Lifespan Research Report

Lifespan Research

The scientific vision to transform patient care

With this brochure and selection of research profiles, we celebrate the ingenuity, creativity, and dedication of hundreds of our scientists, students, and trainees across our academic medical center.

This is one of our key missions as an academic health system. We support the basic, translational, and clinical research – across all our 18 clinical departments and within our interdisciplinary research centers – to improve patient care in our community, in our region, and throughout the world.

The scientific vision to transform patient care.

Our scientists and clinicians are working on an incredibly broad range of exciting topics, from the development of an artificial wrist implant in our own laboratories to discovering and testing a novel treatment for a deadly water-borne parasite in southeast Asia. Whether we are discovering and testing specific diagnostics or treatments to improve and save lives, or seeking to understand the biology of adolescent sleep in order to better inform educational and public health policies, a critical step in all our research programs is the movement of our discoveries out of our labs and into clinical use to improve health care.

Translating our discoveries from lab to clinical use often requires commercialization. For the most part, this last and crucial step makes it necessary for us to support our scientists in patenting their inventions, in partnering with commercial entities, and in launching new companies to make their discoveries widely available. We are proud of our active support for commercializing the intellectual property discovered within the Lifespan Health System, because these activities eventually lead to the improvement of medical care for millions of people throughout the world.

1

The Lifespan Health System is the largest biomedical research institution in Rhode Island.

Our system supports:

Timothy J. Babineau, MD President & CEO

• N early 350,000 square feet of both basic and clinical research laboratories across our hospital campuses and within the ”Knowledge District” in Providence, Rhode Island • Approximately 350 active investigators who engaged in research within our institutions • O ver 550 staff who work full-time to support Lifespan’s research mission in many critically important ways • A bout $80 million per year in total research grant and contract support for our research, most of which is awarded to us annually by the National Institutes of Health • C ore laboratory facilities for electron microscopy, digital imaging and analyses, genomics, proteomics, and molecular pathology

John Murphy, MD EVP for Physician Affairs

• A state-of-the-art robotic medical simulation center for both research and education of our medical and nursing staff, residents, fellows, and even local high-school students • A robust, efficient, professional Office of Research Administration (ORA) that manages all grants and contracts, coordinates the activity of our three AAHRPP-accredited Institutional Review Board (IRB) panels, handles intellectual property, and many more functions that are vital to our research system • W e are the host institution for three separate NIH Centers for Biomedical Research Excellence: Stem Cell Biology, Cancer Development, and Skeletal Health Repair We are proud to be the major academic teaching affiliates for The Warren Alpert Medical School of Brown University. Virtually all our scientists are faculty of the medical school – and we collaborate intensely with that institution. In addition, we are actively forging deeper partnerships with our colleagues at the University of Rhode Island, at the Rhode Island School of Design, and with a large number of R&D corporate partners, so that we will continue to add to our growing list of discoveries and inventions to transform patient care.

Peter J. Snyder, PhD SVP & Chief Research Officer

The profiles in these pages are mere examples of the wonderful advances in health care that are made possible only because of our institutional commitment to biomedical research.

Peggy McGill Administrative Director Office of Research Administration

2

4 Lubricin offers real promise for prevention of arthritis, and so much more

12 Brain sensor promises objective pain assessment

9 Our sleep research is helping to guide sound public policy

Holographic imaging research program enables clear 3D visualization of patient anatomy

14 Trapping a killer: CIHR poised for Phase I testing of malaria vaccine candidate

18 Surgeons and Industry collaborate to develop more ‘palatable’ options for lasting weight loss

10

17 Thermal accelerant that boosts effectiveness of tumor ablation discovered

20 Full out press on concussions delivers a strong impact

23 Wrist implant pinpoints the vital midcarpal joint to restore function

3

Lubricin offers real promise for prevention of arthritis, and so much more

Synovial cavity

Lubricin appears to delay or prevent osteoarthritis that comes from trauma, injury or even the wear and tear of aging.

4

Gregory Jay, MD, PhD, first started studying Lubricin, Proteoglycan 4, more than three decades ago and never dreamed it would become his life’s work. Today, his vision for the potential of this versatile and resilient protein, is on the verge of being realized as a clinical and commercial success.

Lubricin, which is naturally occurring in synovial fluid and on the surface of cartilage, functions both as a lubricant and an anti-adhesive in the body. As a lubricant, it can improve medical outcomes involving areas of the body that involve mucosal barriers — such as eye, visceral and cartilage surfaces — by restoring or supplementing the lost mucin. As an anti-adhesive, it can protect vulnerable organs, such as the bowel or joints from developing post-surgical scarring and adhesions.

“Currently we practice medicine one patient at a time. Soon we’ll be able to stop a disease, to practice medicine a disease at a time.”

