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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.

REFERENCE/SOURCE

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:

2017

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

https://pharmaceuticalintelligence.com/2017/06/11/ultra-pure-melatonin-product-helps-maintain-sleep-for-up-to-7-hours/

2016

Sleep Science

Genetic link to sleep and mood disorders

https://pharmaceuticalintelligence.com/2016/02/27/genetic-link-to-sleep-and-mood-disorders/

2015

Sleep quality, amyloid and cognitive decline

https://pharmaceuticalintelligence.com/2015/10/31/sleep-quality-amyloid-and-cognitive-decline/

2013

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

https://pharmaceuticalintelligence.com/2013/02/23/httpwww-ncbi-nlm-nih-govpubmed22561555/

 

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

Curator: 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 role of melatonin is important in regulating natural sleep and wake cycles. Typically, melatonin levels decline with age, significantly decreasing after age 40. An estimated 50 to 70 million Americans are affected by sleep difficulties – a process regulated by melatonin — and long-term sleep deprivation has been associated with negative health consequences, including an increased risk of diabetes, hypertension, heart attack, stroke, obesity, and depression.

Clinical data from a new pharmacokinetic study suggests that REMfresh®, the first and only continuous release and absorption melatonin (CRA-melatonin), helps maintain sleep for up to 7 hours. REMfresh® contains 99 percent ultra-pure melatonin and is sourced in Western Europe, a factor that is significant and important to many sleep specialists.

Three research abstracts on the REMfresh® data were published in an online supplement in the journal, Sleep, and were presented recently at the 31st Annual Meeting of the Associated Professional Sleep Societies LLC (APSS).

REMfresh Photo

Image SOURCE: Photograph courtesy of Physician’s Seal®

How REMfresh® Works

REMfresh® (CRA-melatonin) mimics the body’s own 7-hour Mesa Wave™, a natural pattern of melatonin blood levels during a normal night’s sleep cycle.

The study demonstrated the continuous release and absorption of 99 percent ultra-pure melatonin in REMfresh® (CRA-melatonin) was designed to induce sleep onset and provide continuous, lasting restorative sleep over 7 hours.

The scientifically advanced, patented formulation, 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® (CRA-melatonin) is not a drug, there is no drug hangover.

REMfresh MesaCurveNew-1

Image SOURCE: Diagram courtesy of Physician’s Seal®

 

Data Based on Scientifically Advanced Delivery Technology

According to the primary study author, David C. Brodner, M.D., “These study results represent an unparalleled breakthrough in drug-free, sleep maintenance that physicians and patients have been waiting for in a sleep product.” Dr. Brodner is a sleep specialist who is double board-certified in Otolaryngology – Head and Neck Surgery and Sleep Medicine and is the founder and principle physician at the Center for Sinus, Allergy, and Sleep Wellness in Palm Beach County, Florida.

Dr. Brodner said, “Melatonin products have been used primarily as a chronobiotic to address sleep disorders, such as jet lag and shift work. The patented delivery system in REMfresh mimics the body’s own natural sleep pattern, so individuals may experience consistent, restorative sleep and have an improved quality of life with this drug-free product.”

Study Findings With REMAKT

The study findings are based on 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).

The study found that melatonin levels with REMfresh® 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.

Additional analysis presented showed that REMfresh® (CRA-melatonin) builds upon the body of evidence from prolonged-release melatonin (PR-M), 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 faster 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.

REFERENCE/SOURCE

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

REMfresh® press release, June 5, 2017 (http://www.prnewswire.com/news-releases/scientifically-advanced-delivery-technology-in-sleep-management-debuts-at-sleep-2017-with-clinical-data-showing-remfresh-the-first-and-only-continuous-release-and-absorption-melatonin-helps-maintain-sleep-for-up-to-7-hours-300468218.html)

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:

2017

Sleep Research Society announces 2017 award recipients including Thomas S. Kilduff, PhD, Director, Center for Neuroscience at SRI International in Menlo Park, California

https://pharmaceuticalintelligence.com/2017/04/28/sleep-research-society-announces-2017-award-recipients-including-thomas-s-kilduff-phd-director-center-for-neuroscience-at-sri-international-in-menlo-park-california/

2016

Sleep Science

Genetic link to sleep and mood disorders

https://pharmaceuticalintelligence.com/2016/02/27/genetic-link-to-sleep-and-mood-disorders/

2015

Sleep quality, amyloid and cognitive decline

https://pharmaceuticalintelligence.com/2015/10/31/sleep-quality-amyloid-and-cognitive-decline/

2013

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

https://pharmaceuticalintelligence.com/2013/02/23/httpwww-ncbi-nlm-nih-govpubmed22561555/

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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.

 

REFERENCE/SOURCE

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.

Other related articles 

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

2016

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

https://pharmaceuticalintelligence.com/2016/01/25/use-of-sensors-data-and-devices-to-improve-health-san-francisco-april-5-6-2016-wearable-tech-digital-health-conferences/

2015

New Spinal Cord Repair Strategy using 3D Cell Growth

https://pharmaceuticalintelligence.com/2015/10/31/new-spinal-cord-repair-strategy-using-3d-cell-growth/

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

https://pharmaceuticalintelligence.com/2015/11/21/unsupervised-mobile-and-wireless-brain-computer-interfaces-on-the-horizon/

Diffuse optics detects spinal cord ischemia – Optics.org

https://pharmaceuticalintelligence.com/2015/05/07/diffuse-optics-detects-spinal-cord-ischemia-optics-org/

Essential for Rehabilitation

https://pharmaceuticalintelligence.com/2015/12/03/essential-for-rehabilitation/

Read Full Post »


Medical 3D Printing and Metals in use in Medical Devices,
Presentation by Danut Dragoi, PhD

The main objective of medical 3D printing (M3DP) is to build solid / semi-solid / scaffolds / or gel structures from bio-compatible materials that can be utilized in medicine in order to correct, alleviate, support certain surgeries, or even cure some diseases based on medical / biological principles applied to human body.

Materials that replace bones are metals like Ti, Ti alloys, Tantalum, Gold, Silver, Zr and other. For replacement of teeth is traditionally used a combination of Ti-pivots and ceramic / polymers / or in some cases Hydroxylapatite (HA) coated Ti.

In order to produce a metallic object implantable in the human body, most useful technology is 3D printing of metals, commonly known as AT (addition manufacturing) technology. A definition of 3D printing is a process for making a physical object from a three-dimensional digital model, typically by laying down many successive thin layers of a material. If a printer system uses metal powders and binder instead of normal ink the printed layer by layer will develop a 3D object.

The printed object may be an orthopedic bone replacement, a tooth pivot or an artificial tooth. The picture on Slide 4 shows a Laser Sintering System (SLM) for Medical 3D Printing for metals, find specs in here.

Slide 4

Slide4

The machine shown on Slide 5 is one of the three metal printers from SLM Solutions using the technology of Selective Laser Melting, find specs in here,
Slide 5

Slide5
Feature highlight: for aerospace and medical orthopedics. Large build volume.
Material: Stainless steel, tool steel, aluminium, titanium, cobalt-chrome, inconel
Build capacity: 19.68 x 11.02 x 12.80 in. / (500 x 280 x 325 mm)
Build rate: 70 cm³/h
Resolution/Layer thickness: 20 – 200µm
Machine dimensions: 118 x 98 x 43 in.

An important aspect of metal source for M3DP is the shape of the particles, uniform size distribution and chemical purity. Using a new manufacturing approach, Zecotek, a company in Germany, link in here, developed metallic powders that can be successfully used in M3DP. Next Slide 6 shows some characteristics of this breakthrough technology.

Slide6
Slide 7

Slide7

More information on Slide 7 can be found in here.

Slide 8

Slide8

Information on Slide 8 can be found in here .
Slide 9

Slide9

Information on Slide 9 can be found in here, which is a novelty in terms of materials, the fusion for the first time between a Ti alloy and a ceramic.
Slide 10

Slide10The schematic on Slide 10 can be found in here . SLS technology is in wide use around the world due to its ability to easily make very complex geometries directly from digital CAD data. While it began as a way to build prototype parts early in the design cycle, it is increasingly being used in limited-run manufacturing to produce end-use parts. Here is how it is working. The powders are in a compartment controlled by a piston going one small step up, the roller swipes to the right a thin layer of metallic powder on the second compartment controlled by a piston that goes only one small step down, due to the fact that the printed model starts to grow up. The tip of the laser beam melts the powder or fusion the particles according with a real drawing section of the model. The process is repeated until the model is done. The key element of this technology is the laser scan device that follows exactly the drawing section of the model.

Slide 12

Slide12

Slide 12 shows a 3D printed foot that is light and well manageable for the patient. The picture can be found at this link in here. This prosthetic introduces the traces concept on light-weighting of replaceable parts for human body.
Slide 13

Slide13

Slide 13 shows a 3D printed light orthopedic pieces that are using the concept of light-weighting using traces. Their picture can be found here.

