MedicalResearch.com: Medical Research Exclusive Interviews May 12 2015

MedicalResearch.com
Exclusive Interviews with Medical Research and
Health Care Researchers from Major and Specialty Medical
Research Journals and Meetings
Editor: Marie Benz, MD
info@medicalresearch.com
May 13 2015
For Informational Purposes Only: Not for Specific Medical Advice.

Medical Disclaimer | Terms and Conditions
• The contents of the MedicalResearch.com Site, such as text, graphics, images, and
other material contained on the MedicalResearch.com Site ("Content") are for
informational purposes only. The Content is not intended to be a substitute for
professional medical advice, diagnosis, or treatment. Always seek the advice of
your physician or other qualified health provider with any questions you may have
regarding a medical condition. Never disregard professional medical advice or
delay in seeking it because of something you have read on the Hemodialysis.com
Site!
• If you think you may have a medical emergency, call your doctor or 911
immediately. MedicalResearch.com does not recommend or endorse any specific
tests, physicians, products, procedures, opinions, or other information that may be
mentioned on the Site. Reliance on any information provided by
MedicalResearch.com or other Eminent Domains Inc (EDI) websites, EDI
employees, others appearing on the Site at the invitation of MedicalResearch.com
or EDI, or other visitors to the Site is solely at your own risk.
• The Site may contain health- or medical-related materials that are sexually explicit.
If you find these materials offensive, you may not want to use our Site. The Site
and the Content are provided on an "as is" basis.
Read more interviews on
MedicalResearch.com

Emergency Room Coding Of Heart Failure Diagnosis Validated
MedicalResearch.com Interview with:
Justin A. Ezekowitz, MBBCh MSc
Associate Professor, University of Alberta
Co-Director, Canadian VIGOUR Centre Director, Heart Function Clinic
Cardiologist, Mazankowski Alberta Heart Institute
• Medical Research: What is the background for this study?
Dr. Ezekowitz: Heart Failure is a prevalent health issue that carries high morbidity and
mortality. Most epidemiologic research derives information from hospital discharge
abstracts, but emergency department visits are another source of information. Many have
assumed this code is accurate in the emergency department but uncertainty remains.
• In our study, we assessed patients at their presentation to Emergency Department, which is
usually the first medical contact for acutely ill patients with heart failure.
• The objective of our study was to compare administrative codes for acute heart failure (I50.x)
in the emergency department against a gold standard of clinician adjudication.
Read the rest of the interviews on MedicalResearch.com
Content NOT an endorsement of efficacy and NOT intended as specific medical advice.

• Medical Research: What are the main findings?
Dr. Ezekowitz: Emergency department administrative data is highly correlated with a clinician
adjudicated diagnosis. The positive predictive value of acute heart failure as the main
diagnosis was 93.3% when compared to clinician adjudication, supported by standardized
scoring systems and elevated BNP.
• Medical Research: What should clinicians and patients take away from your report?
• Dr. Ezekowitz: The code for acute heart failure in emergency department administrative data
has a high Positive Predictive Value and may be used in outcomes research.

• Medical Research: What recommendations do you have for future research as a result of
this study?
• Dr. Ezekowitz: Studies using administrative codes should exercise caution when evaluating
codes related to the acute disease, especially when a diagnosis may evolve, such as in the
emergency department. Further validation of other disease states is required, and
researchers should use validated, disease-specific scoring systems supported by biomarker or
imaging where possible.
• Citation:
•
• Frolova N, Bakal JA, McAlister FA, et al. Assessing the Use of International Classification of
Diseases-10th Revision Codes From the Emergency Department for the Identification of
Acute Heart Failure. JCHF. 2015;3(5):386-391. doi:10.1016/j.jchf.2014.11.010.
•
• MedicalResearch.com Interview with: Justin A. Ezekowitz, MBBCh MSc (2015). Emergency
Room Coding Of Heart Failure Diagnosis Validated

Bystander CPR Allows Many Cardiac Arrest Patients To Return To Work
Kristian Kragholm, MD, PhD-student
Cardiovascular Research Center, Department of Anesthesiology,
Aalborg University Hospital
Medical Research: What is the background for this study?
Dr. Kragholm: During 2001-2010 in Denmark, survival to 30 days and 1 year more than doubled.
Whether this substantial improvement in survival was accompanied by good functional recovery
in survivors was not clear. Discharge neurological status or post-discharge follow-up assessments
were not systematically recorded in Denmark but through nationwide registries employment
outcomes were available. Therefore, we examined return to work as a marker of favorable
neurological outcome in 30-day survivors of out-of-hospital cardiac arrest in a nationwide study
in Denmark between 2001-2011.

Dr. Kragholm: More than 75% of all 30-day out-of-hospital survivors in Denmark during
2001-2011 who were employed prior to arrest returned to work
• Not only did the majority of these survivors return to work, survivors also sustained work
without any long-term sick absences for a median time of 3 years and maintained the same
income after arrest as before arrest.
• Finally, relative to survivors who did not receive bystander cardiopulmonary resuscitation
(CPR), chances for return to work were increased by approximately 40% if bystanders had
provided CPR in multivariable adjusted modeling.

• Dr. Kragholm: Contrary to a belief that survival and cognitive outcomes following out-of-
hospital cardiac arrest are poor, we show that the great majority of survivors of working age
who were employed prior to arrest recovered not only to return to work but also to maintain
employed to earn the same salary as prior to arrest.
• Importantly, more survivors were capable of returning to work if bystanders had provided
CPR. In Denmark, CPR courses became mandatory in elementary schools in 2005 and when
acquiring a driver’s license in 2006 as well as dispatcher-assisted CPR was introduced at
emergency dispatch centers. Healthcare providers and policy makers should set the scene for
offering community-based CPR courses as well as dispatcher-assisted guidance of bystanders
to perform CPR should be implemented.

this study?
• Dr. Kragholm: It would be interesting to see results on return to work rates from other sites
and countries. Although our findings are very uplifting, return to work is only meaningful to
study in survivors of working age. Therefore, together with my research team, we are
currently examining other long-term function parameters that can be assessed in all survivors
irrespective of their age.
Citation:
• Return to work in out-of-hospital cardiac arrest survivors : A nationwide register-based
follow-up study. / Sørensen, Kristian Dahl Kragholm ; Wissenberg, M.; Fonager, Kirsten;
Jensen, Svend Eggert; Lippert, F. K.; Christensen, E. F. ; Hansen, P. A. ; Lang-Jensen, T.;
Henriksen, O. M. ; Torp-Pedersen, Christian; Rasmussen, Bodil Steen

Connecting Chronically Ill Patients To Safety Net Clinics Reduced ER Visits
Karoline Mortensen, Ph.D. Assistant Professor
Department of Health Services Administration University of Maryland
College Park, MD
Dr. Mortensen: For twenty years, use of hospital emergency departments has been on the rise in
the United States, particularly among low-income patients who face barriers to accessing health
care outside of hospitals including not having an identifiable primary health care provider. Almost
half of emergency room visits are considered “avoidable.” The Emergency Department-Primary
Care Connect Initiative of the Primary Care Coalition, which ran from 2009 through 2011, linked
low-income uninsured and Medicaid patients to safety-net health clinics.

College Park, MD
Medical Research: What are the main findings?
Dr. Mortensen: “Our study found that uninsured patients with chronic health issues – such as
those suffering from hypertension, diabetes, asthma, COPD, congestive heart failure, depression
or anxiety – relied less on the emergency department after they were linked to a local health
clinic for ongoing care,” says Dr. Karoline Mortensen, assistant professor of health services
administration at the University of Maryland School of Public Health and senior researcher.
“Connecting patients to primary care and expanding the availability of these safety-net clinics
could reduce emergency department visits and provide better continuity of care for vulnerable
populations.”

