ngs for infectious disease diagnostics: an opportunity for growth

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Page 1: NGS for Infectious Disease Diagnostics: An Opportunity for Growth

© 2016 CMC Consulting Group. All Rights Reserved.

Your Global Partner for Growth in Healthcare

LEARN MORE www.cmc-co.net

Next Generation Sequencing (NGS) for Infectious Disease

Diagnostics: An Opportunity for Growth

Osman Aijazi Management Consulting Division

Page 2: NGS for Infectious Disease Diagnostics: An Opportunity for Growth

Osman Aijazi

CMC Consulting Group

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INTRODUCTION

TYPES OF DNA MUTATIONS11

Next generation sequencing (NGS) has emerged as a new technology positioned to solve the challenges of traditional diagnosis. Conventional diagnostic techniques, which rely on proper pathogen identification, are not capable of diagnosing every patient and cause many laboratories to experience difficulties in clinical diagnosis of infectious diseases. As personalized medicine paves the way of new medical developments, NGS will present new opportunities for companion diagnostics across the medical spectrum. This paper serves as an overview of the innovative solutions addressed by NGS, the current status of the market and associated business opportunities.

BACKGROUND OF DNA SEQUENCING

The human genome contains the secrets to understanding every aspect of the human body. Cracking the code of the genome has been a scientific holy grail, the obtainment of which has revolutionized science and medicine. The human genome contains deoxyribonucleic acid (DNA), a double-helix structure comprised of nucleotide base-pairs11 which carry the genetic instructions used in the development and function of all living organisms.11 By sequencing the DNA samples of their patients, clinicians can understand the formation of genes and identify abnormalities. DNA sequencing is the process by which researchers use laboratory techniques to determine the order of nucleotide bases in gene formation.1 The human genome contains approximately 3 billion base-pairs, each placed in a specific order to ensure the formation of 20,000-25,000 genes.11 When the structure of a gene or chromosome is changed, a mutation is formed. Mutations include insertions-deletions, copy number variations, point mutations, translocations, and inversions, which can result in cancers, genetic disorders, and infectious diseases. Understanding mutations has launched a new era of healthcare centered around personalized medicine. Today, clinical laboratories can analyze a patient’s genetic structure and determine the genetic predisposition of a disease. Doctors can prescribe treatments that are specialized to work for that patient based on their unique genetic mutations. The result is both improved quality of care and efficient, better treatment regimes, and cost-saving healthcare.

MUTATION DEFINITION

Insertions-Deletions The addition or subtraction of nucleotides from a DNA sequence.

Copy Number Variations When the number of copies of a gene is altered.

Point Mutations A substitution of one nucleotide base for another (i.e. an A for a T).

Translocations The movement of a segment of DNA from one chromosome to another.

Inversions A 180° rotation of a DNA segment, so that it is reversed from its original structure.

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OVERALL NGS MARKET OVERVIEW The potential of DNA sequencing was not fully understood when the Human Genome Project, led by Craig Venter, was completed in 2003.25 At the time the sequencing, which was executed utilizing Sanger sequencing, took over 13 years and $3 billion. Just two years later, 454 Life Sciences released the first commercially available NGS sequencer.28 In less than a decade after the initial gene sequencing, NGS technology enabled a single-genome to be sequenced within hours for as low as $1,000.28 The result within the scientific and healthcare communities has been an exponentially accelerated pace of research in the understanding and treatment of diseases. Today, NGS technology is used for two main applications: research and clinical diagnostics. This paper will focus on the diagnostic applications of the technology, particularly in relation to infectious diseases. The NGS market has enormous growth potential, making it one of the most intriguing markets to watch in modern healthcare. The global NGS market has been estimated to total $2.8 billion in 2014 and is expected to reach $13.5 billion by 2022 with a CAGR of 21.7% from 2015-2022.12 The global market for infectious disease diagnostics has been estimated to be $18 billion by 2019 with a CAGR of 7.9% from 2014-2019.12 The extensive overlap of these two rapidly expanding markets gives rise to the vast market opportunity for infectious disease diagnostics through NGS. The current NGS market is dominated by two major players: Illumina and Thermo-Fisher Scientific (Under its Life Technologies brand). Illumina has the greatest market share, estimated to be over 70%.12 Featured NGS systems by Illumina include the MiSeq, HiSeq and NextSeq models.28 Thermo-Fisher’s popular models include the Ion Torrent PGM and the Ion Proton systems. Prices for these NGS instruments can range from $50,000-$750,000, depending on the brand, model, and throughput.28 Additional costs are incurred by laboratories that utilize the technology by way of reagents, data analysis software, and additional labor.