Slide 14

Slide14

Slide 14 shows tiny parts obtained with 3D printing technology, details in here.

Slide 15

Slide15

A second way to obtain solid parts is using a 3D Bioplotter, link in here .

EnvisionTec’s 3D-Bioplotter builds its products in much the same way as a traditional 3D printer. However, instead of using plastics, metals or resins, the Bioplotter uses biologic materials to form a scaffold that will be used to grow more advanced cellular cultures.

Just like a traditional 3D printer, the 3D-Bioplotter can be fed a 3D model generated in a CAD program or from a CT scan. Users can slice and hatch a 3D model to define how it will be printed. That information is then translated to code and shipped off to the Bioplotter where the real work begins.

While prototype objects in the mechanical, architectural and civil worlds can be built from a single material, in the biological world it’s rare that the desired objects have a uniform material. To meet that reality, the Bioplotter can print a model in 5 different materials making it suitable for more complex cellular assemblies.

This ability to jet different materials during a single build requires the 3D-Bioplotter to change print heads. It comes equipped with a CNC-like tool holder that can be programmed to change “print-heads” based on the material being extruded. Most bio-engineering builds favor porosity. This machine’s ability to change print heads can also help alter the flow and spacing of successive print layers to give users greater control of their models.

Slide 16

Slide16

The scaffold on slide 16 obtained with a 3D Bioploter, is useful in dentistry to augment the base of the future implantable tooth. The fixation in the picture is made of Vivos Dental’s OsteoFlux product, link see in here.
Slide 17

Slide17

Slide 17 Metals in medical dental implants, Ti becomes fused with the bone, and the tooth attached to one end of the Ti pivot, see link in here.

Slide 18

Slide18

Slide 18, Hot plasma spray bio-ceramics is the solution that doctors used for biocompatibility of an artificial jaws, link in here.

Slide 20

Slide20On slide 20 the traditional Ti casting is compared with Ti 3D printing from the powders. The advantage of 3D method is low cost and high productivity. This link in here is for traditional method, and this link here for 3D printing method.
Slide 21

Slide21Slide 21 For 3D Bioploter made by EnvisionTec we notice the usage of materials such as metal followed by post-processing sintering, Hydroxylapatite, TCP, Titanium. Using a preciptation method the machine can handle Chitosan, Collagen, 2-component system of the two possible combination: Alginate, Fibrin, PU, and Silicone. More details in here.

Slide 26

Slide26

Slide 26 shows two ultra-miniature medical pressure sensors in the eye of a needle, for details see the link in here.

Slide 27

Slide27

Slide 27 The electrodes of the bio-mems implanted on the surface of the heart are made of Gold for the electrical contact and good bio-compatibility. Classes of materials and assembly approaches that enable electronic devices with features – area coverage, mechanical properties, or geometrical forms – that would be impossible to achieve using traditional, wafer-based technologies. Examples include ’tissue-like’ bio-integrated electronics for high resolution mapping of electrophysiology in the heart and brain. The research on bio-integrated electronics can be found here.

Slide 28

Slide28

Slide 28 shows a polymeric material for determining pressure inside the eye, which is useful to monitor patients at risk from glaucoma. Again the circular electrode is made of Gold and its role is that of an antena to transmit data to a iPhone / receiver about the intraocula pressure data.
Slide 29

Slide29

The device in slide 29 is a bio-MEMS implantable for drug dosage. It has multiple micro-needles that are equivalent to a needle of a normal syringe, but painless since theyr tips do not reach the pain receptors. This picture taken from here, shows a side size of the MEMS of about 25 mm.

Slide 30

Slide30

Slide 30 lists some effects of metals in human body. Traces of heavy metals are dangerous for human body. Human body is made of light elements C,H,N,O. Heavy metals: Pb, Hg, accumulate in the body, they disrupt the metabolic processes since they are very toxic to humans. Therefore, heavy metals don’t have “+” physiological effects and Al as element is known to produce Alzheimer’s which has been implicated as a factor. According to the Alzheimer’s Society, the medical and scientific opinion is that studies have not convincingly demonstrated a causal relationship between aluminium and Alzheimer’s disease. Nevertheless, some studies, cite aluminium exposure as a risk factor for Alzheimer’s disease. Some brain plaques have been found to contain increased levels of the metal. Research in this area has been inconclusive; aluminium accumulation may be a consequence of the disease rather than a causal agent, see link in here.
Slide 31

Slide31

Slide 31 shows percent distribution of elements in human bodies, It is interesting that Ti is not making the list, see link in here.

Slide 32

Slide32

Slide 32 has Ti element circled on the Table of the elements, we notice that Zr as element was found to be a bio-compatible element too just like Ti. It is very possible from chemical point of view that all elements in Ti group have same property. The only inconvenient of elements bellow Ti is that they are heavier and their density should be adapted closer to that of human body.
Slide 33

Slide33

Slide 33 is a plot of stress (MPa) of some human implantable materials as a function of Young modulus E (GPa), their principal mechanical characteristic. There are crystalline materials such as: MgZnCa, MgZr, etc.) as well as amorphous materials bio-compatible such as: MgZnCa BMG, Ca based BMG, Sr based BMG, etc.) that have important mechanical strength that can be used in various applications. The circle in green centered on the point (75GPa, 650 MPa) is that for HydroxylApatite, which is a component of teeth and bones. Further details on this plot can be found at this link here,  .

Magnesium and its alloys are suitable materials for biomedical applications due to their low weight, high specific strength, stiffness close to bone and good biocompatibility. Specifically, because magnesium exhibits a fast biodegradability, it has attracted an increasing interest over the last years for its potential use as “biodegradable implants”. However, the main limitation is that Mg degrades too fast and that the corrosion process is accompanied by hydrogen evolution. In these conditions, magnesium implants lose their mechanical integrity before the bone heals and hydrogen gas accumulates inside the body. To overcome these limitations different methods have been pursued to decrease the corrosion rate of magnesium to acceptable levels, including the growth of coatings (conversion and deposited coatings), surface modification treatments (ion implantation, plasma surface modification, etc) or via the control of the composition and microstructure of Mg alloys themselves.

Slide 34

Slide34

Slide 34 shows two types of three point bending tests, one in which the flexural stress is plotted against displacement and second in which the stress intensity factor is plotted against the length of the crack extended beyond the notch. It is interesting that both plots can differentiate between young and aged bones. The plots can be downloaded from here,  where more experimental details and explanation can be found.

Slide 35

Slide35

Slide 35 shows the geometry for 3 point bending for fracture toughness testing. in which the stress intensity factor can be considered as a function of delta a, the depth of the notch at various values of loads. The equation of stress intensity factor can be found here.

Slide 36

Slide36

Slide 36 describes a family of stress-strain curves as function of composition for four Ti alloys. As we can see the mechanical strength of Ti alloys is well above 400 MPa, which is more than enough for replacement of bones that have a lower mechanical strength of about 175 MPa. The plot in this slide can be reviewed at this site.
Slide 37

Slide37

Slide 37 Mechanical strength of cortical bone, see link in here,  and mechanical strength of Ti alloys, seen in here.

The comparison shows a limit of elasticity of 160 MPa which is well below 400 MPa of Ti alloys or even simply Ti element which has a yield strength of 434 MPa, see link video here.
Slide 38

Slide38

Slide 38 provides information about the oxide layer on Ti binding biological tissues. Rutile and Anatase, are the two crystalline species of TiO2 formation on Ti surface. Rutile is less bio-reactive than Anatase, info in here, http://cdn.intechopen.com/pdfs-wm/33623.pdf . The metal work function changes as a consequence of the formation of the passivisation layer (the oxide), but ΔΦ is positive for rutile and negative for anatase, info in here, http://pubs.acs.org/doi/abs/10.1021/jp309827u?journalCode=jpccck .

Slide 39

Slide39

Slide 39 provides information about the crystal structures of three species of Titanium oxide: Rutile, Anatase, and Brookite. As seen from the slide, the density varies with the crystal structure. The valence of Ti in these structures is 4+, same as Carbon in many organic molecules.
Slide 40

Slide40

Slide 40 provides information about the crystal structures of Titanium monoxide. As seen from the slide, the density is the highest among all Titanium oxides. The crystal structure of Titanium monoxide is shown in this slide. The valence of Ti in these structure is 2+, that makes this oxide special in applications.
Slide 41

Slide41

Slide 41 provides information about two metals, Ti and Zr that are used in human body implantable. An explanation of why these two metals are bio-compatible is given in this slide. As we know not all metals are inert/not reactive in human body environment. As a fact bulk cubic structures of metals is less preferred such as Al, Cu, Nb, Pb, etc.. Based on a symmetry remark for living structures (carbohydrates, nucleic acids, lipids and proteins), the lower implantable metals symmetry the better. As an example Lysozyme (S.G. P43212, space group number 96) as a possible interface material with an implantable metal such as Au, Ti, Zr, admits lower space groups such as Ti ( P63/mmc. Space group number: 194). Gold is not preferred for multiple reasons too: it has a high symmetry S.G. 225 (Fm-3m) 96<225, it has has a high density 19.32 g/cc, and it is expensive.

