MedicalResearch.com: Medical Research Exclusive Interviews January 7 2014

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
January 7 2015
For Informational Purposes Only: Not for Specific Medical Advice.

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Healthy Aging Brain Care Tool Allows Quick Assessment of Cognitive Function
MedicalResearch.com Interview with:
Patrick Monahan, Ph.D.
Associate Professor
Indiana University School of Medicine and School of Public Health
• Medical Research: What is the background for this study?
• Dr. Monahan: Primary care providers need a clinical practical (e.g., brief, inexpensive, simple,
user-friendly, easily standardized, and widely available) multidomain instrument to measure
and monitor the cognitive, functional, and psychological symptoms of patients suffering from
multiple chronic conditions. The tool also needs to be sensitive to change so that providers
can use it to monitor patient outcomes and adjust the care plan accordingly. We created such
a tool and then investigated its psychometric properties (in other words, reliability and
validity) in our study of 291 older patients (aged 65 and older) who had at least one recent
visit to our urban primary care clinics in Indianapolis, Indiana. These patients had presented
with evidence of cognitive or depression problems because these patients and their
caregivers were participating in a collaborative care model for such patients.
• Medical Research: What are the main findings?
• Dr. Monahan: The Healthy Aging Brain Care (HABC) Monitor demonstrated excellent
reliability and validity in this study where patients self-reported their symptoms. Our
previous study also showed excellent reliability and validity of the HABC Monitor when the
patients’ symptoms were reported by their informal caregiver.
Read the rest of the interviews on MedicalResearch.com
Content NOT an endorsement of efficacy and NOT intended as specific medical advice.

Healthy Aging Brain Care Tool Allows Quick Assessment of Cognitive Function
Patrick Monahan, Ph.D.
Associate Professor
Indiana University School of Medicine and School of Public Health
• Medical Research: What should clinicians and patients take away from your report?
• Dr. Monahan: The patient Self-Report HABC Monitor can be used along with the Caregiver-report version
of the tool to provide useful feedback (via monitoring of symptoms) for modifying care plans.
• Medical Research: What recommendations do you have for future research as a result of this study?
• Dr. Monahan: We are in the process of developing a briefer 10-item version of the HABC Monitor which
was requested by our clinical colleagues for the busy primary setting. As with the current tool, the briefer
version is relevant for all primary care patients, but especially relevant for patients and their caregivers
being treated with a collaborative care model for treating depression and cognitive impairment, given the
importance of the cognitive, psychological, and functional domains. However, those domains are
important for all patients in primary care who may suffer from a variety of chronic conditions. In addition,
we are building on the HABC Monitor to develop a broader multidomain (but still relatively brief, for
example, 20-item) tool that covers additional domains, such as actionable physical symptoms, to monitor
the symptoms patients who attend primary care with a range of multiple chronic conditions such as
cancer, diabetes, stroke, dementia, traumatic brain injury, heart failure, depressive disorders, anxiety
disorders, and chronic musculoskeletal disorders.
• Citation:
• The Healthy Aging Brain Care (HABC) Monitor: Validation of the Patient Self-Report Version of the Clinical
Tool Designed to Measure and Monitor Cognitive, Functional, and Psychological Health
Clinical Interventions in Aging
• Patrick O Monahan,1 Catherine A Alder,2–4 Babar A Khan,1–3 Timothy Stump,1 Malaz A Boustani1–4
• December 2014 Volume 2014:9 Pages 2123—2132
http://dx.doi.org/10.2147/CIA.S64140

Stem Cells Can Be Grown From Blood Of Deceased Patients
Dr. Dhruv Sareen, PhD
Director, iPSC Core Facility Regenerative Medicine Institute Research Scientist, Neurobiology Research
Cedars-Sinai, Los Angeles CA
• Medical Research: What is the background for this study? What are the main findings?
Dr. Sareen: We have developed a novel method to re-create brain and intestinal stem cells from
patients who died decades ago, using stored blood samples. Using the iPS cell technology at
Cedars-Sinai this new method now allows us to apply to alive as well as deceased patient blood
cells. Our study, published in the journal STEM CELLS Translational Medicine, highlights the power
of this technology for many deceased patients that were diagnosed with debilitating diseases, such
as inflammatory bowel disease (IBD) and motor neuron diseases (spinal muscular atrophy and ALS).
Patients had their blood samples stored away at Cedars-Sinai when they were alive decades ago. At
that time all researchers could have done was collect and bank their blood cell lines for research
purposes. The iPS cell technology wasn’t even on scientists radar then. With novel developments in
my lab we have figured out how to reliably create new stem cell lines from patient blood samples
stored away in large cell banks. We have also shown that these recreated stem cells can efficiently
make neurons specific to the spine (motor) and cells of the gut. Since it is very difficult to get
unlimited access to research affected cells and tissues from the patients, our discoveries now allow
us such important capabilities. Thus, now we are not limited to animal models of disease, but can
use these patient-specific stem cells to better pinpoint potential causes of these devastating
illnesses.
• Dr. Sareen: This research, published in the journal STEM CELLS Translational Medicine, could yield
new therapies for people who suffer from aggressive motor-neuron and gut-related IBD conditions
that proved fatal to the deceased patients who long-ago volunteered their blood samples. Using
patient iPS cells that we can recreate unlimited number of cell types that are much more relevant
as they are the ones affected during disease. This provides researchers with better platform
systems to screen for thousands of candidate drugs in the future.