Results from initial human clinical trials conducted in Europe validate Lubricin‘s effectiveness in treating dry eye disease.

Gregory Jay, MD, PhD

Articular cartilage

Articular cartilage

Synovial fluid

Lubricin forms end-grafted brush structures on cartilage surfaces. As cartilage is compressed the apposing carpets of end-grafted brushes interact and repel.

Synovial fluid

Articular cartilage

Lubricin is secreted by synovial fibroblasts and superficial zone chondrocytes in the articular cartilage.

5

Lubris has reached a deal with Novartis to license the proprietary manufactured lubricin for ophthalmic indications outside Europe, including as a dry eye treatment.

A comprehensive preclinical model conducted by Braden Fleming, PhD, and Gregory Jay, MD, PhD, of the Center of Biomedical Research Excellence for Skeletal Health and Repair at Rhode Island Hospital has validated the ability of lubricin to restore lubrication and slow cartilage loss due to trauma or surgery. Markers of inflammation and joint damage were improved. Results from initial clinical trials conducted in Europe and published in the journal Ocular Surface validate its effectiveness in treating dry eye disease.

Lubricin creates a chemical boundary that prevents cells from attaching. This is most easily demonstrable simply by drawing an “X” with Lubricin in a petri dish.

The “X” literally marks the spot as cells grow all around the Lubricin, leaving the “X” clearly visible and pristine.

Alternatively, a drop of water spreads on plastic that has been coated with lubricin, where normally it would bead due to the hydrophobic effects.

When a patient has arthroscopic surgery, the joint’s natural lubricant is washed away.

Validating research has revealed significant cartilage preservation and confirmed that the inflammation levels were reduced after joints were injected with Lubricin following joint trauma.

6

“Currently we practice medicine one patient at a time,” says Dr. Jay, an Emergency Medicine physician at Rhode Island Hospital and professor of Emergency Medicine and Engineering at The Warren Albert Medical School and School of Engineering of Brown University. “Soon we’ll be able to stop a disease, to practice medicine a disease at a time.”

“For the most part in medicine, we are not curing anything but just helping to manage diseases,” Dr. Jay explains.

“Lubricin appears to delay or prevent osteoarthritis that comes from trauma, injury or even the wear and tear of aging. We know that the inflammation process erodes cartilage; Lubricin protects it and encourages natural lubricin to be expressed. This could have as significant an impact on protecting joints similar to the effect that a dental sealant has when protecting teeth.”

Lubricin is present in the meibomian gland, lacrimal gland and mucous layer on the ocular surface.

Framingham, Mass, Lubris employs four people and is poised for rapid expansion from this first commercialized venture for Lubricin. The gene involved is known as PRG4 in GenBank and Lubricin is its expressed protein.

Lubricin’s ability to relubricate joints, combined with the proven ability of the body to retain Lubricin that is injected, could have an immediate and lasting difference for orthopedic patients. When a patient has arthroscopic surgery, the joint’s natural lubricant is washed away. This loss can hinder the body’s ability to preserve the cartilage that remains after the trauma and the surgery. Validating research has revealed significant cartilage preservation and confirmed that the inflammation levels were reduced after joints were injected with Lubricin. A clinical trial will occur in the future to confirm these outcomes.

“The initial patent for Lubricin is for lubricating cartilage. We are trying to identify as many therapeutic opportunities that we can take advantage of for economy of scale.”

The key to bringing all of this to fruition is that Jay and his colleagues have developed a scalable way using cells in the lab that manufacture lubricin. With unwavering support from the Lifespan Health System, to launch a new company to advance this technology, Dr. Jay is now the co-founder and Chief Medical Consultant for Lubris, the biotech company formed to develop and commercialize Lubricin. Based in

Some of the other potential applications of Lubricin are the prevention of post-surgical adhesions by preventing cells from building tissues, a treatment for carpal tunnel syndrome by preventing the accumulation of scar tissue, for treatment of dry mouth, a common side-effect for people in treatment for throat and neck cancers, and for inflammatory joint conditions like gout.

7

Lubris employs four people and is poised for rapid expansion from this first commercialized venture for Lubricin .

Lifespan ‘gets it.’

Gregory Jay, MD, PhD

Lubris, Inc., which our healthcare system has financial interest in, is looking first at commercialization in Europe where it could be regulated as a device which will streamline regulatory approval for multiple applications. However, in April 2017, Lubris reached a deal with Novartis, the global healthcare company headquartered in Switzerland, to license ECF843, Lubris’ proprietary recombinant form of human lubricin, for ophthalmic indications outside Europe, including as a dry eye treatment. Under the agreement, Lubris retains rights to commercialize products outside ophthalmology.

Lubricin can protect vulnerable organs such as the bowel or joints from developing post-surgical scarring and adhesions.

