Posts Tagged ‘Technology’

#JPM19 Conference: Lilly Announces Agreement To Acquire Loxo Oncology, Volume 2 (Volume Two: Latest in Genomics Methodologies for Therapeutics: Gene Editing, NGS and BioInformatics, Simulations and the Genome Ontology), Part 1: Next Generation Sequencing (NGS)

#JPM19 Conference: Lilly Announces Agreement To Acquire Loxo Oncology

Reporter: Gail S. Thornton


News announced during the 37th J.P. Morgan Healthcare Conference (#JPM19): Drugmaker Eli Lilly and Company announced its plans to acquire Loxo for $8 billion, as part of its oncology strategy, which focuses  “opportunities for first-in-class and best-in-class therapies.”   


Please read their press release below.

INDIANAPOLIS and STAMFORD, Conn.Jan. 7, 2019 /PRNewswire/ —

  • Acquisition will broaden the scope of Lilly’s oncology portfolio into precision medicines through the addition of a marketed therapy and a pipeline of highly selective potential medicines for patients with genomically defined cancers.
  • Loxo Oncology’s pipeline includes LOXO-292, an oral RET inhibitor being studied across multiple tumor types, which recently was granted Breakthrough Therapy designation by the FDA and could launch in 2020.
  • Loxo Oncology’s Vitrakvi® (larotrectinib) is an oral TRK inhibitor developed and commercialized in collaboration with Bayer that was recently approved by the FDA.
  • Lilly will commence a tender offer to acquire all outstanding shares of Loxo Oncology for a purchase price of$235.00 per share in cash, or approximately $8.0 billion.
  • Lilly will conduct a conference call with the investment community and media today at 8:45 a.m. EST.

Eli Lilly and Company (NYSE: LLY) and Loxo Oncology, Inc. (NASDAQ: LOXO) today announced a definitive agreement for Lilly to acquire Loxo Oncology for $235.00 per share in cash, or approximately $8.0 billion. Loxo Oncology is a biopharmaceutical company focused on the development and commercialization of highly selective medicines for patients with genomically defined cancers.

The acquisition would be the largest and latest in a series of transactions Lilly has conducted to broaden its cancer treatment efforts with externally sourced opportunities for first-in-class and best-in-class therapies. Loxo Oncology is developing a pipeline of targeted medicines focused on cancers that are uniquely dependent on single gene abnormalities that can be detected by genomic testing.  For patients with cancers that harbor these genomic alterations, a targeted medicine could have the potential to treat the cancer with dramatic effect.

Loxo Oncology has a promising portfolio of approved and investigational medicines, including:

  • LOXO-292, a first-in-class oral RET inhibitor that has been granted Breakthrough Therapy designation by the FDA for three indications, with an initial potential launch in 2020.  LOXO-292 targets cancers with alterations to the rearranged during transfection (RET) kinase. RET fusions and mutations occur across multiple tumor types, including certain lung and thyroid cancers as well as a subset of other cancers.
  • LOXO-305, an oral BTK inhibitor currently in Phase 1/2. LOXO-305 targets cancers with alterations to the Bruton’s tyrosine kinase (BTK), and is designed to address acquired resistance to currently available BTK inhibitors. BTK is a validated molecular target found across numerous B-cell leukemias and lymphomas.
  • Vitrakvi, a first-in-class oral TRK inhibitor developed and commercialized in collaboration with Bayer that was recently approved by the U.S. Food and Drug Administration (FDA). Vitrakvi is the first treatment that targets a specific genetic abnormality to receive a tumor-agnostic indication at the time of initial FDA approval.
  • LOXO-195, a follow-on TRK inhibitor also being studied by Loxo Oncology and Bayer for acquired resistance to TRK inhibition, with a potential launch in 2022.

“Using tailored medicines to target key tumor dependencies offers an increasingly robust approach to cancer treatment,” said Daniel Skovronsky, M.D., Ph.D., Lilly’s chief scientific officer and president of Lilly Research Laboratories. “Loxo Oncology’s portfolio of RET, BTK and TRK inhibitors targeted specifically to patients with mutations or fusions in these genes, in combination with advanced diagnostics that allow us to know exactly which patients may benefit, creates new opportunities to improve the lives of people with advanced cancer.”

“We are gratified that Lilly has recognized our contributions to the field of precision medicine and are excited to see our pipeline benefit from the resources and global reach of the Lilly organization,” said Josh Bilenker, M.D., chief executive officer of Loxo Oncology. “Tumor genomic profiling is becoming standard-of-care, and it will be critical to continue innovating against new targets, while anticipating mechanisms of resistance to available therapies, so that patients with advanced cancer have the chance to live longer and better lives.”

“Lilly Oncology is committed to developing innovative, breakthrough medicines that will make a meaningful difference for people with cancer and help them live longer, healthier lives,” said Anne White, president of Lilly Oncology. “The acquisition of Loxo Oncology represents an exciting and immediate opportunity to expand the breadth of our portfolio into precision medicines and target cancers that are caused by specific gene abnormalities. The ability to target tumor dependencies in these populations is a key part of our Lilly Oncology strategy. We look forward to continuing to advance the pioneering scientific innovation begun by Loxo Oncology.”

“We are excited to have reached this agreement with a team that shares our commitment to ensuring that emerging translational science reaches patients in need,” said Jacob Van Naarden, chief operating officer of Loxo Oncology. “We are confident that the work we have started, which includes an FDA approved drug, and a pipeline spanning from Phase 2 to discovery, will continue to thrive in Lilly’s hands.”

Under the terms of the agreement, Lilly will commence a tender offer to acquire all outstanding shares of Loxo Oncology for a purchase price of $235.00 per share in cash, or approximately $8.0 billion. The transaction is not subject to any financing condition and is expected to close by the end of the first quarter of 2019, subject to customary closing conditions, including receipt of required regulatory approvals and the tender of a majority of the outstanding shares of Loxo Oncology’s common stock. Following the successful closing of the tender offer, Lilly will acquire any shares of Loxo Oncology that are not tendered into the tender offer through a second-step merger at the tender offer price.

The tender offer represents a premium of approximately 68 percent to Loxo Oncology’s closing stock price on January 4, 2019, the last trading day before the announcement of the transaction. Loxo Oncology’s board recommends that Loxo Oncology’s shareholders tender their shares in the tender offer.  Additionally, a Loxo Oncology shareholder, beneficially owning approximately 6.6 percent of Loxo Oncology’s outstanding common stock, has agreed to tender its shares in the tender offer.

This transaction will be reflected in Lilly’s financial results and financial guidance according to Generally Accepted Accounting Principles (GAAP). Lilly will provide an update to its 2019 financial guidance, including the expected impact from the acquisition of Loxo Oncology, as part of its fourth-quarter and full-year 2018 financial results announcement on February 13, 2019.

For Lilly, Deutsche Bank is acting as the exclusive financial advisor and Weil, Gotshal & Manges LLP is acting as legal advisor in this transaction. For Loxo Oncology, Goldman Sachs & Co. LLC is acting as exclusive financial advisor and Fenwick & West LLP is acting as legal advisor.

Conference Call and Webcast
Lilly will conduct a conference call with the investment community and media today at 8:45 a.m. EST to discuss the acquisition of Loxo Oncology.  Investors, media and the general public can access a live webcast of the conference call through the Webcasts & Presentations link that will be posted on Lilly’s website at www.lilly.com.  The webcast of the conference call will be available for replay through February 7, 2019.

About LOXO-292
LOXO-292 is an oral and selective investigational new drug in clinical development for the treatment of patients with cancers that harbor abnormalities in the rearranged during transfection (RET) kinase. RET fusions and mutations occur across multiple tumor types with varying frequency. LOXO-292 was designed to inhibit native RET signaling as well as anticipated acquired resistance mechanisms that could otherwise limit the activity of this therapeutic approach. LOXO-292 has been granted Breakthrough Therapy Designation by the U.S. FDA for three indications, and could launch as early as 2020.

About LOXO-305
LOXO-305 is an investigational, highly selective non-covalent Bruton’s tyrosine kinase (BTK) inhibitor. BTK plays a key role in the B-cell antigen receptor signaling pathway, which is required for the development, activation and survival of normal white blood cells, known as B-cells, and malignant B-cells. BTK is a validated molecular target found across numerous B-cell leukemias and lymphomas including chronic lymphocytic leukemia, Waldenstrom’s macroglobulinemia, mantle cell lymphoma and marginal zone lymphoma.

About Vitrakvi® (larotrectinib)
Vitrakvi is an oral TRK inhibitor for the treatment of adult and pediatric patients with solid tumors with a neurotrophic receptor tyrosine kinase (NTRK) gene fusion without a known acquired resistance mutation that are either metastatic or where surgical resection will likely result in severe morbidity, and have no satisfactory alternative treatments or have progressed following treatment. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

About LOXO-195
LOXO-195 is a selective TRK inhibitor that is being investigated to address potential mechanisms of acquired resistance that may emerge in patients receiving Vitrakvi® (larotrectinib) or other multikinase inhibitors with anti-TRK activity.

About Eli Lilly and Company
Lilly is a global healthcare leader that unites caring with discovery to create medicines that make life better for people around the world. We were founded more than a century ago by a man committed to creating high-quality medicines that meet real needs, and today we remain true to that mission in all our work. Across the globe, Lilly employees work to discover and bring life-changing medicines to those who need them, improve the understanding and management of disease, and give back to communities through philanthropy and volunteerism. To learn more about Lilly, please visit us at www.lilly.com and www.lilly.com/newsroom/social-channels. C-LLY

About Loxo Oncology
Loxo Oncology is a biopharmaceutical company focused on the development and commercialization of highly selective medicines for patients with genomically defined cancers. Our pipeline focuses on cancers that are uniquely dependent on single gene abnormalities, such that a single drug has the potential to treat the cancer with dramatic effect. We believe that the most selective, purpose-built medicines have the highest probability of maximally inhibiting the intended target, with the intention of delivering best-in-class disease control and safety. Our management team seeks out experienced industry partners, world-class scientific advisors and innovative clinical-regulatory approaches to deliver new cancer therapies to patients as quickly and efficiently as possible. For more information, please visit the company’s website at http://www.loxooncology.com.

Lilly Cautionary Statement Regarding Forward-Looking Statements

This press release contains forward-looking statements about the benefits of Lilly’s acquisition of Loxo Oncology, Inc. (“Loxo Oncology”). It reflects Lillys current beliefs; however, as with any such undertaking, there are substantial risks and uncertainties in implementing the transaction and in drug developmentAmong other things, there can be no guarantee that the transaction will be completed in the anticipated timeframe, or at all, or that the conditions required to complete the transaction will be met, that Lilly will realize the expected benefits of the transaction, that the molecules will be approved on the anticipated timeline or at all, or that the potential products will be commercially successful. For further discussion of these and other risks and uncertainties, see Lillys most recent Form 10-K and Form 10-Q filings with the United States Securities and Exchange Commission (“the SEC”). Lilly will provide an update to certain elements of its 2019 financial guidance as part of its fourth quarter and full-year 2018 financial results announcement. Except as required by law, Lilly undertakes no duty to update forward-looking statements to reflect events after the date of this release.

Loxo Oncology Cautionary Statement Regarding Forward-Looking Statements

This press release contains “forward-looking statements” relating to the acquisition of Loxo Oncology by Lilly. Such forward-looking statements include the ability of Loxo Oncology and Lilly to complete the transactions contemplated by the merger agreement, including the parties’ ability to satisfy the conditions to the consummation of the offer and the other conditions set forth in the merger agreement and the possibility of any termination of the merger agreement, as well as the role of targeted genomics and diagnostics in oncology treatment and acceleration of our work in developing medicines. Such forward-looking statements are based upon current expectations that involve risks, changes in circumstances, assumptions and uncertainties. Actual results may differ materially from current expectations because of risks associated with uncertainties as to the timing of the offer and the subsequent merger; uncertainties as to how many of Loxo Oncology’s stockholders will tender their shares in the offer; the risk that competing offers or acquisition proposals will be made; the possibility that various conditions to the consummation of the offer or the merger may not be satisfied or waived; the effects of disruption from the transactions contemplated by the merger agreement on Loxo Oncology’s business and the fact that the announcement and pendency of the transactions may make it more difficult to establish or maintain relationships with employees, suppliers and other business partners; the risk that stockholder litigation in connection with the offer or the merger may result in significant costs of defense, indemnification and liability; other uncertainties pertaining to the business of Loxo Oncology, including those set forth in the “Risk Factors” and “Management’s Discussion and Analysis of Financial Condition and Results of Operations” sections of Loxo Oncology’s Annual Report on Form 10-K for the year ended December 31, 2017, which is on file with the SEC and available on the SEC’s website at www.sec.gov. Additional factors may be set forth in those sections of Loxo Oncology’s Quarterly Report on Form 10-Q for the quarter endedSeptember 30, 2018, filed with the SEC in the fourth quarter of 2018.  In addition to the risks described above and in Loxo Oncology’s other filings with the SEC, other unknown or unpredictable factors could also affect Loxo Oncology’s results. No forward-looking statements can be guaranteed and actual results may differ materially from such statements. The information contained in this press release is provided only as of the date of this report, and Loxo Oncology undertakes no obligation to update any forward-looking statements either contained in or incorporated by reference into this report on account of new information, future events, or otherwise, except as required by law.

Additional Information about the Acquisition and Where to Find It

The tender offer for the outstanding shares of Loxo Oncology referenced in this communication has not yet commenced. This announcement is for informational purposes only and is neither an offer to purchase nor a solicitation of an offer to sell shares of Loxo Oncology, nor is it a substitute for the tender offer materials that Lilly and its acquisition subsidiary will file with the SEC upon commencement of the tender offer. At the time the tender offer is commenced, Lilly and its acquisition subsidiary will file tender offer materials on Schedule TO, and Loxo Oncology will file a Solicitation/Recommendation Statement on Schedule 14D-9 with the SEC with respect to the tender offer. THE TENDER OFFER MATERIALS (INCLUDING AN OFFER TO PURCHASE, A RELATED LETTER OF TRANSMITTAL AND CERTAIN OTHER TENDER OFFER DOCUMENTS) AND THE SOLICITATION/RECOMMENDATION STATEMENT WILL CONTAIN IMPORTANT INFORMATION. HOLDERS OF SHARES OF LOXO ONCOLOGY ARE URGED TO READ THESE DOCUMENTS CAREFULLY WHEN THEY BECOME AVAILABLE (AS EACH MAY BE AMENDED OR SUPPLEMENTED FROM TIME TO TIME) BECAUSE THEY WILL CONTAIN IMPORTANT INFORMATION THAT HOLDERS OF LOXO ONCOLOGY SECURITIES SHOULD CONSIDER BEFORE MAKING ANY DECISION REGARDING TENDERING THEIR SECURITIES. The Offer to Purchase, the related Letter of Transmittal and certain other tender offer documents, as well as the Solicitation/Recommendation Statement, will be made available to all holders of shares of Loxo Oncology at no expense to them. The tender offer materials and the Solicitation/Recommendation Statement will be made available for free at the SEC’s web site at www.sec.gov

In addition to the Offer to Purchase, the related Letter of Transmittal and certain other tender offer documents, as well as the Solicitation/Recommendation Statement, Lilly and Loxo Oncology file annual, quarterly and special reports and other information with the SEC.  You may read and copy any reports or other information filed by Lilly or Loxo Oncology at the SEC public reference room at 100 F Street, N.E., Washington, D.C. 20549. Please call the Commission at 1-800-SEC-0330 for further information on the public reference room.  Lilly’s and Loxo Oncology’s filings with the SEC are also available to the public from commercial document-retrieval services and at the website maintained by the SEC at www.sec.gov.


Eli Lilly and Company – https://www.lilly.com

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  • More than 77 percent of patients in the REMfresh® Patient Reported Outcomes DURation (REMDUR) study reported achieving 6 or more hours of sleep after taking REMfresh®, the first continuous release and absorption melatonin (CRA-melatonin)
  • More than 91 percent experienced improvements in sleep onset, sleep maintenance and total sleep quality, after taking REMfresh® (CRA-melatonin)
  • Post-marketing, patient-reported outcomes data reinforces clinical trial evidence demonstrating the potential of non-prescription REMfresh®, as a new, non-prescription, drug-free hypnotic (sleep) product designed to achieve 7-hour sleep
  • New data confirms previously presented SLEEP 2017 study showing the patented Ion Powered Pump (IPP) technology in REMfresh® helps extend melatonin-targeted sleep maintenance levels in the body from 3.7 hours (with marketed immediate-release melatonin) to 6.7 hours, while mimicking the pattern of the body’s natural melatonin blood levels during the nightly sleep cycle

Real Time Coverage at SLEEP 2018 meeting, Baltimore.

Reporters: Aviva Lev-Ari, PhD, RN, and Gail S. Thornton, MA

BALTIMORE – (June 6, 2018) – A patient-reported outcomes study presented at SLEEP 2018 provides confirmatory real-world evidence of the previously peer-reviewed and presented data showing the 7-hour action of REMfresh®, a new product for sleep. REMfresh® Ion-Powered Melatoninis the first and only, continuous release and absorption melatonin (CRA-melatonin) to mimic the body’s own 7-hour Mesa Wave, the natural pattern of melatonin blood levels during a normal night’s sleep cycle. This induces sleep onset and provides lasting and restorative sleep for up to 7 hours.

This new data shows a correlative relationship between a 7-hour Mesa Wave pharmacokinetic (PK) profile and real-world evidence of improvements in sleep duration, onset, maintenance and sleep quality after taking REMfresh® (CRA-melatonin).

The post-marketing REMfresh® Patient Reported Outcomes DURation (REMDUR) study was presented at SLEEP 2018, the 32nd Annual Meeting of the Associated Professional Sleep Societies (APSS), LLC, a joint partnership of the American Academy of Sleep Medicine (AASM) and the Sleep Research Society (SRS).


Brodner and Seiden

Pictured here is David C. Brodner, M.D., and David J. Seiden, M.D., FAASM, after presenting the latest study data which found REMfresh is the first and only continuous release and absorption melatonin™ to mimic the body’s own 7-hour Mesa Wave™.


In a sample of 500 patients on REMfresh® (CRA-melatonin) responding to an online survey, 77.6 percent achieved 6 or more hours of sleep compared to 23.6 percent who slept that duration prior to taking REMfresh® (p<.0001). A vast majority of respondents also reported a major or moderate improvement in sleep onset (91.6 percent, p<.0001), sleep maintenance (94.8 percent, p<.0001) and total sleep quality (97.2 percent, p<.0001). More than three-quarters (76.6 percent) of patients indicated they take REMfresh® (CRA-melatonin) nightly. The proportion of patients reporting nightly CRA-melatonin use was significantly greater than the proportion of patients with less than nightly use (p<.0001). Most importantly, over 98 percent of patients reported they were very likely or likely to continue taking REMfresh® (CRA-melatonin) to treat their sleep complaints.