Stem Cells Can Be Grown From Blood Of Deceased Patients
Dr. Dhruv Sareen, PhD
Director, iPSC Core Facility Regenerative Medicine Institute Research Scientist, Neurobiology Research
Cedars-Sinai, Los Angeles CA
• Medical Research: What recommendations do you have for future research as a result of this
study?
• Dr. Sareen: The potential implications of this kind of research are vast. This significant development
provides an easier modality for the creation of powerful patient-specific stem cells (iPS cells).
Potentially, any patient at Cedars-Sinai can have their iPS cells created, thus allowing us to study a
wider range of diseases. In the near term, this technology allows us to generate disease-relevant
cell types (gut and brain) to guide us forward in identifying novel and yet unknown disease
mechanisms in IBD and SMA. When the patient’s blood cells (LCLs) were stored years ago they were
utilized in genetic studies to assess if specific alterations in their DNA code were responsible for
their disease. By now obtaining their iPS cells, then creating affected gut and brain cell types we are
correlating the clues these cells provide with the large wealth of knowledge gained previously from
the genetic studies. This will ultimately allow us to design better drugs. Although we are unable to
help the deceased patients, long term, these iPS cells will also allow us to create healthy versions of
cell types that can regenerate the damaged tissue affected for patients currently suffering with
such diseases. All of these future possibilities will allow us to design better therapies for patients
suffering from SMA and IBD.
• Citation:
• Reliable Generation of Induced Pluripotent Stem Cells From Human Lymphoblastoid Cell Lines
• Robert Barrett, Loren Ornelas, Nicole Yeager, Berhan Mandefro, Anais Sahabian, Lindsay Lenaeus,
Stephan R. Targan, Clive N. Svendsen, Dhruv Sareen
• Stem Cells Trans Med 2014; 3:1429-1434; first published on October 8, 2014;
doi:10.5966/sctm.2014-0121

Human Trafficking During Global Sporting Events Needs More Study
Dr. Rebecca Finkel PhD Queen Margaret University Edinburgh, Scotland, UK and
Madelon Finkel, Ph.D. Director Professor of Clinical Public Health
Weill Cornell Medical College, NY, NY
Drs. Finkel: Human trafficking is as complex human rights and public health issue. One of the
authors (RF) studied the issue at the Vancouver Olympic Games and felt that there needed to
be more research on this topic. Much of the problem is that the issue of human trafficking for
sexual exploitation at mega global sporting events is difficult to quantify given the clandestine
nature of the industry. This is not to say that human trafficking for sexual exploitation does
not occur. It almost certainly exists, but to what extent is the big question and to what extent
do global events have an impact (if at all)? Our article shows that there are few well-designed
empirical studies that address the issue of human trafficking, especially as it relates to mega
sporting events.
• The extant literature presents gaps in:
a) understanding the actual scope of the international human trafficking situation;
b) establishing links between human trafficking and mega sporting events despite anecdotal
testimonies and moral panics often fueled by international media; and,
c) public health implications for victims of human trafficking.
• Drs. Finkel: Findings show a high prevalence of physical and mental violence among those
trafficked compared to non-trafficked women. Sexually transmitted infections and HIV AIDS
are prevalent and preventive care is virtually non-existent. The Public Health implications are
potentially substantial both for the victim and for her sexual partner.

Human Trafficking During Global Sporting Events Needs More Study
Dr. Rebecca Finkel PhD Queen Margaret University Edinburgh, Scotland, UK and
Madelon Finkel, Ph.D. Director Professor of Clinical Public Health
Weill Cornell Medical College, NY, NY
• Medical Research: What recommendations do you have for future research as a result of
this study?
• Drs. Finkel: Human trafficking for sexual exploitation is a hidden problem on a global scale in
plain view with tremendous public health implications. From a research perspective, it is
recommended that a research agenda in this important area be devised with consistent,
robust methodologies and approaches in order to collect reliable data in the areas of human
trafficking, public health, and their intersection during times of mega sporting events. Due to
difficulties quantifying the scope of human trafficking, it is suggested that qualitative and
mixed methods should be employed. Although research could and should involve authorities,
it also would be helpful if it were to go beyond official channels to study people involved in
human trafficking prevention, protection, prosecution and partnerships as well as survivors
themselves in order more fully to comprehend a holistic view of the contemporary landscape
of voluntary and involuntarily sex industries.
• Citation:
• The ‘dirty downside’ of global sporting events: focus on human trafficking for sexual
exploitation
• R. Finkel and M.L. Finkel
Public Health
Available online 29 December 2014