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NGS WORKFLOW NGS can be used to sequence either a whole genome or targeted regions of interest within a patient’s DNA. Regardless of NGS utilization, the process workflow remains constant. The following diagram shows the step-by-step workflow that laboratories use to transform a raw sample to an interpreted DNA sequence.24

SAMPLE ISOLATION

DNA is collected from a patient sample and, in order to remove all unnecessary components other than pure DNA, prepared using special sample preparation kits.

TARGETED ENRICHMENT

The DNA segment that is desired to be sequenced is selected. This region can either be the whole genome or targeted sections of DNA.

LIBRARY CONSTRUCTION After the desired portion of DNA is selected, the fragments of DNA are compiled into a

library, which is run through the sequencer.

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INFECTIOUS DISEASE DIAGNOSTICS

CONVENTIONAL METHODS FOR INFECTIOUS DISEASE DIAGNOSTICS13

NGS RUN

The NGS sequencer reads the DNA fragments that were prepared in the library. Depending on the instrument, and the quantity of DNA being sequenced, the run time can vary from 30 minutes to 6 days.

DATA ANALYSIS

After an NGS run is completed, the sequence is shown on bioinformatics software. This software allows researchers and clinicians to analyze the results and determine any significant patterns, such as mutations, which are present in the sample. Depending on research and diagnostic utilization, there is a variety of bioinformatics software which laboratories can use for results optimization.

INTERPRETATION

After the data is analyzed, results are interpreted to determine ensuing action steps. In a research setting, these action steps can include the identification of new research areas or expansion of research activities to gain insight and answers to existing questions. In diagnostics, future action steps can include determining the clinical significance of specific mutations and seeing if they are associated with diseases for which specific treatments can be identified.

According to the World Health Organization, infectious diseases are among the top ten causes of death, resulting in over 3.5 million annual deaths worldwide. They are caused by pathogens, which are microorganisms such as bacteria, viruses, fungi, and other types of parasites. In order for physicians to diagnose patients with an infectious disease, they first need to identify the source of the pathogen. After identifying the source, physicians can determine any treatments that can eliminate or reduce a patient’s infection. There are four main methods to identify infectious disease pathogens: microscope examination, cell culturing, antibody testing, and genetic testing.

METHOD DESCRIPTION

Microscope Examination Patient samples are stained in a slide and pathogens are observed through a microscope.

Cell Culturing Pathogenic cells are found in the sample and grown in cell media to be observed.

Antibody Testing Antibodies are proteins that are triggered by the immune system to fight infections. Testing for antibodies can help determine pathogens for infectious diseases.

Genetic Testing Pathogens are found in patient samples by testing for traces of their genetic material.

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ISSUES IN INFECTIOUS DISEASE DIAGNOSTICS

NGS IN INFECTIOUS DISEASE DIAGNOSTICS: WHOLE GENOME METAGENOMICS

There is no individual technique that can provide physicians the information to diagnose every infectious disease. However, there are some cases where no techniques yield results, leaving a lot of uncertainty for a patient’s outcome or potential treatment. There are four main issues with current infectious disease diagnostics that cause many patients to go undiagnosed: lack of test breadth, the changing nature of viral sequences, low test sensitivity and a lack of multiplexed testing.