8

Dr. Jay has been fascinated by Lubricin and its potential since 1985 as graduate student and then as a doctoral and medical student at the State University of New York Stony Brook. He continued to pursue this interest when he came to Rhode Island Hospital and Brown University School of Medicine. He credits the culture at Lifespan, the health system which includes Rhode Island Hospital, for helping transform his work from the research bench to the market and ultimately to the bedside.

“Lifespan helped manage conflicts of interest and obtain a small business development grant. This was an example of leveraging the academic research partner to make something possible,” Dr. Jay says. “The leadership and staff within the Office of Research Administration, at Lifespan, is receptive to scientists pursuing research that must be commercialized in order to have broad impact on public health and medical care. Here at Lifespan we have a culture of transparent entrepreneurship.”

“This is the best way to do translational research. You are not going to change the world unless you understand the clinical opportunity and know how to intervene with a well-crafted business approach – which creates potential conflicts. This culture acknowledges that patents are important, almost as much as publishing. Being able to pursue a patent, to protect the intellectual property, then publish requires an organization that values transparency but also understands how to avoid missing opportunity. Lifespan ‘gets it.’”

Our sleep research is helping to guide sound public policy

Mary A. Carskadon, PhD, an international expert on adolescent sleep at Lifespan’s Emma Pendleton Bradley Hospital, and at Brown University’s Alpert School of Medicine. Dr. Carskadon has spent her career building a body of evidence that indicates that most of the nation’s high school start times oppose the teenage body clock. After decades educating school administrators across the country about her findings, she is beginning to see the impact of her research in her home state, Rhode Island. Insufficient sleep in adolescents finally is being recognized as a public health problem. Several school systems are adopting or considering later start times for children to reap the benefits that only a full night of properly-timed sleep can bring. In addition, statewide legislation stipulating an 8:30 a.m. start time has been introduced in Rhode Island and other states.

Dr. Carskadon’s work shows that the tendency for high schools to begin the day at 7 a.m. fights with biological and social factors thereby negatively influencing healthy sleep patterns. In order to obtain a healthy nine hours, students would need to be sleeping by 9:30 p.m., which isn’t likely for most teens because of a delay in the internal body clock that occurs naturally during adolescent maturation.

Mary A. Carskadon, PhD

The research also demonstrates the negative impact sleep deprivation has on adolescents, including increases in impulsivity, depression, and impaired decision making which can lead to more injuries, auto accidents, and of particular relevance to education, reduced ability to concentrate and learn.

“Many scientist do great work but they never get to see the results. I’m the scientist, not the implementer, but I can see how this research is helping communities make decisions that benefit children and adolescents. It can help them now and may even prevent the start of problems or behaviors that could create health issues later in life.”

9

Holographic imaging research program enables clear 3D visualization of patient anatomy for personalized medicine, shared decisionmaking, and enhanced procedural training When Leo Kobayashi, MD, director of innovation and research at the Lifespan Medical Simulation Center and attending physician in the Andrew F. Anderson Emergency Center at Rhode Island Hospital, first saw the Microsoft HoloLens, he immediately realized the significance of its potential healthcare applications.

He wanted to bring it to the Rhode Island Hospital clinical work environment in order to tap into the device’s potential as a visualization and communication tool to be used in healthcare settings. An emergency physician and associate professor of Emergency Medicine at the Warren Alpert Medical School at Brown University, he envisioned using the head-mounted holographic computer to enhance physicianpatient communication and provider education.

10

Within six months, he and his co-investigator, Derek Merck, PhD, director of computer vision and image analysis research at Rhode Island Hospital and assistant professor of Diagnostic Imaging and of Engineering at Brown University, had launched two successful proof-of-concept research efforts: at the Veteran’s Administration Hospital in Providence and in the Lifespan Medical Simulation Center. With Dr. Kobayashi’s clinical and research expertise and Dr. Merck’s diagnostic imaging and computer science background, along with secure, approved access to the hospital’s imaging repository, the team streamlined the holoimaging process and is now well on its way to formally study the device in the hands of physicians and patients in the emergency care and surgical areas at Rhode Island Hospital.

With support provided by Lifespan’s research administration, we have launched several successful collaborative efforts.

“Within 30 minutes from the time of capturing a patient’s CT or MR images, we can render and upload a holoimage into the HoloLens device for clinicians and patients to see,” says Dr. Merck.

The device is very portable, user-friendly and can be paired with additional HoloLens units for shared real-time visualization.

Together, a clinician and a patient can discuss a procedure while looking simultaneously at a 3D holoimage of the patient’s anatomy and pathology. In addition, surgeons can use the device in the operating suite to review operative approaches and interventions; neurosurgical and pediatric plastic reconstructive surgical uses are planned to supplement existing techniques such as stereotactic guidance and 3D printing.