Many At-Risk Adolescents Have Access To Firearms In Home
Joseph A Simonetti, MD MPH Research Fellow
Harborview Injury Prevention & Research Center
University of Washington Seattle, WA, USA
Dr. Simonetti: Studies have consistently shown that children living in households where firearms
are stored safely have a lower risk of suffering firearm injuries, including lethal firearm injuries,
compared to those living in households where firearms are stored unlocked and/or loaded. Safe
firearm storage is widely recommended by public health experts, professional medical societies,
and gun rights organizations, especially for households where children might be suffering from
mental heath and substance abuse issues that put them at increased risk for suicide or
unintentional injury. Our goal was to find out if those recommendations were being effectively
implemented in the community. To do this, we used survey data that assessed mental health
conditions and firearm access among a nationally representative sample of US adolescents.
• Dr. Simonetti: First, we confirmed previous findings that a large proportion of US adolescents have
access to a firearm in the home. Of those who reported living in a home with a firearm, 40% said
they could immediately access and shoot the firearm.
• Second, the prevalence of most mental health diagnoses was similar between adolescents who did
and did not report firearm access. However, a greater proportion of adolescents with firearm
access had drug and alcohol disorders compared to adolescents who reported living in a home with
a firearm but did not have access to the firearm.
• The main finding was that children with mental health risk factors for suicide were just as likely to
report in-home firearm access as those without identified risk factors. This finding held true even
when comparing firearm access between children with no identified risk factors and those who
reported a recent suicide attempt, who arguably have the highest suicide risk in this sample.

• Dr. Simonetti: For clinicians – this study shows that a large proportion of US adolescents have
access to firearms in the home, and those with mental health risk factors for suicide were
just as likely to report in-home firearm access as those without identified risk factors. A
number of studies have demonstrated effective ways to promote safe firearm storage in
clinical settings. Importantly, several studies have shown that parents are not offended when
providers ask about safe firearm storage during clinical encounters.
• For parents – Safe firearm storage includes keeping firearms locked, unloaded, separate from
locked ammunition, and ensuring that children don’t know how to access those firearms.
Studies have consistently shown that children living in homes with safely-stored firearms are
less likely to be shot, and safe firearm storage is widely recommended by gun rights
organizations and public health officials. Trigger locks and gun lockboxes can be purchased for
less than $10 online, and in common stores such as Walmart and Costco.

this study?
• Dr. Simonetti: There is an obvious disconnect between generally agreed upon
recommendations for firearm safety practices and what we’re actually doing in the
community. Additional studies are needed to determine how best to promote safe firearm
storage in US households through clinical and community-based interventions, especially for
households with children and children with mental illness.
• Studies of physicians have shown that not all clinicians are asking about guns in the home, or
how those guns are stored. Future studies are needed to identify ways to address barriers to
asking about firearm ownership and storage in clinical settings, especially for clinicians caring
for children with increased risk of self-inflicted injuries.
• Citation:
• Simonetti JA, Mackelprang JL, Rowhani-Rahbar A, Zatzick D, Rivara FP. Psychiatric
Comorbidity, Suicidality, and In-Home Firearm Access Among a Nationally Representative
Sample of Adolescents. JAMA Psychiatry. Published online December 30, 2014.
doi:10.1001/jamapsychiatry.2014.1760.
•

Alternatives To Hysterectomy May Be Underutilized
Lauren Corona BS
Wayne State University School of Medicine
Detroit, MI
Response: Hysterectomy is the most commonly performed major gynecologic surgery in the United
States. This study sought to examine how often alternative treatment is considered prior to
hysterectomy for benign indications and how often pathology in the surgical specimen supports the
need for hysterectomy. We utilized data from the Michigan Surgical Quality Collaborative, a
statewide hospital collaborative, and limited the analysis to patients having a hysterectomy for
uterine fibroids, abnormal uterine bleeding, endometriosis, and/or pelvic pain. Alternative
treatment to hysterectomy was not documented prior to surgery in 38% (i.e. no documentation
that the patient declined, was unable to tolerate, or failed any alternative treatment). A
progesterone intrauterine device (IUD) was the least utilized form of alternative treatment,
documented in only 12% of patients. In addition, nearly 1 in 5 (18.3%) had pathology reported that
did not support the need for hysterectomy—i.e. the uterus was described as normal or
unremarkable or only had minor amounts of pathology. Women <40 years had the highest rate of
unsupportive pathology at 38%.
• Response: Our study suggests that there are opportunities to increase the utilization of alternative
treatments before hysterectomy. The American Congress of Obstetrics and Gynecology supports
the use of hormonal therapy, operative hysteroscopy, endometrial ablation, and the levonorgestrel
IUD for management of symptoms related to benign gynecologic conditions. Alternative treatments
should be offered to patients contemplating hysterectomy so that they make an informed decision
regarding surgery. This practice has the potential to empower patients, yield significant cost savings
and avoid unnecessary surgery.