COMMON INFECTIOUS DISEASE DIAGNOSTIC CHALLENGES18

By looking at a patient’s whole genome, NGS technology is able to provide clinicians a new strategy for analyzing etiologies to clinical disease. The whole genome metagenomics method is a novel technique for conducting genetic testing for pathogens within patient samples.16 In this technique, all of the DNA in a patient sample is sequenced and then analyzed by powerful bioinformatics software to filter out the relevant pathogens responsible for infectious diseases.9,10 NGS can be useful to diagnose outbreaks of viruses such as ebola and HIV, as well as acute infectious diseases like pneumonia, diarrheal disease, meningitis, encephalitis, and hemorrhagic fever. There are four main advantages of using NGS technology to diagnose infectious diseases. They include: wider testing breadth, less sample requirements, multiplexing capabilities, and more comprehensive information. However, as less than 0.1% of genetic material corresponds to a pathogen associated with a disease, the corresponding difficulty arises from the sheer amount of data generated by sequencing all of a sample’s genetic material for review.

CHALLENGE DESCRIPTION

Lack of Test Breadth Many laboratories have difficulties diagnosing infectious diseases in patients because they are only testing for one disease at a time.

Changing Nature of Viral Sequences Viruses are difficult to find because their genetic material have a unique ability to mutate in order to survive environmental changes.

Low Test Sensitivity As there is often only a small trace of a pathogen in a given clinical sample, current testing may not detect its presence due to the low sensitivity of common tests.

Lack of Multiplexed Testing Many diseases can result from multiple pathogens. There are few tests that allow doctors to test for all potential pathogens associated with a particular disease at the same time.

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ADVANTAGES OF NGS WHOLE GENOME METAGENOMICS9, 18

NGS

NGS INFECTIOUS DISEASE OPPORTUNITIES18

ADVANTAGE DESCRIPTION

Wider Testing Breadth NGS technology can test the whole genome, allowing it to detect any pathogen in a sample with only one sequencing run.

Less Sample Requirements Because NGS technology has multiplexing capability, only one sample is required per patient as opposed to multiple samples and tests. This is crucial because obtaining samples with infected cells can be difficult.

More Comprehensive Information NGS bioinformatics software can give laboratories more thorough information about a patient sample than any other type of test for infectious diseases.

Multiplexing Capabilities NGS technology can test for multiple specific pathogens in one sequencing run, reducing turnaround time for diagnosis.

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© 2015 CMC Consulting Group. All Rights Reserved.

CHALLENGES OF INFECTIOUS DISEASE DIAGNOSTICS: A BUSINESS OPPORTUNITY

BUSINESS OPPORTUNITIES IN INFECTIOUS DISEASE DIAGNOSTICS18, 19

NGS technology advancements and challenges in infectious disease diagnostic testing are driving business activity. Clinical labs, startups, and large companies are tackling diagnostic issues and competing in the race for the most effective NGS infectious disease diagnostic test. To date, there is no FDA approved NGS test for infectious diseases on the market, causing a stir of competition in a reimbursement-driven testing landscape. Even Illumina, a firm with a dominant presence in the cancer

and inherited disease testing markets, does not have a comprehensive infectious disease workflow.

CHALLENGE DESCRIPTION BUSINESS OPPORTUNITY

Regulatory Approval There are no regulatory approved NGS tests for diagnosing infectious diseases.

Develop a test that is regulatory approved for laboratories to implement in their workflows.

Turnaround Time From sample preparation to bioinformatics, current NGS infectious disease workflows are too long to be used effectively in a clinical setting.

Create a workflow that can reduce the NGS testing turnaround time as much as possible.

Data Analysis NGS bioinformatics pipelines need to be improved to effectively identify potential pathogens as quickly and accurately as possible. There is also a demand for effective data storage and management.

Develop a bioinformatics software that can analyze patient samples and detect pathogens as quickly as possible for clinical use.