“The real-world evidence reported today in REMDUR provides further confirmation that REMfresh® represents a significant advance in the use of melatonin as a baseline therapy for treating sleep complaints,” said David C. Brodner, M.D., a leading sleep specialist who is Double Board-Certified in Otolaryngology — Head and Neck Surgery and Sleep Medicine, founder and principle Physician at the Center for Sinus, Allergy, and Sleep Wellness, in Palm Beach County, Florida, and Senior Medical Advisor for Physician’s Seal, LLC®.

“REMfresh® Ion-Powered Melatoninhas been shown to be an effective drug-free solution that is now available to the millions of Americans in need of a good night’s sleep, many of whom seek new therapies that will induce sleep and keep them asleep until the morning, without causing residual effects they’ll feel the next day. With its unique delivery system that imitates the body’s own natural sleep pattern, REMfresh® has revolutionized the role of melatonin, when delivered in the CRA form. It is no longer just a treatment for jet lag, but the CRA-melatonin found in REMfresh® has been shown to provide substantial relief to individuals having nightly sleep challenges,” said Dr. Brodner.

The scientifically advanced, patented delivery system in REMfresh® (CRA-melatonin), called Ion Powered Pump (IPP™) technology, replicates the way in which the body naturally releases and absorbs melatonin, unlike conventional melatonin sleep products. Since REMfresh® is not a drug, there is no drug hangover.

Nearly one-third of U.S. adults sleep less than the recommended seven hours daily.[1],[2] Increasing evidence suggests an association between sub-optimal sleep duration and adverse health outcomes including a higher risk of diabetes, hypertension, heart attack, stroke, obesity and depression.[3] A pooled analysis of 16 studies and over one million patients found short sleep duration corresponded with greater risk of morbidity and mortality.[4]

 REMDUR Study Design

The post-marketing REMfresh® Patient Reported Outcomes DURation (REMDUR) study was designed to obtain real-world evidence about patients’ sleep patterns, duration of sleep before and after REMfresh® (CRA-melatonin), daily REMfresh® (CRA-melatonin) use, onset of action, sleep maintenance, quality of sleep, and overall satisfaction with REMfresh® (CRA-melatonin).

Patients with sleep disturbances in the general population who received a sample of CRA-melatonin (REMfresh®) from their physicians were invited to complete a 12-question survey. Survey responses were received from 500 patients.

Confirmation of the REMAKT Clinical Study

REMDUR confirmed clinical trial findings from REMAKT (REM Absorption Kinetics Trial), a U.S.-based randomized, crossover pharmacokinetic (PK) evaluation study in healthy, non-smoking adults that compared REMfresh® (CRA-melatonin) with a market-leading, immediate-release melatonin (IR-melatonin).[5]

The study results, peer-reviewed and presented last year at SLEEP 2017, showed that melatonin levels with REMfresh® (CRA-melatonin) exceeded the targeted sleep maintenance threshold for a median of 6.7 hours, compared with 3.7 hours with the leading IR-melatonin. Conversely, the levels of the market-leading IR-melatonin formulation dramatically increased 23 times greater than the targeted levels of exogenous melatonin for sleep maintenance and had a rapid decline in serum levels that did not allow melatonin levels to be maintained beyond 4 hours.

The REMfresh® (CRA-melatonin) studies build upon the body of evidence from prolonged-release melatonin (PR-M), marketed in Europe, which demonstrated in well-conducted, placebo-controlled studies, statistically significant improvement in sleep quality, morning alertness, sleep latency and quality of life in patients aged 55 years and older compared with placebo. REMfresh® (CRA-melatonin) was designed to overcome the challenges of absorption in the intestines, thereby extending the continual and gradual release pattern of melatonin through the night (known as the Mesa Wave, a flat-topped hill with steep sides). There was a fast time to Cmax, which is anticipated to result in improved sleep onset, while the extended median plateau time to 6.7 hours and rapid fall-off in plasma levels at the end of the Mesa Wave, may help to improve sleep maintenance and morning alertness.

Conventional melatonin products have had challenges at mimicking the profile of a Mesa Wave™. The scientific work behind REMfresh® (CRA-melatonin) sought to overcome these challenges by having the melatonin formulation in a matrix that maintains a patented, solubility-enhancing pH environment to help with the transport to the brush border of the gut and its subsequent absorption.

Designed as a hydrogel matrix tablet, REMfresh® (CRA-melatonin) provides rapid release of the melatonin from the surface of the tablet, as the hydrogel release-controlling matrix is setting up in the acidic environment (pH of 1 to 3.5) in the stomach. As the tablet moves into the higher pH (5.5 to 6.5) environment of the small-intestine, which is above the pKa of melatonin (~4.0), the acidic moiety in the tablet is designed to maintain the pH within the tablet below 4.0 for 7+ hours. The hydrogel matrix, after proper hydration, allows continuous release of the active melatonin and acidic moiety into the lumen of the intestines.

Melatonin: The Body’s Natural Sleep Ingredient

Melatonin is produced by the pineal gland in the brain and is the body’s natural sleep ingredient. Melatonin levels normally begin to rise in the mid-to late evening and remain high for the majority of the night. Levels begin to decline towards early morning, as the body’s wake cycle is triggered. As people age, melatonin levels can drop by as much as 70 percent[6] and their bodies may no longer produce enough melatonin to ensure adequate sleep.

Other available products, such as immediate-release melatonin, help initiate the onset of sleep but are usually unable to sustain prolonged sleep maintenance due to an immediate burst of melatonin, which is quickly degraded due to its relatively short half-life (60 minutes). Absorption in the lower digestive tract is limited by melatonin’s limited ability to be absorbed in a low acidity or neutral pH environment.

Importance of Sleep

Sleep is an essential part of every person’s life. The body requires a certain amount of sleep in order to properly rest, repair and renew itself. Sleep is customarily divided in four different stages, with each stage having a different effect. These four stages are:

N1, N2, deep sleep and REM sleep. The body moves among these four stages several times while asleep. If sleep is disrupted for any reason, a person’s body may not have a chance to properly restore itself, especially if it is struggling to get to the later stages, called deep sleep and REM sleep. Studies have shown that sound and sufficient sleep is important for learning, memory and a healthy immune system. A regular pattern of deep sleep and REM sleep will help a person begin the next day feeling refreshed and ready to go.

About Non-Prescription REMfresh®

REMfresh® (CRA-melatonin) is the first and only, continuous release and absorption formulation of UltraMel® melatonin (available as 2 mg and 5 mg and with a 0.5 mg anticipated in the second half of 2018). UltraMel® melatonin is a high-quality, 99 percent ultra-pure melatonin sourced from Western Europe exclusively for Physician’s Seal®.

REMfresh® (CRA-melatonin) is a dietary supplement and is regulated under the Federal Dietary Supplement Health and Education Act, which does not require pre-approval. Melatonin has been in common use for over two decades and has a well-established profile of safe use by millions of people around the world. As with all supplements, individual results may vary.

REMfresh® (CRA-melatonin) is non-habit forming and does not contain narcotics, hypnotics, barbiturates, sedatives, antihistamines, alcohol or other harsh or additive chemicals. The usual adult recommended dose is 1-2 tablets 30-60 minutes before bedtime. Follow specific dosing instructions found on the back of the box for proper use of supplements.

REMfresh® (CRA-melatonin) is available at Walmart, Rite Aid and CVS/pharmacy. In 2017 REMfresh® was ranked as  the #1 recommended brand for sleep management by sleep doctors[7].

About Physician’s Seal®

Physician’s Seal® is the innovator of REMfresh®, the first and only continuous release and absorption, 99 percent ultra-pure melatonin (CRA-melatonin) that mimics the way the body naturally releases and maintains melatonin over a 7-hour period. Physician’s Seal®, founded in 2015, is a privately held company based in Boca Raton, Florida. It is committed to bringing cutting-edge life science applications to doctors and their patients. For more information, visit www.remfresh.com and connect with us on Facebook and You Tube.

Its sister subsidiary, IM HealthScience® (IMH) is the innovator of IBgard® and FDgard® for the dietary management of Irritable Bowel Syndrome (IBS) and Functional Dyspepsia (FD), respectively. In 2017, IMH added Fiber Choice®, a line of prebiotic fibers, to its product line via an acquisition. IMH® is a privately held company based in Boca Raton, Florida. It was founded in 2010 by a team of highly experienced pharmaceutical research and development and management executives. The company is dedicated to developing products to address overall health and wellness, including conditions with a high unmet medical need, such as digestive health. The IM HealthScience® advantage comes from developing products based on its patented, targeted-delivery technologies called Site Specific Targeting® (SST®). For more information, visit www.imhealthscience.com to learn about the company, or www.IBgard.com,  www.FDgard.com,and www.FiberChoice.com.

This information is for educational purposes only and is not meant to be a substitute for the advice of a physician or other health care professional. You should not use this information for diagnosing a health problem or disease. The company will strive to keep information current and consistent but may not be able to do so at any specific time. Generally, the most current information can be found on www.remfresh.com. Individual results may vary.

Data Presented at SLEEP 2018 Poster Session on Sleep Maintenance/Sleep Quality

Tuesday, June 5, 2018, 5-7pm

  • (Abstract 0419, Poster Board #104) Improvement in Sleep Maintenance and Sleep Quality with Ion Powered Pump Continuous Release and Absorption Melatonin: Results from a Self-Reported Patient Outcomes Study
    • David J. Seiden, M.D., FAASM, David C. Brodner, M.D., Syed M. Shah, Ph.D.

Visit Physician’s Seal® at booth 220 to learn more about REMfresh®.

The abstract is published in an online supplement of the journal, Sleep, which is available at http://www.sleepmeeting.org/docs/default-source/default-document-library/abstractbook2018.pdf?sfvrsn=2

[1] Ford, E.S., Cunningham, T.J., & Croft, J.B. (2015, May 1). Trends in Self-Reported Sleep Duration among US Adults from 1985 to 2012. Sleep, 38(5):829-832. doi: 10.5665/sleep.4684.

[2] Watson, N.F., Badr, M.S., Belenky, G., Bliwise, D.L., Buxton, G.M., Buysse, D.,…Tasali, E. (2015). Joint Consensus Statement of the American Academy of Sleep Medicine and Sleep Research Society on the Recommended Amount of Sleep for a Healthy Adult: Methodology and Discussion. Journal of Clinical Sleep Medicine, 11(8):931-952. doi:10.1176/appi.ajp.158.11.1856.

[3] Colten, H.R., & Altevogt, B.M. (Eds). (2006). Sleep Disorders and Sleep Deprivation: An Unmet Public Health Problem.  Institute of Medicine (US) Committee on Sleep Medicine and Research. Washington, DC: National Academies Press (US). doi: https://doi.org/10.17226/11617.

[4] Cappuccio, F.P., D’Elia, L., Strazzullo, P.,&  Miller, M.A. (2010). Sleep duration and all-cause mortality: a systematic review and meta-analysis of prospective studies. Sleep, 33(5):585-592

[5] For this clinical trial, the head-to-head comparison was with the 5 mg form; a 2 mg form of the comparator was not available.

[6] Zisapel, N. (2010). Melatonin and sleep. The Open Neuroendocrinology Journal, 3: 85-95.

[7] Among primary care physicians with a certification in sleep disorders who recommended a brand of modified-release melatonin. Quintiles IMS ProVoice July-September 2017 survey.


Physician’s Seal® and REMfresh® (www.remfresh.com)

Dr. David C. Brodner, Center for Sinus, Allergy, and Sleep Wellness (http://www.brodnermd.com/sleep-hygiene.html)

Other related articles published in this Open Access Online Scientific Journal include the following:


Ultra-Pure Melatonin Product Helps Maintain Sleep for Up to 7 Hours



Sleep Science

Genetic link to sleep and mood disorders



Sleep quality, amyloid and cognitive decline



Day and Night Variation in Melatonin Level affects Plasma Membrane Redox System in Red Blood Cells



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3D Printing Technique with Non-Contact Ultrasonic Manipulation Technology

Reporter: Irina Robu, PhD

The 3D printer we think more frequently in combination with PCBs is the DragonFly 2020 from Nano Dimension which works with different with all kinds of materials in addition to PCBs as they are a great 3D printing player in electronic space.

The Ultrasound Research group at Neurotechnology (http://www.neurotechnology.com) has proclaimed a new 3D printing method using ultrasonic manipulation which are totally hands off and non-contact tech behind it, permitting for the handling of parts and particles down to submillimeter range without causing damage to sensitive components. According to the project lead for Neurotechnology Ultrasound Research Group, Dr. Osvaldas Putkis, “Ultrasonic manipulation can handle a very large range of different materials, including metals, plastics and even liquids. Not only can it manipulate material particles, it can also handle components of various shapes. Other non-contact methods, like the ones based on magnetic or electrostatic forces, can’t offer such versatility”.

Since the work from the Ultrasound Research Group embodies a new technological application, Neurotechnology has filed a patent on their system. Neurotechnology describes ultrasonic manipulation as a “non-contact material handling method which uses ultrasonic waves to trap and move small particles and components.”  It is well known that ultrasonic manipulation of particles exploits the acoustic radiation force to deliver a contactless handling method for particles suspended in a fluid. In an ultrasonic standing wave field, the viscous torque induces the rotation of an object. Alongside the translation of particles due to the acoustic radiation force an additional controlled degree of rotation is obtainable. Consequently, there is a growing interest in spreading the field of application of ultrasonic particle manipulation to the deposition of micro and nanowires and for the assembly of micro objects.

Ultrasonic transducers are arranged in an array used to position electronic components in the creation of a PCB, utilizing a camera to detect accurate positioning. Continuing on with the hands-off theme, a laser solders the PCB components after their non-contact manipulation into placement. 3D printing and PCB manufacture are increasingly coming together, as advanced technologies benefit the creation of devices in electronics, including via 3D printed workstations for PCBs.

Even though their method works with all types of materials, we expect to see further applications beyond PCB assembly.


Neurotechnology Develops 3D Printing Method with Non-Contact Ultrasonic Manipulation Technology

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Swiss Paraplegic Centre, Nottwil, Switzerland – A World-Class Clinic for Spinal Cord Injuries

Author: Gail S. Thornton, M.A.

Co-Editor: The VOICES of Patients, Hospital CEOs, HealthCare Providers, Caregivers and Families: Personal Experience with Critical Care and Invasive Medical Procedures

The Swiss Paraplegic Centre (SPC, www.paraplegie.ch) in Nottwil, Switzerland, is a privately owned, leading acute care and specialist hospital employing more than 1,500 health professionals in 80 different occupations that focuses on world-class primary care and comprehensive rehabilitation of patients with spinal cord injuries. In addition to the SPC’s extensive range of medical and therapeutic care, treatment and services, the hospital offers advisory services, as well as research in the areas of paraplegia [paralysis of the legs and lower body, typically caused by spinal injury or disease], tetraplegia [also known as quadriplegia, paralysis caused by illness or injury that results in the partial or total loss of use of all four limbs and torso], prevention and related conditions. With 150 beds, the SPC provides modern facilities for rehabilitation and therapy, diagnostics, surgery, ongoing care, orthopedic technology, as well as social services and 24-hour emergency care.

In its 26-year history, the SPC has provided treatment and care to more than 20,000 in-patients. That number continues to grow exponentially due to the reputation of the SPC. In fact, the SPC’s staff performs their duties with effectiveness, expediency and cost-efficiency measures, requiring highly developed process-led medicine, centered around the needs of the patient.

The areas of medical specialty and centers of excellence include the Swiss Paraplegic Centre (SPC), the Swiss Spinal Column and Spinal Cord Centre (SWRZ), the Centre for Pain Medicine (ZSM) and the Swiss Olympic Medical Center (SOMC). These centers respectively offer patients cutting-edge medical treatment based on the most advanced research in areas covering treatment and rehabilitation cases of acute paraplegia, vertebral and spinal cord surgery, as well as services relating to pain management, sports medicine and preventive health checks.

Alongside the core focus on paraplegiology, the SPC is also equipped with the necessary medical facilities, allowing for the lifelong care of paraplegic patients. The SPC provides individually-tailored, comprehensive treatment in three phases (acute, reactivation and integration) using highly skilled staff and state-of-the-art equipment. The aim is always to re-establish a patient’s personal functionality, self-image and lifestyle to the fullest possible extent, with a holistic approach to treatment that includes mental, physical and psycho-social aspects, such as career, family and leisure activities.

Specialist services available at the SPC include amongst others orthopedics, neuro-urology, pain medicine, sports medicine, prevention, clinical research, emergency medicine, vehicle conversion and rehabilitation techniques. Medico-therapeutic treatments, such as physiotherapy, ergotherapy and training therapy are available, alongside advice and counseling services, such as professional reintegration.

The SPC is the largest of Switzerland’s four special hospitals for paraplegics and tetraplegics located in Nottwil/Lucerne, a town in central Switzerland on the shores of Lake Sempach. The other three facilities are in Basel, Sion and Zurich. Nowadays, the SPC consistently treats more than 60 percent of people with spinal cord injury in Switzerland and is fully occupied year-round. 

Image SOURCE: Photographs courtesy of Swiss Paraplegic Centre, Nottwil, Switzerland.  Interior and exterior photographs of the hospital.

Below is my interview with Hospital Director Dr. Med. Hans Peter Gmünder, M.D., which occurred in March, 2017.

 As a privately owned clinic with a specialty in the rehabilitation of patients with spinal cord injuries, how do you keep the spirit of research and innovation alive?

Dr. Med. (medicinae) Gmünder: The goal of the Swiss Paraplegic Foundation, an umbrella organization that encompasses the Swiss Paraplegic Centre, is to create a unique network of services for people with spinal cord injury, from primary care through to the end of their lives. Its aim is to provide comprehensive rehabilitation and to reintegrate those affected into family life, society and the working environment.

We want to maintain our pioneering and leading role in the fields of acute medicine, rehabilitation and lifelong assistance to people with spinal cord injuries. By providing a comprehensive network of services featuring solidarity, medical care, integration and lifelong assistance, as well as research all in one place, we are unique in Switzerland and in other countries around the world.

People with spinal cord injury rely upon our network of services, which are at their disposal throughout their lives. The challenge facing us is to continually adapt these services to reflect current research and treatment to comply with our mission of delivering high-quality services. The trust which has been placed in us obliges us to continue our success story.

We have our own research department, closely linked to the Swiss Paraplegic Centre, and dedicated employees who draw upon their wide-ranging professional networks to stay on top of the latest international research.