College Park, MD
• Dr. Mortensen: The project provides promise not only for hospitals in Maryland but
throughout the nation to improve health care experiences and outcomes for their patients.
Shared learning systems were an integral component of the project so participants were
learning from each other and sharing best practices throughout the project and that learning
has now been documented and can be replicated in other communities.
• “We created a learning system that permits us to sustain improved communication between
patients and their providers, between hospital discharge planners and community based
clinics, and across five hospitals operating in Montgomery County” says Barbara H. Eldridge,
Manager of Quality Improvement at the Primary Care Coalition.
• The initiative has proven successful in Montgomery County, Maryland and is being replicated
in communities in other parts of the country.
• Citation:
• Linking Uninsured Patients Treated In The Emergency Department To Primary Care Shows
Some Promise In Maryland
• Theresa Y. Kim, Karoline Mortensen, and Barbara Eldridge
• Health Aff May 2015 34:5796-804; doi:10.1377/hlthaff.2014.1102

Genes Identified That May Be New Drug Targets In HER2 Breast Cancer
Ahmad M. Khalil, PhD
Assistant professor, Department of Genetics and Genome Sciences
Case Western Reserve University School of Medicine
• MedicalResearch: What is the background for this study? What are the main findings?
• Dr. Khalil: This study aimed to identify other genes that work synergistically with the
oncogene HER2 in HER2positive (HER+) breast cancer. The gene HER2 is amplified in those
patients, which results in excess activities that promote uncontrolled cell growth. There are
drugs that target HER2 and diminish its activity. However, these drugs can work initially, but
patients relapse; or sometimes, the drugs don’t work at all in some patients.
• Thus, by identifying other genes that work synergistically with the HER2 gene, we now have
more genes to target by various drugs or compounds to destroy the tumor. The challenge
was how to identify the key genes that work synergistically with HER2, especially in human
subjects. To that end, we used clinical samples from a clinical trial of a drug that is known to
inhibit HER2 activity to identify those genes. To further refine our list, we used cell culture
models of the disease to also inhibit HER2. By combining those data sets, we identified 44
protein-coding genes.
• Next, we wanted to make sure that those genes stand a third independent filter. For that
part, we interrogated those 44 genes in HER2+ tumors vs matched normal tissues from The
Cancer Genome Atlas database — a collection of hundreds of tumors and normal tissues. Of
the 44 genes, 35 genes passed this third filter. By examining the known functions of those
genes, we can deduce that those genes work cooperatively with HER2 to promote
carcinogenesis.

• There are currently known drugs that target some of those genes. We will use these drugs in
combination with a drug that target HER2 to determine if the combination works better at
destroying the tumor entirely.
• Lastly, we found that a special type of genes that we previously discovered, called lincRNAs,
could also affect the oncogenic activity of HER2. These lincRNAs can also be targeted with
HER2 to eliminate the tumor.

• MedicalResearch: What should clinicians and patients take away from your report?
• Dr. Khalil: We now have a small set of genes that can be targeted for therapeutics in HER2+
breast cancer. We still need to do those studies to identify potential drugs that can be
effective and eventually safe for clinical trials, but our study has now narrowed down the
number of genes to study, which is a major step.

• MedicalResearch: What recommendations do you have for future research as a result of
this study?
• Dr. Khalil: It is critical to look at genes and pathways directly in human patients, in addition to
cell culture models and/or animal models. In many cases, things that are discovered in these
other systems do not work when tested in human patients. This is a very unique aspect of
our study. We identified those genes by examining human tumors before and during
inhibition of the HER2 gene in vivo.
• Citation:
• Integrative transcriptome-wide analyses reveal critical HER2-regulated mRNAs and lincRNAs
in HER2+ breast cancer
• Callie R. Merry,Sarah McMahon,Cheryl L. Thompson,Kristy L. S. Miskimen,Lyndsay N. Harris,
Ahmad M. Khalil
Breast Cancer Research and Treatment
April 2015, Volume 150, Issue 2, pp 321-334

Decreasing Financial Burden Of IVF May Encourage Single Embryo Transfers, Reduce Multiple Births
Dmitry Kissin, MD
Health scientist
CDC Division of Reproductive Health
Dr. Kissin: Due to the frequent transfer of more than one embryo during assisted reproductive
technology (ART) treatments, such as in vitro fertilization (IVF), many ART-conceived children are
born as multiples (twins, triplets and higher order). Multiple births, even twins, carry increased
risk for both mothers and children. In the U.S., the practice guidelines published by the American
Society for Reproductive Medicine (ASRM) and the Society for Assisted Reproductive Technology
(SART) provide recommendations on how many embryos to transfer in order to balance safety
with the effectiveness of assisted reproductive technology. In an effort to reduce multiple births
and associated complications, it is important to evaluate embryo transfer practices that
contribute to these outcomes.

Dmitry Kissin, MD
Health scientist
Medical Research: What are the main findings?
Dr. Kissin: Using data from the CDC’s National ART Surveillance System (NASS), we found that the
majority of ART-related multiple births in the U.S. resulted from assisted reproductive technology
cycles practiced in accordance with ASRM/SART guidelines and involved the transfer of two
embryos. Almost half of ART-related multiple births resulted from transferring two fresh
blastocysts (embryos cultured for 5/6 days) to favorable- or average-prognosis patients less than
35 years and donor-egg recipients, or two frozen/thawed embryos to patients less than 35 years.

Dmitry Kissin, MD
Health scientist
• Dr. Kissin: Clinicians practicing IVF know that the decision on the number of embryos to
transfer is always a balance between trying to maximize the chance of pregnancy and
minimize the chance of multiple birth. The substantial reduction of assisted reproductive
technology-related multiple (both twin and triplet or higher order) births in the U.S. could be
achieved by single embryo transfers among young patients or recipients of donor eggs.

Dmitry Kissin, MD
Health scientist
this study?
• Dr. Kissin: One of the major barriers to widespread implementation of single embryo transfer
in the U.S. is the high out-of-pocket cost of assisted reproductive technology, often not
covered by health insurance. Some countries have been successful in achieving marked
reductions in multiple births when they removed financial pressures for infertility patients by
covering assisted reproductive technology in exchange for mandatory single embryo transfer
in the best prognosis groups. Future research on whether such approach will work in the
United States is needed and requires coordinated efforts by multiple stakeholders, as
outlined in CDC’s “National Public Health Action Plan for the Detection, Prevention and
Management of Infertility”.
• Citation:
• Fertil Steril. 2015 Apr;103(4):954-61. doi: 10.1016/j.fertnstert.2014.12.127. Epub 2015 Jan
27.
• Embryo transfer practices and multiple births resulting from assisted reproductive
technology: an opportunity for prevention.
• Kissin DM1, Kulkarni AD2, Mneimneh A2, Warner L2, Boulet SL2, Crawford S2, Jamieson DJ2;
National ART Surveillance System (NASS) group

Timely Pertussis Vaccination Important For Preventing Infant Deaths
MedicalResearch.com Interview with: Tejpratap S.P. Tiwari, MD
Meningitis and Bacterial Vaccine Preventable Diseases Branch
Division of Bacterial Diseases National Center for Immunization and Respiratory Diseases
Division of Global HIV/AIDS, Center for Global Health Centers for Disease Control and Prevention,
Atlanta, Georgia
Medical Research: What is the background for this study? What are the main findings?
Dr. Tiwari: Infants younger than one year old in the United States are at highest risk for severe
outcomes from pertussis and death. The first childhood pertussis vaccine dose is recommended
at 2 months old, with additional doses in the first year of life at 4 and 6 months. Studies have
established that pertussis vaccines can protect against pertussis disease, complications, and
hospitalization in infants when 1 to 3 doses are administered by six months old. This study’s
findings suggest that the first pertussis vaccine dose and appropriate antibiotic treatment protect
infants against death, hospitalization, and pneumonia. Improved on-time infant vaccination (at 2,
4, and 6 months) could potentially prevent up to 1 out of every 4 infant pertussis deaths.