Many metals have a degree of leachability in human body fluids except the rare/precious metals Au, Pt, Ir that are expensive as implants. The coatings of Ti with a tiny thin layer of oxide or laser coated organic ceramics, makes Ti as the best choice as human body implantable with extremely low leachability in human body fluids.
Slide 42

Slide42

Slide 42 provides crystallographic information on Ti crystal structure, unit cell size and directions.
Slide 43

Slide43

Slide 43 provides information on Zr metal as the second choice on human body implantables. The crystal structure of Zr is same as Ti, with hexagonal close packed (HCP) unit cell. The HCP cell is shown together with a body center cubic (BCC) unit and face close cubic (FCC) unit for comparison reason.
Slide 44

Slide44

Slide 44 shows the Table of major biomedical metals and alloys and their applications. More details about materials in the Table can be found here.

Slide 45

Slide45

The Table on Slide 45 shows a comparison of mechanical properties for three metal alloys. Notice the the increase of the ultimate tensile strength of Ti 64, from 434 MPa for Titanium (see slide 37) to 900 MPa for Ti 64. More data about other materials can be found here.

Slide 46

Slide46

Slide 46 lists some medical devices as they were created by the inventor Alfred Mann’s companies. Such devices are:
-rechargeable pacemaker,
-an implant for deaf people,
-an insulin pump and a
-prosthetic retina. (Mel Melcon, Los Angeles Times)
Slide 47

Slide47

Slide 47 As we imagine, the implanted devices should be coated with one of these Ti, Zr, ceramic coated Ti and Stainless Steel. Three example are given as: Ti-plates and rods, 3D printed Jaws + plasma coated HAp, Gold nano-wires.
Slide 48

Slide48

In the example on slide Slide 48, the pacemaker casing is made of titanium or a titanium alloy, electrodes are made of metal alloy insulated with polyurethan polymers, more info in here.

Slide 49

Slide49

The second device shown in slide 49 is an implant for deaf people, whose surface in contact with human body fluids is coated with Ti. More info on how this implant works can be found in here.
Slide 50Slide50The insulin pump shown in slide 50 is a schematic of the pump controlled electronically by a control algorithm device, a sensor, an electronic receiver that connects with an iPhone through an wireless channel.
Slide 51Slide51

The prosthetic retina on slide 51 is an example of a bio-MEMS based optical sensor that takes the outside image through a tiny camera, the electrical signal of the camera is sent to a receiver and then to an array of micro-electrodes tacked to the retina which send electrical impulses to the brain through the optical nerve. More details can be found in here.

Slide 52Slide52Slide 52 describes how easily available bio-compatible metal powders
can revolutionize 3D printing for medical implants. The surgical implants need to generate expected responses from neighboring cells and tissues. Cell behavior (adhesion, functional alteration, morphological changes, and proliferation) is strongly affected by the surgical implants’ surface properties. Surface topography, surface chemistry, and surface energy influence decisively the biological response to an implanted device.
The well controlled 3D printing atmosphere (neutral gases and restricted oxygen) guarantees the high purity of the 3D printed parts and preserves the materials’ properties.
The advantages of 3D printing for medical applications is thoroughly discussed in here.

Slide 53Slide53

Slide 53 shows five conclusions of the presentation, in which 1) many engineered metals are mechanically resistant in human body, but prone to certain corrosion if not coated,
2) Ti, Zr coated bio-ceramics are bio-compatible materials in human body, 3) medical devices implants and MEMS are useful as heart stent, orthopedic prosthetic, prosthetic retina, 3) M3DP has low costs, high quality, long life cycle and 4) Metal/bio-ceramic and Vivos dental’s synthetic bone for oral augmentation is a solution for today’s dental health care.
Slide 54Slide54Slide 54 shows conclusions regarding the hardware of the presentation, in which: 6) there are two types of metal 3D printing hardware for medical applications: Selective Laser Melting / Selective Laser Sintering, and 3D Bioploter (metal powder mixed with binder and further thermal treatment to remove binder and sinter the metallic matrix in a solid object that can be used as a replacement. Thank you for your attention!

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Novel Mechanisms of Resistance to Novel Agents

 

Curators: Larry H. Berstein, M.D. FACP & Stephen J. Williams, Ph.D.

For most of the history of chemotherapy drug development, predicting the possible mechanisms of drug resistance that ensued could be surmised from the drug’s pharmacologic mechanism of action. In other words, a tumor would develop resistance merely by altering the pathways/systems which the drug relied on for mechanism of action. For example, as elucidated in later chapters in this book, most cytotoxic chemotherapies like cisplatin and cyclophosphamide were developed to bind DNA and disrupt the cycling cell, thereby resulting in cell cycle arrest and eventually cell death or resulting in such a degree of genotoxicity which would result in great amount of DNA fragmentation. These DNA-damaging agents efficacy was shown to be reliant on their ability to form DNA adducts and lesions. Therefore increasing DNA repair could result in a tumor cell becoming resistant to these drugs. In addition, if drug concentration was merely decreased in these cells, by an enhanced drug efflux as seen with the ABC transporters, then there would be less drug available for these DNA adducts to be generated. A plethora of literature has been generated on this particular topic.

However in the era of chemotherapies developed against targets only expressed in tumor cells (such as Gleevec against the Bcr-Abl fusion protein in chronic myeloid leukemia), this paradigm had changed as clinical cases of resistance had rapidly developed soon after the advent of these compounds and new paradigms of resistance mechanisms were discovered.

speed of imitinib resistance

Imatinib resistance can be seen quickly after initiation of therapy

mellobcrablresistamplification

Speed of imatinib resistance a result of rapid gene amplification of BCR/ABL target, thereby decreasing imatinib efficacy

 

 

 

 

 

 

 

 

 

 

Although there are many other new mechanisms of resistance to personalized medicine agents (which are discussed later in the chapter) this post is a curation of cellular changes which are not commonly discussed in reviews of chemoresistance and separated in three main categories:

Cellular Diversity and Adaptation

Identifying Cancers and Resistance

Cancer Drug-Resistance Mechanism

p53 tumor drug resistance gene target

Variability of Gene Expression and Drug Resistance

 

Expression of microRNAs and alterations in RNA resulting in chemo-resistance

Drug-resistance Mechanism in Tumor Cells

Overexpression of miR-200c induces chemoresistance in esophageal cancers mediated through activation of the Akt signaling pathway

 

The miRNA–drug resistance connection: a new era of personalized medicine using noncoding RNA begins

 

Gene Duplication of Therapeutic Target

 

The advent of Gleevec (imatinib) had issued in a new era of chemotherapy, a personalized medicine approach by determining the and a lifesaver to chronic myeloid leukemia (CML) patients whose tumors displayed expression of the Bcr-Abl fusion gene. However it was not long before clinical resistance was seen to this therapy and, it was shown amplification of the drug target can lead to tumor outgrowth despite adequate drug exposure. le Coutre, Weisberg and Mahon23, 24, 25 all independently generated imatinib-resistant clones through serial passage of the cells in imatinib-containing media and demonstrated elevated Abl kinase activity due to a genetic amplification of the Bcr–Abl sequence. However, all of these samples were derived in vitro and may not represent a true mode of clinical resistance. Nevertheless, Gorre et al.26 obtained specimens, directly patients demonstrating imatinib resistance, and using fluorescence in situ hybridization analysis, genetic duplication of the Bcr–Abl gene was identified as one possible source of the resistance. Additional sporadic examples of amplification of the Bcr–Abl sequence have been clinically described, but the majority of patients presenting with either primary or secondary imatinib resistance fail to clinically demonstrate Abl amplification as a primary mode of treatment failure.

This is seen in the following papers:

Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification.Gorre ME, Mohammed M, Ellwood K, Hsu N, Paquette R, Rao PN, Sawyers CL. Science. 2001 Aug 3;293(5531):876-80. Epub 2001 Jun 21.

and in another original paper by le Coutre et. al.