We have a few examples that we’d like to share with you.

  • In 2013, the World Health Organization (WHO) published its first international health report on the topic of spinal cord injury, “International Perspectives on Spinal Cord Injury.” It was developed in collaboration with Swiss Paraplegic Research in Nottwil and a team of international experts.
  • In the summer of 2014, the Swiss Paraplegic Centre became the first rehabilitation center in Switzerland to implement exoskeletons [external covering for the body that provides both support and protection] in the rehabilitation and training of patients with spinal cord injury. Our experiences are included in an international study, and will contribute to the development of useful mobility aids for people with spinal cord injuries.

At the end of October 2016, an estimated 9,000 visitors came to Nottwil for two days of celebrations to mark five anniversaries — the Swiss Paraplegic Foundation turned 40, the Swiss Paraplegics Association was 35, the Swiss Paraplegic Centre celebrated 25 years, Swiss Paraplegic Research reached 15 years, and it was the 80th birthday of the founder and honorary president, Dr. Med. Guido A. Zäch, M.D.

What draws patients to the Swiss Paraplegic Centre?

Dr. Gmünder: We support people with spinal cord injuries throughout their lives. It is the unique, holistic approach to acute medicine, rehabilitation and lifelong medical, professional and social assistance that draws patients from Switzerland and many other countries to our clinic in Nottwil.

For example, in cases where we have individuals involved in serious accidents, the comprehensive rehabilitation of a patient with spinal cord injury begins at the scene of the accident. The aim of comprehensive assistance follows in three stages – acute, reactivation and integration phase – through the appropriate, individual deployment of specialist personnel and instruments. We rescue the individual at the scene of the accident and provide the right acute therapy. What follows is an initial rehabilitation through specialists in diagnosis, surgery, therapy and care, and then comes lifelong support and care with the aid of specialists.

Following the disproportionately high percentage of people with tetraplegia admitted to the Centre for initial rehabilitation in 2014, our specialist clinic reported a higher proportion of people with paraplegia in 2015. Spinal cord injuries resulted from an accident in around half of all initial rehabilitation cases: falls led to the spinal cord injury in the case of 43 percent of people affected, sports accidents with 35 percent and road traffic accidents in 18 percent. In fact, 52,482 nursing days were clocked for a total of 1,085 in-patients who were discharged from the clinic after initial rehabilitation or follow-up treatment in 2015.

In fact, some of our patient success stories mentioned on our web site involve these individuals:

“I was a cheesemaker for 33 years with my own dairy; gardening was my second love. That was before I had my accident helping out on my son’s farm. I need a new hobby now that I will enjoy, that will fill my time and give me something to do when I get back home. Making art out of lime wood could appeal to me. While it is difficult for me to make the small cuts in the wood as I lack strength in my hand, patience will reap rewards. My most important objective? To be able to stand on my own feet and take a few steps again. I should have achieved that by the time I am discharged from the clinic in five months.” — Josef Kobler (58), tetraplegic following an accident.

“Since being diagnosed with a spinal cord injury, I come back to Nottwil a lot. For instance, to go the Wheelchair Mechanics Department to have the settings of my new wheelchair optimized. It replaces my legs and must fit my body perfectly. However, in most cases I attend the Centre for Pain Medicine of the SPC as an outpatient in order to have the extremely severe pains and muscle cramps, which I suffer from every day, alleviated. They became so severe that I had a pain pump with medication implanted at the SPC. It is apparent now that unfortunately the effect isn’t permanent. We are now giving electrostimulation a try. This involves applying electrodes to the vertebral canal. If I could finally get my pain under control, I would be able to return to work and set up my own business. That is my biggest wish. I have had an idea about what I could do.” — Hervé Brohon (41), paraplegic following an accident.

“I have always been passionate about cooking and have enjoyed treating my family and guests to my dishes and to the aperitifs that I have created myself. I absolutely want to be able to do that again. As independently as possible, of course. That is my objective. I have availed of the opportunity on a few occasions to try out the obstacle-free practice apartment and kitchen at the SPC. If I am able to go home in four weeks, my kitchen will also be adapted to be wheelchair-friendly. Whether I am cooking for two, four or six people is a much bigger consideration as a wheelchair user. I now have to consciously allow for time and effort. However, one thing is certain: I can’t wait to welcome my first guests.” — Isa Bapst (73), paraplegic following an accident.

How is the Swiss Paraplegic Centre transforming health care?

Dr. Gmünder: The Swiss Paraplegic Centre offers an integrated healthcare structure, including a wide range of medical specialists covering every aspect of medical care for those with spinal cord injuries.

In selected core disciplines for the care of people with spinal cord injuries, we also treat a large number of patients without spinal cord injuries. This relates primarily to pain medicine, spine- and spinal cord surgery and respiratory medicine.

In fact, the Swiss Paraplegic Foundation, our umbrella organization, has been an unbelievable success story, operating a network of services to benefit people with spinal cord injury.

Our Chairman of the Board of Trustees, Dr. Sc. Techn. (scientiae technicarum) Daniel Joggi, knows what it’s like to become totally dependent as he has been in a wheelchair for the past four decades.

Dr. Joggi tells his story: “I have been a wheelchair user ever since I had a skiing accident 39 years ago. I know what it is like to become totally dependent from one second to the next. How doggedly you have to battle to recover as much of your mobility as possible and, more especially, to be able to live a self-determined life again after a long process of resilience. The inner resolve it takes to plot a new course in life, to have relationships with others from a different perspective and to acquire new job skills. Therefore, I am eternally grateful along with all the other people in Switzerland with paraplegia and tetraplegia for the help, support and great solidarity that allow the Foundation to deliver all the services which are so immensely valuable to us.”

At the Swiss Paraplegic Centre, a 24-hour emergency department is staffed to handle any emergency. Please provide your thoughts on this critical component of diagnosis and care for newly diagnosed patients.

Dr. Gmünder: Yes, our Centre is recognized by the Swiss Union of Surgical Societies as a specialist clinic for first-aid treatment of paraplegics.

Statistics and experience clearly show that in 80 out of 100 cases, the damage to the spine and the spinal cord is not definite immediately after an accident. In the first six hours, there are real chances to mitigate or even avoid an imminent cross-paralysis. After that it is usually too late.

In addition to transferring an individual directly to the SPC, appropriate acute care is another important criterion for the success of the individual affected by spinal cord issues. That means that individuals are in the right place for the subsequent, comprehensive rehabilitation.

The benefits for our patients are:

  • Emergency service around the clock by specialists trained to minimize damage to the spinal cord and spine;
  • Admission and treatment of all patients with paraplegia from all over Switzerland;
  • Specific knowledge and practical experience in comprehensive rehabilitation of paraplegics;
  • Comprehensive range of medical and therapeutic services under one roof;
  • Modern equipment for precise, careful diagnostics and operations;
  • Consultancy and network for external experts in areas not covered by the SPC;
  • Interdisciplinary work in well-established teams; and
  • Central location proximity and quick access from all parts of the country.

What is your connection to the Swiss Paraplegic Research and its mission of getting “strategy into research” and “research into practice?”

Dr. Gmünder: The Swiss Paraplegic Research (SPR), connected to the Swiss Paraplegic Centre, is part of the Swiss Paraplegic Foundation (SPF) and is an integral part of the Nottwil campus.

It is the mission of Swiss Paraplegic Research to sustainably improve the situation of people with paraplegia or tetraplegia through clinical and interdisciplinary research in the long-term. The areas that are aimed to be improved are functioning, social integration, equality of opportunity, health, self-determination and quality of life.

Our Swiss Paraplegic Research has been supported by the Federal Government of Switzerland and by the Canton of Lucerne for eight years as a non-university research institution. We are proud of this accomplishment.

Our main research domains are in the areas of aging, neuro-rehabilitation, musculo-skeletal health, preserving and improving function of upper limbs, pain, pressure sores, respiration, urology and orthopedics.

The goal of Swiss Paraplegic Research is to promote the study of health from a holistic point of view, by focusing on the ‘lived experience’ of persons with health conditions and their interaction with society. We are, therefore, establishing a research network for rehabilitation research from a comprehensive perspective on a national and international level. This network will make it possible to practically apply the latest research findings to provide the best possible care and reintegration for people with paraplegia or tetraplegia.

This year, we received the approval of 18 new research projects and we had a total of 36 studies in progress under review, undertaken by and with the involvement of the Clinical Trial Unit (CTU), the department for clinical research at the Centre. For example, the successful implementation of a multi-center study on the use of walking robots (exoskeleton) merits special mention. Research was carried out in that study into the wide range of effects of maintaining movement for people with spinal cord injury.

The CTU will continue to carry out research in Rehabilitation Engineering in a cooperation with Burgdorf University of Applied Science and the research group headed by Professor Kenneth Hunt. The “Life and Care” symposium on breathing and respiration organized by the CTU provided a platform for an international knowledge exchange with national and international experts. This is crucial for further scientific development in respiratory medicine. In 2015, the CTU also launched the CTU Central Switzerland, in association with Lucerne Cantonal Hospital and the University of Lucerne. It supports clinics which are actively engaged in research with specific services, thereby enhancing Switzerland’s standing as a center of research.

How does the Swiss Paraplegic Foundation support your vision?

Dr. Gmünder: The Swiss Paraplegic Group includes the Swiss Paraplegic Foundation, which was established in 1975, two partner organizations — the Benefactors’ Association and the Swiss Paraplegics Association, and six companies owned by the Foundation. Those six companies are the Swiss Paraplegic Centre, the Swiss Paraplegic Research, Orthotec AG, ParaHelp AG, Sirmed Swiss Institute of Emergency Medicine AG, Seminarhotel Sempachersee AG.

The Swiss Paraplegic Foundation, founded by Dr. Med. Guido A. Zäch in 1975, is a solidarity network for people with spinal cord injuries, unrivaled anywhere in the world. Its work is based on the vision of medical care and comprehensive rehabilitation for people with paraplegia and tetraplegia, with a view towards enabling them to lead their lives with self-determination and with as much independence as possible, supported by the latest advances in science and technology.

The unique network of services of the Foundation is a strategic mix of Solidarity, Research, Medicine and Integration and Lifelong Assistance. Let me elaborate on these services.

  • Solidarity
    • The Foundation provides a comprehensive range of services for every area of a person’s life who has a spinal cord injury. The Nottwil campus serves to be a center of excellence for integration, assistance and lifelong learning for our patients.
    • The Foundation ensures that its benefactors and donors are aware of our list of services and can support us longer term.
    • The Foundation establishes a national and international network that will guarantee better basic conditions for people with spinal cord injury.
    • The Foundation encourages training of specialized personnel in the field of spinal cord injury.
  • Research
    • The Foundation contributes to the sustainable improvement of health, social integration, equal opportunities and self-determination of people with spinal cord injury by carrying out rehabilitation research.
    • The Foundation works closely with the World Health Organization (WHO) and encourages exchanges with universities and institutions locally and globally for the latest scientific findings and conducts academic training at the University of Lucerne.
    • The Foundation develops high-quality care standards for its patients.
  • Medicine
    • The Foundation offers all medical services needed for professional acute care and rehabilitation of people with spinal cord injury and encourages patients to become involved in their therapy and to take responsibility for their lives.
    • The Foundation strengthens relationships with partners in specific disciplines and local institutions to benefit people with spinal cord injury.
    • The Foundation is a member of committees with political influence to ensure that its patients receive highly specialized medical care.
  • Integration and Lifelong Assistance
    • The Foundation establishes a network throughout Switzerland to help people with spinal cord injury.
    • The Foundation offers comprehensive services to meet people’s needs to improve their integration into society.
    • The Foundation encourages people with spinal cord injury to lead an independent life and educate family and friends so they can provide the necessary support.

Moreover, in cases of hardship, the Foundation makes contributions towards the cost of walking aids, equipment and amenities for people with paraplegia and tetraplegia. It also takes on uncovered hospital and care costs.

 Current market research shows that the Swiss Paraplegic Foundation ranks among the three most highly rated aid organizations in Switzerland. Can you please elaborate on why?

Dr. Gmünder: That is true. The Foundation is highly rated in terms of goodwill, innovation, competence and effectiveness. In addition, it is regarded as undoubtedly the most competent organization representing people with disabilities in Switzerland, according to several market research surveys.

So that we can continue to meet the demand for our patients, families and other visitors, plans are under way to upgrade our clinic and hotel on our premises.

We generally have interest from visitors to visit our Centre. Our guided tours and events enabled the general public to see how the foundation concept is put into practice, day in, day out. In Nottwil, 160 guides provided more than 11,000 visitors with a glimpse into the operations at our specialist clinic.

Additionally, we organized more than 5,000 scientific meetings attended by more than 170,000 people in 2015. And our wheelchair athletes take part in two major competitions, the IPC Athletics Grand Prix and the UCI Para-cycling World Championships, at our Nottwil site. It is our hope to continue to motivate individuals with spinal cord injuries to be involved in healthy exercise.

Since you became Hospital Director, how have you changed the way that you deliver health care or interact with patients?

Dr. Gmünder: It is important to me that the patients and their needs are the focus of our efforts. As such, one of my main tasks is to align our processes with our patients.

Here are some examples:

We started construction with a newly expanded Intensive Care Medicine, Pain Medicine and Surgical Medicine department last year to provide patients with an expanded variety of cross-linked treatments.

Certified as a nationwide trauma center, our Swiss Spinal Column and Spinal Cord Centre has become increasingly recognized throughout the country with large numbers of non-paralyzed patients, who have severe spinal cord injury, being referred to our facility. It is under the medical leadership of the Head of Department Dr. Med. Martin Baur, M.D. This highly specialized acute care facility recently received certification as a specialist center for traumatology within the Central Swiss Trauma Network.

We believe in developing the next generation of professionals and our Department of Anesthesia was recognized as a center of further training; the first two junior doctors have been appointed and postgraduate courses in anesthesia nursing are already available.

Our Swiss Weaning Centre, where individuals learn to breathe without a machine, has brought specialists from Intensive Care Medicine, Speech Therapy, RespiCare and Spinal Cord Medicine even closer together in a new process structure for respiratory medicine. At the same time, the Swiss Weaning Centre reported increased referrals from university hospitals and private clinics, as well as numerous successes with patients who had proved to be difficult to wean from respiratory equipment.

Our Centre for Pain Medicine, one of the largest pain facilities in the country, reported a further increase in inpatient treatments. Epiduroscopy, which was introduced in 2014, has proved to be a success. It is a percutaneous, minimally invasive procedure which is used in the diagnosis and treatment of pain syndromes near the spinal cord.

We reached a milestone in tetra hand surgery. The team of our doctors has been consulting at two other spinal cord injury centers and have used these occasions to show doctors around the country what possibilities there are for improved hand and grip functions, leading to an enhanced quality of life.

In what ways do you rehabilitate the whole patient? Why is this important early on in treatment?

Dr. Gmünder: In accordance with our vision, we are not just focusing on physical rehabilitation but on the entire person in their social environment (leisure, work, housing, mobility). Due to our broad organizational structure, we have many resources at our disposal. The rate of reintegration for people who did their primary rehabilitation at the Swiss Paraplegic Centre is almost 65 percent – one of the highest in the world.

Because we work to address diagnosis, treatment and management of traumatic spinal cord injuries with our patients, we take great care in working with patients on their medical disabilities, physical disabilities, psychological disabilities, vocational disabilities, social aspects and any health complications. That means that we not only treat patient’s medically, but also we treat them through therapy and complementary medicine, such as art therapy, sports and water therapy and homeopathic medicine.

At the SPC, we nurture a culture which is characterized by common values and shared objectives, namely commitment, leadership, a humane approach, cooperation and openness and fairness in our dealing with one another and with our patients.

As you follow patients throughout their rehabilitation and treatment, what are you most proud of at the Centre? 

Dr. Gmünder: Research has shown that early referral of a patient with a traumatic spinal injury lessens the complications, shortens the length of time in the hospital and is, therefore, more cost-effective.

We are confronted by individuals every day whose abilities have been limited by disease, trauma, congenital disorders or pain – and we are focused on enabling them to achieve their maximum functional abilities. Our patients have a better outcome and quality of life, patient-focused treatment, ongoing case management, and lifelong care.

It’s important to emphasize that our comprehensive rehabilitation of individuals with spinal cord injuries begins on the first day after the accident or trauma. On one hand, the medical treatments with paraplegia or tetraplegia are performed by a multidisciplinary medical team. And on the other hand, it is our goal to give those individuals their personality and life structure as quickly – and as best – as possible. An individual’s medical condition affects their psychological, physical and social aspects of life.

We focus on individualized treatment for the greatest possible independence for our patients. When patients are satisfied with our work and its results, they can resume a self-determined life. That is our greatest joy.

Hans Peter Gmuender

Image SOURCE: Photograph of Hospital Director Hans Peter Gmünder, M.D., courtesy of Swiss Paraplegic Centre, Nottwil, Switzerland.

Hans Peter Gmünder, M.D.
Hospital Director

Hans Peter Gmünder, M.D., assumed the role of Hospital Director of the Swiss Paraplegic Centre in 2011.  He is a German-Belgian double citizen.

Previously, Dr. Gmünder was Chief Physician and Medical Director of the Rehaklinik Bellikon, a rehabilitation and specialist clinic for traumatic acute rehabilitation, sports medicine, professional integration and medical expertise for 10 years in the canton of Aargau, Switzerland. He began his career at the Swiss Paraplegic Centre in the 1990s as Assistant and Senior Physician, and later as Chief Physician and Deputy Chief Physician.

He completed a B.S. degree in Business Administration at SRH FernHochschule Riedlingen in 2010 and an M.D. degree at Freie Universität Berlin in 1987.

He is married to Sabeth and is the father of two children.

Editor’s note:

We would like to thank Claudia Merkel, head of public relations, Swiss Paraplegic Centre,  for the help and support she provided during this interview.


The Swiss Paraplegic Centre (http:// www.paraplegie.ch), Nottwil, Switzerland.