Alternatives To Hysterectomy May Be Underutilized
Lauren Corona BS
Wayne State University School of Medicine
Detroit, MI
this study?
• Response: Research exploring how to optimize use of alternative therapy before
hysterectomy is needed. An intervention such as a pre-operative checklist itemizing
alternatives to hysterectomy (Hullfish et al. FPMRS 2012) has the potential to increase use of
alternative treatment and to decrease the number of hysterectomies done with unsupportive
pathology. In addition, understanding barriers to use of effective but less often utilized
alternative treatment such as the levonorgestrel IUD is important. Finally, examining how use
of alternatives to hysterectomy affect patient satisfaction is especially important as it will
focus research on patient centered outcomes. These types of efforts could improve the
quality of care for women potentially needing hysterectomy and could lead to significant cost
savings.
• Citation:
• Use of other treatments before hysterectomy for benign conditions in a statewide hospital
collaborative
Lauren E. Corona, BS, Carolyn W. Swenson, MD, Kyle H. Sheetz, MD, Gwendolyn Shelby, RN,
Mitchell B. Berger, MD, PhD, Mark D. Pearlman, MD, Darrell A. Campbell Jr., MD, John O.
DeLancey, MD Daniel M. Morgan, MD
American Journal of Obstetrics and Gynecology

Hypertension Medication May Enhance Tuberculosis Treatment
Shashank Gupta, Ph.D.
Center for Tuberculosis Research
Department of Medicine, JHU, Baltimore, Maryland, USA
Dr. Gupta: Verapamil is an efflux pump inhibitor drug that has been used to treat hypertension and other cardiac conditions
in patients. Adding verapamil to standard tuberculosis (TB) treatment accelerates both the killing activity of the regimen in
mouse model. We have recently shown in vitro that supplementing bedaquiline with verapamil profoundly decreases the
MIC of bedaquiline in the wild type strain M. tuberculosis H37Rv, and also in drug-susceptible and drug-resistant clinical
isolates. The MIC of another anti-mycobacterial drug clofazimine against M. tuberculosis H37Rv also decreased significantly
in the presence of verapamil.
• Bedaquiline is the first drug to be approved by the USFDA in last forty years for the treatment of multidrug-resistant
tuberculosis (MDR-TB). Bedaquiline usage in patients presents several safety concerns including increased mortality and
hepatic-related adverse drug reactions. Bedaquiline also prolongs the QT interval in patients, which is a measure of the time
between the start of the Q wave and the end of the T wave in the heart’s electrical cycle. In a phase 2 trial involving patients
with advanced MDR-TB, a significantly higher number of participants receiving bedaquiline died than those receiving
placebo although the causes of mortality were not directly attributable to the drug. Thus strategies to reduce the human
dose of bedaquiline while retaining antibacterial activity may be valuable. We hypothesized verapamil may potentiate the
killing of M. tuberculosis by bedaquiline and accelerate clearance of mycobacteria that in an in vivo infection model.
Shortening treatment regimens and reducing the required doses may be a promising strategy to reduce the incidence of
bedaquiline-related adverse effects and thereby improve MDR-TB treatment outcomes.
• In this study, we investigated the effect of verapamil on the activity of bedaquiline against M. tuberculosis in a mouse model
of TB infection. In addition to investigating the effects of verapamil on the full human bioequivalent dose of bedaquiline (25
mg/kg), we also used a sub-optimal dose of bedaquiline (12.5 mg/kg) daily, with or without verapamil to test if verapamil
may potentiate the activity of bedaquiline. We have also determined if verapamil can protect bedaquiline monotherapy
from the development of resistance.
• Using mouse model of tuberculosis, we have shown lower doses of bedaquiline together with verapamil have the same
antibacterial effect as the higher toxic doses. A lower dose of bedaquiline will cause no or less severe side effects. Verapamil
also protected bedaquiline against the development of resistant mutants of the bacteria in the animals.