Atlanta, Georgia
• Dr. Tiwari: Clinicians should ensure timeliness of the first pertussis vaccine dose at 2 months
to help prevent infant pertussis death. Additional efforts to protect infants who are too
young for vaccination also need to be prioritized. This can be done by reinforcing the recent
Advisory Committee on Immunization Practices recommendation for use of the pertussis
vaccine called Tdap during the third trimester of each pregnancy, so that mothers may pass
on antibodies to their babies to help protect them until they are old enough for their own
immunization. For more information about maternal Tdap vaccination, visit
www.cdc.gov/pertussis/pregnant.

Atlanta, Georgia
this study?
• Dr. Tiwari: In this study, 24% of nonfatal infant cases and 64% of infant deaths occurred
among infants who were too young to receive the first childhood pertussis vaccine dose. This
highlights the importance of protect these infants through vaccination recommendations for
pregnant women in the United States as well as the need to assess how to best to protect
those most vulnerable to pertussis complications and death.
• Citation:
• First Pertussis Vaccine Dose and Prevention of Infant Mortality
• Tejpratap S.P. Tiwari, Andrew L. Baughman, and Thomas A. Clark
• Pediatrics peds.2014-2291; published ahead of print May 4, 2015, doi:10.1542/peds.2014-
229

Deficient Calcium Channels Weaken Immune Response To ChronicInfections
MedicalResearch.com Interview
Dr. Ludovic Desvignes PhD.
Assistant Professor, Departments of Medicine and Pathology
NYU Langone Medical Center
• MedicalResearch: What is the background for this study?
• Dr. Desvignes: This study is the result of a collaboration at NYU Langone Medical Center,
between the laboratories of Dr. Stefan Feske and Dr. Joel Ernst, my mentor. Dr. Feske and
colleagues had developed a mouse model of rare, inherited mutations he had identified in
infants. These mutations occur in the genes for STIM1 and ORAI1, which are crucial for
calcium flux in cells of the immune system. The young patients affected by these mutations
suffer from severe, recurrent and chronic infections that often cause death before their first
birthday. In particular, some of these patients cannot control infection with BCG, which is a
normally innocuous strain of mycobacteria administered to protect against tuberculosis (TB).
TB is a chronic infection and one of the leading causes of infection-related death worldwide.
Going into this study, Dr. Feske and colleagues knew that without functional calcium
channels, immune cells do not function properly. However, they did not fully understand how
these channels contribute to immune responses to infectious pathogens in a living organism
and in particular, for pathogens that cause chronic infections such as TB. This is why Dr. Ernst
and I collaborated with Dr. Feske and provided him with our clinical and research expertise in
TB.

• MedicalResearch: What are the main findings?
• Dr. Desvignes: Dr. Feske’s mice are genetically engineered to lack STIM1 in a certain type of
immune cells, known as T cells or T lymphocytes. We infected these mice with
Mycobacterium tuberculosis, the bacterium causing TB. Mycobacterium tuberculosis causes
chronic infection by manipulating the immune system even in healthy people. The first very
surprising result of our study was that mice lacking calcium flux in T cells handled acute TB
fairly well. Only during the chronic phase of infection did they become unable to control
mycobacterial growth and developed a strong inflammation in their lungs, which was due to
an infiltration by different types of immune cells, including T cells. We discovered that the
accumulation of STIM1-deficient T cells in the lungs resulted from the cells’ inability to die,
which is a normal mechanism to limit an immune response and prevent excessive
inflammation.

• Another immune control mechanism that failed in the absence of STIM1 is mediated by a
subset of T cells called induced regulatory T cells, or iTreg cells. These cells are essential to
prevent normal immune responses from going “overboard” by suppressing the functions of
other immune cells, including T cells. We found that calcium signals are required for the
development of iTreg cells and that their numbers were strongly reduced in the lungs of
infected STIM1-deficient mice. We therefore think that the lack of iTreg cells in the absence
of STIM1 contributes to the severe lung inflammation in chronic TB.
• The third finding that really surprised us was that T cells accumulating in the lungs of STIM1-
deficient mice produced large amounts of a protein called interferon gamma. While
interferon gamma is required to control Mycobacterium tuberculosis, it is also a very potent
promoter of inflammation and too much of it can lead to tissue damage. Dr. Feske and
colleagues had previously observed that calcium fluxes promote the production of interferon
gamma in T cells cultured in vitro and we expected the STIM1-deficient T cells to be defective
in the production of that protein. During chronic TB, however, calcium signaling turned out to
be not only dispensable for the production of interferon gamma by T cells but it was actually
required to limit its production and thus, to control inflammation.

• Dr. Desvignes: Our research is primarily aimed at understanding the fundamental
mechanisms of how calcium channels regulate the immune response to chronic inflammation
and infections, and we think that our findings may help other scientists to develop new drugs
and vaccines that improve immune responses to infections. Of course, we hope that this
study helps clinicians understand, and maybe treat, the infectious diseases observed in those
rare patients with mutations in STIM1 and ORAI1.
• From a drug discovery perspective, it is important to note that several pharmaceutical
companies are currently exploring applications for calcium channel blockers, for instance in
the treatment of autoimmune or inflammatory diseases, like Multiple Sclerosis, psoriasis or
chronic obstructive pulmonary disease (COPD). Inhibition of calcium channels is an effective
strategy to suppress certain forms of inflammation. Based on our results, inhibition of
calcium channels may however suppress important immune regulatory mechanisms that are
required to prevent an overwhelming immune response. During chronic or latent infections
such as TB, hepatitis or with herpes viruses, constant triggering of the immune system,
without appropriate shutdown mechanisms when calcium channels are inhibited, could
result in harmful inflammation.

this study?
• Dr. Desvignes: There are pressing and exciting avenues that should be explored as a direct
follow up to our study. For example, we have experimental evidence that inhibition of
calcium channels, by genetic deletion or pharmacological inhibition of STIM1 or ORAI1
proteins, prevents the development of T cell-mediated autoimmune diseases such as
Multiple Sclerosis and Crohn’s disease in mice. To assess the safety of calcium channel
inhibition in patients with these diseases, it will be necessary to test if the degree of
inhibition required for treatment increases the risk of reactivating latent or chronic infections
such as TB.

• TB remains a global health issue and we are in dire need of a new, more efficacious vaccine.
In this respect, our study serves as a cautionary tale and provides ideas to develop better
vaccines. For example, a vaccine preparation that would induce large amounts of interferon
gamma may seem like a good idea to control Mycobacterium tuberculosis but it could result
in uncontrolled, harmful inflammation, and even fuel the infection. Now that we understand
better some of the players and the mechanisms of the immune response to TB, we can target
specific elements of the immune response that will help fight the infection while limiting its
deleterious effects.
• Citation:
• STIM1 controls T cell–mediated immune regulation and inflammation in chronic infection
• Ludovic Desvignes, Carl Weidinger, Patrick Shaw, Martin Vaeth, Theo Ribierre, Menghan Liu,
Tawania Fergus, Lina Kozhaya, Lauren McVoy, Derya Unutmaz, Joel D. Ernst, Stefan Feske
• Published May 4, 2015
Citation Information: J Clin Invest. 2015. doi:10.1172/JCI80273.