Induction of resistance to the Abelson inhibitor STI571 in human leukemic cells through gene amplification. le Coutre P1, Tassi E, Varella-Garcia M, Barni R, Mologni L, Cabrita G, Marchesi E, Supino R, Gambacorti-Passerini C. Blood. 2000 Mar 1;95(5):1758-66

The 2-phenylaminopyrimidine derivative STI571 has been shown to selectively inhibit the tyrosine kinase domain of the oncogenic bcr/abl fusion protein. The activity of this inhibitor has been demonstrated so far both in vitro with bcr/abl expressing cells derived from leukemic patients, and in vivo on nude mice inoculated with bcr/abl positive cells. Yet, no information is available on whether leukemic cells can develop resistance to bcr/abl inhibition. The human bcr/abl expressing cell line LAMA84 was cultured with increasing concentrations of STI571. After approximately 6 months of culture, a new cell line was obtained and named LAMA84R. This newly selected cell line showed an IC50 for the STI571 (1.0 microM) 10-fold higher than the IC50 (0.1 microM) of the parental sensitive cell line. Treatment with STI571 was shown to increase both the early and late apoptotic fraction in LAMA84 but not in LAMA84R. The induction of apoptosis in LAMA84 was associated with the activation of caspase 3-like activity, which did not develop in the resistant LAMA84R cell line. LAMA84R cells showed increased levels of bcr/abl protein and mRNA when compared to LAMA84 cells. FISH analysis with BCR- and ABL-specific probes in LAMA84R cells revealed the presence of a marker chromosome containing approximately 13 to 14 copies of the BCR/ABL gene. Thus, overexpression of the Bcr/Abl protein mediated through gene amplification is associated with and probably determines resistance of human leukemic cells to STI571 in vitro. (Blood. 2000;95:1758-1766)

This is actually the opposite case with other personalized therapies like the EGFR inhibitor gefinitib where actually the AMPLIFICATION of the therapeutic target EGFR is correlated with better response to drug in

Molecular mechanisms of epidermal growth factor receptor (EGFR) activation and response to gefitinib and other EGFR-targeting drugs.Ono M, Kuwano M. Clin Cancer Res. 2006 Dec 15;12(24):7242-51. Review.

Abstract

The epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases, including EGFR, HER2/erbB2, and HER3/erbB3, is an attractive target for antitumor strategies. Aberrant EGFR signaling is correlated with progression of various malignancies, and somatic tyrosine kinase domain mutations in the EGFR gene have been discovered in patients with non-small cell lung cancer responding to EGFR-targeting small molecular agents, such as gefitinib and erlotinib. EGFR overexpression is thought to be the principal mechanism of activation in various malignant tumors. Moreover, an increased EGFR copy number is associated with improved survival in non-small cell lung cancer patients, suggesting that increased expression of mutant and/or wild-type EGFR molecules could be molecular determinants of responses to gefitinib. However, as EGFR mutations and/or gene gains are not observed in all patients who respond partially to treatment, alternative mechanisms might confer sensitivity to EGFR-targeting agents. Preclinical studies showed that sensitivity to EGFR tyrosine kinase inhibitors depends on how closely cell survival and growth signalings are coupled with EGFR, and also with HER2 and HER3, in each cancer. This review also describes a possible association between EGFR phosphorylation and drug sensitivity in cancer cells, as well as discussing the antiangiogenic effect of gefitinib in association with EGFR activation and phosphatidylinositol 3-kinase/Akt activation in vascular endothelial cells.

 

Mutant Variants of Therapeutic Target

 

resistant subclones in tissue samples and Tyrosine Kinase tumor activity

 

Mitochondrial Isocitrate Dehydrogenase and Variants

Mutational Landscape of Rare Childhood Brain Cancer: Analysis of 60 Intercranial Germ Cell Tumor Cases using NGS, SNP and Expression Array Analysis – Signaling Pathways KIT/RAS are affected by mutations in IGCTs

 

AND seen with the ALK inhibitors as well (as seen in the following papers

Acquisition of cancer stem cell-like properties in non-small cell lung cancer with acquired resistance to afatinib.

Hashida S, Yamamoto H, Shien K, Miyoshi Y, Ohtsuka T, Suzawa K, Watanabe M, Maki Y, Soh J, Asano H, Tsukuda K, Miyoshi S, Toyooka S. Cancer Sci. 2015 Oct;106(10):1377-84. doi: 10.1111/cas.12749. Epub 2015 Sep 30.

In vivo imaging models of bone and brain metastases and pleural carcinomatosis with a novel human EML4-ALK lung cancer cell line.

Nanjo S, Nakagawa T, Takeuchi S, Kita K, Fukuda K, Nakada M, Uehara H, Nishihara H, Hara E, Uramoto H, Tanaka F, Yano S. Cancer Sci. 2015 Mar;106(3):244-52. doi: 10.1111/cas.12600. Epub 2015 Feb 17.

Identification of a novel HIP1-ALK fusion variant in Non-Small-Cell Lung Cancer (NSCLC) and discovery of ALK I1171 (I1171N/S) mutations in two ALK-rearranged NSCLC patients with resistance to Alectinib. Ou SH, Klempner SJ, Greenbowe JR, Azada M, Schrock AB, Ali SM, Ross JS, Stephens PJ, Miller VA.J Thorac Oncol. 2014 Dec;9(12):1821-5

Reports of chemoresistance due to variants have also been seen with the BRAF inhibitors like vemurafenib and dabrafenib:

The RAC1 P29S hotspot mutation in melanoma confers resistance to pharmacological inhibition of RAF.

Watson IR, Li L, Cabeceiras PK, Mahdavi M, Gutschner T, Genovese G, Wang G, Fang Z, Tepper JM, Stemke-Hale K, Tsai KY, Davies MA, Mills GB, Chin L.Cancer Res. 2014 Sep 1;74(17):4845-52. doi: 10.1158/0008-5472.CAN-14-1232-T. Epub 2014 Jul 23

 

 

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Huge advance in burn surgery

Curator: Larry H. Bernstein, MD, FCAP

 

 

26-Hour Face Transplant Made Possible with 3D Printing

By On Thu, Nov 19, 2015

One fateful night back in 2001, a former volunteer firefighter from Mississippi named Patrick Hardison bravely entered a burning home seeking to rescue anyone who might be stuck inside. When the burning house collapsed upon Hardison, he was left with critical injuries that completely disfigured his facial features, leaving him complete unrecognizable even to his own wife and children. This horrific accident forced Hardison onto the operating table over 70 times, where traditional surgical operations were only adding to the mental and physical strain he had been undergoing since the fire had left him disfigured.

 

3dprint)nyu_rodriguez_patrick_smaller

It wasn’t until Dr. Eduardo D. Rodriguez, a plastic surgeon at NYU’s Langone Medical Center, came up with a plan to give Hardison a full face transplant. The plan involved finding a ‘donor’ who matched in hair color, skin color, blood type, and who also has a similar skeletal structure to Hardinson. Once the selected donor was found, Rodriguez and his staff utilized 3D Systems’ Virtual Surgical Planning (VSP) technology, which allows for adequate surgical preparation by offering cutting guides over an actual 3D scan of the bone structure of both the patient and the donor.

 

VSP Technology

 

VSP Technology

VSP technology is able to create these surgical templates by using medical scan data, which are transformed into 3D models and, in some cases, are even 3D printed for a visual aid. 3D Systems’ Medical Modeling team actually assisted in the printing of these templates, using a biocompatible 3D printing material that is easily sterilized, and can, therefore, be safely utilized within the confines of an operating room.

 

 

3dprint)nyu_before_after

 

Using the careful surgical plan the Rodriguez and his team prepared on 3D Systems’ VSP technology, Hardinson received an extremely successful surgery and suddenly had all of the features of a human face again for the first time in years. Although the intensive surgery took Rodriguez and over 100 other individuals who assisted in the operation a whopping 26 hours to complete, the surgery would have likely been impossible to even plan without the preparation help offered by 3D Systems and their Virtual Surgical Planning technology. Now, thanks to Dr. Rodriguez, 3D Systems’ Medical Modeling team, and the rest of the NYU’s Langone Medical Center staff, Patrick Hardison can finally smile at the world, once again.

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Information Management in Health Research

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

Researchers find Potential Security Hole in Genomic Data-sharing Network

http://www.scientificcomputing.com/news/2015/10/researchers-find-potential-security-hole-genomic-data-sharing-network

Jennie Dusheck, Stanford University

Sharing genomic information among researchers is critical to the advance of biomedical research. Yet genomic data contains identifiable information and, in the wrong hands, poses a risk to individual privacy. If someone had access to your genome sequence — either directly from your saliva or other tissues, or from a popular genomic information service — they could check to see if you appear in a database of people with certain medical conditions, such as heart disease, lung cancer or autism.

Work by researchers at the Stanford University School of Medicine makes that genomic data more secure. Suyash Shringarpure, Ph.D., a postdoctoral scholar in genetics, and Carlos Bustamante, Ph.D., a professor of genetics, have demonstrated a technique for hacking a network of global genomic databases and how to prevent it. They are working with investigators from the Global Alliance for Genomics and Health on implementing preventive measures.

The work, published October 29, 2015, in The American Journal of Human Genetics, also bears importantly on the larger question of how to analyze mixtures of genomes, such as those from different people at a crime scene.

A network of genomic data sets on servers, or beacons, organized by the National Institutes of Health-funded Global Alliance for Genomics and Health, allows researchers to look for a particular genetic variant in a multitude of genomic databases. The networking of genomic databases is part of a larger movement among researchers to share data. Identifying a gene of interest in a beacon tells researchers where to apply for more complete access to the data. A central assumption, though, is that the identities of those who donate their genomic data are sufficiently concealed.