Dr. Kobayashi notes that this likely wouldn’t have happened as quickly or smoothly elsewhere. “As a tertiary care and referral center, we aren’t so over-specialized that we don’t see a full spectrum of patients. We have access to the people with the clinical acumen to determine if the idea is applicable, the creative minds and energy to work together on a variety of projects, and Lifespan’s excellent relationships with Alpert Medical School and Brown University are integral to our success. With support provided by Lifespan’s research administration, everything fell into place and, within half a year, we have launched several successful collaborative efforts. That would have been difficult, if not impossible, in other organizations.”

Numerous teams worldwide are working on healthcare applications for augmented reality. Dr. Kobayashi and Dr. Merck’s collaborative efforts are notable for the inclusive, multi-disciplinary, and broad nature of their ongoing and planned applications as well as the tight integration with clinician investigations.

“Within 30 minutes from the time of capturing a patient’s CT or MR images, we can render and upload a holoimage into the HoloLens device for clinicians and patients to see”

ED use-case topology for shared holoimage visualization to facilitate patient care discussions.

Leo Kobayashi, MD

Derek Merck, PhD 11

With support and encouragement from the Lifespan Health System, we have launched a new company to advance this technology.

Brain sensor promises objective pain assessment

Anyone who has been treated for pain is familiar with the 1-10 numerical pain scale that clinicians have used for decades to assess pain and treat symptoms. While the scale can be helpful, it is subjective and open to interpretation by patients and clinicians and is no help when treating non-verbal patients, toddlers or animals.

Carl Saab, PhD, is a researcher in neurosurgery at Rhode Island Hospital and associate professor of neuroscience at The Warren Alpert School of Medicine at Brown University. Now, after 20 years of researching pain at the molecular level, he is on the verge of introducing a drastically different diagnostic model for use in quantifying levels of pain.

Dr. Saab has developed and successfully tested an objective pain measurement method that will give clinicians more information and provide a visual of the impact and intensity of the pain registered by the patient’s brain.

12

Historically, pain has been addressed as a symptom of another problem or disease. The common treatment has been to prescribe pain medications, which is only a temporary measure at best, often resulting in adverse side effects and addiction. The current opiate addiction crisis is a clear indicator that current diagnosis and treatment for chronic pain is not sufficient. “There is now a paradigm shift to recognize chronic pain as a separate disease, as its own entity,� says Dr. Saab, who has authored six papers (including for the journal Nature Scientific Reports) and written a book chapter on chronic pain all within the past year. He notes that conditions like phantom limb pain, diabetic neuropathy, fibromyalgia, migraines and others reveal the need for more insights into the science of pain that could lead to better treatment options.

Currently there is no objective way to diagnose chronic pain and fewer ways to reduce it.

Using a wearable sensory device we can assess pain, and give it a score.

Pain level

Carl Saab, PhD

It is the only metric in some cases such as children, non-verbal patients, and animals in pain.

Rather than developing another opiate-derivative or pain pill, Saab’s research is focused on finding a “neurophysiological biomarker” to improve diagnosis and thus achieve a better treatment. “We can’t open the brain to see what’s happening but we can use a wearable device to record brain activity.

“We know that pain manifests as a pattern of neuronal activity or “firing” in the brain,” he says. “Using a wearable sensory device (similar to a portable EEG), we can detect these firings, assess pain, and give it a score.

We’ll be able to pinpoint the area of the brain involved and identify patterns of brain activity for different pain states.”

This could be a game-changer for chronic pain patients who struggle for years, searching for accurate diagnosis and relief from what can become a debilitating condition, and for clinicians who have no measurement tools and little to offer patients whose pain persists despite all efforts to manage it.

“Currently there is no objective way to diagnose chronic pain and fewer ways to reduce it,” Dr. Saab says. “This will be convenient to use for patients and clinicians. It is not a lie detector test. The verbal report will still be used. This is a tool to augment the patient’s assessment and to provide more information. It will shift the dynamics of the conversation between

the patient and provider. It is also the only metric in some cases such as children, non-verbal patients, and animals in pain like dogs with arthritis or horses with lameness.”

Dr. Saab is collaborating with a major device manufacturer to produce a customized headset that will hold the electrodes used to record the data on a smartphone or computer which will transmit it for analysis. He and his team have created an algorithm to interpret the data and color code it by intensity, like the bands of color that indicate the temperature on a weather map.

Developing the algorithm was the most intricate and time-consuming part of the project. The team has created a prototype of its headset and is working on contracts with industry partners.

“We are poised to move this project from the lab setting to the real-world setting. We have validated it in mice and rat models and have now moved to testing in healthy humans, using hand in ice cold water tests, as well as pain patients,” Dr. Saab says. “With support and encouragement from the Lifespan Health System and Rhode Island Hospital, we have launched a new company to advance this technology.”