Hospitals Vary In Treatment Of 22-24 Week Preterm Infants
Mr. Matthew A. Rysavy, B.S and Edward Bell, MD
Department of Pediatrics, University of Iowa
Iowa City, IA
• Medical Research: What is the background for this study? What are the main findings?
• Response: We were interested in understanding reasons for differences in outcomes among
extremely preterm infants among hospitals. This has been shown in many studies. We found
that differences among hospitals in whether treatment was initiated for infants born at very
early gestations (22, 23, 24 weeks’ gestation) accounted for a lot of the variation in hospital-
level outcomes at these gestational ages

Iowa City, IA
• Response: In the editorial accompanying our study, Professor Marlow writes: “Information on
survival, morbidity, and policies regarding active intervention should be available to assist
parents in making an informed choice about transfer to a specialist hospital, if feasible, and
the level of intervention provided after birth.” Ultimately, the care of individual infants must
be decided by the parents and doctors based on the best available information. We hope
that, by unpacking some of the differences in hospital outcomes, our study sheds some light
on what this information is and how to better obtain it.

Iowa City, IA
• Medical Research: What recommendations do you have for future research as a result of this
study?
• Response: There are still many important questions about differences in hospital outcomes that
need further study. For example, in our study, among hospitals that initiated treatment for 100% of
infants born at 24 weeks of gestation, rates of risk-adjusted survival still varied from 42 to 70%. It
seems important to understand other reasons for the variation in outcomes among hospitals.
• Also, there are important questions about how to better make decisions about treatment. The
prognosis of extremely preterm infants is often fairly uncertain, and physicians and families have to
make decisions based on very limited information. Gestational age alone is not the best indicator
of prognosis. Some infants born at 22 weeks survive and do well and many others do not; likewise,
some but not all, infants born at 26 weeks or later do well. This is why it is important not to use
gestational age as the sole criterion for making decisions about treatment. We need to understand
better issues related to the prognosis of extremely preterm infants to improve their care.
• Citation:
• Between-Hospital Variation in Treatment and Outcomes in Extremely Preterm Infants
• Matthew A. Rysavy, B.S., Lei Li, Ph.D., Edward F. Bell, M.D., Abhik Das, Ph.D., Susan R. Hintz, M.D.,
Barbara J. Stoll, M.D., Betty R. Vohr, M.D., Waldemar A. Carlo, M.D., Seetha Shankaran, M.D.,
Michele C. Walsh, M.D., Jon E. Tyson, M.D., M.P.H., C. Michael Cotten, M.D., M.H.S., P. Brian Smith,
M.D., M.P.H., M.H.S., Jeffrey C. Murray, M.D., Tarah T. Colaizy, M.D., M.P.H., Jane E. Brumbaugh,
M.D., and Rosemary D. Higgins, M.D. for the Eunice Kennedy Shriver National Institute of Child
Health and Human Development Neonatal Research Network
• N Engl J Med 2015; 372:1801-1811 May 7, 2015
• DOI: 10.1056/NEJMoa1410689

Orthopedic Patients and Their Families At Risk For Opioid Abuse
Hassan R. Mir, MD, MBA
and
Dr. Brent J. Morris, M.D.
Dr. Mir: The past few decades have seen an alarming rise in opioid use in the United States,
and the negative consequences are dramatically increasing. The US represents less than 5%
of the world’s population, yet consumes 80% of the global opioid supply. Management of
pain is an important part of patient care, however, the increased usage of opioids for the
treatment of pain has led to several unanticipated aftereffects for individual patients and for
society at large.
• Orthopaedic surgeons are the third highest prescribers of opioid prescriptions among
physicians in the United States. Orthopaedic patients can experience a tremendous amount
of pain with acute injuries and chronic conditions, and the treatment plan may involve opioid
prescriptions for relief of discomfort. A significant number of orthopaedic patients and their
families are at risk for repercussions from opioid use. We must work together to decrease the
use of opioids for musculoskeletal pain.
• Clinicians should aim to control pain and improve patient satisfaction while avoiding
overprescribing opioids. A comprehensive strategy of risk assessment is needed to identify
patients who may be at risk for opioid abuse. Objective measures including patient history,
recognition of aberrant behavior, urine drug testing, state prescription drug–monitoring
programs, and opioid risk-assessment screening tools may be necessary in select cases.

and
• Medical Research: What should patients and clinicians take away from your report?
• Dr. Mir:
• 3 tips for patients:
• Ask your doctor about ways to control your pain with minimal use of opioids.
• Do not seek opioids from multiple physicians as “doctor shopping” for pain medication is
dangerous.
• Seek help if you or a family member are becoming dependent on opioids.
• 3 tips for clinicians:
• Counsel patients and establish reasonable expectations for pain as a part of treatment plan
discussions and follow-up visits.
• Establish a standard pain protocol for specific surgical and nonsurgical treatment plans with
an opioid taper.
• Be aware of available objective risk-assessment tools and state prescription drug monitoring
programs to use as adjuncts to clinical experience and judgment when dealing with
challenging patient scenarios.

and
this study?
• Dr. Mir: There are several areas of potential research with regard to opioid medications and
musculoskeletal pain, many of which are already underway looking at the potential
detrimental effects of opioid medications on clinical outcomes. Other areas for potential
research include alternative multi-modal pain control regimens, clinician education, patient
education, electronic health records, clinical practice guidelines, and prescription drug
monitoring programs all as means to decrease the widespread use of opioid medications for
musculoskeletal pain in the United States.
• Citation:
• J. Morris, H. R. Mir. The Opioid Epidemic: Impact on Orthopaedic Surgery. Journal of the
American Academy of Orthopaedic Surgeons, 2015; 23 (5): 267 DOI: 10.5435/JAAOS-D-14-
00163

Comprehensive Stroke Centers Save Lives In Patients With Hemorrhagic Stroke
James S McKinney, MD, FAHA
Assistant Professor of Neurology Rutgers-Robert Wood Johnson Medical School
Medical Director, RWJUH Comprehensive Stroke Center New Brunswick, NJ 08901
Medical Research: What is the background for this study? What are the main findings?
Dr. McKinney: The current study evaluated outcomes of patients admitted to New Jersey
hospitals with hemorrhagic stroke, including intracerebral hemorrhage (bleeding into the brain)
and subarachnoid hemorrhage (bleeding along the surface of the brain) between 1996 and 2012
using the Myocardial Infarction Data Acquisition System (MIDAS) administrative database. The
New Jersey Department of Health and Senior Services designates certain hospitals as
comprehensive stroke centers (CSCs). We found that patients admitted to comprehensive stroke
centers with hemorrhagic stroke were less likely to die than those admitted to other hospital
types. This was particularly true for those patients admitted with subarachnoid hemorrhage,
which is usually caused by a ruptured aneurysm.

• Dr. McKinney: The stroke center designation process works to identify hospitals that are
dedicated to providing the resources to quickly diagnose and treat stroke patients. Patients
with complex or serious strokes, such as hemorrhagic stroke, should be treated at hospitals
with an appropriate spectrum of resources to manage their condition. Our study indicates
that CSC care may lower mortality for patients with hemorrhagic stroke.

this study?
• Dr. McKinney: The current study used administrative data and was unable to adjust for all
potential confounding variables, particularly stroke severity. Further, we only were able to
study stroke care in New Jersey using statewide department of health stroke center
designations. Further research should look at outcomes of hemorrhagic stroke patients
admitted to stroke centers adjusting for stroke severity and in other geographic regions.
• Citation:
• James S. McKinney, Jerry Q. Cheng, Igor Rybinnik, John B. Kostis, and the Myocardial
Infarction Data Acquisition System (MIDAS 22) Study Group. Comprehensive Stroke Centers
May Be Associated With Improved Survival in Hemorrhagic Stroke. Journal of the American
Heart Association, May 2015 DOI: 10.1161/JAHA.114.001448

Childhood Obesity Presents Opportunities and Challenges
Rebecca Jones, MSPH
Nutrition and Health Sciences Program
Graduate Division of Biological and Biomedical Sciences Emory University
• Response: Obesity in children is associated with a wide range of conditions later in life
including heart disease, cancer, and diabetes. Even prior to adulthood, children can be
affected by a host of non-communicable diseases which are affected by weight status of the
child. With an increase in children who are overweight or obese globally, Dr. Chan, Director-
General of the World Health Organization, announced a new initiative to combat childhood
obesity at the 2014 World Health Assembly. Within childhood obesity the pre-school (under
age 5) years are a critical period for prevention due the association of adiposity rebound and
obesity in later years as well as the early establishment of taste preferences and attitudes
around healthy eating habits. Recent evaluation of incident obesity in the United States has
demonstrated a component of the course to obesity is already established by the age of five
years.

