concerns
are likely to vary depending on the type of genetic testing
performed. A distinction should be made between diagnostic and
predictive genomics.
In diagnostic genomics, the signs and symptoms of an individual
are due to the presence of a (usually Mendelian) genetic condition.
By definition, symptoms are already present; the genetic testing
is an attempt to explain the condition. This is true of someone
with refractory high cholesterol levels as well as someone with
who has symptoms consistent with cystic fibrosis.
In predictive genomics, there may be no clearly definable symptoms
or syndrome since testing may be utilized to predict the risk
of developing some future condition. Effective therapeutics
may be available and primary and secondary preventative strategies
may be attempted. Precision in predictive genomics depends on
numerous factors: the penetrance of the mutation, polygenic
synergy, and environmental co-factors that affect gene expression.
The current general consensus is that every individual has the
right to seek genetic information. That right must remain inviolate.
However, the person seeking genetic information should be encouraged
to share and discuss the information acquired with other family
members, since their risk may also be affected.
It is the duty of the practitioner to inform each patient of
the risks and benefits associated with genetic testing. The
practitioner should present the pros and cons as objectively
as possible without trying to sway the patient. Such objectivity
is known as non-directive counseling. A general concern for
the patient may be: "Does the stress of knowing he or she
has a genetic anomaly outweigh the benefits of knowing?"
Fortunately, in functional genomic testing, practical intervention
strategies are available and genetic diagnosis will likely do
far more to relieve stress rather than to increase it. Furthermore,
phenotypic or physiologic progress may be monitored using functional
laboratory testing. Genovations™ predictive genomic diagnostics
may be the first step towards comprehensive risk reduction or
comprehensive treatment strategy.
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Is patient privacy protected? |
Confidentiality
Genovations™ is dedicated to safeguarding patient privacy and the
confidentiality of all patient information. For this reason, your genetic
test results are protected by a security code that is disclosed only to the
health care provider who ordered your test. Your information otherwise will
only be utilized internally for company operational purposes and as required
by law. Your records, electronic and hard copy, will be maintained under a
strict policy of confidentiality.
Our laboratory will not release any patient records or details
pertaining to services provided to any patients with any person
outside the Laboratory, including insurance companies, unless
expressly authorized by the patient through their practitioner.
Additional resources for information related to privacy of genomic information:
THE GENETIC PRIVACY ACT AND COMMENTARY
George J. Annas, JD, MPH - Leonard H. Glantz, JD - Patricia A. Roche, JD
http://www.bumc.bu.edu/www/sph/lw/pvl/act.html
Principles of Screening: Report of The Subcommittee on Screening of the American College of Medical Genetics Clinical Practice Committee
American College of Medical Genetics
http://www.faseb.org/genetics/acmg/pol-26.htm
Does Genetic Research Threaten Our Civil Liberties?
By Philip Bereano, Ph.D., J.D.
http://www.actionbioscience.org/genomic/bereano.html
Ethical Issues in Pharmacogenetics
By Carol Isaacson Barash, Ph.D.
http://www.actionbioscience.org/genomic/barash.html
The Next Step
Until now practitioners have been able to measure is pathology,
function, and environmental aspects of phenotype. Now, with
the advent of Genovations™ predictive genomic diagnostics,
practitioners can measure genotypic predisposition to many
illnesses as well. For the first time in the history of human
medicine, we can now truly measure the genetic predeterminants
of an individual’s health. Medicine can assuredly never
be the same. As a clinician committed to using the most specific
and effective clinical diagnostics for your patients, the
time to begin utilizing genomic testing and intervention strategies
is now.
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Sources
Office of Genetics and Disease Prevention:
Gene-Environment Interaction Fact Sheet. Atlanta, GA: Centers
for Disease Control and Prevention, 2000. Available at http://www.cdc.gov/genetics/info/files/text/GeneEnviro.pdf
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©2002 Genovations™, a product of Great Smokies Diagnostic Laboratory
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