13

Trapping a killer: CIHR poised for Phase I testing of malaria vaccine candidate

Jonathan Kurtis, MD, PhD, founder and director of the Lifespan Center for International Health Research (CIHR), knows firsthand how devastating malaria can be. He contracted the disease as a young undergraduate student working on a coral reef ecology project in Kenya. His life-threatening encounter with this disease, which infects 10 people every second and kills a child every two minutes, transformed his life.

The encounter with malaria fueled his drive to understand and stop the disease that he labeled “a capricious killer of the innocents”.

He changed the direction of his career and as a result, met Dr. Jennifer Friedman, an epidemiologist and the director of clinical studies at CIHR. The husband-and-wife research team has worked in the field and in the lab for decades to identify the pathogenic mechanisms of morbidity for two leading infectious disease killers, specifically malaria and schistosomiasis. After decades of research

and validating tests, the CIHR team is poised for phase I trials in humans of a vaccine against malaria, which has eluded scientists for generations.

According to Dr. Kurtis, “There’s always talk about eradicating malaria. The World Health Organization (WHO) tried it in the 1950s and 1960s. We’ve made gains with bed nets, artemisinin treatment and insecticides to limit the mosquito population. Yet, 640,000 people, mostly children under the age of 2, die from malaria each year. It is the greatest single killer on our planet.

If we could reduce that by even 20 percent, it would be the greatest single accomplishment in modern medicine.”

Malaria infects 10 people every second and kills a child every two minutes

14

Jennifer Friedman, MD, PhD, MPH and Jonathan Kurtis, MD, PhD

Drs. Friedman’s and Kurtis’ research focused on a subset of children living in malaria endemic areas who seemed to have developed a natural immunity to the disease.

Using modern molecular biology techniques, they identified the parasite proteins which were targets of antibodies that resistant, but importantly not susceptible, children, had made. Further study revealed that vaccination of mice with these parasite proteins resulted in protection from challenge infections. Lastly, they surveyed the antibody responses to these vaccine candidates in over 750 children living in malaria endemic areas. Children with antibodies to one of these parasite proteins, PfSEA-1, never developed severe malaria, while children without antibodies to PfSEA-1 had many episodes of severe malaria.

Dr. Kurtis and his team have identified eight additional candidates for a malaria vaccine.

Using the field-to-lab-to-field approach, Dr. Kurtis and his team have identified eight additional candidates for a malaria vaccine. These candidates have been validated in several multi-year studies. The next phase will be a Phase I safety and immunogenicity study performed at the Clinical Research Center at Rhode Island Hospital. This study will consist of enrolling 50 -100 participants for a 12-week study.

The participants will receive three doses of the vaccine and then the team will test the serum from the vaccinated participants to see if it contains antibodies which can kill the parasite in culture. The researchers work under a series of grants from the National Institutes of Health and the Gates Grand Challenges in Global Health.

“As physicians and scientists, we know that we are not going to solve the social and economic problems that create the conditions where malaria thrives,” Dr. Kurtis says. “So, we focus on what we can do… to create a vaccine.”

15

the Lifespan Health System has been instrumental in supporting our research program.

Jonathan Kurtis, MD, PhD

Instead of trying to block the parasite from getting into the red blood cell, we decided to block it from getting out of the blood cell.

Release of malaria parasites from red blood cell

“Malaria parasites live inside red blood cells. Most vaccine approaches for malaria have tried to block the parasite from invading red blood cells. Unfortunately the parasite only needs 140 microseconds to get into the red blood cell so these previous efforts have been fighting an impressive time barrierthe antibodies can only attack the parasite while it is outside of the red cells, and 140 microseconds is not a lot of time,” Dr. Kurtis says.

“Instead of trying to block the parasite from getting into the red blood cell, we decided to block it from getting out of the blood cell and spreading to additional red blood cells. The process of parasite maturation and subsequent escape from the red blood cell lasts for several days. Antibodies to our vaccine candidate PfSEA-1 block the parasites escape from the red cell.

If they can’t get out, they can’t replicate… They can’t survive.

It’s like being trapped in a burning house.”

16

Drs. Kurtis and Friedman are currently evaluating cellular immune responses to PfSEA-1 and their other vaccine candidates in a cohort of Kenyan children, conducting vaccine trials in non-human primates, and planning for follow-on Phase I studies at RIH. “Institutional and departmental resources and funding, provided by the Lifespan Health System, has been instrumental in supporting our research program, protecting the intellectual property, and supporting our external funding efforts. This support is vital to facilitate progress in developing a vaccine for the greatest single agent killer of children on our planet.”