“The beacon system is an elegant solution that allows investigators to ‘ping’ collections of genomes,” said Bustamante. Investigators on the outside of a data set can ping and ask which data set has a particular mutation. “This allows people studying the same rare disease to find one another to collaborate.”

Beacons’ vulnerability

But many genomic data sets are specific to a condition or disease. A nefarious user who can find the match for an individual’s genome in a heart disease beacon, for example, can infer that the individual — or a relative of that person — likely has heart disease. By “pinging” enough beacons in the network of beacons, the hacker could construct a limited profile of the individual. “Working with the Global Alliance for Genomics and Health, we’ve been able to demonstrate that vulnerability and, more importantly, how to put policy changes in place to minimize the risk,” said Bustamante.

To protect donors’ identities, the organizers of the network, which is called the Beacon Project, have taken steps, such as encouraging beacon operators to “de-identify” individual genomes, so that names or other identifying information are not connected to the genome.

Despite such efforts, Shringarpure and Bustamante calculated that someone in possession of an individual’s genome could locate that individual within the beacon network. For example, in a beacon containing the genomes of 1,000 individuals, the Stanford pair’s approach could identify that individual or their relatives with just 5,000 queries.

Genomic information isn’t completely covered by the federal law that protects health information, and the consequences for a person whose information is disclosed can be significant. For example, although the national Genetic Information Nondiscrimination Act prevents health insurers from denying someone coverage or raising someone’s premiums because they have a particular genetic variant, the act does not apply to other forms of insurance, such as long-term care, disability or life insurance.

Approaches for better security

The Beacon Project has the potential to be enormously valuable to future genetic research. So, plugging this security hole is as important to Shringarpure and Bustamante as to the Global Alliance for Genomics and Health. In their paper, the Stanford researchers suggest various approaches for making the information more secure, including banning anonymous researchers from querying the beacons; merging data sets to make it harder to identify the exact source of the data; requiring that users be approved; and limiting access in a beacon to a smaller region of the genome.

The beacon system is an elegant solution that allows investigators to ‘ping’ collections of genomes.

Peter Goodhand, executive director of the Global Alliance for Genomics and Health, said, “We welcome the paper and look forward to ongoing interactions with the authors and others to ensure beacons provide maximum value while respecting privacy.”

Goodhand also said that the organization’s mitigation efforts, which adhere to the best practices outlined in its privacy and security policy, include aggregating data among multiple beacons to increase database size and obscure the database of origin; creating an information-budgeting system to track the rate at which information is revealed and to restrict access when the information disclosed exceeds a certain threshold; and introducing multiple tiers of secured access, including requiring users to be authorized for data access and to agree not to attempt specific risky scenarios.

Shringarpure and Bustamante are also interested in applying the technique described in their study to the area of DNA mixture interpretation, in which investigators seek to identify one DNA sequence in a mixture of many similar ones. The DNA mixing problem is relevant to forensics, studies of the microbiome and ecological studies. For example, Bustamante said, if a weapon used in a crime had DNA from several people on it, DNA mixture interpretation can help investigators pick out the DNA of a particular person, such as the suspect or the victim, revealing whether they touched the weapon. In fact, investigators could potentially use the same type of analysis used on the beacon network to look for individuals who may have touched a railing in a subway station or other public space.

This research was partially supported by the National Institutes of Health (grant U01HG007436).Stanford’s Department of Genetics also supported the work. Bustamante is on the scientific advisory boards for Ancestry.com, Personalis, Liberty Biosecurity and Etalon DX. He is also a founder and chair of the advisory board for IdentifyGenomics. None of these entities played a role in the design, interpretation or presentation of the study. Stanford University’s Office of Technology Licensing has evaluated the work presented in the paper for potential intellectual property and commercial rights.

 

Computational Models to Sort out the Genetic Chaos of Cancer Cells

http://www.scientificcomputing.com/news/2015/10/computational-models-sort-out-genetic-chaos-cancer-cells

University of Luxembourg

Scientists have developed a method for analyzing the genome of cancer cells more precisely than ever before. The team led by Prof. Antonio del Sol, head of the research group Computational Biology of the Luxembourg Centre for Systems Biomedicine of the University of Luxembourg, is employing bioinformatics: Using novel computing processes, the researchers have created models of the genome of cancer cells based on known changes to the genome. These models are useful for determining the structure of DNA in tumors.

“If we know this structure, we can study how cancer develops and spreads,” says del Sol. “This gives us clues about possible starting points for developing new anticancer drugs and better individual therapy for cancer patients.”

The LCSB researchers recently published their results in the scientific journal Nucleic Acids Research.

“The cause of cancers are changes in the DNA,” says Sarah Killcoyne, who is doing her PhD at the University of Luxembourg and whose doctoral thesis is a core component of the research project. “Mutations arise, the chromosomes can break or reassemble themselves in the wrong order, or parts of the DNA can be lost,” Killcoyne describes the cellular catastrophe: “In the worst case, the genome becomes completely chaotic.” The cells affected become incapable of performing their function in the body and — perhaps even worse — multiply perpetually. The result is cancer.

If we are to develop new anticancer drugs and provide personalized therapy, it is important to know the structure of DNA in cancer cells. Oncologists and scientists have isolated chromosomes from tumors and analyzed them under the microscope for decades. They found that irregularities in the chromosome structure sometimes indicated the type of cancer and the corresponding therapy.

“Sequencing technologies have made the identification of many mutations more accurate, significantly improving our understanding of cancer,” Sarah Killcoyne says. “But it has been far more difficult to use these technologies for understanding the chaotic structural changes in the genome of cancer cells.”

This is because sequencing machines only deliver data about very short DNA fragments. In order to reconstruct the genome, scientists accordingly need a reference sequence — a kind of template against which to piece together the puzzle of the sequenced genome.

Killcoyne continues: “The reference sequence gives us clues to where the fragments overlap and in what order they belong together.” Since the gene sequence in cancer cells is in complete disarray, logically, there is no single reference sequence. “We developed multiple references instead,” says Sarah Killcoyne. “We applied statistical methods for our new bioinformatics approach, to generate models, or references, of chaotic genomes and to determine if they actually show us the structural changes in a tumor genome.”

These methods are of double importance to group leader del Sol, as he states: “Firstly, Sarah Killcoyne’s work is important for cancer research. After all, such models can be used to investigate the causes of genetic and molecular processes in cancer research and to develop new therapeutic approaches. Secondly, we are interested in bioinformatics model development for reapplying it to other diseases that have complex genetic causes — such as neurodegenerative diseases like Parkinson’s. Here, too we want to better understand the relationships between genetic mutations and the resulting metabolic processes. After all, new approaches for diagnosing and treating neurodegenerative diseases are an important aim at the Luxembourg Centre for Systems Biomedicine.”

Citation: Mathematical ‘Gingko trees’ reveal mutations in single cells that characterize diseases. Sarah Killcoyne et al. Identification of large-scale genomic variation in cancer genomes using reference models , Nucleic Acids Research (2015). DOI: 10.1093/nar/gkv828

 

 

Mathematical ‘Gingko trees’ reveal mutations in single cells that characterize diseases

DOI: 10.1093/nar/gkv828

Seemingly similar cells often have significantly different genomes. This is often true of cancer cells, for example, which may differ one from another even within a small tumor sample, as genetic mutations within the cells spread in staccato-like bursts. Detailed knowledge of these mutations, called copy number variations, in individual cells can point to specific treatment regimens.

The problem is that current techniques for acquiring this knowledge are difficult and produce unreliable results. Today, scientists at Cold Spring Harbor Laboratory (CSHL) publish a new interactive analysis program called Gingko that reduces the uncertainty of single-cell analysis and provides a simple way to visualize patterns in copy number mutations across populations of .

The open-source software, which is freely available online, will improve scientists’ ability to study this important type of genetic anomaly and could help clinicians better target medications based on cells’ specific mutation profiles. The software is described online today in Nature Methods.

Mutations come in many forms. For example, in the most common type of mutation, variations may exist among individual people—or cells—at a single position in a DNA sequence. Another common mutation is a copy number variation (CNV), in which large chunks of DNA are either deleted from or added to the genome. When there are too many or too few copies of a given gene or genes, due to CNVs, disease can occur. Such mutations have been linked not only with cancer but a host of other illnesses, including autism and schizophrenia.

Researchers can learn a lot by analyzing CNVs in bulk samples—from a tumor biopsy, for example—but they can learn more by investigating CNVs in . “You may think that every cell in a tumor would be the same, but that’s actually not the case,” says CSHL Associate Professor Michael Schatz.

“We’re realizing that there can be a lot of changes inside even a single tumor,” says Schatz. “If you’re going to treat cancer, you need to diagnose exactly what subclass of cancer you have.” Simultaneously employing different drugs to target different cancer subclasses could prevent remission, scientists have proposed.