Hypertension Medication May Enhance Tuberculosis Treatment
Shashank Gupta, Ph.D.
Center for Tuberculosis Research
Department of Medicine, JHU, Baltimore, Maryland, USA
• Dr. Gupta: Our finding that verapamil potentiates bedaquiline raises the possibility of extending
these findings to TB patients where the daily doses of bedaquiline may be reduced when co-
administered with verapamil. A lower human dose of bedaquiline is likely to reduce the frequency
of bedaquiline-related adverse effects such as QTc prolongation and hepatic toxicity.
study?
• Dr. Gupta: In the study, we have used a single dose of verapamil with bedaquiline in the mouse
infection experiment. It is interesting to determine if there is a dose effect of verapamil on
potentiating the bedaquiline activity. Also, it is pertinent to take the results and test in other
tuberculosis animal models that might more closely resemble human TB. The results of this study
can be used in designing a clinical trial in humans where the lower doses of bedaquiline with
verapamil can be used to treat patients successfully with fewer side effects.
• Citation:
• Verapamil Increases the Bactericidal Activity of Bedaquiline against Mycobacterium tuberculosis
in a Mouse Mode
Shashank Gupta, Sandeep Tyagi, and William R. Bishai
• Antimicrob. Agents Chemother. AAC.04019-14; Accepted manuscript posted online 20 October
2014, doi:10.1128/AAC.04019-1

Elders Requiring Fewer Hospital Days After Aortic Valve Surgery
Karthik Murugiah MBBS
Fellow in Cardiovascular Medicine Yale School of Medicine
Center for Outcomes Research and Evaluation (CORE) New Haven, CT 06510
Response: Aortic valve disease is common among older people and frequently requires valve replacement.
1-year survival after open surgical aortic valve replacement is high (9 in 10 survive the year after surgery).
Our study focuses on the experience of these survivors in terms of the need for hospitalization during the
year after surgery.
• Among patients >65 years of age enrolled in Medicare who underwent surgical replacement of their aortic
valve and survived at least one year, 3 in 5 were free from hospitalization during that year. Both, the rates
of hospitalization and the average total number of days spent in the hospital in the year following surgery
have been decreasing all through the last decade (1999 to 2010).
• Response: Surgical valve replacement is becoming safer over time. Our previous study showed that over
the last decade 1-year survival after aortic valve replacement increased from 86% to 89%. Our present
study shows that the majority of these survivors are free from hospitalization and the need to be
hospitalized is continually decreasing (from 44% to 41%).
• These days, newer techniques of valve replacement not requiring open surgery have emerged. Some
studies show them to be comparable in mortality outcomes. However, there is no comparable data for the
need for hospitalization, which is equally important to patients. Further, our previous study showing
declining mortality and the present one showing the decreasing need for hospitalization indicate that
these newer procedures are pitted against a continually improving target.
• There are certain sub-groups of patients like patients older than 85, female or black patients and those
undergoing bypass surgery at the same time, who have higher rates of re-hospitalization. Focusing on
these high risk sub-groups may further reduce rates of readmission following AVR. In addition, among
those hospitalized almost half were hospitalized within 30 days, indicating the need to monitor patients
closely during this period of heightened risk.

Elders Requiring Fewer Hospital Days After Aortic Valve Surgery
Karthik Murugiah MBBS
Fellow in Cardiovascular Medicine Yale School of Medicine
Center for Outcomes Research and Evaluation (CORE) New Haven, CT 06510
this study?
• Response: As a large proportion of the hospitalized patients were hospitalized within the first
30 days it indicates the potential to improve post op care, discharge practices and transition
in care. However, in order to develop targeted interventions, further research is needed to
illuminate the underlying reasons for hospitalization during this period in this particular
population of patients.
• Citation:
• Trends in Hospitalizations Among Medicare Survivors of Aortic Valve Replacement in the
United States From 1999 to 2010
Karthik Murugiah, MD , Yun Wang, PhD, John A. Dodson, MD, Sudhakar V. Nuti, BA, Kumar
Dharmarajan, MD, MBAa, b, Isuru Ranasinghe, MBChB, PhDa, Zack Cooper, PhD, Harlan M.
Krumholz, MD, SM
The Annals of Thoracic Surgery

Time Means Brain! Fast Treatment for Acute Ischemic Stroke Improves Recovery
Diederik Dippel MD, PhD
Senior Consultant in Neurology
Erasmus MC University Medical Center Rotterdam The Netherlands
Dr. Dippel: MR CLEAN is the first randomized clinical trial to show that intra-arterial treatment of ischemic
stroke to get the clot out, really works. It leads to more recovery and less handicap. Previous studies had
shown that intra-arterial treatment leads to recanalization, but the final proof that the treatment leads to
recovery more often than standard treatment was lacking.
• With standard treatment, less than 1 out of 5 recovers without handicap, but with this new treatment, this
will be 1 out of 3. The treatment did not lead to more complications than standard treatment. The rate of
symptomatic intracranial hemorrhage was similar in both arms.
• Our study differs from previous, neutral trials.
• First, we required patients to have an intracranial arterial occlusion confirmed by neuro-imaging.
• Second, we used third generation thrombectomy devices, such as retrievable stents in most of the cases.
• Third, our trial was conducted in a country with a very good infrastructure, which allowed rapid transfer to
intervention centers, which are spread throughout the country. Our rate of iv tPA in Dutch hospitals is over
11% on average.
• Last, all intervention centers participated, and almost no patients were treated outside the trial.
Moreover, reimbursement of the treatment was conditional on participation in the trial.
• Dr. Dippel: Intra-arterial treatment for acute ischemic stroke in patients with a confirmed intracranial
occlusion of the anterior circulation, who can be treated within 6 hours from onset, is safe and effective.
Confirmation of the occlusion should be done with MRA or CTA. Intra-arterial treatment should be started
as soon as possible. Time is brain!
• We were very happy that we could show that the treatment works at least as well in elderly people, even
in those over 80 years. We also had proof that the treatment works in patients with what at first appears
to be a mild stroke, but often turns out to be al large one if you do not treat.