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CURRENT STATUS OF NGS MARKET ACTIVITY

COMPANY REGION PRODUCT TYPE(S) DESCRIPTION FUNDING

Illumina and bioMérieux

U.S. NGS Service Illumina, the dominant player in the NGS market, and bioMérieux, a leader in in vitro diagnostics, partnered together to launch an NGS service dedicated to infectious disease diagnostics.14

Through a partnership between Illumina and bioMérieux, both global players in healthcare.15

Oxford Nanopore Technologies

U.K NGS Sequencers NGS Assays Sample Prep

Kits Library Prep Kits

Founded in 2005, the company is developing portable NGS sequencing products for the analysis of single molecules.22, 27

Raised a total of $386 million through VC funding. Closed a $109 million round in July 2015 from

new and existing investors in the U.K., U.S., and mainland Europe for product development, manufacturing and commercialization.20

DNAe U.K. NGS Sequencers NGS Assays

Founded in 2003, DNAe aims to revolutionize NGS diagnostic technology by bringing the entire NGS workflow from sample preparation, sequencing, and analysis into one semiconductor chip.4

Secured a $38 million bank facility from Citibank in November 2015 for development of an NGS in vitro diagnostic test for Serious Blood Infections.5

Completed a Series A fundraising round in April 2014 for an undisclosed amount.5

MRIGlobal U.S. NGS Sequencers NGS Assays

Founded in 1977, MRIGlobal is an independent organization that performs contract research for the government and the industry.

Awarded $14.8 million in February 2015 from the Defense Threat Reduction Agency of the U.S. Department of Defense to develop a comprehensive NGS platform for infectious diseases diagnosis.8

Pathoquest France NGS Assays Bioinformatics

Pathoquest is developing a comprehensive NGS assay for diagnosing infectious diseases, including bioinformatics.

Raised $5 million in July 2013 in Series B funding by IDInvest Partners, Aurinvest and Kurma Partners.23

University of California, San Francisco (UCSF) Center for Next-Gen Precision Medicine Diagnostics

U.S. NGS Assays Founded in August 2015, the center will focus on developing NGS assays for diagnosis of encephalitis and meningitis.7

Received $2.4 million in startup funding from the Sandler Foundation and the William K. Bowes, Jr. Foundation.7

Awarded $1.2 million grant from the California Initiative to Advance Precision Medicine, a public-private effort initiated by Governor Edmund Brown Jr.7

CosmosID U.S. Bioinformatics Founded in 2008, CosmosID is a genomic big data company focused on microbiome research, outbreak investigations, and NGS infectious disease diagnostics.3

Received $6 million in Series B funding from investment firm Applied Value Group in January 2016.3

One Codex U.S. Bioinformatics One Codex is creating a platform to analyze pathogen genomic data, enabling applications in clinical diagnostics, food safety, and biosecurity.29

Won a $200,000 award from the Centers for Disease Control (CDC) for its platform analyzing Escherichia coli clinical samples.29

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OXFORD NANOPORE TECHNOLOGIES

ILLUMINA AND BIOMÉRIEUX

Although the NGS infectious disease diagnostics testing market is at an early stage, there are companies that are being funded to develop novel assays and platforms. These firms are developing products that relate to the NGS workflow, whether directly related to sequencing or providing support such as data analytics. The following charts highlight funding, activities and future projects of active firms in the NGS market space:

FEBRUARY 2012

Introduced the MinION, a portable USB Sized NGS Sequencer.27

JULY 2015

Raised $109 million from both new and existing investors in the UK, US and mainland Europe.21

SEPTEMBER 2015

UK research team used Oxford Nanopore technology to develop an NGS diagnostic test for urinary tract infections.30

The assay takes approximately 12 hours from raw sample to data analysis. Published results in the BioRxiv preprint server in mid-September.30

OCTOBER 2015 & BEYOND

Plans to decrease assay TAT of urinary tract infections test from 12 hours to 6 hours using new flow cell technology.