One powerful single-cell analytic technique for exploring CNV is whole genome sequencing. The challenge is that, before sequencing can be done, the cell’s DNA has to be amplified many times over. This process is rife with errors, with some arbitrary chunks of DNA being amplified more than others. In addition, because many labs use their own software to examine CNVs, there is little consistency in how researchers analyze their results.

To address these two challenges, Schatz and his colleagues created Gingko. The interactive, web-based program automatically processes sequence data, maps the sequences to a reference genome, and creates CNV profiles for every cell that can then be viewed with a user-friendly graphical interface. In addition, Gingko constructs phylogenetic trees based on the profiles, allowing cells with similar copy number mutations to be grouped together.

Importantly, Gingko, which Schatz and his colleagues validated by reproducing the findings of five major single-cell studies, also analyzes patterns in the sequence reads in order to recognize, and greatly reduce, amplification errors.

Schatz and his team named their software after the gingko tree, which has many well-documented therapeutic benefits. “We like to think our Gingko ‘trees’ will provide benefits as well,” says Schatz, referring to the graphical way that CNV changes are represented by analysts. Right now, CNV is not a commonly used diagnostic measurement in the clinic. “We’re looking into the best way of collecting samples, analyzing them, and informing clinicians about the results,” says Schatz. He adds that CSHL has collaborations with many hospitals, notably Memorial Sloan Kettering Cancer Center and the North Shore-LIJ Health System, to bring single-cell analysis to the clinic.

For Schatz, Gingko represents a culmination of CSHL’s efforts over the past decade—spearheaded by CSHL Professor Michael Wigler—to pioneer techniques for studying single cells. “Cold Spring Harbor has established itself as the world leader in single-cell analysis,” says Schatz. “We’ve invented many of the technologies and techniques important to the field and now we’ve taken all this knowledge and bundled it up so that researchers around the world can take advantage of our expertise.”

Explore further: A shift in the code: New method reveals hidden genetic landscape

More information: Interactive analysis and assessment of single-cell copy-number variations, Nature, DOI: 10.1038/nmeth.3578

 

Interactive analysis and assessment of single-cell copy-number variations

Tyler GarvinRobert AboukhalilJude KendallTimour BaslanGurinder S AtwalJames HicksMichael Wigler & Michael C Schatz

Nature Methods12,1058–1060(2015)    http://dx.doi.org:/10.1038/nmeth.3578

We present Ginkgo (http://qb.cshl.edu/ginkgo), a user-friendly, open-source web platform for the analysis of single-cell copy-number variations (CNVs). Ginkgo automatically constructs copy-number profiles of cells from mapped reads and constructs phylogenetic trees of related cells. We validated Ginkgo by reproducing the results of five major studies. After comparing three commonly used single-cell amplification techniques, we concluded that degenerate oligonucleotide-primed PCR is the most consistent for CNV analysis.

Figure 2: Assessment of data quality for different single-cell whole genome amplification methods using Ginkgo.

Assessment of data quality for different single-cell whole genome amplification methods using Ginkgo.

(a) LOWESS fit of GC content with respect to log-normalized bin counts for all samples in each of the nine data sets analyzed: three for MDA (top left, green), three for MALBAC (center left, orange) and three for DOP-PCR (bottom left, b…

 

 

Breaking Through the Barriers to Lab Innovation

http://www.technologynetworks.com/LIMS/news.aspx?ID=184014

Author: Helen Gillespie, Informatics Editor, Technology Networks

 

Innovation is a hot topic today and just about every type of laboratory is scrambling to figure out what it means for them. Lab Managers are expected to design profitable new products that enable the research organization to stay competitive in today’s marketplace. This means change. Process change. Systems change. Informatics technologies change. As a result, systemic change is occurring at all levels of the organization, driving the implementation of integrated lab solutions that unlock disparate, disconnected lab data silos and harmonize the IT infrastructure. Getting greater control of lab data is part of this and one of the most critical components of future success and corporate sustainability. As a result, some of the greatest change is taking place in Informatics in laboratories around the world.

Two of the most significant barriers to innovation are outdated informatics tools and inefficient workflows. Moving from paper-based manual methodologies to digital solutions can breathe new life into researcher productivity while enabling forward-looking companies to better compete and excel in today’s rapidly changing business environment.

This article examines the drivers behind the move for greater innovation, challenges, current trends in laboratory informatics, and the tools and techniques that can be used to break through barriers to lab innovation. Several leading informatics vendors provide their views.

Selected Vendors

featured productLaboratories worldwide seeking a single, integrated informatics platform can now standardize on one comprehensive laboratory information management system (LIMS). Thermo Fisher’s integrated informatics solution now comprises method execution, data visualization and laboratory management, and seamlessly integrates with all popular enterprise-level software packages.

“Thermo Scientific SampleManager is a fully integrated laboratory platform encompassing laboratory information management (LIMS), scientific data management (SDMS) and lab execution (LES).”
Trish Meek, Director Strategy, Informatics, Thermo Fisher Scientific

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featured productBIOVIA Unified Lab Management allows for streamlined and more efficient lab workflows and a fully integrated and automated easy-to-deploy process. Based on the BIOVIA Foundation it works as an integration hub for BIOVIA applications as well as all major 3rd party systems and instruments allowing for seamless data transfer.

“BIOVIA Unified Lab Management is part of our unique end-to-end Product Lifecycle support for science-based organizations to improve innovation, quality, compliance, and efficiency.”
Dr. Daniela Jansen, Senior Solution Marketing Manager

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featured productWaters® NuGenesis® Lab Management System uniquely combines data, workflow and sample management capabilities to support the entire product lifecycle from discovery through manufacturing. This user-centric platform encompasses NuGenesis SDMS, compliance-ready data repository, NuGenesis ELN, a flexible analytical electronic laboratory notebook, and NuGenesis Sample Management.

“The NuGenesis LMS readily adapts to existing informatics environments, smoothly linking data from the lab to the business operations of a company, so science-driven organizations can see more, know more and do more.”
Garrett Mullen, Senior Product Marketing Manager, Laboratory Management Informatics, Waters

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The Impact of Corporate Wide Initiatives

There are a number of sweeping changes occurring throughout the corporate world that are turning the spotlight on research laboratories, examining everything from workflows to documentation. These changes are driven by corporate initiatives to increase profits, reduce costs, develop new products and drive operational efficiencies throughout the enterprise. These are not new goals, but the methodologies for achieving these goals have changed significantly thanks to the rapid changes in technology. Now, there is a greater focus on how technology can drive innovation throughout the enterprise.

In fact, almost every leading multinational organization nowadays touts innovation as an underlying theme for how they conduct business and develop the next generation products. To be truly innovative however, businesses of all types must embrace innovation at every level of the enterprise – not just in the products under development, but also how those products are being developed.

“Organizations nowadays cannot afford to not look into innovation,” emphasizes Dr. Daniela Jansen, Senior Solution Marketing Manager at BIOVIA. “Now, they are questioning how product quality is being supported by innovation throughout the end-to-end product lifecycle. The time is past when researchers looked to a single functionality to make a difference. Now, all software needs to drive innovation, to drive costs down and to drive efficiency.”

Garrett Mullen, Senior Product Marketing Manager at Waters Corporation, offers another perspective. “We drive innovation by addressing the challenges. Sometimes it is specific to the market, such as petrochemical or pharmaceutical, sometimes it is specific to the task, such as sample registration for the QA/QC department. All markets are suffering from similar challenges, whether it is products coming off patent or waning market share. So there is a big focus on what they can do about it, from controlling costs to simplifying processes.”

Operational excellence plays a significant role in corporate initiatives for innovation, and this is where the initiatives drill down into the research laboratories. According to Trish Meek, Director of Product Strategy for the Informatics business at Thermo Fisher Scientific, “Executives are looking more closely at the lab as part of a more holistic view of operational efficiencies across the entire organization. There’s a larger expectation than ever before that there is hidden value in the lab, and that can be found in optimizing efficiencies and more fully integrating processes across the lab and throughout the rest of the manufacturing or production process. Executive metrics now include the lab as they analyze data from all aspects of their operations in order to improve their processes, improve the quality of their products and drive profitability. Executives are now mining and reviewing data to determine how to make operations better from a holistic perspective, and that is causing the spotlight to be on the lab more than it ever was.”

A key aspect of operational excellence is that it goes hand in hand with product quality. Not only is there a need to expedite innovation to deliver new products, those new products need to be high quality and to comply with changing environmental regulations and consumer expectations. As a result, research organizations are reviewing their Informatics infrastructure and streamlining laboratory operations.

Further, the technology that supports lab Informatics has been evolving rapidly, delivering new functionality that is changing the way research can be performed.  This points to the heart of the matter: current technology is enabling new workflows (such as digital collaboration) while delivering greater access to research and also enabling better examination of the research (such as through the ‘Cloud’). This paradigm shift is happening at many levels, from how research is performed to how the data is shared, with technology at the center of the shift.