Time Means Brain! Fast Treatment for Acute Ischemic Stroke Improves Recovery
Diederik Dippel MD, PhD
Senior Consultant in Neurology
Erasmus MC University Medical Center Rotterdam The Netherlands
• Medical Research: What recommendations do you have for future research as a result of this study?
• Dr. Dippel: Still more studies like MR CLEAN need to be done, we would like to have our findings confirmed. We need to
determine the relationship between time since onset and effect of the treatment and we certainly need to find out which
additional medication, such as antiplatelet agents and anticoagulants should be given and when this should be done. There
is a large gap between the chances of recanalization on the one hand, and the chance of good recovery on the other. We
need to close that gap. This will require efforts in basic and in clinical research. There is a lot of work ahead of us.
• Citation:
• A Randomized Trial of Intraarterial Treatment for Acute Ischemic Stroke
• Olvert A. Berkhemer, M.D., Puck S.S. Fransen, M.D., Debbie Beumer, M.D., Lucie A. van den Berg, M.D., Hester F. Lingsma,
Ph.D., Albert J. Yoo, M.D., Wouter J. Schonewille, M.D., Jan Albert Vos, M.D., Ph.D., Paul J. Nederkoorn, M.D., Ph.D., Marieke
J.H. Wermer, M.D., Ph.D., Marianne A.A. van Walderveen, M.D., Ph.D., Julie Staals, M.D., Ph.D., Jeannette Hofmeijer, M.D.,
Ph.D., Jacques A. van Oostayen, M.D., Ph.D., Geert J. Lycklama à Nijeholt, M.D., Ph.D., Jelis Boiten, M.D., Ph.D., Patrick A.
Brouwer, M.D., Bart J. Emmer, M.D., Ph.D., Sebastiaan F. de Bruijn, M.D., Ph.D., Lukas C. van Dijk, M.D., L. Jaap Kappelle,
M.D., Ph.D., Rob H. Lo, M.D., Ewoud J. van Dijk, M.D., Ph.D., Joost de Vries, M.D., Ph.D., Paul L.M. de Kort, M.D., Ph.D.,
Willem Jan J. van Rooij, M.D., Ph.D., Jan S.P. van den Berg, M.D., Ph.D., Boudewijn A.A.M. van Hasselt, M.D., Leo A.M.
Aerden, M.D., Ph.D., René J. Dallinga, M.D., Marieke C. Visser, M.D., Ph.D., Joseph C.J. Bot, M.D., Ph.D., Patrick C. Vroomen,
M.D., Ph.D., Omid Eshghi, M.D., Tobien H.C.M.L. Schreuder, M.D., Roel J.J. Heijboer, M.D., Koos Keizer, M.D., Ph.D., Alexander
V. Tielbeek, M.D., Ph.D., Heleen M. den Hertog, M.D., Ph.D., Dick G. Gerrits, M.D., Renske M. van den Berg-Vos, M.D., Ph.D.,
Giorgos B. Karas, M.D., Ewout W. Steyerberg, M.D., Ph.D., H. Zwenneke Flach, M.D., Henk A. Marquering, Ph.D., Marieke E.S.
Sprengers, M.D., Ph.D., Sjoerd F.M. Jenniskens, M.D., Ph.D., Ludo F.M. Beenen, M.D., René van den Berg, M.D., Ph.D., Peter J.
Koudstaal, M.D., Ph.D., Wim H. van Zwam, M.D., Ph.D., Yvo B.W.E.M. Roos, M.D., Ph.D., Aad van der Lugt, M.D., Ph.D., Robert
J. van Oostenbrugge, M.D., Ph.D., Charles B.L.M. Majoie, M.D., Ph.D., and Diederik W.J. Dippel, M.D., Ph.D. for the MR CLEAN
Investigators
• N Engl J Med 2015; 372:11-20January 1, 2015DOI: 10.1056/NEJMoa1411587