Rebecca Jones, MSPH
Our main finding is the necessity for better surveillance and comparability of weight status,
particularly overweight and obesity, in children under five across countries in the European
region. 60% of countries within the region have some form of published data on this particular
population however they vary based on level of national representation, cut-off criteria, age and
gender. All these different factors can significantly change the prevalence estimates making it
very difficult to ascertain the full nature of the problem. Based on the data which was available
the European Region has reason for concern about overweight and obesity in young children.

Rebecca Jones, MSPH
Medical Research: What should clinicians and patients take away from your report?
Response: Historically, a fat child meant a healthy child and the concept of bigger as better was
widely accepted. This perception has begun to shift, however clinicians and patients need to
continue to be made aware of the importance of a healthy weight even at such young ages. It is
vital that clinicians discuss with patients the long-term problems which can result from an
unhealthy weight in children under 5.

Rebecca Jones, MSPH
this study?
• Response: Future research needs to comprehensively evaluate the weight status of children
under five, underweight and overweight, within countries with an aim towards having data
which is comparable with other countries across the region. This research is pivotal to help in
the future development of comparable core indicators for inclusion in national health
surveillance systems. To begin to impact the weight status of children in the region, policy
makers first need a knowledge base of prevalence estimates of nutritional status.
• Citation:
• Abstract presented at the European Congress on Obesity May 2015
T7:PO.011 Surveillance of Overweight including Obesity in Children Under 5: Opportunities
and Challenges for the European Region
Jones R.1,2, Breda J.2
1Department of Public Nutrition, Rollins School of Public Health, Emory University, Atlanta,
Georgia, 2Department of Nutrition, Physical Activity and Obesity, Division Noncommunicable
Diseases and Lifecourse, World Health Organization European Regional Office, Copenhagen,
Denmark

Obese Patients Face Stigma and Discrimination
MedicalResearch.com Interview with: Claudia Sikorski
Dr. rer. med. Claudia Sikorski, Dipl.-Psych.
Institut für Sozialmedizin, Arbeitsmedizin und Public Health (ISAP)
Institute of Social Medicine, Occupational Health and Public Health
Universität Leipzig, Medizinische Fakultät
Leipzig
Response: Obesity is a highly stigmatized condition. People with obesity are often regarded a
lazy, slow and sloppy. One consequence of these negative attitudes may be discrimination,
e.g. the unfair treatment of individuals with obesity. This study, conducted by Jenny
Spahlholz, myself and colleagues reviews observational and experimental studies that
investigated the occurrence and nature of discrimination in obesity.
• Response: We find that patients with obesity are indeed faced not only with negative
attitudes but also with unfair treatment in every-day life in numerous domains. Heavier
individuals and women report more experiences of discrimination and may therefore be
more prone to psychosocial effects such as low self-esteem.

Obese Patients Face Stigma and Discrimination
MedicalResearch.com Interview with: Claudia Sikorski
Dr. rer. med. Claudia Sikorski, Dipl.-Psych.
Institut für Sozialmedizin, Arbeitsmedizin und Public Health (ISAP)
Institute of Social Medicine, Occupational Health and Public Health
Universität Leipzig, Medizinische Fakultät
Leipzig
this study?
• Response: We would like to find out more about the mechanisms of stigmatization and
discrimination. We also need to re-think legislative protection for individuals with obesity.
• Citation:
• upcoming ECO abstract :
• Obesity and Discrimination – A Systematic Review
• Spahlholz J.1,2, Baer N.2, König H.H.3, Riedel-Heller S.G.2, Sikorski C.1,2
• 1Leipzig University Medical Center, IFB AdiposityDiseases, Leipzig, Germany, 2Institute of
Social Medicine, Occupational Health and Public Healt (ISAP), Leipzig University, Leipzig,
Germany, 3Department of Medical Sociology and Health Economics, University Medical
Center

Measures To Reduce Sugary Drinks Gains Public Acceptance
Dr. Dragos Petrescu
Department of Public Health and Primary Care
Cambridge
• Response: Consumption of sugar-sweetened beverages is a major contributor to obesity,
particularly in children. Recent systematic reviews provide good evidence that reducing
portion size reduces consumption. Similarly, evidence suggests that container shapes and
product placement in supermarkets can influence consumption. The public acceptability of
“nudging” — altering properties such as the size, the shape, and location of sugar-sweetened
beverages — to improve public health is unknown. Here we compared the acceptability in UK
and USA samples of government interventions to reduce consumption of sugar-sweetened
beverages: three nudge interventions (limiting portion size, changing container shape, and
changing shelf location) and two traditional interventions (increased taxation and an
education campaign).
• We found that for the majority of UK and USA samples, the education campaign and the
three nudge interventions were acceptable, with education attracting most support. By
contrast, only a minority of participants supported taxation.

Dr. Dragos Petrescu
Cambridge
• Response: Nudge interventions to reduce consumption of sugary drinks appear to be
acceptable to the public. Policymakers can be reassured about the public acceptability of
nudging to reduce sugar-sweetened beverages consumption; however our results suggest
taxation to lower consumption would not be popular with the majority of both the UK and
US populations.

Dr. Dragos Petrescu
Cambridge
this study?
• Response: Future research is needed to explore how best to communicate to the public in
order to increase support for unpopular but likely effective policies, such as increased
taxation.
• Citation: Abstract presented at the European Congress on Obesity
• Public acceptability in the UK and USA of nudging to reduce obesity: The example of reducing
sugar-sweetened beverages consumption
• Petrescu D.C.1, Hollands G.J.1, Ng Y.1, Marteau T.M.1
• 1Behaviour and Health Research Unit, University of Cambridge

Sleep Loss Impairs Decision Making
Hans P.A. Van Dongen, Ph.D.
Director, Sleep and Performance Research Center Research Professor, College of Medical Sciences
Washington State University Spokane, Spokane, WA
• Research: Our main interest is in better understanding why people sometimes are able to
manage perfectly well with sleep loss, while at other times sleep loss can have profoundly
negative effects. We found that sleep deprivation reduces the effectiveness of signals used to
tell when you are right or wrong, an effect we labeled feedback blunting.
• Subjects in the study performed a decision making task that was simple but required
feedback, i.e., a signal indicating the response was correct or incorrect, to perform correctly.
We found that people who were sleep deprived were no longer able to use the feedback
information to make correct responses. And when people had to adapt to unexpected
changes in when to respond, sleep deprived people were completely unable to adapt to
these changing circumstances.
• The finding of feedback blunting in this study indicates that people who are sleep deprived
not only have trouble sustaining attention to details in the environment (a well established
effect of sleep loss), they also have trouble changing the focus of attention to deal with
changing circumstances.

• An interesting paradox in the research literature has been that people have been shown in
many circumstances to perform complex tasks at a very high level while sleep deprived. Yet,
we know from real-world experience that sleep deprived people can make catastrophic, life-
threatening decisions that they would never have made if they were well rested. The current
study is the first to shed light on this issue. It showed that sleep deprived people who get
feedback, telling them that their actions are not effective, are less capable of changing their
behavior.
• The study is part of a line of research in which we are trying to identify how sleep loss
changes specific components of cognition, and how these changes may lead to serious
problems in everyday life activities. Being able to study and understand these effects of sleep
deprivation under controlled conditions is an important step toward preventing human error
under real world conditions.