Barriers to Innovation: The Migration from Paper to Digital

Legacy paper-based activities in the lab are perhaps one of the greatest barriers to innovation. Data captured in paper lab notebooks is typically difficult to find, read or share. Written observations are often transcribed incorrectly. Tests and experiments are repeated because prior data is lost or inaccessible. Even though many lab activities are conducted electronically, certain steps are often still conducted on paper. Such repetitious manual activities are one of the greatest impediments to productivity. These workflow gaps are slowly being replaced with seamless digital activities.

One of the most interesting aspects of the drive for innovation is the ability to take advantage of the technology tools now available, which deliver a significant new range of functionality to users. Electronic Lab Notebooks (ELNs), for instance, can now be connected in the Cloud so that scientists anywhere can collaborate and share research data. This is important because not only is the transition to ELN’s happening on a local level, it is part of a larger global movement toward distributed research as a result of changes in how research organizations are now managing their operations. Large multinationals with research centers distributed around the globe are enabling their scientists to collaborate easily and efficiently with ELN’s as part of their effort to streamline operations.

Quote2.jpg“It is still surprising to see paper in the lab,” states Meek. “It’s in many cases a cultural issue – a comfort level – which makes it hard to move away from paper, and it’s a system everyone knows. Despite its flaws, paper is infinitely flexible, but in general it is terribly inefficient with regards to big data and computational power. Now, the need to look at all the data, and have all the data available is far more important, meaning that the move away from paper or manual data management is now more important than ever.”

“It continues to be about paper in many labs,” Jansen confirms. “But you need to look at the entire chain of cause and effect and the role that paper plays. Now, it’s about what drives the entire organization, not localized practices. This means that there’s a focus on reducing the time spent on documentation and removing barriers. There’s a focus on getting quality designed into the process, getting greater efficiency, and connecting the disparate silos of data the impede innovation. One way to do this is to use an open science-aware framework like the BIOVIA Foundation to integrate processes and applications from different providers. And virtual experiments that enable scientists to identify potential new products earlier in the process can significantly save time and money.“

Cost savings are one of the key reasons organizations make the transition from paper to digital practices. “We’ve found that processes went from hours to minutes when you eliminate the numerous manual review processes and transcriptions and replace them with electronic processes,” explains Mullen. “For example, in the past one central analytical lab at a company might have performed all LC [liquid chromatography] testing. Users submitted samples via email and the samples were boxed, tests requested, samples were received and registered at the central lab, etc. Very labor intensive. A digital solution changes all that. Now the new NuGenesis web interface enables the user to register the sample, enter the samples, specify the tests digitally, and thus reduce transcription errors and expedite the process. An automatic acknowledgement that the samples are approved is sent and the testing processes start. This eliminates the manual tasks associated with checking that everything is accurate. The time and cost savings are enormous.”

quote3.jpgOther factors are influencing the migration from paper to digital lab processes, including the recession and the heightened merger and acquisition activity. Many organizations have downsized, are running leaner, and employ fewer researchers. Yet the productivity demands remain as high as when there was more staff. Thus, there’s an increased need to ensure that researcher activities are more efficient. Manual workflows are out of sync in the digital environment.

Adopting Next Generation Technology

While there are numerous paper-based workflows in research labs worldwide, the vast majority of these labs have adopted some level of technology, including informatics software solutions. What began with instrument-specific software solutions, such as Thermo Scientific ChromeleonTM chromatography data system (CDS), has expanded to numerous application-specific and task-specific systems as computers have become an integral part of the lab work environment. Laboratory Information Management Systems (LIMS) have been commercially available since the early 1980’s. The increase in demand for fast turnaround and greater volumes of sample testing and analysis drove the growth in these solutions. NuGenesis® introduced the first Scientific Data Management System (SDMS) to help capture, catalog and archive lab data better in the 1990’s. ELN’s were one of the last lab systems to become a ubiquitous tool mainly because of the challenge of managing unstructured data versus structured data, but technology has overcome this issue too.

The increase in computing power accelerated the Informatics vendors’ ability to deliver faster, better, more comprehensive software tools. In parallel, the adoption of sophisticated technology by consumers created expectations for similar capabilities in the workplace, driving the demand for hardware such as tablets and other handheld devices as access tools for ELNs, LIMS and other lab software.

Yet while these different lab data and sample management systems have provided significant benefits to the lab, they started as separate systems and thus created separate data repositories that require an interface or middleware to enable data to be shared. But that challenge too is fast disappearing as new technology and new pathways to innovation arise.

“One of the things that Thermo Fisher Scientific is focused on is delivering  integrated informatics,” states Meek. “Traditionally, LIMS delivered specific functionality for R&D or manufacturing labs, but didn’t cover the entire laboratory process. Our customers today want an integrated solution that covers the complete lab workflow. So, we built an Integrated Informatics platform to combine many of these together so that they’re no longer separate silos with different data in different systems. Now, lab data management, method execution and scientific data management is done within the SampleManagerTM solution making its much more than just a LIMS. All of the functionality for scientific method and data management is now part of the same solution.” SampleManager has continued to evolve to offer greater functionality for our customers, so that now it has become the enabler for our customers to better manage their lab, and save their companies time and valuable financial resources formerly necessary to purchase, implement and support multiple software systems. Our goal is to continue to build upon the SampleManager platform so we can offer the greatest degree of functionality to our customers.”

“What is happening is that LIMS are now being supplemented with ELN and LES toolsets. Everyone is moving towards a center space, where LIMS become ELNs, etc.,” explains Mullen. Waters recently introduced the NuGenesis® Lab Management System (LMS) as an alternative to LIMS. Based on the NuGenesis SDMS, the LMS offers significantly more functionality that can be switched on as components are needed for various workflow and sample management tasks.

Mullen continues, “The NuGenesis LMS can create the testing protocol procedure to ensure that the tests are done correctly. It can specify the values and results, the upper and lower limits, etc., then pull the test values back into the worksheet. Results are instantly flagged as in or out of specification.  If reagents are expired or an instrument needs calibration, these are flagged automatically. The result is much faster transaction times than traditional paper-based processes.”

Quote4.jpg“For BIOVIA, when we talk about the benefits of our solutions, we’re talking about workflow efficiencies, cost savings, compliance and brand reputation,” states Jansen. “As a vendor, we support organizations by driving innovation, by strengthening the R&D pipeline while ensuring quality in their processes and outcomes. Now that BIOVIA is part of Dassault Systèmes,” Jansen continues, “we’re engaging in much larger conversations because we can now support the entire lab to plant process expanding our solutions to the 3D Experience platform. From ELNs to LIMS to virtual molecular modeling with our Discovery or Materials StudioTMsolution, BIOVIA offers an integrated, unified experience that is transforming how our customers are improving product quality, collaborating across sites, reducing cycle times and reducing costs. The bottom line is the ability to rapidly, easily and accurately transfer and utilize knowledge.”

Each of these vendors offers a different path to a similar end, with solutions that deliver greater access to not just legacy data but also the astounding volumes of data being created in labs worldwide. The ability to turn that data into knowledge that is accessible, accurate and reusable is necessary to fuel the new product demands both inside and outside the enterprise. Next generation technology is being developed and implemented with increasing rapidity to address these market requirements.

Conclusions

Corporate demand for innovation at every level of the enterprise is helping to drive laboratory innovation, from the tools adopted to perform research to the processes used to manage that research and all the associated data, samples, reagents, tests and more.

Operational excellence has risen to the top of corporate agendas, driven in part by the availability of technology that can support a global approach to better manage the entire product lifecycle, from initial research to final product. Now, informatics solutions exist that can support every stage of the process whether the organization engages in pharmaceutical research and needs to identify promising candidates early in the process, or whether the organization develops consumer product goods that have a short product lifecycle and thus require a constant stream of new products to maintain market share.

Information integration is playing a major role in breaking through the barriers to lab innovation. As a result, there is a significant transformation underway in the informatics tools to integrate the solutions so that data is no longer inaccessible in single purpose system. For some time there have been LIMS with ELN capabilities, CDS with LIMS functions, ELNs with sample management attributes, and more. Now, the need to exchange and move data quickly and easily from one user to another has driven the availability of integrated collaborative environments that can share laboratory data cross-team, cross-location and cross organizations.

At the core of these changes is the need to more rapidly address the larger business challenges in the lab through more efficient, more market-oriented new product development. And that’s the bottom line: informatics technology can be used as an enabling tool to solve both business challenges and lab challenges. Informatics vendors all approach the market requirements differently, depending on their own corporate culture, but all strive to enable their customers to innovate.

 

Bioinformatics beyond Genome Crunching

Flow Cytometry, Workflow Development, and Other Information Stores Can Become Treasure Troves If You Use the Right IT Tools and Services

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    Shown here is the FlowJo platform’s visualization of surface activation marker expression (CD38) on live lymphocyte CD8+ T cells. Colors represent all combinations of subsets positive and negative for interferon gamma (IFNγ), perforin (Perf), and phosphorylated ERK (pERK).