Thermal accelerant that boosts effectiveness of tumor ablation discovered Damian Dupuy, MD, and William Park, PhD, know that not all research and innovation takes place in a lab. As a result of very informal conversations, between these two diagnostic imaging experts, an idea took shape for a Thermal Accelerant (TA) that has since been shown to enhance the effectiveness of tumor ablation. Ablation is Damian Dupuy, MD, and William Park, PhD a minimally invasive surgical method used to destroy cancerous tumors. The use of TA extends the reach of microwaves to the periphery of a tumor where cells are able to survive and can result in a recurrence.

The compound can be used to deliver the heat exactly where the interventional radiologist wants it to go. When it is injected into a patient and heat is applied, the medium forms a gel which is visible under CT scan. The radiologist is then able to target in real time specific areas of the tumor to ensure the optimal level of heat needed to ablate the tumor reaches the entire area.

In addition to being more effective, treatment with the TA improves control and may even save money since fewer antennae, which cost about $2,000 each, may be needed. Two patents have been filed for the nontoxic, safe compound which functions like a wifi booster, delivering a stronger signal without requiring additional hardware.

Dr. Dupuy is formerly the director of ablation services at Rhode Island Hospital and professor in diagnostic imaging at Brown University Medical School. Dr. Park is the director of molecular imaging at Rhode Island Hospital and assistant professor in diagnostic imaging research at Brown. Dupuy is a pioneer in RFA, an image-guided technology that uses heat to kill, or ablate, tumor cells. Park is a medicinal chemist by training with more than two decades of academic and pharmaceutical R&D experience. Both of the scientists were working on ways to increase the effectiveness of image-guided tumor ablation.

Combining their expertise and insights led to the discovery of a solution that likely would not have materialized collaborations fostered by having basic researchers and physicians working together in close proximity, within our hospital.

17

We are barely scratching the surface of treating obesity.

Surgeons and Industry collaborate to develop more ‘palatable’ options for lasting weight loss Sivamainthan Vithiananthan, MD, our chief of the minimally invasive and bariatric surgery program at The Miriam Hospital, knows about the failure — and the successes — of weight loss initiatives in the United States. Obesity is a growing epidemic, second only to smoking as a top cause of preventable deaths in the U.S. Yet, patients are often reluctant to seek treatment until they have gone from a healthy person to one with multiple chronic illnesses.

“Although there are serious medical issues related to obesity, only 1% of our patient population actually gets care. They don’t seek treatment because they are afraid of the solution, even though it is very effective and has a strong track record,” Dr. Vithiananthan says.

In addition, the stigma associated with obesity — that it’s the patient’s “fault” due to lack of self-control or discipline to eat less and exercise more — prevents patients from taking the first step and doctors from referring them for medical treatments to address obesity.

“Diet and exercise alone have a 95% failure rate,” says Dr. Vithiananthan. “There is only a 5% chance that a person who loses weight through just diet and exercise will keep it off for

18

five years or more. By contrast, with bariatric bypass 60% of the patients lose the weight and keep it off. It’s more than just the surgery, it’s long-term care and support.”

Sixty percent of Rhode Islanders have a weight problem, he says.

However, the idea of major surgery and the inherent risks of any surgery is a deterrent to treatment. They shy away from surgery even though obesity is very likely to contribute to major medical issues such as diabetes and cardiovascular disease.

So, when Dr. Vithiananthan and two of his colleagues — Dr. G. Dean Roye and Dr. Beth Ryder – were contacted about the idea of working with a research team at the Boston Scientific Corporation to explore ways to help more patients, they were all in.

“We know that we need to seek alternatives that are more palatable,” Dr. Ryder says. “There is a vast need for better treatments. We are barely scratching the surface of treating obesity.”

The surgeons collaborated with a team of engineers and scientists from Boston Scientific for several months in late 2016. Dr. Peter Snyder, Senior Vice President and Chief Research Officer at Lifespan connected the two groups.

The team has identified several innovative procedures that are being submitted for patent protection now. Some represent completely novel approaches.

[our corporate partner’s] approach was radically different than what we’ve been trained to do.

Sivamainthan Vithiananthan, MD

Beth Ryder, MD

“The fact the hospital reached out to our group and then to industry to form this unique collaboration is remarkable,” Dr. Roye notes, adding that Boston Scientific put extensive resources into this project. For several months, the surgeons met with and were shadowed by three or four engineers or scientists at a time who followed them on rounds and during office hours and observed surgeries and post-op consultations.

Dr. Ryder notes, “Device manufacturers are usually most concerned with placing and removing devices. That wasn’t the case here. Boston Scientific was very aware that it’s not that simple.

It was great to see how interested they were in the entire process from when a patient first comes into the office to discuss options through surgery, into recovery and beyond. They even went to support groups and talked to patients and family members.”

The question they came to us with was simply, “How can we improve the treatment?,” Dr. Roye says. “They didn’t have a clinical background and we didn’t have an engineering background. Their approach was radically different than what we’ve been trained to do. Their questions challenged me to revisit everything, to challenge assumptions about what could be done and consider why we do things a certain way.”