• Research: One important lesson is not to ignore the effect of sleep loss just because it hasn’t
had much impact in the past. The study findings imply that when circumstances change from
the everyday routine is when sleep deprivation will cause the biggest problems. Thus, getting
adequate sleep is as important as any other measure taken to promote health and safety.
• Sleep loss is inescapably linked with shift work, extended work hours, and emergency
situations, as well as with sleep disorders and many other medical conditions. In today’s fast-
paced society, people are often called upon to make critical decisions under dynamically
changing circumstances and with potentially major consequences. Our study indicates that
the circumstances that cause people to be sleep deprived are often precisely the
circumstances when the effects of sleep deprivation can be the most dramatic.

• There are two specific things to note.
• First, sustaining attention, even for brief periods of time, is very difficult for people who are
sleep deprived. Any task that requires sustained attention is likely to lead to problems under
conditions of sleep loss. If you are doing something that is well practiced and there is no
novelty or ambiguity to deal with, you can keep doing that task while sleep deprived, but
occasional errors will pop up.
• Second, any task that requires evaluating changes in the environment, e.g., new events, or
changing or ambiguous circumstances, is going to be particularly difficult when people are
sleep deprived. That means you may not recognize signals that would ordinarily allow you to
avoid errors or prompt you to change your course of action. Serious problems arise even in
well practiced activities when you must continually evaluate the environment and adapt to
changing circumstances.

this study?
• Research: Most conventional test used to measure the impact of sleep loss rely on either
subjective measures of sleepiness or objective measures of inability to sustain attention.
While useful, these approaches miss the importance of situations that demand attending to
signals to change our current pattern of behavior. Future research focusing on people’s
processing of feedback information can lead to improved assessment and prediction of
failures that can arise from sleep loss.
• In addition, we know that there are individual differences in susceptibility to sleep loss, and
better understanding the mechanisms of sleep loss effects on performance is a key step in
understanding these individual differences.
• Citation:
Feedback Blunting: Total Sleep Deprivation Impairs Decision Making that Requires Updating
Based on Feedback
• Journal Sleep: VOLUME 38, ISSUE 05
http://dx.doi.org/10.5665/sleep.4668
• Paul Whitney, PhD; John M. Hinson, PhD; Melinda L. Jackson, PhD; Hans P.A. Van Dongen,
PhD

Viagra Derivatives May Block Malaria Transmission
Dr. Gordon Langsley
Laboratoire de Biologie Cellulaire Comparative des Apicomplexes,
Institut Cochin, INSERM U1016, CNRS UMR 8104, Faculté de Medecine
Université Paris Descartes, Paris
Response: We have been studying the role of cAMP-dependent PKA signaling in Plasmodium
falciparum-infected red blood cells for some time; see just a few examples: PMID: 25522250;
PMID: 22626931; PMID: 18248092; PMID: 11559352 and we came to the conclusion that
intra cellular cAMP levels regulate infected red blood cell deformability and adhesion to for
example, brain endothelial cells.
• Response: Drugs that manipulate (alter) cAMP levels in Plasmodium-infected erythrocytes
have the potential to become one day new anti-malaria drugs and the proof of principal is
the demonstration we provide for inhibitors of phosphodiesterases (PDEs) and deformability
of transmissable (step V) gametocytes and their potential to block transmission of malaria.

Viagra Derivatives May Block Malaria Transmission
Dr. Gordon Langsley
Laboratoire de Biologie Cellulaire Comparative des Apicomplexes,
Institut Cochin, INSERM U1016, CNRS UMR 8104, Faculté de Medecine
Université Paris Descartes, Paris
this study?
• Response: First, we do not propose that Viagra should be used as a transmission blocking
anti-malaria drug, but rather derivatives, lacking its erectile function, could become malaria
transmission blocking drugs.
• We envisage in the next couple of years performing clinical trials to test the efficacy of PDE
inhibitors to reduce transmission of malaria
• Citation:
• Ghania Ramdani, Bernina Naissant, Eloise Thompson, Florence Breil, Audrey Lorthiois, Florian
Dupuy, Ross Cummings, Yoann Duffier, Yolanda Corbett, Odile Mercereau-Puijalon, Kenneth
Vernick, Donatella Taramelli, David A. Baker, Gordon Langsley, Catherine Lavazec. cAMP-
Signalling Regulates Gametocyte-Infected Erythrocyte Deformability Required for Malaria
Parasite Transmission. PLOS Pathogens, 2015; 11 (5): e1004815 DOI:
10.1371/journal.ppat.1004815

Frequent Emergency Department Users More Likely To Die Or Be Admitted
Dr. Brian Rowe, MD, MSc, CCFP(EM), FCCP
Professor, Department of Emergency Medicine
University of Alberta, Edmonton, Alberta, Canada
• MedicalResearch: What is the background for this study?
• Dr. Rowe: Frequent users are also called “familiar faces” or “heavy users” and they represent
an important sub-group of patients in the emergency setting, with often complex needs that
contribute to overcrowding and excess health care costs. The evidence suggests that
frequent users account for up to one in 12 patients seeking emergency care, and for around
one in four of all visits.

• MedicalResearch: What are the main findings?
• Dr. Rowe: Frequent users of emergency department care are more than twice as likely to die,
be admitted to hospital, or require other outpatient treatment as infrequent users, concludes
an analysis of the available evidence, published in Emergency Medicine Journal.
• These conclusions are based on a thorough search of seven electronic databases of relevant
research relating to the frequency and outcomes of emergency department use by adults.
Out of a total of more than 4000 potential studies, 31 relevant research reports published
between 1990 and 2013 were included in the final analysis. Frequent users were variably
defined as visiting emergency care departments from four or more times up to 20 times a
year.
• Among the seven studies looking at deaths, the analysis showed that frequent attenders at
emergency care departments were more than twice as likely to die as those who rarely
sought emergency care. Most of the studies included hospital admission as an outcome, and
these showed that frequent users were around 2.5 times as likely to be admitted as
infrequent users. Ten studies looked at use of other hospital outpatient care, and these
showed that frequent users were more than 2.5 times as likely to require at least one
outpatient clinic after their visit to the emergency care department.

MedicalResearch: What should clinicians and patients take away from your report?
Dr. Rowe: Our results suggest that, despite heterogeneity, frequent users are a distinct and high
risk group. Clinicians should be aware of the important risks associated with this group of
patients. Frequent users should not be discouraged from attending emergency departments;
however, an organized care plan should be developed.

this study?
Dr. Rowe: The lack of any consensus as to what constitutes a frequent user is striking, they
emphasize, and this makes it difficult to permit comparison and come up with potentially
generalizable recommendations. Proactive, targeted treatment may help patients and
clinicians. Further research on these remaining issues is urgently required.
• Citation:
• Mortality, admission rates and outpatient use among frequent users of emergency
departments: a systematic review
• Jessica Moe, Scott Kirkland, Maria B Ospina, Sandy Campbell, Rebecca Long, Alan Davidson,
Patrick Duke, Tomo Tamura, Lisa Trahan, Brian H Rowe
• Emerg Med J emermed-2014-204496Published Online First: 7 May 2015
doi:10.1136/emermed-2014-204496

Breast Cancer Risk Reduction of Prophylactic Salpingo-Oophorectomy May Be Overestimated For Some BRCA1 Carriers
Bernadette A.M. Heemskerk-Gerritsen, Ph.D.
Department of Medical Oncology
Erasmus MC Cancer Institute Roterdam, the Netherlands
• Dr. Heemskerk-Gerritsen: Women with a BRCA1 or BRCA2 mutation have substantially higher
risks of developing both primary and contralateral breast cancer (BC) and ovarian cancer than
women from the general population. Options to reduce these increased cancer risks include
risk-reducing mastectomy (RRM) and/or risk-reducing salpingo-oophorectomy (RRSO). The
latter intervention obviously reduces the risk of developing ovarian cancer, but has been
reported also to reduce the risk of developing a subsequent breast cancer with
approximately 50%. However, studies on the efficacy of risk-reducing surgery in BRCA1/2
mutation carriers are confined to observational studies, thus challenging several
methodological issues. Consequently, previous studies on breast cancer risk-reduction after
RRSO may have been influenced by bias associated with selection of study subjects, bias
associated with start of follow-up, or by confounding, and breast cancer risk-reduction may
have been overestimated.
• In the current study, we revisited the association between risk-reducing salpingo-
oophorectomy and breast cancer risk in BRCA1/2 mutation carriers, focusing on the impact of
different analytical methods and potential types of bias.