Choosing the right rehabilitation facility is one of the most important decisions a survivor of a brain or spinal cord injury will make as the type and quality of care will have a significant impact on the patient’s long-term outcome. The top 10 rehabilitation centers in the United States are (http://www.brainandspinalcord.org/2016/04/15/top-ten-rehabilitation-hospitals-usa/):

  1. Rehabilitation Institute of Chicago
  2. TIRR Memorial Hermann
  3. Kessler Institute for Rehabilitation
  4. University of Washington Medical Center
  5. Spaulding Rehabilitation Hospital, Massachusetts General Hospital
  6. Mayo Clinic
  7. Craig Hospital
  8. Shepard Center
  9. Rusk Rehabilitation at NYU Langone Medical Center
  10. Moss Rehab

The Rehabilitation Institute of Chicago (https://www.sralab.org/new-ric), located in Chicago, Illinois, has been ranked as the number one rehabilitation hospital in the United States for the past 24 years by U.S. News and World Report. It is a 182-bed research facility that focuses solely on rehabilitation in many areas, including spinal cord, brain, nerve, muscle and bone, cancer and pediatric. For example, the rehabilitation course for patients with spinal cord injury requires precise medical and nursing expertise, respiratory and pulmonary care and sophisticated diagnostic and therapeutic equipment. For several years, the hospital has dedicated investments in talent, space and equipment that attract a high volume of patients with challenging conditions. The high volume, diversity of condition and greater complexity enables them to expand their experience in helping patients recover from spinal cord injury. Primary goals for patients include the emergence of meaningful motor function, sensation, coordination and endurance, resolution of respiratory and vascular instability, and overall continued medical recovery from the injury or disease.

The Spaulding Rehabilitation Hospital Boston (http://spauldingrehab.org/about/facts-statistics) is ranked number five in the country by U.S. News and World Report and number one in New England.  As a unique center of treatment excellence and a leading physical medicine and rehabilitation research institution, Spaulding Boston is comprised of major departments in all areas of medicine requiring rehabilitation. They are a nationally recognized leader in innovation, research and education.  The facility also has been the source of significant treatment innovations with dramatic implications for a range of conditions, including amputation and limb deficiencies, brain injury, cardiac rehabilitation, pulmonary rehabilitation and spinal cord injuries, to name a few. http://spauldingrehab.org/conditions-and-treatments/list.

Whether individuals are adjusting to a life-altering illness or recovering from a back injury, they will find the care they need within the Spaulding Rehabilitation Network.  Rehabilitation specialists have the training, experience, resources and dedication to help individuals:

  • Regain function after a devastating illness or injury,
  • Develop skills to be active and independent when living with chronic illness and/or disability,
  • Recover from surgery, work and sports injuries, and
  • Grow to the fullest physical, emotional, cognitive and social potential. http://spauldingrehab.org/conditions-and-treatments/

The ACGME accredited Harvard Medical School/ Spaulding/ VA Boston Fellowship Program in  Spinal Cord Injury (SCI) Medicine is a 12-month training program that offers advanced clinical training in SCI, a strong didactic component, and opportunities for research with protected elective time.  The curriculum is designed to provide exposure to the full spectrum of SCI care and includes rotations at VA Boston, Spaulding Rehabilitation Hospital, and Brigham & Woman’s Hospital. Requirements include prior completion of an approved residency program in a specialty such as physical medicine and rehabilitation, neurology, internal medicine, family practice, surgery, or other specialties relevant to spinal cord injury.  http://spauldingrehab.org/education-and-training/spinal-cord-fellowship.

Specifically, the Spaulding Rehabilitation Network is at the forefront of innovative treatment for major disabling conditions, including spinal cord injury (SCI), traumatic brain injury (TBI), other traumatic injuries, stroke, and neuromuscular disorders such as multiple sclerosis, cerebral palsy, and Parkinson’s disease. At Spaulding, the treatment goals go far beyond immediate rehabilitation to address long-term health and function, as well as giving patients encouragement and hope as they return to their lives in the community.

The hub of their spinal cord injury program is the Spaulding-Harvard Spinal Cord Injury Model Systems (SCIMS) Rehabilitation Program, led by experts at Spaulding Boston, a Center of Excellence in spinal cord injury rehabilitation. With the guidance of their  physicians and other rehabilitation specialists and access to some of the most advanced technologies available today, their patients have the resources to strive for their highest level of neurorecovery – and to develop successful, enriching strategies for independent living.

When potentially life-altering spinal cord injury occurs, the Spaulding Rehabilitation Network clinicians are dedicated to pioneering improved therapies that can make all the difference to a patient’s immediate and long-term recovery. Their goal is to support a patient’s return to an active, productive and fulfilling life.

Whether the spinal cord injury is due to traumatic injury or illness, their team of experts will develop a treatment plan in collaboration with the patient and family. Depending on the severity of the injury, their teams work on improving function in: walking, balance and mobility; speech, swallowing and breathing; thinking (cognition), behavior and safety; dressing, bathing and other activities of daily living; incontinence, bowel and bladder function.

Their commitment is to offer a full spectrum of rehabilitation services for adults and children with spinal cord injury:

  • Intensive, hospital-level rehabilitation with goal-directed therapy 3 – 5 hours a day, at least 5 days a week for inpatients.
  • Long-term care and rehabilitation for patients with complicating conditions.
  • Cutting-edge spinal cord injury technologies and therapeutic techniques.
  • Emphasis on family participation throughout the course of care. with an inpatient comprehensive training and education series.
  • Seamless transition to multi-disciplinary outpatient rehabilitation.
  • Coordination of care with Spaulding’s outpatient centers.
  • Vocational training, participation in research, support groups.

Spaulding Rehabilitation Network is the official teaching partner of the Harvard Medical School Department of Physical Medicine and Rehabilitation (PM&R). The Spaulding network’s facilities are members of Partners HealthCare, founded by Massachusetts General Hospital and Brigham and Women’s Hospital. The knowledge and expertise of this entire healthcare system is available to patients and caregivers. Their continuum of superb healthcare ensures that patients will find the care they need throughout their journey and the strength they need to live their life to the fullest.

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Other related articles were published in this Open Access Online Scientific Journal include the following:


Use of Sensors, Data and Devices to improve Health, San Francisco, April 5-6, 2016: Wearable Tech + Digital Health Conferences


New Spinal Cord Repair Strategy using 3D Cell Growth

Unsupervised, Mobile and Wireless Brain–Computer Interfaces on the Horizon

Diffuse optics detects spinal cord ischemia – Optics.org

Essential for Rehabilitation

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A New Standard in Health Care – Farrer Park Hospital, Singapore’s First Fully Integrated Healthcare/Hospitality Complex

Author: Gail S. Thornton, M.A.

Co-Editor: The VOICES of Patients, HealthCare Providers, Caregivers and Families: Personal Experience with Critical Care and Invasive Medical Procedures

Farrer Park Hospital, Singapore’s newest private healthcare service provider, headed by newly appointed Chief Executive Officer Timothy Low, M.D., is a private, acute tertiary institution that represents an innovation in hospital administration, incorporating the latest technology to support better decision making for better patient outcomes and shorter hospital stays along with the beauty of nature and art to enhance the patient experience. The hospital, opened in March 2016, is sited within Singapore’s first, fully integrated healthcare and hospitality complex, called Connexion, which is Asia’s first, integrated lifestyle hub for healthcare and wellness. Connexion houses the 220-bed Farrer Park Hospital with its more than 300-accredited specialists and 18 operating rooms, a 10-floor specialist Medical Center, along with a five-star hotel and spa. In 2016, Farrer Park Hospital was awarded best new hospital of the year in Asia Pacific by Global Health and Travel Awards.

Farrer Park Hospital at Connexion at night

Image SOURCE: Photograph courtesy of Farrer Park Hospital, Singapore. An integrated healthcare and hospitality complex, called Connexion, Asia’s first, integrated lifestyle hub for healthcare and wellness, which includes Farrer Park Hospital.  

The hospital is also a teaching site for undergraduate medical training, providing enhanced medical care, service quality and professional integrity and value. Supported by approximately 600 hospital staff, specialists at Farrer Park Hospital provide a range of services, such as cardiology, oncology, orthopedic surgery, gastroenterology and ophthalmology. A 24-hour emergency department provides attention for acute illnesses and the hospital has the most modern facilities for diagnostic imaging, nuclear medicine, radiotherapy and clinical laboratories.

Image SOURCE: Photographs courtesy of Farrer Park Hospital, Singapore. Left is a deluxe suite, top right is Farrer Park Hospital lobby, bottom right is Farrer Park Hospital building.

Medical tourism — the process of traveling outside your country of residence to receive medical care — represents a worldwide, multi-billion-dollar business that is expected to grow considerably in the next decade. Interestingly, Singapore’s medical tourism market is projected to grow by 8.3 percent annually and reach revenue of USD $1.36 billion a year by 2018.

My first question is: Why has Singapore emerged in the past few years as an international healthcare and research hub?

Dr. Low:  With Singapore’s excellent patient services and its dedication to research and wellness, the country continues to remain as the top destination for those seeking medical care. By providing convenience and trust in our medical sector, there is no doubt that it will continue to expand and grow. Our dedication is towards the patient, cutting-edge technology and personalized care. This makes Singapore a multi-faceted medical hub and a center of excellence. Patient can receive excellent standard of medical treatment, comparable to the Europe and the USA.

Currently, we are attracting foreign patients who expect five- or six-star hotel service, because we’re a private hospital. That’s why I’m strict about appearances. We have to look as groomed, and we need to be as personable, as those in hospitality and the airlines.

Please describe the concept behind Farrer Park Hospital as Singapore’s first, fully integrated healthcare and hospitality complex.

Dr. Low: The Farrer Park Hospital was designed and built to be a hospital of the future, combining innovation in medical care and medical education. The hospital was initially created by medical specialists to respond to the growing challenges of healthcare in Singapore and, more broadly, throughout the Asia Pacific region. We have ‘reimagined’ private healthcare in order to enhance medical care, service quality, professional integrity and value.

We are leading the way in healthcare innovation as we are a premier institution for medical care and education that is based upon three important tenets for the patient — comfort, fairness and value. In fact, our top accredited medical staff, along with state-of-the-art equipment and technology, contributes to increased efficiency, reduced cost, and most, importantly improved patient outcomes.

As an innovation in hospital administration, Farrer Park Hospital embraces technology and improves medical care through its state-of-the-art equipment that facilities telemedicine consulting services across the world. To create a conducive environment for medical professionals, the hospital’s 18 operating rooms are linked via fiber-optic connections to various locations through the Connexion complex, including the hospitals’ education center and lecture hall, teaching clinics and tutorial rooms as well as the hotel’s function rooms. In addition to being equipped with the latest in useful medical technology, the hospital has state-of-the-art information technology which enables seamless and rapid flow of information between the admission services, inpatient areas, operating theaters, diagnostic and therapeutic centers, clinical laboratories and medical clinics. We also are the country’s first private hospital to become a teaching site, with the medical students from Lee Kong Chian School of Medicine at Nanyang Technological University.

What is the type of environment you are creating at Farrer Park Hospital?

Dr. Low: Our care philosophy extends beyond healing and the management of disease to engaging with our patients as partners in pursuit of good health and providing an oasis for healing and relaxation. Throughout our facility, patients will find that attention has been given to every aspect and detail of our facility – from the comfort of our patients, to its impact on the environment, to the speed and ease of obtaining medical attention and to the maintenance of hygiene.

As healthcare players go, we are small and that has made us very aware of our challenges. As such, we have encouraged a culture of innovation, to grasp opportunities quickly. Healthcare is a very traditional industry, resistant to change and thus tend to be laggards in technology. Farrer Park Hospital, however, embraces technology. The seamlessness of information flow was the focus at the onset of the project. This hospital was planned technologically to be relevant for the next 20 years.

Being an institution built by healthcare practitioners has its advantages. We achieve painstaking perfection in our attention to detail. The hospital has many practical features that serve the needs of practitioners and patients while the hoteliers add details for comfort, luxury and aesthetics.

Our hospital is also supported by a hospital staff, who provide a range of specialty services, such as cardiology, oncology, orthopedic surgery, gastroenterology and ophthalmology, along with a 24-hour emergency clinic, which provides immediate care for acute illnesses. The hospital also has the most modern facilities for diagnostic imaging, nuclear medicine, radiotherapy and clinical laboratories. There is even a holistic service which focuses on screening, preventive medicine and lifestyle enhancement.

What is your perspective of engaging with patients?  

Dr. Low: The hospital’s care philosophy extends beyond healing and the management of disease to engaging patients in pursuit of good health. Healing does not end after a successful operation. It is not just about coming to the hospital for a procedure and then recuperating at home. It is about having the best and most comfortable services to get the patient on their feet. And having a family support structure close by, where relatives can stay close to the hospital, is essential in the rehabilitation process. That is why, as part of Connexion, the hospital is Asia’s first, integrated lifestyle hub for healthcare and wellness that is linked to a five-star hotel and spa.

Patients are treated by an experienced team of medical and health specialists in an environment meticulously designed to maximize comfort and efficiency while promoting well-being, rest and recovery.

How are you positioned technologically to be a leader in developing first-rate patient care? 

Dr. Low: We have taken the lead in many areas. Our facility is wired completely, any tests and treatments is automated whenever possible and the information is sent in real time to all stakeholders who require it. Our doctors can access this technology and make decisions as if they are in the hospital anywhere in the world.

What type of physician are you attempting to attract?

Dr. Low: The environment at Farrer Park Hospital is about clinical and service excellence, supported by physical and technological constructs that facilitates both these endeavors. We are building a culture of fairness and promoting decision making that is free from self-interest and toward better patient outcome. The doctors who join us must be aware that we take our code of comfort, fairness and value seriously.

What is the thinking behind the philosophy of incorporating nature and art into healthcare in Farrer Park Hospital?

Dr. Low: The architecture of Farrer Park Hospital and Connexion reflects the deep commitment to creating a true learning environment. Synergies between our hospital along with a closely linked hotel stimulate many innovations for improving the healthcare experience. The concept of a hospital near a hotel is not new, however, to integrate it to the level that we have is something novel. We followed a biophilic architecture approach throughout the facility, incorporating nature and art to enhance healing. Hospitals are traditionally not the best place for recuperation. We strive to have the restful ambiance of a hotel, in addition to proximity of doctors and family under the same roof, as well as using technology to enable seamless and speedy decision making; all this in support of better patient outcome and shorter stays.

You could say we are different in how we view private healthcare. A traditional hospital would not carve out 15 gardens at multiple levels throughout the facility so that patients and families can have places to feel the warmth of the sun and breathe fresh air whenever they like. The facility also hosts a private collection of over 700 commissioned Asian paintings meant to enhance the healing environment.

In land-scarce Singapore, a typical businessperson would not have fewer paid parking lots, making them one and a half times the size of a standard lot to allow a patient on crutches to comfortably extend the car door fully to disembark. A standard project manager would not insist that contractors construct a curved sink so that surgeons will not have water dripping down his elbows after scrubbing his or her hands, or a bath bench with a cut out that allows patients to sit while washing themselves. This may seem unnecessary but these innovative approaches translate to actual benefits to people who ‘value’ them.

Everyone has the same end goal, a good experience and better patient outcome. Our strategy is simple. We take our responsibilities to patients, their families and the clinicians seriously. Attend to their needs, anticipate their wants, and find the best way to address these concerns through innovation and technology. This ultimately brings value to patients.

How does nature and art come together at Farrer Park Hospital?

Dr. Low: The hospital, hotel and specialist center share and enjoy 15 gardens created at multiple levels in the building. One of the gardens, The Farm @ Farrer, grows fruits, vegetables and herbs for the hotel kitchens, and at the same time, is a large outdoor green space for recovering patients to stroll and sun. Uniquely, Farrer Park Hospital patients enjoy meals prepared by chefs in the hotel’s kitchens and confectionery.

Our inpatient food service, for example, is also automated, so whatever appears on the electronic screen on a patient’s personal tablet matches their dietary restrictions. The menu is a matrix of over 200 items customized by hotel chefs and our hospital nutritionist. Food that is fresh, delicious and safe for patient consumption is our primary focus.

Not only do we benchmark ourselves with hospitals, but also we take our inspiration from other industries. We believe to be at the top, you need to look beyond, break through and recreate process models and apply them for use in healthcare.

Dr. Timothy Low Photo

Image SOURCE: Photograph of Chief Executive Officer Timothy Low, M.D., courtesy of Farrer Park Hospital, Singapore.

Chief Executive Officer of Farrer Park Hospital, Timothy Low, M.D., brings a strong leadership background in managing award-winning hospitals. Prior to his current role, Dr. Low served as CEO of Gleneagles Hospital in Singapore. Through his leadership, the hospital established itself as a six-star private healthcare provider, clinching 14 local and regional awards including the prestigious Asian Hospital Management Award as well as the the ‘National Work Redesign Model Company’ by Spring Singapore, a governing agency for innovation in Singapore. Under his leadership, revenues exceed 42 percent to over USD $100 million.

Having also served in senior management positions for pharmaceutical and medical device industries in the Asia Pacific region, Dr. Low’s breath of exposure allowed him to pioneer the establishment of a global contract research organization, validating Singapore as its regional headquarters.

With more than 28 years of experience in the health care industry with such leading companies as Covidien, Covance and Schering-Plough, Dr. Low brings with him a strong background of leadership within the business and medical community. With his vast experience and contributions to the industry, Dr. Low is listed in the ranks of Stanford Who’s Who.

Dr. Low received his Bachelor of Medicine and Bachelor of Surgery from the National University of Singapore (NUS) and is also a graduate of the NUS Graduate School of Business, Stanford University Executive Program and the Singapore Management University Asia Pacific Hospital Management Program.


Tan, W. (2016). Farrer Park Hospital patients can recuperate at adjoining hotel to ease ward crunch. The Straits Times. Retrieved from  http://www.straitstimes.com/singapore/health/farrer-park-hospital-patients-can-recuperate-at-adjoining-hotel-to-ease-ward-crunch

Tan, W. (2016). New Farrer Park Hospital aims to offer ‘affordable’ private care. The Straits Times. Retrieved from http://www.straitstimes.com/singapore/health/new-farrer-park-hospital-aims-to-offer-affordable-private-care


Anonymous (2012). Singapore Medical Tourism: Farrer Park Healthcare and Hospitality Complex Will Open in 2013. International Medical Travel Journal. Retrieved from http://www.imtj.com/news/singapore-medical-tourism-farrer-park-healthcare-and-hospitality-complex-will-open-2013/

Retrieved from http://news.asiaone.com/news/yourhealth/farrer-park-hospital-appoints-new-ceo

Retrieved from http://today.mims.com/topic/farrer-park-hospital-opened-with-a-call-for-healthcare-changes-to-adapt-for-an-ageing-population-

Retrieved from http://www.farrerpark.com/hospital/Pages/Home.aspx

Retrieved from http://www.straitstimes.com/singapore/health/new-farrer-park-hospital-aims-to-offer-affordable-private-care

Retrieved from http://www.bca.gov.sg/friendlybuilding/FindBuilding/Building.aspx?id=4534

Retrieved from http://www.ttgasia.com/article.php?article_id=23292

Other related articles were published in this Open Access Online Scientific Journal include the following: 


Third Annual BioPrinting and 3D Printing in the Life Sciences, 21-22 July 2016 at Academia, Singapore General Hospital Campus


Patient Satisfaction with Hospital Experience


Cardiac Surgery Theatre in China vs. in the US: Cardiac Repair Procedures, Medical Devices in Use, Technology in Hospitals, Surgeons’ Training and Cardiac Disease Severity 

Risk Factor for Health Systems: High Turnover of Hospital CEOs and Visionary’s Role of Hospitals In 10 Years

Hospitals in China

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Reporter: Aviva Lev-Ari, PhD, RN

Vinod Khosla of A Khosla Ventures investment, in a Fortune Magazine article, “Technology will replace 80% of what doctors do”, on December 4, 2012


 Vinod Khosla is the founder of Khosla Ventures, a venture capital firm in Menlo Park, CA. A longer version of this story can be found here on its website.