Unmet Material Needs May Lead To Poor Diabetes Control
Seth A. Berkowitz, MD, MPH
Division of General Internal Medicine
Massachusetts General Hospital, Boston
Dr. Berkowitz: Prior studies had looked the association between single unmet basic material needs
and diabetes control, but hadn’t necessarily looked at multiple things people may not be able to
afford, which more closely mirrors real-life. Also, prior studies had been done in a ‘pre-Affordable
Care Act’ setting, while, by being in Massachusetts, our study was conducted in a setting of near-
universal healthcare coverage that is similar to what the rest of the US is moving towards. We found
that difficulties meeting basic material needs, such as difficulties affording food, known as food
insecurity, and having financial barriers to taking medications, called cost-related medication
underuse, are associated with worse diabetes control and increased use of costly health services in
diabetes patients, despite near-universal health insurance coverage
• Dr. Berkowitz: Historically, patients come in for office visits or hospitalizations, but the majority of
their time, the majority of the time that determines their health, is spent outside the healthcare
system. Healthcare systems are increasingly being held accountable for health outcomes, but these
outcomes may be determined by situations that most healthcare systems have limited experience
in dealing with. This study, and the body of literature on what are sometimes called ‘social
determinants of health’ suggest that simply increasing access to healthcare that does not address
root causes of illness may be missing a big piece of what patients need to stay healthy and manage
their illnesses. Despite insurance coverage, unmet basic needs were common, associated with
worse diabetes control, and high use of expensive health services. If we do not try to address these
needs specifically, we may make little progress in improving health for vulnerable diabetes patients.

Unmet Material Needs May Lead To Poor Diabetes Control
Seth A. Berkowitz, MD, MPH
Division of General Internal Medicine
Massachusetts General Hospital, Boston
this study?
• Dr. Berkowitz: Because healthcare systems often have little experience in helping patients
meet material needs, there is a lot we still don’t know.
• First and foremost, we don’t actually know whether helping patients meet material needs
will improve their health. We think it should, but this needs to be tested.
• Secondly, we need to determine what approaches work best–linking patients with existing
community resources, more generous prescription drug coverage, providing nutritious food,
etc. Also, we need to know who can do this effectively and efficiently–a community health
worker, a resource specialist within a clinic, a case manager?
• Citation:
• Berkowitz SA, Meigs JB, DeWalt D, et al. Material Need Insecurities, Control of Diabetes
Mellitus, and Use of Health Care Resources: Results of the Measuring Economic Insecurity in
Diabetes Study. JAMA Intern Med. Published online December 29, 2014.
doi:10.1001/jamainternmed.2014.6888.

Non-Small Cell Lung Cancer: Stereotactic Radiation Plus Chemo Improved Survival
Dr. Puneeth Iyengar, MD, PhD.
Assistant Professor Director of Clinical Research
Dept of Radiation Oncology Co-leader, Thoracic Disease Oriented Team Harold Simmons Cancer Center
UT Southwestern Medical Center Dallas, TZ
• Response: Stage IV Non-small cell lung cancer (NSCLC) remains a disease of limited survival, in the range of
one year for a majority of patients who historically have gone on to receive systemic therapy only. Disease
in this patient population most often recurs in the sites of original gross disease. With greater
understanding of the biology and patterns of failure that occur in stage IV NSCLC, it is becomingly
increasingly obvious that there are subsets of patients, those with limited sites of metastatic disease, who
may benefit with more aggressive local therapy in addition to systemic agents to effectuate longer
progression free survival (PFS) and potentially overall survival (OS). Since failures of treatment occur most
commonly in original gross deposits, local non-invasive therapy in the form of stereotactic body radiation
therapy (SBRT) may offer a means to curtail the recurrences, perhaps as a way to shift the time to and
patterns of failure.
• To address these concepts, a multi institutional single arm phase II study was conducted at UT
Southwestern Medical Center in Dallas and University of Colorado Medical Center. Twenty-four patients
with limited metastatic NSCLC (fewer than or equal to six sites of disease including the primary) who had
progressed through at least one systemic therapy regimen were treated with SBRT to all sites of gross
disease and the EGFR inhibitor erlotinib with progression free survival the primary end point. The results
of the study were very significant, with a PFS in this study cohort of 14.7 months, compared to historical
ranges of 2-4 months, and an OS of 20.4 months, compared to historical ranges of 6-9 months for this
same patient population. The SBRT treatments were found to be very safe and efficacious– only 3 out of
47 measurable lesions irradiated recurred with a concomitant shift in failure patterns from local to distant
sites. As importantly, EGFR status was evaluated in 13 patient tumors, with none harboring the most
common mutations. One could, therefore, predict that with a mutation enriched population, the
combination of EGFR inhibitor and SBRT may have offered even greater PFS and OS benefits. Our
observations also suggest that the SBRT treatments probably contributed the most to the dramatic PFS
and OS outcomes.
• These findings were published in the Journal of Clinical Oncology in the December 1, 2014 print issue with
an accompanying editorial.