• First, we replicated the analyses of four previously performed studies, to examine if our
Dutch cohort was comparable with the cohorts used in the previous studies. We replicated
the approximately 50% breast cancer risk reduction after RRSO in the Dutch cohort.
• Second, we estimated the effect of RRSO on breast cancer risk in the Dutch cohort using a
revised analytical approach for observational studies in BRCA1/2 mutation carriers in order to
minimize bias as much as possible. Using this method of analysis, we found no evidence of
first BC risk-reduction after RRSO in BRCA1/2 mutation carriers.

• Dr. Heemskerk-Gerritsen: From the results, we concluded that in previous studies, breast
cancer risk reduction after RRSO in BRCA1/2 mutation carriers may have been overestimated
because of bias. We suggest that counselors, clinicians, and researchers should consider the
potential impact of bias in previous and future observational studies on this topic. For the
present, we advise caution in the message regarding breast cancer risk reduction after RRSO,
at least for BRCA1 mutation carriers.

this study?
• Dr. Heemskerk-Gerritsen: We are very interested in the risk estimates in the previous study
cohorts when using our proposed design and analytical method, and in validation of our
findings. Additionally, further research with longer follow-up and larger numbers of especially
BRCA2 mutation carriers is warranted to explore differential effects on BC risks after RRSO for
BRCA1 and BRCA2 mutation carriers.
• Citation:
• Breast Cancer Risk After Salpingo-Oophorectomy in Healthy BRCA1/2 Mutation Carriers:
Revisiting the Evidence for Risk Reduction
• J Natl Cancer Inst. 2015 Mar 18;107(5). pii: djv033. doi: 10.1093/jnci/djv033

Electronic Medical Records Did Not Improve Stroke Outcomes Or Quality Of Care
Karen E. Joynt, MD MPH Cardiovascular Division,
Brigham and Women’s Hospital and VA Boston Healthcare System
Department of Health Policy and Management Harvard T.H. Chan School of Public Health
• Dr. Joynt: While there is a great deal of optimism about the potential of Electronic Health
Records (EHRs) to improve health care, there is little national data examining whether
hospitals that have implemented EHRs have higher-quality care or better patient
outcomes. We used national data on 626,473 patients with ischemic stroke to compare
quality and outcomes between hospitals with versus without EHRs. We found no difference
in quality of care, discharge home (a marker of good functional status), or in-hospital
mortality between hospital with versus without EHRs. We did find that the chances of having
a long length of stay were slightly lower in hospitals with EHRs than those without them.

• MedicalResearch: What should patients and providers take away from this report?
• Dr. Joynt: In our sample, EHRs were not associated with overall higher-quality care or better
outcomes. Though Electronic Health Records may be necessary for an increasingly high-tech,
transparent health care system, as currently implemented, they do not appear to be
sufficient to improve outcomes for this important disease.

• MedicalResearch: What future research do you recommend as a result of this study?
• Dr. Joynt: Future research should find ways of leveraging EHRs to improve care and
outcomes – electronic tools have the potential to improve care, but in order to do so, need to
be integrated into clinical workflow and provide meaningful information to the clinician. We
don’t yet know enough about how best to use Electronic Health Records to improve care, or
what type of innovations in electronic tools might really improve outcomes, and that is an
important area of research.
• Citation:
• Joynt KE, Bhatt DL, Schwamm LH, et al. Lack of Impact of Electronic Health Records on
Quality of Care and Outcomes for Ischemic Stroke. J Am Coll Cardiol. 2015;65(18):1964-1972.
doi:10.1016/j.jacc.2015.02.059.

Red Blood Cell Surface Molecule May Be Target For New Malaria Vaccine and Treatment
Manoj Duraisingh Ph.D.
John LaPorte Given Professor of Immunology and Infectious Diseases Harvard T.H. Chan School of Public Health
Department of Immunology and Infectious Diseases Boston, Massachusetts
• Dr. Duraisingh: The malaria parasite P. falciparum is one of the most important pathogens of
humans, with enormous mortality resulting from blood-stage infections, when parasites
replicate exponentially in red blood cells. Although anti-Plasmodial drugs are in clinical use,
widespread and increasing parasite drug-resistance has contributed to an ongoing public
health crisis, and we urgently need to find novel approaches to prevent and treat disease.
• Targeting host red blood cell molecules presents an unexploited alternative. However, the
highly differentiated and enucleated red blood cell poses a significant technical hurdle for
genetic experimentation, due to the lack of a nucleus.
• Here we have developed a novel, forward genetic screen to identify critical factors of malaria
infection of red blood cells in an unbiased fashion. Our screen takes advantage of recent
advances in human stem cell biology that enable the ex vivo culture of red blood cells from
nucleated hematopoietic precursors which are amenable to in vitro genetics.
• We have now identified a surface molecule CD55 (alias Decay-Accelerating Factor, DAF) as an
essential host factor required for the invasion of red blood cells by P. falciparum. We
demonstrate that this protein is required by all P. falciparum strains tested (laboratory and
field) for invasion. Furthermore, we demonstrate that CD55 acts at the initial stage of
invasion when the P. falciparum parasite attaches to the surface of the red blood cell.
• Collectively, our findings indicate that CD55 is an ideal target for the development of new
host-directed and vaccine therapeutics for malaria.

• Dr. Duraisingh: Parasites have evolved to use multiple surface protein receptors to enter red
blood cells. Targeting specific receptors was previously thought to be problematic as the
notion was that the parasite would simply invade using alternative receptors. Here we have
identified an essential surface protein, CD55, required by all P. falciparum parasites for entry
into the cell.
• Blocking this interaction between CD55 and the parasite should be a very powerful approach
in the development of blood-stage therapeutics. This could be either through the
development of a drug-like molecule in the form of a CD55-mimetic, or through the
identification of the parasite molecule that binds to the CD55 protein, which would
immediately become a top vaccine candidate.
• Our unbiased screening approach can also be used to identify novel host molecules that the
parasite needs for growth in the red blood cell. Targeting host molecules by drugs instead of
the parasite would have the advantage that host molecules in the fully differentiated and
enucleated red blood cell cannot change to become resistant to drugs. The evolution of drug-
resistance in parasitic targets remains one of the greatest challenges of malaria control.

this study?
• Dr. Duraisingh: In the future, we would very much like to explore the exploitation of CD55 for
the development of host-targeted therapeutics, as is used in HIV. In addition, CD55 provides a
starting point for the search of a parasite ligand that binds to it. As the interaction is
essential, the putative CD55-binding protein could be pursued for vaccine development.
Finally, CD55 is a blood group protein, and there are a few polymorphisms in this molecule
that are at high prevalence in African populations that bear the brunt of malaria, and may
confer protection against malaria. It would of great interest to study the effect of these CD55
polymorphisms on human selection by the malaria parasite.
• Citation:
• A forward genetic screen identifies erythrocyte CD55 as essential for Plasmodium falciparum
invasion
• Elizabeth S. Egan, Rays H. Y. Jiang, Mischka A. Moechtar, Natasha S. Barteneva, Michael P.
Weekes, Luis V. Nobre, Steven P. Gygi, Joao A. Paulo, Charles Frantzreb, Yoshihiko Tani, Junko
Takahashi, Seishi Watanabe, Jonathan Goldberg, Aditya S. Paul, Carlo Brugnara, David E. Root,
Roger C. Wiegand, John G. Doench, and Manoj T. DuraisinghScience 8 May 2015: 711–714.
[DOI:10.1126/science.aaa3526]