The Longer Version:

“20% doctor included”: speculations & musings of a technology optimist

by Vinod Khosla


In recent talks at the University of California, San Francisco and other venues, I laid out my thesis on how mobile devices, big data, and artificial intelligence will disrupt healthcare. I believe it is inevitable that the majority of physicians’ diagnostic and prescription work (physicians do other work too) will be replaced with smart hardware and software, and healthcare will become better, more consistent across physicians, and more scientific. The remaining 20% of physicians’ work will be AMPLIFIED, giving them better capability. Given the importance of having clarity on what I hypothesized (my forecasts are directional guesses rather than precise predictions) about how healthcare might change, I’d like to make clarify my views and respond to some of the recent commentary.

Let me start with a summary:

  1. Healthcare today is often really the “practice of medicine” rather than the “science of medicine”. In the worst cases of the practice of medicine, doctors just take moderately educated shots in the dark when it comes to patient care. Physicians should be much more scientific and data-driven. That’s hard for the average physician to pull off without technology, because of the increasing amount of data and research released every year. Next-generation medicine will be the scientific arrival at diagnostic and treatment conclusions and real testing of what’s actually going on in your body. And, it will be much more personalized than your physician can provide. Data science will be key to this.
  2. Technology makes up for human deficiencies and amplifies strengths – MDs and even other less trained medical professionals can do much more than they do now. By 2025 more data-driven, automated healthcare will displace up to 80% of physicians’ diagnostic and prescription work. It will AMPLIFY physicians by arming them with more complete, synthesized, and up-to-date research data, all leading to better patient outcomes. Computers are much better than people at organizing and recalling information. They have larger and less corruptible memories, remember more complex information much more quickly and completely, and make far fewer mistakes than a hot shot MD from Harvard. Contrary to popular opinion, they’re also better at integrating and balancing considerations of patient symptoms, history, demeanor, environmental factors, and population management guidelines than the average physician.
  3. The healthcare transition will start incrementally and develop slowly in sophistication, much like a great MD who starts with seven years of med school and then spends a decade training with the best practitioners by watching, learning, and experiencing. Expect many laughing-stock attempts by “toddler MD computer systems” early in their evolution and learning. These systems will grow with the help of the top MDs and AMPLIFY them so everyone can have the best, most researched care, not the average, overburdened, and rushed doctor the average person gets today!  In fact, the very best MDs will be an integral part of designing and building these advanced systems.
  4. The systems of 10-15 years from now (which is the time frame I am talking about) will overcome many of the short-term deficiencies of today’s technologies. By analogy, using today’s technology then would be like our carrying the multi-pound phones from 1987 (they were floor mounted cell phones with big handsets and heavy cords) in our pockets rather than iPhones. There will be point innovations that seem immaterial, but, when there are enough of them, they will integrate with each other and start to feel like a revolution. In the meantime, expect these early systems and tools to be the butt of jokes from many a writer or MD. Early printers, typically “dot matrix”, did not exactly cut it for business correspondence, let alone replace traditional means. Early medical systems will be used in non-critical roles or under physician supervision. Eventually, this shift in how healthcare is delivered will allow for less money to be spent on capital equipment, cutting health care costs. It will allow us to provide care to those who don’t have it now. And, it will prevent simple things from getting worse before being addressed.
  5. The human element of care, provided by humane humans, not rushed, overloaded MDs, will still be around. These people may have MDs anyway, but they won’t need ten or twenty years of medical school training. Or, when they have the training, they will become much better diagnosticians and caregivers. Beyond diagnosis and treatment, there are many things doctors do that won’t be replaced.
  6. The problem in healthcare is not with doctors, many of whom are accomplished, caring, honest, and compassionate providers. The problem is the incredible increase in complexity of the newly enabled data (some extrinsic), vast amounts of research, longitudinal health records, and histories without the self-reporting inaccuracies of the patient that allows for the much more integrative analysis that is now possible.  The problem is also the misalignment of incentives in medicine, where organizations try to maximize revenue (extra surgeries anyone?) at the expense of optimizing care. This is why innovation will most likely happen from the outside. It is also important to realize that I refer to the “AVERAGE GLOBAL doctor” or healthcare concern, not every doctor or company. The standards of performance in some parts of the world and in some parts of this country are very different than those in the best metropolitan hospitals in the United States. I also note that 50% of MD’s are below average though every doctor most people  know is above average!


Practice vs. science

One of my principal concerns about healthcare today is that it’s often really the “practice of medicine” rather than the “science of medicine”. Take modern medicine’s view towards fever as an example. For 150 years, doctors have routinely prescribed antipyretics (aspirin, acetaminophen, etc.) to help reduce fever, since fever was viewed as an inability of the body to regulate itself and therefore needed to be reduced aggressively in all cases. But in 2005, researchers at the University of Miami, Florida, ran a study of 82 intensive care patients, for whom protection from high temperatures was traditionally thought to be important. The patients were randomly assigned to receive antipyretics either if their temperature rose beyond 101.3°F (the “standard treatment”) or only if their temperature reached 104°F. As the trial progressed, seven people getting the standard treatment died, while there was only one death in the group of patients allowed to have a higher fever. At this point, the trial was stopped because the team felt it would be unethical to allow any more patients to get the standard treatment. So when something as basic as fever reduction is a hallmark of the “practice of medicine” and hasn’t been challenged for 100+ years, we have to ask “what else might be practiced due to tradition rather than science?”

In the worst cases of the practice of medicine, the “average” doctors just take moderately educated shots in the dark when it comes to patient care. A diagnosis is partially informed by the patient’s medical history (but often not really), partially informed by symptoms (but patients aren’t very good at communicating what’s really going on), and mostly informed by pharma advertising and the doctor’s half-remembered lessons from medical school (which are laden with cognitive biases, recency biases, and other very human errors, besides potentially having been obsoleted by more recent research). Many times, if you ask three doctors to look at the same problem, you’ll get three different diagnoses and three different treatment plans. As a patient, how do you feel when a doctor keeps changing his mind about your disease over time? How do you feel if different doctors say different things about your disease? Today, this happens often. In some areas, psychiatry for example, doctors frequently disagree on diagnoses. Research has found that psychiatrists using the Diagnostic and Statistical Manual of Mental Disorders (DSM), the standard desk reference for psychiatric diagnoses, have dangerously low diagnostic agreement. The DSM V uses a statistic called the “kappa” to measure the level of agreement between psychiatrists (ranging from 0 for no agreement and 1 for complete agreement). In research trials, the DSM V, which is set to be published in May 2013, generates a kappa of 0.2 for generalized anxiety disorder and 0.3 for major depressive disorder. Scientific American described these results for the standard of psychiatric care as “two pitiful kappas”. And often, there are errors of omission where a diagnosis is just missed entirely.

The net effect of all this is patient outcomes that are far inferior to and more expensive than what they should be. The current benchmarks of performance aren’t good enough, and it’s trivially easy to find study after study that demonstrates the shortcomings of the practice of medicine. A Johns Hopkins study found that as many as 40,500 patients die in an ICU in the US each year due to misdiagnosis, rivaling the number of deaths from breast cancer. Yet another study found that ‘system-related factors’, e.g. poor processes, teamwork, and communication, were involved in 65% of studied diagnostic error cases.  ‘Cognitive factors’ were involved in 75%, with ‘premature closure’ (sticking with the initial diagnosis and ignoring reasonable alternatives, or, more fancifully termed, the “confirmation bias”) as the most common cause. These types of diagnostic errors also add to rising healthcare expenditures, costing $300,000 per malpractice claim.

Physicians should be much more scientific and data-driven in providing patient care. That’s hard to pull off without technology, because of the increasing amount of data and research released every year. For example, standard operating procedure involves giving the same drug to millions of people even though we know that each patient metabolizes medication at different rates and with different effectiveness. Many of us are even resistant to aspirin. Each person should be treated differently, but the average doctor can’t handle the information required to do that. Nor does he have enough time or knowledge to do it. Healthcare needs to become much more about data-driven deduction and less about trial-and-error. Next-generation medicine will be the scientific arrival at diagnostic and treatment conclusions based on probabilities and real testing of what’s actually going on in your body. And, it will be much more personalized than your physician can provide. Systems will utilize more complex models of interactions within the human body and much more sensor data than a human MD could comprehend to suggest diagnosis. Thousands of baseline and disease mulit-ohmic (genomic, metabolomics, microbiomic, and other) data points, more integrative history, and demeanor will go into each diagnosis. Ever-improving dialog manager systems will help make data capture and exploration from patients more accurate and comprehensive.  Data science will be key to this. In the end, this would reduce costs, reduce physician workloads, and improve patient care. Doctors will also be able to tailor their explanations to the health literacy level of patients using common-language terms and adapting the sophistication level using computerized dialog managers. These computerized managers will be patient, unlike your typical “doctor in a hurry” with the usual unfortunate case overload. This matters because, according to the Institute of Medicine, nearly 100M US adults have “limited health literacy skills” that are most likely to affect their health outcomes!


Replacing 80% of what doctors do?

At the heart of my view is that much of what physicians do (checkups, testing, diagnosis, prescription, behavior modification, etc.) can be done better by well-designed sensors, passive and active data collection, and analytics, without necessarily taking away from the human element of care (especially in the 2020’s decade when this technology will be in its fifth or tenth evolution)! Let’s take a brief look at a standard physical as an example. During a physical, a patient will get measured in multiple ways – from weight and blood pressure to pulse and respiration. A nurse, doctor, or other caregiver will spend 15–30 minutes to run through all these different routines. Every single one of these measurements could be done in real-time by the patient in more representative environments at home if he or she just had the right sensors hooked up wirelessly to a mobile device. All that data could be measured and transmitted to the doctor’s office in less time and for less money than it takes to gas up the car and get to the hospital in the first place (leave aside sitting in the waiting room). ZocDoc* allows patients to check in for an appointment and provide basic information ahead of time. This type of form could easily be expanded to include vitals. And our “dialog manager” could ask many follow-on questions and probe other symptom possibilities, providing a more complete patient record WHILE reducing the amount of time the doctor has to spend with the patient, if any!). No doubt, the best doctors will likely do this better than our dialog manager, even for the next one or two decades. But, the system will be an immediate dramatic improvement compared to the average hurried and overloaded doctor (or worse, the developing world “no medical-school doctor” living within 50 miles of a rural patient)!

Of course, doctors aren’t supposed to just measure. They’re supposed to consume all that data, carefully consider it in context of the latest medical findings and the patient’s history, and figure out if something’s wrong. Computers can take on much of diagnosis and treatment work, and even do these functions better than an average doctor could (while considering more options and making fewer errors). What if you’re a heart patient? It’s a simple fact that most doctors couldn’t possibly read and digest all of the latest 5,000 research articles on heart disease. In fact, most of the average doctor’s medical knowledge is from when they were in medical school, and cognitive limitations prevent them from remembering the 10,000+ diseases humans can get.

Computers are much better than people at organizing and recalling information. They have larger and less corruptible memories, remember more complex information much more quickly and completely, and make far fewer mistakes than a hotshot MD from Harvard. Contrary to popular opinion, they’re also better at integrating and balancing considerations of patient symptoms, history, demeanor, environmental factors, and population management guidelines than the average physician. Besides, who wants to be treated by the average or below-average physician? Remember, 50% of MDs are below-average!  Not only that, computers have much lower error rates. Shouldn’t we take advantage of that when it comes to our health?!

Technology makes up for human deficiencies and amplifies strengths – MDs and even other less trained medical professionals can do much more. Eventually, computers will replace 80% of what doctors do but amplify the doctor’s capabilities, reducing misdiagnosis, in what they do by arming them with more complete, synthesized, and up-to-date data, all leading to better patient outcomes. Physicians spend too much time doing things computers can do, and we should give them more time for things that uniquely require human involvement, like providing patients “warm & fuzzies”, comforting kids in pediatric care, making inherently subjective decisions that require empathy or a consideration of ethics, and providing a friendly ear for lonely patients. Some of these functions may not need medical school training at all, but rather draw on more empathic skills and could actually be done by non-MDs. Lifecom, an AI diagnostics engine company, showed in clinical trials that medical assistants using a knowledge engine were 91% accurate in diagnosis without using labs, imaging, or exams. Another clinical study by the same company demonstrated that greater than 75% of cases can be safely triaged to be treated by RNs, with the remainder handled by doctors. Another study at MassGen found that 25% of the time, a medical record for patients who wound up with ‘high risk diagnoses’ had ‘high information clinical findings’ before a physician eventually made the diagnosis — in other words, there was a significant delay that might have been avoided had a clinical decision support system been used to parse the notes!

Initially, many doctors will be against this transition and won’t support it, but new technologies will make the receptive doctors much better at their job – quicker, more accurate, and more fact-based. There is a tremendous opportunity here in the influx of data that has never before been available. At first, computers will just help in decision support, starting by leveraging guidance from the very best doctors. Eventually (sometime in the next 10-15 years), computers will become better diagnosticians than your average doctor. Once we have a large enough dataset on different people in different situations, along with an addressable database of research studies, we will be amazed at how much better computers can do over today’s patient outcomes. We’ll be able to identify patterns and interactions among various areas of physiology in ways that weren’t possible before, making the link between changes in one area of the body causing symptoms in another area. Doctors will struggle to keep up, but then will increasingly rely on these tools to make decisions. Over time, they will increase their reliance on technology for triage, diagnosis, and decision-making, so that we’ll need fewer doctors and every patient will receive the best care. Diagnosis and treatment planning will be done by a computer, used in concert with the empathetic support from medical personnel selected and trained more for their caring personalities than for their diagnostic abilities. No brilliant diagnostician with bad manners, a la “Dr. House”, will be needed in direct patient contact. He can best serve as the trainer for the new “Dr. Algorithm”, which we’ll use to provide the diagnosis, while the most humane humans , (nurse practitioners or other medical professionals) will provide the care.

Eventually, computers will model and track your entire health state. They’ll read your mood by analyzing your facial expression; gauge your social activity through the number of emails you sent, calls you made, or things you tweeted; track your mobility and activity from your GPS as Ginger.io* does in assisting mental health patients or Jawbone* UP band; and monitor your vitals through your food intake, galvanic skin response, heart rate, and skin temperature, among other things. No doctor could be this integrative. There are already numerous startups (and others soon to be launched) that plan to collect health data in a frictionless, easy way in order to create better baseline systems models of the body for patients. Others will do predictive analytics on that information and head off problems before they arise. Still more will suggest lifestyle approaches to improve the way people live. Some of this change is already happening, but this quiet rumbling of data-driven diagnostics will become an avalanche in the future, playing out similarly to the explosion of cellphones. Imagine today’s systems, improved 10X by a decade or two of evolution and competition. Nobody expected cell phones to take over India in 2000, but now in 2012, few people remember that cell phones weren’t expected to be universal (AT&T even killed off their mobile business in the 80s because McKinsey told them the total US market would be less than a million devices by 2020).

Device- and data-driven healthcare will also extend the reach of medicine. It will change public health, especially in the developing world. A country like India needs ten times as many doctors to serve everyone well, and that’s not affordable. Most doctors there don’t have access to the latest, expensive research journals and couldn’t assimilate all the information contained in them even if they had the time, patience, and inclination to read them. A mobile phone could provide the needed testing and diagnosis to the remotest villages and at very affordable costs. This type of care is just not possible using today’s medical school graduates, who tend to be clustered around cities.


Systems will start as clumsy toddlers and develop to maturity and efficiency!

Don’t expect ace diagnosis systems overnight. They may start as seemingly minor point innovations or as clumsy-sounding systems not ready for prime time.

Imagine using a device like the AliveCor* iPhone case to take an ECG after every workout. What about every time you feel lightheaded or numb? What about every single morning, just like diabetics who measure their blood sugar multiple times a day? Now what if you could get an ECG case for free and do measurements for less than $1/test? If you’re a heart patient, this device and others like it would capture a lot more information than your annual or semiannual ECG check at the doctor’s office. Not only that, the office check will cost hundreds to even thousands of dollars, and what’s more, you probably wouldn’t be exhibiting any symptoms during the in-person visit anyway if your condition is intermittent. What if you instead sent 500 ECGs to your doctor over the course of a year for less than it costs to get one ECG done in the hospital? What do you think the average physician would do with all that valuable data? He or she would have no clue what to do with it, which is why we’d need software to “auto-diagnose” the ECG. Today, most heart disease is identified only after patients have heart attacks. But imagine having preventative cardiac care, with every at-risk patient having an ECG every morning for less than a buck. After being trained to identify abnormalities, machine-learning software could predict episodes indicated by the ten or so ECGs out of that set of 500 that the cardiologist should pay attention to (before getting to a point computers can do an EKG read themselves for pennies), simultaneously making his or her job easier AND more effective. We could discover most heart disease well before a heart attack or stroke and address it at a fraction of the cost of care that would be needed following such a trauma. But we need a decade of data to be really good at it.

Many dermatology appointments could be handled by CellScope* which produces low-cost iPhone attachments for imaging skin moles, rashes, ear infections, and (in the future) your retina or throat. The resulting images, taken at home, could be processed by sophisticated algorithms running in the cloud to detect patterns that warrant closer inspection (e.g. SkinVision uses the fractal nature of patterns in a skin image to determine more accurately than most general physicians whether you have skin cancer). You might get a diagnosis a lot faster than it takes to get a doctor’s appointment and then take your child to the clinic. And follow-up ‘visits’ could happen every six or twelve hours! A device like the Eyenetra* could give you an eye test and fit you for eyeglasses at little cost or hassle. Technology could handle diagnoses, lab orders, and writing prescriptions, asking for human assistance or input only when necessary.