G. Dean Roye, MD

The surgeons found this collaboration invigorating. “They told us ‘Don’t hold back. Don’t put any boundaries on your ideas.

Don’t worry about the money or whether it’s practical at this stage. Don’t accept work arounds. Tell us what the ideal situation would be, what the issues are and we’ll find a solution.’ We aren’t used to thinking that way,” says Dr. Vithiananthan.

The Boston Scientific team was impressed with the access they were provided, he says. “I don’t think this could have been done as well or as seamlessly anywhere else. We have all components of obesity treatment within the Lifespan system and so we looked at it in a holistic way. And, as a teaching hospital, we are used to having surgical residents follow us so this was no different.”

The team has identified several innovative procedures that are being submitted for patent protection now. Some are improvements on existing technologies, whereas others represent completely novel approaches.

At the onset of the project, Dr. Roye says, his hope was “that we discover a ‘better mousetrap’ so we can improve overall health for even more patients,” and this unusual and innovative team may deliver on that hope.

19

It is not clear what degree of impact is needed to cause a concussion

Full out press on concussions delivers a strong impact

Two prominent researchers at Lifespan from very different fields of expertise – orthopedics and hematology – are collaborating to investigate concussions, an area that is often considered the sole domain of neurology.

Americans sustain about 3.8 million sports and recreation related concussions annually, according to the Centers for Disease Control (CDC). High school athletes, whose developing brains are more vulnerable to injury, are at particular risk.

JJ Trey Crisco, PhD, associate director of the Center of Biomedical Research Excellence for Skeletal Health and Repair at Rhode Island Hospital, is known for his expertise in biomechanics and in sports safety and related athletic equipment. Peter Quesenberry, MD, is the director of hematology/oncology research at Rhode Island Hospital and The Miriam Hospital, and he is renowned for his work in stem cell research.

Although sports-related concussions are far too common, it is not clear what degree of impact is needed to cause a concussion, the impact of concussions received when the brain is still developing, and the long-term impact of multiple concussions over a lifetime.

Recently, these two scientists have been striving to better understand concussions — a medical condition that affects millions of Americans annually, can have a lifelong impact on patients, and may even increase the risk of other diseases such as dementia, Parkinson’s or Alzheimers.

20

Dr. Crisco has been on the forefront of studying athlete’s concussions to help design more effective protective gear and influence rules and regulations to prevent or reduce concussions.

Meanwhile, Dr. Quesenberry realized that work he and his team were doing related to vesicles (membrane-enclosed sacs that are particles of cells) in saliva that are biomedical indicators of the neuro-inflammatory process might be able to help in the diagnosis and treatment of concussions.

“vesicles could be a biomarker for sub concussion head injury.”

Dr. Crisco has been on the forefront of studying athlete’s concussions to help design more effective protective gear and influence rules and regulations.

JJ Trey Crisco, PhD

Peter Quesenberry, MD

Dr. Crisco has done extensive work developing head impact recording technology over a 12-year period and then researching concussions in college football players, including Dartmouth, Virginia Tech and Brown University. The NIHsupported study employed protective helmets equipped with accelerometers, like those used in automobile air bags, to detect and measure head impacts during practice and games.

“This research is being used by many institutions. For example, Ivy League schools with football programs have already changed the rules,” Dr. Crisco says. “They now have ‘no contact practices’ to limit exposure. New helmet performance testing, using a five-star rating system, have been instituted by looking at where concussions were occurring.”

There is still much work to be done. “Currently, we can’t adequately prevent concussions with helmets because we don’t have enough data to develop design standards — yet,” Dr. Crisco says.

Dr. Quesenberry realized that work he and his team were doing related to vesicles in saliva might be able to help in the diagnosis and treatment of concussions.

Dr. Crisco also launched a study using the sensor-equipped helmets in Pop Warner football, for children ages 9 – 12 since there is virtually no data on head injuries amongst youth.

They studied two teams in Barrington and two teams each in communities near Wake Forest and Virginia Tech.

Dr. Crisco’s NIH-supported study employed protective helmets equipped with accelerometers to detect and measure head impacts.

The ability to obtain data from individuals prior to and immediately following a measureable hit captured Dr. Quesenberry’s attention. His team joined Dr. Crisco on the sidelines of the playing field and measured the level of neuroinflammatory markers in the saliva of players before and after the game and after any hits to the head.

This research is based on Dr. Quesenberry’s ongoing work with bone marrow cells. “When we injected bone marrow cells into the brain of a mouse, we noticed that it quickly appeared in the oral cavity indicating a direct connection between the brain and the oral cavity,” he says.

21

...with the hospital’s support we are working on obtaining a patent and a small business development grant to move forward.