Nondisclosure Agreements in Medical Malpractice Settlements May Limit Transparency
William M. Sage MD JD
James R. Dougherty Chair for Faculty Excellence
School of Law The University of Texas
Response: We reviewed settlement agreements in malpractice claims closed by The
University of Texas System as part of a larger study on incorporating patient perspectives into
safety improvement funded by the Agency for Health Care Research and Quality. Over the
five years studied, we found that 88.7% of the 124 settlement agreements that met our study
criteria contained non-disclosure provisions, but with little standardization or
consistency. Restrictions on disclosure, which selectively burdened patients and their
families, seemed broader than needed to protect health care providers from disparagement
or to avoid attracting additional litigation.
• Nearly half of the agreements (46.4%) prohibited disclosure of the underlying facts, which
may be inconsistent with emerging principles of patient safety and compassionate care, and
26.4% prohibited reporting to regulatory bodies, a restriction that the health system
subsequently eliminated in response to our findings. Settlements reached after tort reform
took full effect in Texas had stricter non-disclosure provisions than earlier settlements,
suggesting greater leverage by defendants notwithstanding the reduced risk of additional
litigation.

• Response: Silence and secrecy around medical error can persist even in a well-intentioned
academic health system that faces little litigation risk and generally attempts to treat patients
fairly and transparently. The findings are important because they remind us how concerned
professionals can be about reputation and how uncomfortable publicity can make them, even
when science and ethics have advanced to favor greater information exchange.

this study?
• Response: Many health care organizations are implementing “communication and
resolution” programs involving medical injuries. These programs include vigilant detection of
errors, full disclosure to patients and families, timely redress of injuries, and detailed
feedback to improve patient safety. Based on our study, biases and habits involving
settlement need to be re-examined in these and other settings, and best practices developed
and disseminated.
• Citation:
• Sage WM, Jablonski JS, Thomas EJ. Use of Nondisclosure Agreements in Medical Malpractice
Settlements by a Large Academic Health Care System. JAMA Intern Med. Published online
May 11, 2015. doi:10.1001/jamainternmed.2015.1035.

Wide US Regional Variation In Organ Donation Rates
Dr. David Goldberg MD, MSCE
Assistant Professor of Medicine LDI Fellow, Leonard Davis Institute, University of Pennsylvania
Medical Director for Living Donor Liver Transplantation, Hospital of the University of Pennsylvania
• Dr. Goldberg: While there are data that demonstrate differences in authorization (consent)
rates for deceased donation among racial and ethnic minorities, it is unknown how these
differences contribute to geographic differences in the number of deceased organ donors. It
has been postulated that geographic differences in the distribution of racial and ethnic
minorities may contribute to differences in the deceased organ supply, yet there have been
no empiric data to support this. Using data on “eligible deaths,” defined as potential brain-
dead organ donors <=70 years of age, we demonstrated that even after accounting for
differences in the racial/ethnic demographics of the potential donor population, there are
dramatic differences in authorization (consent) rates across geographic areas that are not
explained by demographics alone. If the source of these differences could be identified, then
there could be large increases in the number of organ donors, and lifesaving transplants, in
areas with lower authorization rates.

Wide US Regional Variation In Organ Donation Rates
Dr. David Goldberg MD, MSCE
Assistant Professor of Medicine LDI Fellow, Leonard Davis Institute, University of Pennsylvania
Medical Director for Living Donor Liver Transplantation, Hospital of the University of Pennsylvania
• Dr. Goldberg: The rates of authorization for donation among potential brain-dead organ
donors varies dramatically across the United States, and these differences are not explained
solely by donor demographics, including race/ethnicity.
this study?
• Dr. Goldberg: It is necessary to identify what the root causes of the geographic differences in
authorization rates are so that interventions can be applied to increase authorization rates,
thus increasing the number of lifesaving transplants, in those areas that with lower rates.
• Citation:
• Increasing the Number of Organ Transplants in the United States by Optimizing Donor
Authorization Rates
Goldberg,1 B. French,2 P. Abt,3 R. Gilroy.4
• 1Department of Medicine, University of Pennsylvania, Philadelphia, PA
2Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, PA
3Department of Surgery, University of Pennsylvania, Philadelphia, PA
4Department of Medicine, University of Kansas Medical Center, Kansas City, KS.
• 2015 American Transplant Congress

Genetic Variants Explain Differences in Age Of Onset Of Huntington’s Disease Symptoms
Kristina Bečanovič Ph.D.
Department of Clinical Neuroscience
Karolinska Institutet, Stockholm, Sweden.
Dr. Becanovic: While the symptoms normally debut in middle-age, there is wide individual
variation in how Huntington disease manifests itself, and even though two people carry the exact
same genetic mutation that codes for the huntingtin protein, there can be up to a 20-year
difference in onset of motor symptoms. This suggests that genetic variants, transcription factors
and environmental factors could contribute to the observed differences in disease expressivity. As
the identification of regulatory factors of the huntingtin gene would be targets for therapeutic
intervention, we set out to study the regulation of the huntingtin gene as it has not been well-
known which factors regulate the expression levels. We were interested in identifying both
genetic variants and transcription factors that are of importance for gene regulation. We
therefore used DNA from Huntington disease patients to study the regulation of the huntingtin
gene promoter in cells.

Dr. Becanovic: This study presents multiple findings that are of potential interest for
clinicians, patients and other researchers.
• Most people who develop Huntington’s disease have a normal and a mutated huntingtin
gene. In the present study, we found that when the genetic variant was on the gene copy
that codes for the normal Huntington protein, the patients developed motor symptoms on
average four years earlier than expected; on the other hand, the genetic variant had a
protective effect when sitting on the gene copy that codes for the mutated protein, which is
toxic for the brain. These patients developed their motor symptoms on average ten years
later than expected. We showed that NF-ĸB which is known to be a central player in the
inflammatory response, acts as a transcription factor regulating huntingtin gene expression,
but that the genetic variant hindered the binding of NF-ĸB which led to lower levels of the
huntingtin protein.This study suggests that the genetic variant therefore leads to lower levels
of the normal or the mutated protein depending on which gene copy it sits on, and that this
explains the differences in disease onset. Our results emphasize the importance of “allelic
imbalance”, where the yin-yang relationship of the normal and the mutant Huntington
protein is of significance, and when altered, affects the Huntington disease age of onset in
patients.

• Dr. Becanovic: Our findings are important for the development of disease-modifying
treatments, which not only reduce the symptoms but also protect the brain. Much research
has gone into silencing the expression of the huntingtin protein, something that will be
tested in patients within the near future. Our work is the first to support the claim that this
type of therapy could help people with Huntington’s disease by slowing the progression of
the disease. This work further supports continued efforts on allele-specific silencing
approaches in Huntington disease. This work also suggests the identified genetic variant to be
used as a prognostic marker in Huntington disease patients.

MedicalResearch.com: Medical Research Exclusive Interviews May 12 2015

MedicalResearch.com: Medical Research Exclusive Interviews May 12 2015

Recommandé

Recommandé

Contenu connexe

Tendances

Tendances (20)

Similaire à MedicalResearch.com: Medical Research Exclusive Interviews May 12 2015

Similaire à MedicalResearch.com: Medical Research Exclusive Interviews May 12 2015 (20)

Plus de Marie Benz MD FAAD

Plus de Marie Benz MD FAAD (18)

Dernier

Dernier (20)

MedicalResearch.com: Medical Research Exclusive Interviews May 12 2015