Every metabolic process that has a volatile byproduct causes changes in your breath. Adamant* is a very risky startup that’s attempting to produce a chip that can detect hundreds of gases in your breath. If you’re asthmatic, it can measure the level of nitrous oxide and predict whether you’re at risk of having an attack. If you’re diabetic and have ketones in your breath, it can detect that too and tell you that your body is undergoing ketosis. It can detect if you have lung cancer and even tell you what type of lung cancer. It will even detect whether you’re burning fat or sugars during exercise, because each results in different component concentrations in your breath. This little chip will do all this inexpensively, for far less than a big, expensive CT scanner that’ll just tell you that you have a nodule in your lungs but can’t tell you what kind of lung cancer you have. Eventually, you won’t have a doctor stare at you and tell you that you look well; instead, your doctor will be able to look at the levels of hundreds of compounds in your breath and know whether you’re well.

Speaking of looking well, a startup named Ginger.io* determines patients’ mental health based on a variety of metrics. It can monitor your rate of emailing, tweeting, texting, and calling to gauge your social activity. Using motion sensors and your phone’s GPS, it can even know if you’re hiding in your bedroom, eating in your kitchen, or just staying in bed. By watching for changes in your behavior, it can tell how you’re doing far better than a psychiatrist could possibly determine and actually calls your psychiatrist if you’re in the danger zone of an episode. For example, detecting a behavioral pattern change that’s indicative of bipolar disorder could help us prevent shooting sprees of the type we’ve seen recently.

There are many other startups doing innovative things in healthcare. Proteus is helping address drug non-compliance, one of the biggest problems in medicine. They’ve designed a clever system that combines a pill sensor, a body patch, and a mobile app. They attach a tiny, ingestible sensor to pills that gets activated by stomach acids. When a patient takes the pill, the sensor sends a signal to the body patch, which then relays the signal to the app. This system will allow caregivers to remotely monitor patient adherence by individual, time-stamped pill consumption events. This is a far better solution than having your doctor base a diagnosis on the one-time blood test done in the clinic. Empatica uses sensors on patients’ wrists to measure bio-signals that correlate with emotion. Imagine having a continuous and, more importantly, accurate and objective measurement of your emotions for a month instead of only the latest, biased description that you might give (or forget to give) to your hurried physician. Several companies are also improving remote monitoring and diagnosis in the clinical setting. AirStrip Technologies provides real-time vital signs to physicians’ mobile devices. Sotera Wireless provides a battery-powered mobile device for monitoring vital signs. Agile Diagnosis and Lifecom are improving clinical decision-making by providing decision trees with probability-based outcomes for physicians at the point of care. These and other startups are forcing us to rethink healthcare from diagnostics to treatment.

This is only the beginning of the many generations of improvement that are likely to happen in the next two decades, but we have already begun to see meaningful impacts on healthcare. Studies have demonstrated the ability of computerized clinical decision support systems to lower diagnostic errors of omission significantly, directly countering the ‘premature closure’ cognitive bias. Isabel is a differential diagnosis tool and, according to a Stony Book study, matched the diagnoses of experienced clinicians in 74% of complex cases. The system improved to a 95% match after a more rigorous entry of patient data. Even IBM’s fancy Watson computer, after beating all humans at the very human intelligence-based task of playing Jeopardy, is now turning its attention to medical diagnosis. It can process natural language questions and is fast at parsing high volumes of medical information, reading and understanding 200 million pages of text in 3 seconds.

Right now, Isabel and Watson require physicians to ask follow-up questions of the patient, a point of inefficiency and potential cognitive bias introduction. But, Lifecom has the medical text-parsing, knowledge-base generation, and runtime diagnostic capabilities of Watson, while also being able to automatically propose a follow-on question or test to eliminate candidates from the differential diagnosis list. This accelerates the diagnostic process and lessens biases introduced by the human element of question-framing. Watson also relies on machine-learned, purely statistical relationships among symptoms, findings, and causes, whereas a system like Lifecom adds to that ability the use of a medical ontology, the web of physiological, anatomical, and other concepts, as well as their interrelationships. It’s too early to tell which approach will work better in the long term, but the point is that these systems will continue to evolve and, eventually, won’t need physicians as intermediaries.

In the beginning, these point innovations will seem immaterial, but, when there are enough of them, they will integrate with each other and start to feel like a revolution. The medical devices and software systems of 2020 will be as different from today’s computers as the car floor-mounted, multi-pound cell phones with bulky handset cords of 1986 are from today’s iPhones!


Digital first-aid kits

The confluence of all these different sensing, monitoring, and communication technologies will naturally lead to the creation of ‘digital first aid kits’ that cost < $100 and can used at home between doctor visits. These kits will include mobile apps to help patients determine how serious a new medical problem might be, as well as monitoring devices that can track and analyze blood pressure, A1c levels, ECG waveforms, blood oxygen levels, skin/ear/ENT conditions, social interaction, and other indicators of how well patients are managing their diabetes, asthma, depression, and other chronic conditions. Clinical staff will help train patients on these devices and apps, and, using software, they’ll help them interpret health trend data and provide recommendations during return visits.


Healthcare service stations of the future

The emergence of healthcare service stations, found in your local pharmacy or supermarket, will be another exciting phenomenon resulting from the proliferation of devices and data. These walk-in stations will be convenient — 75% of the US population lives within a 5-minute drive of a Walgreens. Right now, you can go to most of these stores and get some basic advice, receive a flu shot, or have your eyes checked, but not much else. In the near future, new technologies will enable many more services, providing high-quality care at low cost. In these centers, pharmacists and nurse practitioners will take patient histories, do simple exams, and prescribe medications or follow-on tests, aided by computerized diagnostics and telemedicine well before 2025.

Patients will be able to walk into these advanced healthcare stations without appointments and give their medical updates to personally-chosen avatars on private screens. These avatars will serve as healthcare concierges, elucidating symptoms, wirelessly uploading data collected by sensors on the patient’s phone, suggesting tests (to be done by the patient using easy-to-use tools on-site or at home), and giving prescriptions through a clinical support system, whose ability to diagnose and recommend effective treatments will have been validated against the best general practitioners and specialists. Software will help RNs diagnose illnesses, recommend effective treatment options, and refer patients to specialists when necessary. In ten years, it’s likely that genetic testing will be routine, extending diagnostic capability and allowing treatment selection based on genotype. Nurse practitioners will perform exams and take image scans using inexpensive, disposable tools (some of which might be part of the digital first-aid kit). Images will be analyzed in real-time by diagnostic software and transmitted to an on-call specialist, who pulls up patient information, stored in the cloud, and connects with the NP and patient using telepresence systems. Assessment and treatment apps will be prescribed, downloaded, and installed on patients’ phones, just as easily as prescriptions for cold medicine. And avatars will be accessible while patients are at home, providing real continuity of care. Ultimately, with ubiquitous walk-in clinics in the retail setting driven by powerful decision-support software, the distribution of healthcare professionals will change in parallel with the distribution channel. The pyramid will flatten, with many more RN-level professionals trained to effectively leverage software and interact with patients, and many fewer expensive MDs specialized to handle what will become the long tail of care.


The human element

Some of the critics of more automated healthcare argue that medicine isn’t just about inputting symptoms and receiving a diagnosis; it’s about building personal relationships of trust between providers and patients. The move towards sensor-based, data-driven healthcare doesn’t mean that we’ll get rid of human interaction. Serotonin administered by comforting humans and the placebo effect are only a few of many ways that complex interactions help recovery, and we shouldn’t lose these tools (instead, let’s understand them better, quantify them, and amplify them). Providing good bedside manner, giving comfort, and answering certain types of questions can often be handled better by a person than a machine, but you don’t need a medical degree to do that (except in some specialty areas like surgery or research). Nurses, nurse practitioners, social workers, and other types of less expensive, non-MD caregivers could do this just as well as doctors (if not better) and spend more time providing personal, compassionate care. For a while, surgery and other procedures may require human doctors with greater knowledge than a nurse practitioner. The point is that not every function doctors do will be replaced, but the majority will be done in less time and with greater efficacy over the next two decades. At the other end, some surgical procedures requiring extreme precision (e.g. tumor irradiation) are best handled by surgical robots or robots and humans working in concert.

Consider hospital discharge for a moment. You might think this is a function that could (or should) only be performed by a human being. Interestingly, a Boston Medical Center study showed that patients preferred receiving discharge instructions from a computer instead of a human and appreciated the amount of time and information provided by the computer. Additionally, patients with lower health literacy reported a significantly greater bond with the computer compared to patients with higher health literacy, supporting the notion that computers can provide adequate emotional support in certain circumstances.

I’m not advocating the removal of the human front-end to patient care. I’m arguing that we should focus on building robust back-end sensor technology and diagnostics through sophisticated machine learning and artificial intelligence operating on clinical and non-clinical data in greater volumes than humans can handle, in order to create a much more comprehensive understanding of patients. What’s more, these combined hardware/software systems will do better at follow-ups than over-burdened, time-constrained doctors. They’ll recognize and flag exceptions in ECGs, respiration, movement, or anything else for caregivers to respond to in more targeted ways, actually improving provider-patient interactions and health outcomes.

A transition to automation has already happened in several other areas where we once thought human judgment was required. When you’re on board that cross-country flight from New York to Los Angeles, most of the flying is being done by auto-pilot, not by a human (though a human is there for certain emergency situations). Investing was long considered a unique bastion of human judgment. Algorithmic trading now drives the vast majority of volume in the stock markets, with computers long ago replacing gesturing traders wearing funny-looking coats in the stock pits. Cars have been parking themselves and avoiding accidents using lane-assist for some time now, and Google already has a self-driving car that’s had zero accidents driving more than 300,000 miles on normal streets (a much harder problem than automating many physician functions). Most humans couldn’t drive that much without at least hitting a curb or two. Within a few decades, vehicles with steering wheels will become as quaint a concept as hand-cranked engines. David Cope at University of Santa Cruz has even developed software that has matched  original Bach and a music professor composing in the Bach tradition in the music’s “Bachness” to the chagrin of many.The same mental shift about human involvement and its gradual replacement by computers will also happen in healthcare. This would create a much more comprehensive understanding of patients and actually improve provider-patient interactions and health outcomes with more personalized treatment. In the end, physicians will be able to spend more, higher quality time with each patient, as if they had only 300 to manage, rather than 3,000 (though he will be able to manage 10,000+ patients with computer assist)! Caregivers will actually have MORE time to spend talking to their patients, making sure they understand, socializing care, and finding out the harder-to-measure pieces of information from patients because they will be spending a lot less time gathering data and referring to old notes. And they will be able to handle many more patients, reducing costs in the system.


The source of healthcare innovation

Where will all this innovation in healthcare come from? Some believe we have to work within the constraints of the medical establishment in order to advance it. I disagree. Some will follow reluctantly, and some will try to lead, but most organizations in traditional healthcare will fight this trend towards reduced costs because it reduces profits. That’s why the system will most likely be disrupted by outsiders. Land-line phone call rates didn’t decline until mobile operators changed the rules of what a phone call should cost. Remember how expensive long distance calling was not very long ago?

Innovation seldom happens from the inside because existing incentives are usually set up to discourage disruption, and doctors and hospitals are all invested in doing things the same way. If a hospital could cure you in half the time, would they be willing to cut their business in half? Pharma companies push marginally different drugs instead of generic solutions that may actually be better for patients because they don’t necessarily want to cure you; they want you to be a drug subscriber and generate recurring revenue for as long as possible. They’d rather sell you a cholesterol-lowering drug than encourage you to eat healthier and reduce their own profits. If they permanently reduced your cholesterol, they would lose a customer! Psychiatrists in general have the same problem with incentives. They don’t get paid to cure you; they get paid to treat you over multiple expensive therapy sessions that never end. What would you rather do as a therapist: have a steady stream of repeat patients that fill your hours or have to attract new patients? The former has minimal patient acquisition costs. Medical device manufacturers, like those that build and sell huge scanning systems, don’t want to cannibalize sales of their expensive equipment by providing cheaper, more accessible monitoring devices like a $29 * ECG machine. The traditional players will lobby/goad/pay/intimidate doctors and regulators to reject these new devices, emptily claiming that they aren’t “as good” and provide only 90% of the functionality (but at 5% of the cost). Expecting the medical establishment to do anything different is like expecting them to reduce their own profits.  To be fair, these are generalizations and there are many great doctors and many ethical organizations and people. The point is that the incentives in healthcare make innovation from within extremely unlikely. Fortunately, it doesn’t matter if the establishment tries to do this or not, because it will happen regardless. And it may start at the periphery, e.g. with the 40 million uninsured people in this country or the hundreds of millions of people in India with no access to any doctor. There aren’t enough rural doctors in India and few of them have access to the New England Journal of Medicine or a CT scanner or even reliable electricity. But, most potential patients have cell phones. This shift in how healthcare is delivered will allow for less money to be spent on capital equipment, cutting health care costs. It will allow us to provide care to those who don’t have it now. It will help avoid errors and provide basic services to those who cannot afford full healthcare services. And, it will prevent simple things from getting worse before being addressed.

There has been much ado in the blogs about how Silicon Valley and outsiders don’t understand healthcare and hence should not or cannot try to understand and innovate in it. As I explained above, and granting the rare exceptions, it is hard for insiders to innovate within a system, at least when it comes to radical innovation.  That’s not to say these Silicon Valley and other outsider “innovators” won’t leverage the system or have partners and doctors from inside helping them. Lifecom’s CEO is a trauma surgeon and teaches surgery and critical care on faculty. One of Proteus’ founders is an MD, as is one of the founders of AirStrip Technologies. IBM Watson is working with . Many others work with  in testing and studying their ideas and technologies. Most startups we are funding have MDs on their team and collaborate with other healthcare partners.

The reality is that healthcare has to move in this direction in order to make it affordable to everyone. There are many arguments and challenging questions in the blogs about this point of view. Some have answers, many reflecting naivety in understanding how technology increments and evolves, and many questions and criticisms don’t have answers. But, just because an answer doesn’t exist today does not mean it that it won’t be found or that we won’t find workarounds. Some things will come as tradeoffs to make healthcare more affordable. My guesstimates will be wrong on many counts as new technologies and approaches, and sometimes unforeseen problems, emerge. Many comments have come from good and passionate doctors (there are plenty of them around) and bloggers who have health insurance and can afford good care. I personally worry about the bottom half of doctors globally who are too rushed, too overburdened, too mercenary, or too out of date with their education, especially in the developing world.

Entrepreneurs can come at these challenges from the outside or inside the system and inject new insight.  They can ask naïve questions that get at the heart of assumptions that may be both pervasive and unperceived. They can leverage the many insiders at the right time to provide real understanding of medicine. They can build smart computers to be objective cost minimizers WHILE being care optimizers. Domain expertise can have a place, and the smartest doctors aren’t outraged at this idea (just the ones with knee-jerk reactions). People always react against technological progress, and many don’t have the imagination to see how the world is changing. But, there will be many good doctors willing to assist in this transition. Eric Topol (author of “The Creative Destruction of Medicine”) and Dr. Daniel Kraft, have called for a data-driven approach to healthcare and are examples of insiders who think like outsiders. There’s no question that many naïve innovators from outside the system, maybe even 90% of them, will attempt this change and fail. But, a few of these outsiders will succeed and change the system. They will get the appropriate help from insiders and leverage their expertise. And there will be many good doctors willing to assist in this transition.

This evolution from an entirely human-based to an increasingly automated healthcare system will take time, and there are many ways in which it can happen, but it won’t take as long as people think. The move will happen in fits and starts along different pathways, with many course corrections, steps backward, and mistakes as we figure out the best approach forward. It’s impossible to predict how this will ultimately happen. It may be the case that all significant efforts will have to be catalyzed by outsiders. The healthcare system might actually start responding to these threats from the inside and change as a result. Maybe we’ll start seeing disruption at the fringes along slippery but shallow slopes. The transition could start as a hundred small changes in different areas of medicine and in different ways, ending with an overhaul of healthcare that takes place over a couple decades. During all this, many or most in this effort will fail, but a few will succeed and change the world. For those of us who support entrepreneurs and companies that help create this change, most investments will be lost but more money will be made than lost through the few successes. None of us knows for sure how this space will turn out, but there’s a huge opportunity for technologists, entrepreneurs, and other forward-thinkers to reduce healthcare expenditures and improve patient care at the very same time.


* A Khosla Ventures investment

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Modeling Targeted Therapy

Reporter: Larry H. Bernstein, MD, FCAP

Some Perspectives on Network Modeling in Therapeutic Target Prediction
R Albert, B DasGupta and N Mobasheri
Biomedical Engineering and Computational Biology Insights 2013; 5: 17–24    http://dx.doi.org/BECBI/Albert_DasGupta_ Mobasheri
Key steps of a typical therapeutic target identification problem include synthesizing or inferring the complex network of interactions relevant to the disease, connecting this network to the disease-specific behavior, and predicting which components are key mediators of the behavior

Journal of Computational Biology

Journal of Computational Biology (Photo credit: Wikipedia)

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New Imaging device bears a promise for better quality control of breast-cancer lumpectomies – considering the cost impact

Author and Curator: Dror Nir, PhD

Couple of days ago I have posted on breast-cancer mammography screening and associated costs; Not applying evidence-based medicine drives up the costs of screening for breast-cancer in the USA. Treatment of breast-cancer represents much heavier cost-burden. According to the following publication: Variability in Reexcision Following Breast Conservation Surgery made in JAMA: “Failure to achieve appropriate margins at the initial operation will require additional surgery with re-excision rate estimates ranging from 30% to 60%. These additional operations can produce considerable psychological, physical, and economic stress for patients and delay use of recommended adjuvant therapies. A high percentage (10%-36%) of women requiring reexcision undergo total mastectomy. Thus, the effect of reexcision on altering a patient’s initial treatment of choice is significant.”

 Considering that ~70% of the 285,000 new patients diagnosed with breast cancer each year undergoes lumpectomy, this data represents significant cost. Not to mention morbidity, stress and reduce quality of life for the patients. In my post Optical Coherent Tomography – emerging technology in cancer patient management I discussed the potential of OCT in controlling the quality of lumpectomies in-situ. A workflow that represents potential to reduce the costs of repeated lumpectomies.

Last week, Dune Medical Devices, Inc., the company that developed the MarginProbeTM System, an intra-operative tissue assessment device to be used as accessory during lumpectomies of early-stage breast cancer, has received Premarket Approval (PMA) by the United States Food and Drug Administration.

MarginProbe system


FDA approval of the MarginProbe System was based on a 664 patient prospective, multi-center, randomized, double arm study to evaluate the effectiveness of MarginProbe in identifying cancerous tissue along the margins of removed breast tissue during initial lumpectomy procedures. MarginProbe, which uses electromagnetic “signatures” to identify healthy and cancerous tissue, was found to be over three times more effective in finding cancer on the margin during lumpectomy, compared to traditional intra-operative imaging and palpation assessment. This enabled surgeons to significantly reduce the number of patients with positive margins following initial surgery.