Also working on a blood-based NGS diagnostic assay for sepsis, a life threatening complication from infection.30

NOVEMBER 2014

Announced a partnership to develop an NGS epidemiological solution to enable service labs to genotype disease agents.15

DECEMBER 2015

Launched bioMérieux EpiSeq, a service that offers characterization of bacteria for hospitals using NGS.26

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MRI GLOBAL

PATHOQUEST

DNAE

JANUARY 2015

Raised $24 million to acquire nanoMR, a rare cell isolation firm.

NanoMR has a immunomagnetic Pathogen Capture System (PCS) that DNAe hopes to use for developing its future NGS infectious disease diagnostic tests.4

NOVEMBER 2015

Received a $38 million bank note from Citibank to fund an NGS blood test for sepsis.6

The firm plans to use nanoMR’s technology to develop the sample preparation portion of the assay’s workflow. Raises $109 million from both new and existing investors in the UK, US and mainland Europe.

2016

Projected to conduct clinical trials for the NGS sepsis blood test.6

2017

Plans to launch the NGS sepsis blood test.6

MARCH 2011

Raised approximately $2.5 million by Kurma Life Science Partners to develop an NGS assay for infectious disease diagnostics.23

JULY 2013

Raised $5 million in Series B financing from Idinvest and Aurinvest in order to conduct clinical trials of its NGS infectious disease assay. The test combines NGS and a cloud based bioinformatics software.23

FEBRUARY 2015

Awarded a $14.8 million grant in a three-year contract from the Defense Threat Reduction Agency of the US Department of Defense to develop a complete NGS system to diagnose infectious diseases. The goal is to use patient blood and saliva samples to generate sequences of pathogens for diagnosis.8

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UCSF CENTER FOR NEXT-GEN PRECISION MEDICINE DIAGNOSTICS

COSMOSID

ONE CODEX

AUGUST 2015

With $3.6 million in funding, the Center for Next-Gen Precision Medicine Diagnostics was created to develop tests to improve diagnosis for infectious diseases causing inflammation in the brain and surrounding tissues. The center is initially focusing on developing tests for encephalitis and meningitis.7

JANUARY 2016

Raised a $6 Million Series B fundraising round from Applied Value Group to develop a single, rapid test to identify all microorganisms in a sample (bacteria, viruses, fungi, and parasites) and characterize their attributes (antibiotic resistance, virulence, etc.).3

FEBRUARY 2015

Won a $200,000 award from the Centers for Disease Control (CDC) for its platform to analyze platform analyzing Escherichia coli. Although the platform is in beta mode, the CDC has noted its power to rapidly identify the disease from complex samples and provide valuable clinical information.29

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FUTURE OUTLOOK FOR NGS IN INFECTIOUS DISEASE DIAGNOSTICS The market for NGS technology is at an early stage and presents many exciting opportunities. Current laboratory developed tests utilizing NGS technology have already been clinically proven to be more effective than conventional diagnostic techniques for infectious diseases. The next step for competitors in the market is to develop an assay that is commercially available for laboratories to implement. There are numerous factors that will drive or inhibit the use of NGS in the infectious disease testing space in the future:

KEY DRIVERS

Demographic factors: aging population, increased natality, increasing number of infectious disease patients every year

Expectation of revised reimbursement codes for NGS testing by the FDA

Reduced cost of sequencing per sample, making NGS more comparable with other infectious disease tests

New technologies with faster turnaround time from sample to data analysis

Improvements in bioinformatics and data analysis methods

Increased government funding for infectious disease bioinformatics, such as a $2.3 million budget announced for fiscal 2016 from the CDC.2

KEY INHIBITORS

Uncertainty around FDA timing and requirements for NGS testing reimbursement code changes