     

     

     

     

     

     

     

     

     

    Advances in bioinformatics are no longer limited to just crunching through genomic and exosomic data. Bioinformatics, a discipline at the interface between biotechnology and information technology, also has lessons for flow cytometry and experimental design, as well as database searches, for both internal and external content.

    One company offering variations on traditional genome crunching is DNAnexus. With the advent of the $1,000 genome, researchers find themselves drowning in data. To analyze the terabytes of information, they must contract with an organization to provide the computing power, or they must perform the necessary server installation and maintenance work in house.

    DNAnexus offers a platform that takes the raw sequence directly from the sequencing machine, builds the genome, and analyzes the data, and it is able to do all of this work in the cloud. The company works with Amazon Web Services to provide a completely scalable system of nucleic acid sequence processing.

    “No longer is it necessary to purchase new computers and put them in the basement,” explains George Asimenos, Ph.D., director of strategic projects, DNAnexus.  “Not only is the data stored in the cloud, but it is also processed in the cloud.”

    The service provided by DNAnexus allows users to run their own software. Most users choose open source programs created by academic institutions.

    DNAnexus does not write the software to process and analyze the data. Instead, the company provides a service to its customers. It enables customers to analyze and process data in the cloud rather than buying, maintaining, and protecting their own servers.

    “Additionally, collaboration is simplified,” states Dr. Asimenos. “One person can generate the data, and others can perform related tasks—mapping sequence reads to the reference genome, writing software to analyze the data, and interpreting results. All this is facilitated by hosting the process, data, and tools on the web.”

    “When a customer needs to run a job, DNAnexus creates a virtual computer to run the analysis, then dissolves the virtual computer once the analysis is complete,” clarifies Dr. Asimenos. “This scalability allows projects to be run expeditiously regardless of size. The pure elasticity of the system allows computers to ‘magically appear’ in your basement and then ‘disappear’ when they are no longer being used. DNAnexus takes care of IT infrastructure management, security, and clinical compliance so you can focus on what matters: your science.”

    Merging IT and Flow Cytometry

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    Life scientists are being overwhelmed by the huge amounts of data they generate for specialized projects. They not only look for solutions within their own organizations but also increasingly enlist the help of service companies to help them with Big Data overload. [iStock/IconicBestiary]

    Technical advances in flow cytometry allows the labeling of individual cells with up to 50 different markers; 12,000 cells can be counted a second. This flood of information overwhelms traditional methods for data processing in flow cytometry.

    “FlowJo software offers a solution to this problem,” asserts Michael D. Stadnisky, Ph.D., CEO, FlowJo. “With an open architecture, our software serves as a platform that lets researchers run whatever program or algorithm they wish. Scientists can focus on the biological questions without having to become computer programmers.”

    FlowJo presents an intuitive and simple user interface to facilitate the visualization of complex datasets.

    While still in development (beta testing), FlowJo is offering plug-ins. Some of them are free, and others are for sale. They include software components for automatic data analysis, the discovery of trends and identification of outliers, and the centralization of data for all researchers to access. Applications for FlowJo range from traditional immunology to environmental studies, such as assessments of aquatic stream health based on analyses of single-cell organisms.

    “Ultimately, FlowJo wants to offer real-time analysis of data,” discloses Dr. Stadnisky. “Presently, we have the capacity to process a 1,536-well plate in 15 minutes.”

    FlowJo’s platform has benefitted users such as the University of California, San Francisco. Here, researchers in the midst of Phase I clinical trial were facing 632 clinical samples with 12 acquisition runs and 12 different time points. By employing FlowJo, the researchers realized a 10-fold reduction in the time spent analyzing all data.

    Clients have also integrated other data types. For example, they have integrated polymerase chain reaction (PCR), sequencing, and patient information with data from FlowJo, which facilitates this type of cross-functional team work. The data output from FlowJo, the company maintains, is easily accessible by other scientists. The platform is available as a standalone system that can be installed on a company’s computers or be hosted on the cloud.

    Optimizing Experiments

    One dilemma facing large pharmaceutical companies is the need to optimize conditions with a very limited supply of a precious reagent. Determining the best experimental design is crucial to avoid wasting valuable resources.

    Roche has used a commercially available electronic tool to build a workflow support tool. “This application allows scientists to set up their experiments more efficiently,” declares Roman Affentranger, Ph.D., head of small molecular discovery workflows, Roche. “The tool assists scientists in documenting and carrying out their work in the most effective manner.”

    “Frequently, a quick formulation of a peptide is necessary to hand over to a toxicologist for animal testing,” continues Dr. Affentranger. “The formulation of the peptide needs to be optimized for the pH, the type of buffer, and the surfactants, for example. The tool we developed evaluates the design of the scientist’s experiment to use the minimum amount of the precious resource, the peptide in question.

    “Testing these various conditions rapidly turns into a combinatorial problem with hundreds of tubes required, using more and more of the small sample. Our system assists scientist in documenting and carrying out work, taking the place of finding a colleague to evaluate your experimental design.”

    “The data is entered electronically rather than printed out as hardcopy and glued into a notebook,” points out Dr. Affentranger. “Consequently, the information is readily accessible within the lab, across labs, and across the global environment we all work in today.”

    Indexing Internal Content

    Another issue facing large, multinational pharmaceutical companies is finding material that they previously acquired. This could be as simple as a completed experiment, an expert in a content area, or an archive-bound business strategy analysis.

    To address this issue, a company could index its internal content, much the way Google indexes the Internet. At a large company, however, such a task would be onerous.

    Enter Sinequa, a French-based company that provides an indexing service. The company can convert more than 300 file formats such as pdfs, Word documents, emails, email attachments, and PowerPoint presentations into a format that its computers can “read.”

    According to Sinequa, a large enterprise, such as a pharmaceutical company, may need to cope with 200 to 500 million highly technical documents and billions of data points. This predicament is akin to the situation on the web in 1995. It was necessary to know the precise address of a website to access it. This unnecessary complication was eliminated by Google, which indexed everything on the web. Analogously, Sinequa offers the ability to index the information inside a company so that searches can yield information without requiring inputs that specify the information’s exact location.

    With this kind of search ability, a company can turn its information trove into a treasure trove. Put another way, information can be made to flow, keeping applications turning like turbines, generating the “data power” needed to reposition drugs, reduce time to market, and identify internal and external experts and thought leaders.

    “Sinequa offers a kind of Google algorithm customized for each customer,” details Xavier Pornain, vice president of sales and alliances at Sinequa. “At least 20,000 people use the technology generated by Sinequa. Modern companies create lots of data; we make it searchable.”

    The data searched is not limited to internal documents. Sinequa can also add in external databases or indexing sites such as PubMed, Medline, and Scopus. Of demonstrated flexibility, the search engine can run one version inside a company firewall and another one in the cloud.

    Emulating Intelligence Approaches

    A different search approach, one that leverages the experience of the intelligence community, it taken by the Content Analyst Company. With this approach, a company can comb through internal and external content stores to find relevant information that has value not only as output, but as input. That is, the information can cycle through the search engine, turning its machine learning gears.

    “By adapting to the voice of the user, our software package, Cerebrant, has been very successful in the intelligence and legal communities,” says Phillip Clary, vice president, Content Analyst. “For typical indexing services, such as Google and PubMed, people do huge searches using a long list of key words. A simpler scenario is to write a few sentences, enter the text, and get all the related relevant items returned. Cerebrant can take the place of an expert to sift through all the results to find the relevant ones.”

    Typical searches often yield confounding results. For example, if a user were to ask Google to generate results for the word “bank,” the top results would be financial institutions. Then there would be results for a musical band/person named Bank. Eventually, long past the first page of results, there would be information about the kind of bank that borders a stream or river course. Such results would frustrate a scientific user interested in tissue banks or cell line repositories.

    “In the past, companies have approached the problem of obtaining germane results by attempting to create databases with curation and controlled vocabulary,” notes Clary. “This is how Google works. All those misspelled words have to be entered into the code.

    “Cerebrant functions by learning how the information relates to itself. This was a powerful tool for the intelligence community, because the program can look at all kinds of information (emails, texts, metadata) and make connections within the unstructured data, even when users attempt to veil their meanings by using code words.”

    Search requests composed on Cerebrant can consist of a single sentence or a paragraph describing what sort of information the user wishes to find. This is much more efficient than determining the 30 to 40 keywords you need to use to locate all the information on a complex topic. Then there is still the task of removing the irrelevant finds.

    Cerebrant is a cloud-based application. Generally, it take only about a day to a week to get it up and running. Because it is scalable, Cerebrant can be used by an individual consultant or a multinational conglomerate.

    Given the enormous amount of time, energy, and money invested by the intelligence community, it is refreshing to see a novel application of the wisdom gained from all this work, just as we saw innovative uses of the technology that was developed by the space program.

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