The following publication gives an idea on the clinical performance of MarginProbe:

J Surg Res. 2010 May 15;160(2):277-81. doi: 10.1016/j.jss.2009.02.025. Epub 2009 Mar 31.

Diagnostic performance of a novel device for real-time margin assessment in lumpectomy specimens.

Pappo ISpector RSchindel AMorgenstern SSandbank JLeider LTSchneebaum SLelcuk SKarni T.


Department of General Surgery, Assaf Harofeh Medical Center, Zrifin, Israel. pappo@zahav.net.il



Margin status in breast lumpectomy procedures is a prognostic factor for local recurrence and the need to obtain clear margins is often a cause for repeated surgical procedures. A recently developed device for real-time intraoperative margin assessment (MarginProbe; Dune Medical Devices, Caesarea, Israel), was clinically tested. The work presented here looks at the diagnostic performance of the device.


The device was applied to freshly excised lumpectomy and mastectomy specimens at specific tissue measurement sites. These measurement sites were accurately marked, cut out, and sent for histopathologic analysis. Device readings (positive or negative) were compared with histology findings (namely malignant, containing any microscopically detected tumor, or nonmalignant) on a per measurement site basis. The sensitivity and specificity of the device was computed for the full dataset and for additional relevant subgroups.


A total of 869 tissue measurement sites were obtained from 76 patients, 753 were analyzed, of which 165 were cancerous and 588 were nonmalignant. Device performance on relatively homogeneous sites was: sensitivity 1.00 (95% CI: 0.85-1), specificity 0.87 (95% CI: 0.83-0.90). Performance for the full dataset was: sensitivity 0.70 (95% CI: 0.63-0.77), specificity 0.70 (95% CI: 0.67-0.74). Device sensitivity was estimated to change from 56% to 97% as the cancer feature size increased from 0.7 mm to 6.6 mm. Detection rate of samples containing pure DCIS clusters was not different from rates of samples containing IDC.


The device has high sensitivity and specificity in distinguishing between normal and cancer tissue even down to small cancer features.

Copyright (c) 2010 Elsevier Inc. All rights reserved.

PMID: 19628225

Imagine how cost effective breast cancer management can be if it will involve systems such as these in addition to the systems I discussed in some of my previous posts, for example: What could transform an underdog into a winner?

Written by: Dror Nir, PhD.

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Author and Curator: Dror Nir, PhD


As an entrepreneur who is promoting innovations in medical imaging I often find myself confronted with this question. Usually the issue is raised by a project’s potential financier by the way of the following remarks:

  • The Genome Project opens the road to “Star Track” kind of medicine. No one will need imaging.
  • What about development of new disease-specific markers? Would that put imaging out of business?
  • Soon we will have a way to “fix” bad cells’ DNA.  and so we will have no use for screening

In these situations I always find myself struggling to come up with answers rather than simply saying, ‘Well, it will take more time for these applications to be available than for you to reach your exit….’. I always try to find a quantitative citation to show how much time and money still needs to be invested before patients will be able to profit from that kind of futuristic “sci-fi medicine”.

Last week, a very recent source for such information was brought to my attention.  As a contributor to Leaders in Pharmaceutical Business Intelligence I was asked to review and comment on a recent report published in Nature regarding the progress made in the ENCODE project [1]. I was also asked to assess the influence of the progress in understanding the human genome on imaging-based cancer patients’ management, my field of expertise.

This short report is nicely written and is clear to layman’s (which is what I consider myself in this field) reading. My attention was drawn to some important facts:

  • It took 10 years and $288 Million to realise that 80% of 3 Billion DNA bases comprising the human genome serves a purpose.
  • So far a very small percentage (3% to 4%) of this potential was uncovered in the scope of this project.
  • Already now it is clear that much of the “knowledge” regarding the human genome’s functionality will need to be re-written.
  • Researchers anticipate that future studies using advanced technologies will contribute to better estimation of the knowledge gap.
  • Good news: these studies are leading to better understanding of diseases’ pathological characteristics and to more accurate reporting of disease sources. This gives hope to future development of disease specific drug development.

So, back to the subject of this post: it seems to me that we are quite a few decades and many billions of dollars away from “Star-Trek medicine”. In the foreseeable  future, i.e. at least during my life time (and I hope to live a while longer…), the daily routine of cancer patients’ management will have to rely on workflows constituted of screening, diagnosis, a treatment choice that includes a trial and error type of drugs’ choice, and a long-term post treatment follow-up. Smart imaging promises to increase cost efficiency and medical efficacy of these workflows. And I do hope that our children will benefit from the investment our generation is making in understanding the way the human genome is functioning.

  1. Science 7 September 2012: Vol. 337 no. 6099 pp. 1159-1161
    DOI: 10.1126/science.337.6099.1159 http://www.sciencemag.org/content/337/6099/1159.summary?sid=835cf304-a61f-45d5-8d77-ad44b454e448

Written by Dror Nir

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SDS-PAGE with Taq DNA Polymerase. SDS-PAGE is ...

SDS-PAGE with Taq DNA Polymerase. SDS-PAGE is an useful technique to separate proteins according to their electrophoretic mobility. (Photo credit: Wikipedia)

Proteomics and Biomarker Discovery

Reporter: Larry H. Bernstein, MD, FCAP



Advanced Proteomic Technologies for Cancer Biomarker Discovery

Sze Chuen Cesar Wong; Charles Ming Lok Chan; Brigette Buig Yue Ma; Money Yan Yee Lam; Gigi Ching Gee Choi; Thomas Chi Chuen Au; Andrew Sai Kit Chan; Anthony Tak Cheung Chan

Published: 06/10/2009

This report is extracted from the article above with editing and shortening as much as possible for the reader, and updated from LCGCNA Aug 12,  2012; 8

Part I


This review will focus on four state-of-the-art proteomic technologies, namely 2D difference gel electrophoresis, MALDI imaging mass spectrometry, electron transfer dissociation mass spectrometry and reverse-phase protein array. The major advancements these techniques have brought about biomarker discovery will be presented in this review. The wide dynamic range of protein abundance, standardization of protocols and validation of cancer biomarkers, and a 5-year view of potential solutions to such problems is discussed.

English: Public domain image from cancer.gov h...

English: Public domain image from cancer.gov http://visualsonline.cancer.gov/details.cf?imageid=3483. TECAN Genesis 2000 robot preparing Ciphergen SELDI-TOF protein chips for proteomic  analysis. (Photo credit: Wikipedia)


A common method used for isolating and identifying cancer biomarkers involves the use of serum or tissue protein identification. Unfortunately, currently used tumor markers have low sensitivities and specificities.[2] Therefore, the development of novel tumor markers might be helpful in improving cancer diagnosis, prognosis and treatment.

The rapid development of proteomic technologies during the past 10 years has brought about a massive increase in the discovery of novel cancer biomarkers. Such biomarkers may have broad applications, such as for the detection of the presence of a disease, monitoring of disease clearance and/or progression, monitoring of treatment response and demonstration of drug targeting of a particular pathway and/or target. In general, proteomic approaches begin with the collection of biological specimens representing two different physiological conditions, cancer patients and reference subjects. Proteins or peptides are extracted and separated, and the protein or peptide profiles are compared against each other in order to detect differentially expressed proteins. Commonly, quantitative proteomics is mainly performed by protein separation using either 2DE- or liquid chromatography (LC)-based methods coupled with protein identification using mass spectrometry (MS). Limitations include inability to obtain protein profiles directly from tissue sections for correlation with tissue morphology, limited ability to analyze post-translational modifications (PTMs) and low capacity for high-throughput validation of identified markers. Progress in proteomic technologies has led to the development of 2D DIGE, MALDI imaging MS (IMS), electron transfer dissociation (ETD) MS, and reverse-phase protein array (RPA).

2D Difference Gel Electrophoresis

The 2DE method has been one of the mainstream technologies used for proteomic investigations.[3,4] In this method, proteins are separated in the first dimension according to charge by isoelectric focusing, followed by separation in the second dimension according to molecular weight, using polyacrylamide gel electrophoresis. The gels are then stained to visualize separated protein spots,[5] separating up to 1000 protein spots in a single experiment and  protein spots are then excised and identified using mass spectrometry (MS).[6,7]

We previously used a 2DE approach to compare the proteomic profiles to identify differentially expressed proteins that may be involved in the development of nasopharyngeal cancer, [8]   as well as proteins that were responsive to treatment with the chemotherapeutic agent 5-fluorouracil (5FU) in the colorectal cancer SW480 cell line. Briefly, cell lysates from SW480 cells that were either treated with 5FU or were controls were separated using 2DE. After staining and analysis of the gels, differentially expressed protein spots were excised and identified using MS. The upregulation of heat-shock protein (Hsp)-27 and peroxiredoxin 6 and the downregulation of Hsp-70 were successfully validated by immunohistochemical (IHC) staining of SW480 cells.[9]

The 2D DIGE method improved the 2DE technique. Figure 1 shows how two different protein samples (e.g., control and disease) and, optionally, one reference sample (e.g., control and disease pooled together) are labeled with one of three spectrally different fluorophores: cyanine (Cy)2, 3 or 5. They have the same charge, similar molecular weight and distinct fluorescent properties, allowing their discrimination during fluorometric scanning.[10-12]  The minimal dye causes minimal change in the electrophoretic mobility pattern of the protein, whereas the saturation dye labels all available cysteine residues but causes a shift in electrophoretic mobility labeled proteins.[13]  The same pooled reference sample used for all gels within an experiment is an internal reference for normalization and spot matching.[12] The gel is scanned at three different wavelengths yielding images for each of the different samples, and variation between gels is minimized and difficulties are reduced in correctly matching of protein spots across different gels.[10,11]  Significant advantages of the DIGE technology includes a dynamic range of over four orders of magnitude and full compatibility with MS.  However, careful validations of identified markers using alternative techniques are still needed.

In a study that compared three commonly used DIGE analysis software packages, Kang et al. concluded that although the three softwares performed satisfactorily with minimal user intervention, significant improvements in the accuracy of analysis could be achieved .[14] Moreover, it was suggested that results concerning the magnitude of differential expression between protein spots after statistical analysis by such softwares must be examined with care.[14]

Figure 1.  Procedures for performing a 2D DIGE experiment. CY: Cyanine; DIGE: Differential in gel electrophoresis.

The choice of appropriate statistical methods for the analysis of DIGE data has to be considered. Statistical methodological error can be addressed by the use of statistical methods that apply a false-discovery rate (FDR) for the determination of significance. In this method, q-values are calculated for all protein spots. The q-value of each spot corresponds to the expected proportion of false-positives incurred by a change in expression level of that protein spot found to be significant.

Despite the ease of use and enabling the researcher to select an appropriate FDR according to study requirements, this approach was found to be only applicable to DIGE experiments using a two-dye labeling scheme, as a three-dye labeling approach violated the assumption of data independence required for statistical analysis.[16] Other statistical tests that have been applied for the analysis of DIGE results include significance analysis of microarrays,[7] principal components analysis[17,18] and partial least squares discriminant analysis.[18,19] Detailed discussions of the different statistical approaches applicable to proteomic research are beyond the scope of this review and readers may refer to[18,20] for further reading.

Using 2D DIGE, Yu et al. successfully identified biomarkers that were associated with pancreatic cancer.[21] In the study, 24 upregulated and 17 downregulated proteins were identified by MS. Among those proteins, upregulation of apolipoprotein E, α-1-antichymotrypsin and inter-α-trypsin inhibitor were confirmed by western blot analysis. Furthermore, the association of those three proteins with pancreatic cancer was successfully validated in another series of 20 serum samples from pancreatic cancer patients. Using a similar approach, Huang et al. identified and confirmed the upregulation of transferrin in the sera of patients with breast cancer.[22] When Sun et al. compared the proteomic profiles between malignant and adjacent benign tissue samples from patients with hepatocellular carcinoma, they proved 2D DIGE is not limited to serum or plasma samples.[23] In their study, overexpression of Hsp70/Hsp90-organizing protein and heterogenous nuclear ribonucleoproteins C1 and C2 were identified by 2D DIGE coupled with MS analysis, and the findings were successfully validated by both western blotting and IHC staining. Next, Kondo et al. applied 2D DIGE to laser-microdissected cells from fresh patient tissues.[13] Using this protocol, a 1-mm area of an 8-12-µm-thick tissue section was shown to be sufficient. These examples demonstrate the high sensitivity and broad applicability of 2D DIGE for proteomic investigations using various types of patient samples and provide evidence that 2D DIGE is a powerful technique for biomarker discovery.

MALDI Imaging Mass Spectrometry

A deeper understanding of the complex biochemical processes occurring within tumor cells and tissues requires a knowledge of the spatial and temporal expression of individual proteins. Currently, such information is mainly obtained by IHC staining for specific proteins in patient tissues.[8,24,25] Nevertheless, IHC has limited use in high-throughput proteomic biomarker discovery because only a few proteins can be immunostained simultaneously. MALDI IMS allows researchers to analyze proteomic expression profiles directly from patient tissue sections.[26-28] The protocol begins with mounting a tissue section onto a sample plate (Figure 2). MALDI matrix is then applied onto the tissue sample, which is analyzed by MALDI MS in order to obtain mass spectra from predefined locations across the entire patient tissue section. The mass spectrum from each location is a complete proteomic profile for that particular area. All acquired mass spectra from the entire tissue are then compiled to create a 2D map for that tissue sample. This map could then be compared with those from other tissue samples to identify changes in protein or peptide expression or comparisons of the maps from different areas within the same tissue section could be performed. This technology  importantly allows the high-throughput discovery of novel protein markers. In addition, correlations between protein expression and tissue histology can also be studied easily.

Most studies using MALDI IMS have been performed on frozen tissue sections ranging from 5 to 20 µm in thickness.[26,27,29] After sectioning, a MALDI matrix is applied either by automated spraying or spotting. The matrix of choice is usually α-cyano-4-hydroxy-cinnamic acid for peptides and sinapinic acid (3,5-dimethoxy-4-hydroxycinnamic acid) for proteins.

Figure 2.  Procedures for MALDI imaging. IMS: Imaging mass spectrometry; MS: Mass spectrometry.

Spotting allows the precise application of matrix to areas of interest and minimizes the diffusion of analyte material across the sample, although the imaging resolution achieved by spotting is lower (~150 µm). A laser beam is then fired towards the area of interest on the tissue section to generate protein ions for analysis by a mass analyzer.[29] Among the different mass analyzers, TOF analyzers are the most commonly used owing to their high sensitivity, broad mass range and suitability for detection of ions generated by MALDI. Use of other mass analyzers such as TOF-TOF, quadrupole TOF (QTOF), ion traps (ITs) and Fourier transform-ion cyclotron resonance (FT-ICR) have also been reported in other studies.[30-33]

After obtaining the mass spectra, statistical analysis needs to be performed to identify statistically significant features that could have potential use as biomarkers. But before such analyses can be applied, there has to be background-noise subtraction, spectral normalization and spectral alignment.[34,35,34] Statistical methods used to identify significant differences in peak intensity are symbolic discriminant analysis and principal component analysis. Symbolic discriminant analysis determines discriminatory features and builds functions based on such features for distinguishing samples according to their classification.[36,37] Using this approach, Lemaire et al. found a putative proteomic biomarker from ovarian cancer tissues by MALDI IMS that was later identified to be the Reg-α protein, a member of the proteasome activator 11S.[37] This result was later successfully validated by western blot (protein expression found in 88.8% carcinoma cases vs 18.7% benign disease) and IHC (protein expression found in 63.6% carcinoma tissues vs 16.6% benign tissues).[37] On the other hand, principal component analysis reduces data complexity by transforming data based on peak intensities to information based on data variance, termed ‘principal components’, resulting in a list of significant peaks (principal components) ordered by decreasing variance.[35,38,39] Neither symbolic discriminant analysis or principal component analysis is capable of performing unsupervised classification. This aim requires the use of other methods such as hierarchical clustering.[39,40] In this method identified peaks are clustered as nodes in a pair-wise manner according to similarity until a dendogram is obtained, providing information as to the degree of association of all peak masses in a hierarchical fashion. Peaks that are capable of differentiating between different histological/pathological features could then be chosen for further validation of their value as tumor markers.[39]

In MALDI IMS, protein identification cannot be performed with confidence solely on the molecular weight. However, Groseclose et al. have developed a method using in situ digestion of proteins directly on tissue section.[41] They first used MALDI IMS to obtain a map of the protein and peptide spectra, then spotted a consecutive section of the same tissue sample with trypsin for protein digestion, and then spotted matrix solution onto the digested spots and the resulting peptides are identified directly from the tissue by MS/MS. This modification increases the confidence in protein identification. The time required for MALDI IMS analysis per tissue section is as follows: tissue sectioning, mounting and matrix application: 4-8 h; MALDI image acquisition: 1-2 days; spectral analysis: 1-2 h.[33,39]

Recently, in situ enzymatic digestion has been successfully applied for improving the retrieval of peptides directly from formalin-fixed, paraffin-embedded FFPE tissue samples.[27] Such development has greatly facilitated the application of MALDI IMS in FFPE tissues.[26,42] In fact, Stauber et al. identified the downregulation of ubiquitin, transelongation factor 1, hexokinase and neurofilament M from FFPE brain tissues of rat models of Parkinson disease using this modified technique.[42] The success of performing proteomic profiling using MALDI IMS directly on FFPE tissues opens up great possibility for using archival patient materials in high-throughput biomarker discovery. Novel cancer biomarkers identified using MALDI IMS still require validation by other techniques such as IHC.

Electron Transfer Dissociation MS

Post-translational modifications play important roles in the structure and function of proteins such as protein folding, protein localization, regulation of protein activity and mediation of protein-protein interaction. Two common forms of PTM that have been implicated in cancer development are phosphorylation and glycosylation. Previously, phosphoproteomic studies have led to the identification of novel tyrosine kinase substrates in breast cancer,[43] discovery of novel therapeutic targets for brain cancer[44] and increased understanding of signaling pathways involved in lung cancer formation.[45,46] Conversely, the identification of abnormally glycosylated proteins, such as mucins, has provided novel biomarkers and therapeutic targets for ovarian cancer.[47]

The study of PTM begins with digesting the target protein using enzymes such as trypsin,   introducing the fragments into MS for determination of the sites and types of modification and, at the same time, identification of the protein. The analysis is conventionally carried out using collision-induced dissociation (CID) MS, where peptides are collided with a neutral gas for cleavage of peptide bonds to produce b- and y-type ions (Figure 3). A complete series of peptides differing in length by one amino acid is produced, leading to identification of the protein by peptide-sequence determination. However, for phosphopeptides, the presence of phosphate groups would compete with the peptide backbone as the preferred cleavage site. The end result is a reduced set of peptide fragments, which hinders protein identification, and the exact location of the phosphate group on the peptide cannot be determined accurately when there are more than one possible phosphorylation sites.[48,49]

Figure 3.  Peptide bond-cleavage site for a-, b-, c-, x-, y– and z-type ions.