High initial capital investment required for NGS in clinical labs

Process for research-only labs towards CLIA and FDA approval is long

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CONCLUSION

Infectious disease diagnostics have had an important role in the prevention of disease outbreaks, a major public health concern. While many techniques exist to diagnose infectious diseases, they cannot be guaranteed to work for every patient. Moreover, conventional diagnostic techniques have been inefficient due to their one pathogen per test limitations and inability to identify diseases linked to unknown pathogens. NGS technology can solve these issues through whole genome metagenomics sequencing and has proven to be the diagnostic tool of the future. By sequencing all of the nucleic acids in a sample, NGS testing can detect the sequence for specific pathogens that could be responsible for a disease. The capability to sequence a whole genome enables a diagnostic test to cover a wider variety of pathogens than traditional methods. This is advantageous as no previous knowledge of the pathogen needs to be obtained prior to testing and identification. NGS allows clinicians to use an unbiased, efficient and effective approach towards solving challenging patient cases.17 The scientific and medical communities are just beginning to scrape the surface of understanding the capabilities of NGS technology for patient treatment. As the market place growth potential accelerates, manufacturer and investor interest heats up for this innovative technology, making it one to watch within the personalized healthcare trend.

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GLOSSARY

Chromosomes The thread-like structures that contain genes.

Deoxyribonucleic Acid (DNA) A double-helix chemical structure that contains the genetic information for all living organisms.

DNA sequencing A research technique to determine the order of nucleotide bases in a human body.

Genes Develop an individual’s protein structure.

Human genome The entire code that develops the human body.

Mutation An incorrect sequence of nucleotide bases

Next-generation sequencing (NGS) A new, faster technique to sequence DNA.

Nucleotide bases Chemicals that form genes.

Pathogen A microorganism that is responsible for an infectious disease.

Sanger sequencing A traditional method of DNA sequencing.

Turnaround time The length of time it takes to obtain results from a diagnostic test.

Whole genome metagenomics A technique to diagnose infectious diseases using NGS.

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SOURCES

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generation-sequencing-pdf/. Published 2010. Accessed October 9, 2015.

2. "CDC Earmarks $2.3M for NGS, Bioinformatic Approaches to Combat Infectious Disease."

GenomeWeb. N.p., 27 Aug. 2015. Web. 08 Jan. 2016.

3. "CosmosID Raises $6 Million in Series B Funding." -- ROCKVILLE, Md., Jan. 27, 2016

/PRNewswire/ --. N.p., 27 Jan. 2016. Web. 09 Feb. 2016.

4. "DNA Electronics Buys NanoMR for $24M." GenomeWeb. N.p., 19 Jan. 2015. Web. 08 Jan. 2016.

5. "DNAe Plans to Target Infectious Disease Market with Genotyping, Sequencing Combo

Platform." GenomeWeb. N.p., 15 Oct. 2014. Web. 08 Jan. 2016.

6. "DNAe Secures £25M Bank Facility for Point-of-Care Sepsis Dx." GenomeWeb. N.p., 2 Nov. 2015.

Web. 08 Jan. 2016.

7. Farley, Pete. "New Center Will Advance Life-Saving Genome-Based Diagnostic Tools." UC San

Francisco. N.p., 20 Aug. 2015. Web. 08 Jan. 2016.

8. "Feds Award MRIGlobal $14.8M to Develop NGS Platform for Infectious Diseases."

GenomeWeb. N.p., 23 Feb. 2015. Web. 08 Jan. 2016.

9. Fischer, Nicole, et al. “Rapid metagenomic diagnostics for suspected outbreak of severe

pneumonia.” Emerging infectious diseases 20.6 (2014): 1072. doi: 10.3201/eid2006.131526

10. Fournier, Pierre-Edouard, Gregory Dubourg, and Didier Raoult. "Clinical detection and

characterization of bacterial pathogens in the genomics era. “Genome medicine 6.11 (2014):

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2015.

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12. Global Next-generation Sequencing Market On the Verge of a Quadrupled Competitor Size and a

Clinical Turning Point. Frost and Sullivan. Published in June 2014. Accessed on January 27, 2016.

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Version. N.p., n.d. Web. 09 Feb. 2016.

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22. "Oxford Nanopore Researchers Assemble Bacterial Genomes from Environmental Sample."

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