Peter Quesenberry, MD

“We know that vesicles increase in cerebral spinal fluid during a brain injury. So, we thought, ‘let’s see if vesicles could be a biomarker for sub concussion head injury.’ Since we know it shows up in saliva, we wanted to test that alongside the helmetsensor research.”

Dr. Quesenberry’s team looked at three areas: high school and Brown University football players, head trauma patients in the Rhode Island Hospital Emergency Department and patients in the Chronic Concussion Clinic. They measured the levels before and after games, monitored hits and found that all the players showed an increase in the inflammatory markers. In the ED, they identified markers in 15 patients, only one of whom was suspected of having a concussion. And the clinic provides an opportunity to follow concussion patients over the long term.

Most previous research has been done with severe head injuries and concussions, but Dr. Quesenberry’s team identified these markers in patients whose other symptoms did not warrant the diagnosis of concussion.

Through their related research both teams hope to improve prevention, diagnosis and treatment of concussions. Athletes — including participants in cheerleading, hockey, lacrosse, soccer, wresting, and mixed martial arts — incur many hits to the head during a season or throughout a career. The majority are not severe, but research indicates there is a cumulative effect.

22

These “minor” concussions are difficult to diagnose so patients can continue to play or participate in daily activities without receiving appropriate treatment.

Dr. Quesenberry’s team is also using the biomarker testing in a study with Mixed Martial Arts (MMA) participants. “We measure biomarkers in MMA participants before and after a match to see if they are elevated. We are finding MMA fighters who have been cleared by a doctor and who had not had a significant hit but still had high markers. Some are probably already at the chronic stage,” he says.

This research has broad applications beyond athletics, Dr. Quesenberry notes, including military personnel and motorists.

The team is exploring whether multiple hits (of the markers) may be an indicator of underlying Alzheimer’s, Amyotrophic Lateral Sclerosis (ALS), or Parkinson diseases.

“This has very real applications. It can help in screening individuals who shouldn’t be participating in contact sports to prevent them from developing a problem later it life. It also has potential for discovering interventions to reverse Alzheimer’s by repairing the damaged cells,” Dr. Quesenberry says. “We have a company interested in this research and, with the hospital’s support we are working on obtaining a patent and a small business development grant to move forward.”

JJ Trey Crisco, PhD

Scott W. Wolfe, MD

Wrist implant pinpoints the vital midcarpal joint to restore function Joseph J. Crisco PhD, of Rhode Island Hospital, and his longtime colleague and co-investigator Scott W. Wolfe, MD, of the Hospital for Special Surgery/Weill Medical College of Cornell University, have studied the complexity of the structure and movement of the human wrist for nearly three decades. Specifically, they are investigating the degenerative condition known as scapholunate advanced collapse (SLAC), which occurs following traumatic disruption of the proximal carpal row.

Among the major findings that emerged from their study of wrist motion was the importance of the midcarpal joint to hand and arm function.

Specifically, they studied the previously identified “dart-thrower’s motion”—an important and uniquely human path of motion from radial wrist extension to ulnar wrist flexion. With the 3D imaging technologies they developed to measure wrist kinematics, they demonstrated that surgical restriction of midcarpal motion degrades functional performance.

In early 2017, Drs. Crisco and Wolfe received the American Academy of Orthopaedic Surgeons’ Kappa Delta Lanier Award, which honors their work in Wrist Kinematics and Arthroplasty. Their extensive research has led to the development of a total wrist arthroplasty (TWA) device which has been submitted to the U.S. Food and Drug Administration for approval.

Based on their understanding of wrist motion and its dependence on the full mobility of the midcarpal joint, Drs. Wolfe and Crisco designed and tested the first midcarpal hemi-arthroplasty device. Now, following promising results in a cohort of 20 patients in the United Kingdom the researchers anticipate introducing a modular midcarpal TWA device this year. “dart-thrower’s motion”—an important and uniquely human path of motion from radial wrist extension to ulnar wrist flexion.

23

The Lifespan Mission The Mission on Lifespan is to improve the health status of the people whom we serve in Rhode Island and southern New England through the provision of customer friendly, geographically accessible and high value services.

We believe that this can best be accomplished within the environment of a comprehensive, integrated, academic health system.

The Lifespan Research Mission The mission of Lifespan’s research is to attract and support scientists and clinicians who work at the leading edge of their fields and who have the scientific vision to transform patient care.

To learn more, visit www.lifespan.org/research.

Credits:

Publication year 2018

24

Peter J. Snyder, PhD, Creative Director John Callahan, Project Director Shelly Murphy, Writer Bob Lukens, Logica, Graphic Designer

Rhode Island Hospital/Hasbro Children’s Hospital The Miriam Hospital • Bradley Hospital • Newport Hospital • Gateway Healthcare

Lifespan, 167 Point Street, Providence, RI 02903 Lifespan.org