Electron transfer dissociation is a recently developed dissociation technique for the analysis of peptides by MS, utilizing radiofrequency quadrupole ion traps such as 2D linear IT, spherical IT and Orbitrap™ (Thermo Fisher Scientific Inc., MA, USA) mass analyzers.[48,49] In this technology, peptides are fragmented by transfer of electrons from anions to induce cleavage of Cα-N bonds along the peptide backbone, hence producing c- and z-type ions (Figure 3). In contrast to CID, ETD preserves the localization of labile PTM and also provides peptide-sequence information.[48] But ETD fails to fragment peptide bonds adjacent to proline, which are readily cleaved by CID.[50] A study that compared the performance of CID with that of ETD found that only 12% of the identified peptides were commonly detected between the two techniques. A study reported that CID successfully identified more peptides with charge states of +2 and below, whereas ETD was found to be better at identifying peptide ions with charge states of greater than +2.[51] Therefore, it is suggested that CID and ETD should be used together to complement each other.[52]  Han et al. successfully differentiated the isobaric amino acids isoleucine and leucine from one another by performing CID on the resulting z-ions after ETD. The presence of isoleucine residue was then confirmed by the detection of a specific 29-Da loss from the peptide.[53]  A clear advantage of using ETD for the analysis of phosphopeptides is a near complete series of c- and z-ions without loss of phosphoric acid,[48] greatly facilitating the determination of the phosphorylation sites and the identification of phosphopeptides. Recently, an analysis of yeast phosphoproteome using ETD successfully identified 1252 phosphorylation sites on 629 proteins, whose expression levels ranged from less than 50 to 1,200,000 copies per cell.[54] In another study using ETD, a total of 1435 phosphorylation sites were identified from human embryonic kidney 293T cells, of which 1141 (80%) were previously unidentified. Finally, a study by Molina et al. successfully identified 80% of the known phosphorylation sites in more than 1000 yeast phosphopeptides in one single study using a combination of ETD and CID.[55] In addition, ETD could be applied to investigate other forms of PTM, such as N-linked glycosylations.[56,57] N-linked glycans contain a common core with branched structures. These can be processed by stepwise addition or removal of monosaccharide residues linked by glycosidic bonds, producing highly varied forms of N-linked glycan structures.[58-60] A weakness of analyzing glycopeptides using CID is that cleavage of glycosidic bonds occurs with little peptide backbone fragmentation, so that only the glycan structure is available.[61]  Hogan et al. used CID and ETD together to overcome this problem determining the glycan structure and glycosylation site.[61] ICID was initially used for cleavage of glycosidic bonds that allowed the entire glycan structure to be inferred from the CID spectrum alone. ETD was later performed to dissociate the same peptide that resulted in a contiguous series of fragment ions with no loss of glycan molecules, allowing the identification of both the site of glycosylation and the identity of the glycoprotein.[61] Readers are strongly encouraged to refer to[49] and.[62] In a comprehensive comparison of CID versus ETD for the identification of peptides without PTMs, CID was found to identify 50% more peptides than ETD (3518 by CID vs 2235 by ETD), but ETD provided somewhat better sequence coverage (67% for CID vs 82% for ETD). It turns out that ETD produced more uniformly fragmented ions with intensities that were five- to ten-times lower than those produced by CID.[55] Finally, the best sequence coverage of up to 92% was achieved when consecutive CID and ETD were performed.[55]

This increase in sequence coverage using the combined approach is needed for studies requiring de novo peptide identifications. As such, this strategy is particularly suited for studies involved in the discovery, identification and characterization of novel peptides or proteins and their PTMs for biomarker use. A prerequisite of this technique is that the biological samples under investigation must undergo some form of fractionation before they are amenable to analysis by ETD or CID. This is achieved by the use of LC techniques, such as reverse-phase, strong cation exchange or strong anion exchange chromatography, and serves to reduce the complexity and wide dynamic range of protein-expression levels commonly found in biological specimens. Given the important roles of PTM in the function and activity of proteins, this technology paves the way for exploring the intricate cellular activities within a cancer cell.


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Advanced Proteomic Technologies for Cancer Biomarker Discovery

Part II

Reverse-phase Protein Array

One of the goals of proteomics is to identify protein changes associated with the development of diseases such as cancer.  Even with the rapid development of proteomic technologies during the past few years, analysis of patient samples is still a challenge. Difficulties arise from the fact that[63,64]:

  • Proteomic patterns differ among cell types;
  • Protein expression changes occur over time;
  • Proteins have a broad dynamic range of expression levels spanning several orders of magnitude;
  • Proteins can be present in multiple forms, such as polymorphisms and splice variants;
  • Traditional proteomic methods require relatively large amounts of protein
  • Many proteomic technologies cannot be used to study protein-protein interactions.

The principle of RPA is simple and involves the spotting of patient samples in an array format onto a nitrocellulose support (Figure 4). Hundreds of patient specimens can be spotted onto an array, allowing a comparison of a large number of samples at once.[65] Each array is incubated with one particular antibody, and signal intensity proportional to the amount of analyte in the sample spot is generated.[66] Signal detection is commonly performed by fluorescence, chemiluminescence or colorimetric methods. The results are quantified by scanning and analyzed by softwares such as P-SCAN and ProteinScan, which can be downloaded from[84] for free.[67,68]

Figure 4.  Principle of reverse-phase protein array.

Main advantages of RPA technology include[69-71]:

  • Various types of biological samples can be used;
  • The possibility of investigating PTMs;
  • Protein-protein interactions can be studied;
  • Labeling of patient samples with fluorescent dyes (e.g., 2D DIGE) or mass tags (e.g., isotope-coded affinity tag [ICAT]) are not required;
  • Any samples spotted as a dilution allows quantifying in the linear range of detection;
  • Quantitative measurement of any protein is possible compared to reference standards of known amounts on the same array.

It has been shown that RPA is extremely sensitive as it is capable of detecting up to zeptomole (1 x 10-21 mole) levels of target proteins with less than 10% variance. The analysis of few cell signaling events is known.[65,70,71] The assay sensitivity depends on antibody affinity, which depends upon antigen-antibody pairs.[68] Of course, only known proteins with available antibodies can be identified. Therefore, this method is more suitable for biomarker screening or validation than discovery of novel proteins. To assist researchers in selecting suitable antibodies, two open antibody databases show their western blot results using cell lysates.[72,73,85,86]

One application of RPA is to investigate the signaling pathways in human cancers. Zha et al. compared the survival signaling events between Bcl 2-positive and -negative lymphomas and found that survival signals, independent of Bcl 2 expression, were detected in follicular lymphoma and confirmed by validation with IHC.[71] In another study, patient-specific signaling pathways have been identified in breast cancers using RPA. Bayesian clustering of a set of 54 subjects successfully separated normal subjects from cancer patients based on an epithelial signaling signature. Principal component analysis was capable of distinguishing normal from cancer patient samples by using a signature composed of a panel of kinase substrates.[69] Differences in cell signaling between patient-matched primary and metastatic lesions have also been found using RPA. In the study, six patient-matched primary ovarian tumors probed with antibodies against signaling proteins, and the signaling profiles differed significantly between primary and metastatic tumors and upregulation of phosphor c-kit was capable of distinguishing five of the six metastatic tumors from the primary lesions.[70] These findings suggest that treatment strategies may need to target signaling events among disseminated tumor cells.

Reverse-phase protein array has also been used to validate mathematical models of cellular pathways. The p53-Mdm2 feedback loop is one of the most well-studied cellular-feedback mechanisms.[74] Normally, p53 activates transcription and expression of Mdm2, which, in turn, suppresses p53 activity. This negative-feedback loop ensures the low-level expression of p53 under normal conditions. Mathematical models have previously been used to investigate this negative-feedback loop.[67] Ramalingam et al. has shown, by using RPA, that part of the mechanism of the p53-Mdm2 feedback loop can be explained by current mathematical models.[75]

Another important application of RPA is for the identification of cancer specific antigens.  Using this method serum from 14 lung cancer patients, colon cancer patients and normal subjects were incubated and eight fractions of the cell lysate were recognized by the sera from four patients, while none of the sera from normal individuals was positive.[76] This study demonstrates the diagnostic potential of identifying cancer antigens that induce immune response in cancer patients by using RPA.

Expert Commentary and Five-year View

The development of 2D DIGE in the past few years has provided researchers with a more accurate method for relative quantification of proteins substantially reducing the number of replicates required for 2D gels and increased its applicability for high-throughput biomarker discovery. MALDI MS has immensely facilitated the direct discovery of biomarkers from patient tissue. Even though archival patient tissue samples are a potential source of materials for tumor marker research, high-throughput techniques for biomarker discovery using such samples has been problematic. With the development of MALDI IMS, investigators can now perform studies that aim to discover novel biomarkers directly from tissue sections and are able to correlate their expression with the histopathological changes of tumors. Previously, investigation into the sites of protein PTM has been difficult since MS-dissociation techniques, such as CID, would lead to preferential loss of PTM, but the use of ETD as a complementary peptide ion-dissociation method has allowed researchers to investigate the precise location and structure of the PTM, and to identify peptide sequence with higher confidence.

The rapid technological improvements in proteomic technologies will identify potential biomarkers for clinical use. Independent validation studies using clinical specimens must be performed before such markers can be applied clinically,. In this regard, RPA has added a potential for high-throughput screening or validation of newly found markers. Using this technique, it will be possible for researchers to quantitatively measure and validate novel markers on hundreds of patient samples simultaneously.

A big problem for proteomic researchers iincludes the abundance of proteins in biological samples. This could be partially solved by depletion of abundant proteins or by fractionation of protein samples according to characteristics. It is envisaged that, in the future, proteomic technologies will be developed to a stage that is capable of analyzing complex protein mixtures without preparatory fractionation. Such progress has recently been achieved in LC-MS, where the use of a high-field, asymmetric waveform, ion-mobility spectrometry device as an interface to an IT MS resulted in a more than fivefold increase in dynamic range without increasing the length of the LC-MS analysis.[77]

Another area that needs improvement is the standardization of protocols for patient-sample collection because results were found to be inconsistent among various studies using MS.[78] It is also considered that part of the reason for this inconsistency is due to the differences in sample-collection or sample-handling procedures.[78,79] The Human Proteome Organization previously published its findings on pre-analytical factors that affect plasma proteomic patterns and provides suggestions for sample handling.[80,81] In addition to the pre-analytical stages, it is imperative to stress that consistent and strict adherence to predefined procedures or standards, from sample collection, sample processing, experimentation, data analysis through to result validation, are of utmost importance to minimize variations and achieve consistent and reproducible results.

Any newly identified potential biomarker must also be validated using an independent cohort of patients in order to establish its clinical value, but the translation of results from the laboratory to the clinic has been slow. Consequently, it has been suggested that quantitative MS could be used for the detection of proteins.[82] The increasing availability of MS facilities to researchers worldwide will facilitate the detection, measurement and validation of protein biomarkers using quantitative MS techniques. Even after validation of such results in the laboratory, diagnostic tests will need to be developed for the marker and large-scale clinical trials would also have to be performed to confirm the results.  All these efforts require cooperation of personnel from various disciplines, such as scientists, medical professionals, pharmaceutical companies and governments. Finally, it is hoped that, through improved understanding of the protein expression as cancer progresses will lead to the discovery and development of useful cancer biomarkers for patient diagnosis, prognosis, monitoring and treatment.

Key Issues

  • 2DE coupled with mass spectrometry has been the main workhorse for the proteomic discovery of novel biomarkers in the past 10 years, and the development of 2D difference gel electrophoresis has substantially improved the quantification accuracy of 2DE.
  • MALDI imaging mass spectrometry has allowed the identification of novel proteomic features directly from patient tissue section for correlation with histopathological changes.
  • Electron transfer dissociation mass spectrometry has opened up the possibility of identifying the structure and localization of the post-translational modification and the peptide/protein.
  • Reverse-phase protein array is a powerful tool for the high-throughput validation of novel biomarkers across hundreds of patient samples simultaneously.


63.  States DJ, Omenn GS, Blackwell TW et al. Challenges in deriving high-confidence protein identifications from data gathered by a HUPO plasma proteome collaborative study. Nat. Biotechnol. 24(3),333-338 (2006).

64. Wulfkuhle JD, Edmiston KH, Liotta LA, Petricoin EF 3rd. Technology insight: pharmacoproteomics for cancer – promises of patient-tailored medicine using protein microarrays. Nat. Clin. Pract. Oncol. 3(5),256-268 (2006).

•• Excellent review on the clinical application of reverse-phase protein array.

65. Tibes R, Qiu Y, Lu Y et al. Reverse phase protein array: validation of a novel proteomic technology and utility for analysis of primary leukemia specimens and hematopoietic stem cells. Mol. Cancer Ther. 5(10),2512-2521 (2006).

66. LaBaer J, Ramachandran N. Protein microarrays as tools for functional proteomics. Curr. Opin. Chem. Biol. 9(1),14-19 (2005).

67. Ramalingam S, Honkanen P, Young L et al. Quantitative assessment of the p53-Mdm2 feedback loop using protein lysate microarrays. Cancer Res. 67(13),6247-6252 (2007).

68. Nishizuka S, Ramalingam S, Spurrier B et al. Quantitative protein network monitoring in response to DNA damage. J. Proteome Res. 7(2),803-808 (2008).

69. Petricoin EF 3rd, Bichsel VE, Calvert VS et al. Mapping molecular networks using proteomics: a vision for patient-tailored combination therapy. J. Clin. Oncol. 23(15),3614-3621 (2005).

70. Sheehan KM, Calvert VS, Kay EW et al. Use of reverse-phase protein microarrays and reference standard development for molecular network analysis of metastatic ovarian carcinoma. Mol. Cell Proteomics 4(4),346-355 (2005).

71. Zha H, Raffled M, Charboneau L et al. Similarities of prosurvival signals in Bcl 2-positive and Bcl 2-negative follicular lymphomas identified by reverse phase protein microarray. Lab. Invest. 84(2),235-244 (2004).

72. Major SM, Nishizuka S, Morita D et al. AbMiner: a bioinformatic resource on available monoclonal antibodies and corresponding gene identifiers for genomic, proteomic, and immunologic studies. BMC Bioinformatics 7,192 (2006).

73. Spurrier B, Washburn FL, Asin S, Ramalingam S, Nishizuka S. Antibody screening database for protein kinetic modeling. Proteomics 7(18),3259-3263 (2007).

74. Ciliberto A, Novak B, Tyson JJ. Steady states and oscillations in the p53/Mdm2 network. Cell Cycle 4(3),488-493 (2005).

75. Ma L, Wagner J, Rice JJ, Hu W, Levine AJ, Stolovitzky GA. A plausible model for the digital response of p53 to DNA damage. Proc. Natl Acad. Sci. USA 102(40),14266-14271 (2005).

76. Madoz-Gurpide J, Kuick R, Wang H, Misek DE, Hanash SM. Integral protein microarrays for the identification of lung cancer antigens in sera that induce a humoral immune response. Mol. Cell. Proteomics 7(2),268-281 (2007).

77. Canterbury JD, Yi X, Hoopmann MR, MacCoss MJ. Assessing the dynamic range and peak capacity of nanoflow LC-FAIMS-MS on an ion trap mass spectrometer for proteomics. Anal. Chem. 80(18),6888-6897 (2008).

78. Coombes KR, Morris JS, Hu J, Edmonson SR, Baggerly KA. Serum proteomics – a young technology begins to mature. Nat. Biotechnol. 23(3),291-292 (2005).

78. Hortin GL. Can mass spectrometric protein profiling meet desired standards of clinical laboratory practice? Clin. Chem. 51(1),3-5 (2005).

79. Omenn GS, States DJ, Adamski M et al. Overview of the HUPO plasma proteome project: results from the pilot phase with 35 collaborating laboratories and multiple analytical groups, generating a core dataset of 3020 proteins and a publicly-available database. Proteomics 5(13),3226-3245 (2005).

80. Rai AJ, Gelfrand CA, Haywood BC et al. HUPO plasma proteome project specimen collection and handling: towards the standardization of parameters for plasma proteome samples. Proteomics 5(13),3262-3277 (2005).

• Concise report on several pre-analytical factors that impact the results of plasma proteomic profiling.

81. Mann M. Can proteomics retire the western blot? J. Proteome Res. 7(8),3065 (2008).

Update from LC/GC North America.

Solutions for Separation Scientists. Aug 2012; 30(8).

30 years of LCGC


The key advances in separation science is covered in five areas of the discipline:

  1. sample preparation
  2. gas chromatography(GC) columns
  3. GC instrumentation
  4. liquid cheomatography (LC) columns
  5. LC instrumentation

In the first, there is automated sample preparation in kit form (QuEChERS). A short list of automated sample preparation techniques includes: supercritical fluid extraction (SFE), microwave extraction, automated solvent extraction (ASE), and solid phase extraction (SPE). A panel of experts views the bast basic method of extraction is SPE, and one uses solid phase microextraction with direct immersion and static headspace extraction, along with liquid-liquid extraction.[2] In GC incremental improvements have been made with ionic liquids, multidimentional GC, and fast GC. LC has advanced dramatically with ultra-high pressure LC and superficially porous particles. LC-MS has become standard equipment routinely used in many labs.[1]

Biomarkers have to be detected in a background of 104-106 other components of comparable concentration that also partition with the stationary phase. The partition coefficients of many species are similar, or identical to the biomarker target. The issue is how to select and resolve fewer than 100 biomarkers from a milieu of 1 million components in a complex mixture. The novel idea is to target structure instead of general properties of molecules.[3] How might this work?  A single substrate, metabolite, hormone, or toxin is identified in milliseconds by specific protein receptors. The combinatorial chemistry community has shown that synthetic polynucleotides (aptamers) can be found and amplified that have selectivities approaching antibodies.This is a method well know for years as affinity chromatography. A distinct problem has been the natural process of post translational modification (PTMs), which may create isoforms by addition of a single phosphate ester to be found in the proverbial soup.

1. Bush L. Separation Science: Past, Present and Future. LCGC NA 2012; 30(8):620.

2.McNally ME. Analysis of the State of the Art: Sample Preparation. LCGC NA 2012; 30(8):648-651.

2. Regnier FE. Plates vs Selectivity: An Emerging Issue with Complex Samples.  LCGC NA 2012; 30(8):622.

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