Non-Small Cell Lung Cancer: Stereotactic Radiation Plus Chemo Improved Survival
Dr. Puneeth Iyengar, MD, PhD.
Assistant Professor Director of Clinical Research
Dept of Radiation Oncology Co-leader, Thoracic Disease Oriented Team Harold Simmons Cancer Center
UT Southwestern Medical Center Dallas, TZ
• Medical Research: What should clinicians and patients take away from your report? What
recommendations do you have for future research as a result of this study?
• Response: Non-invasive local treatments like stereotactic body radiation therapy may have a
significant role in altering the stage IV NSCLC disease course by offering hope for better PFS and
even potentially OS outcomes. SBRT in our study was able to delay time to progression when
compared to historical findings and was also able to change patterns of failure, from local to distant
sites. Ultimately, stereotactic body radiation therapy may offer a very important therapeutic
contribution to the overall management of limited metastatic NSCLC patients.
• Our group has proposed a larger study, a phase II randomized trial, that hopes to compare SBRT
used after first line therapy plus sequential maintenance therapy versus maintenance therapy alone
for limited metastatic NSCLC patients. Similar trials have begun in Europe, suggesting a widespread
effort to determine how beneficial local therapies, in the form of SBRT, may be to the metastatic
disease state.
• Citation:
• Phase II Trial of Stereotactic Body Radiation Therapy Combined With Erlotinib for Patients With
Limited but Progressive Metastatic Non-Small-Cell Lung Cancer
• Puneeth Iyengar, Brian D. Kavanagh, Zabi Wardak, Irma Smith, Chul Ahn, David E. Gerber, Jonathan
Dowell, Randall Hughes, Ramzi Abdulrahman, D. Ross Camidge, Laurie E. Gaspar, Robert C. Doebele,
Paul A. Bunn, Hak Choy, and Robert Timmerman
• JCO Dec 1, 2014:3824-3830; published online on October 27, 2014;

Collagen Target May Lead To Treatment Of Wounds, Wrinkles and Fragile Skin
David Granville, BSc, PhD, FAHA
Professor, University of British Columbia
Scholar of the Royal Society of Canada
Director, GEM Facility, Centre for Heart Lung Innovation, St. Paul’s Hospital Founder and CSO, viDA Therapeutics, Inc.
• Dr. Granville: My background is in cardiovascular research. In particular, how age affects blood vessels and
how age affects mechanisms of blood vessel and heart injury and repair. We became interested in skin
aging during a study in which we were studying the role of a protein degrading enzyme known as
Granzyme B in atherosclerosis (hardening of the arteries) and aging. In these studies, we were using a
genetic mouse model that is prone to accelerated aging, and knocked out Granzyme B. Although we were
initially focused on the blood vessels, we also found that Granzyme B-deficient mice exhibited younger-
looking skin. As we started to look into this, we became aware that UV light can induce the skin cells to
produce Granzyme B. As sunlight is believed to be responsible for 80-90% of preventable skin aging, we
generated a solar-simulated light box (with the similar ratios of UVA/UVB to sunlight) to assess
whether Granzyme B played a role in UV-induced skin aging (aka photoaging). We exposed the mice to
repetitive, low dose UV three times per week for 20 weeks. After 20 weeks we observed that Granzyme B
deficient mice exhibited fewer wrinkles. We then wanted to look histologically and biochemically into how
Granzyme B was affecting skin morphology. Granzyme B deficient mice exhibited greater collagen density
compared to mice that possessed Granzyme B. As we looked into the mechanism in more detail, we
determined that Granzyme B was cleaving a protein known as decorin. Decorin is responsible for collagen
fibrillogenesis and assembling collagen into tight bundles. Loss of decorin is associated with a loss of
collagen tensile strength. Interestingly, decorin also protects collagen from destruction by a protein-
degrading enzyme known as MMP1. We showed in the study that by breaking downdecorin, Granzyme B
renders collagen susceptible to MMP1-mediated degradation. In addition, we showed that Granzyme B-
fragmentation of another protein, fibronectin, led to the upregulation of MMP1 in skin fibroblasts. In
summary, the paper showed that UV induced Granzyme B expression in the skin and showed that this
enzyme contributes to the breakdown of extracellular matrix proteins and formation of wrinkles.
• A link to the Aging Cell publication: http://onlinelibrary.wiley.com/doi/10.1111/acel.12298/pdf

• Dr. Granville: While the media and public tend to focus on the perhaps the most obvious
cosmetic implications of our findings, we believe Granzyme B plays a pathologic role (ie.
clinically) in the skin in the impairment of tissue injury and repair. By preventing Granzyme B
our work suggests that we can improve tissue repair/remodelling and increase the integrity
and tensile strength of skin. This could have large implications with respect to skin thinning
and skin tearing that is highly prevalent in the elderly and long-term care facilities. Our
prior studies also suggest a role in chronic wound healing (ie. diabetic wound healing,
pressure ulcers/bed sores). I am also working with viDA Therapeutics to develop Granzyme B
inhibitors for topical applications. Granzyme B is highly elevated in a number of autoimmune
skin conditions. One in particular that we are quite excited about is discoid lupus
erythematosus (DLE). Granzyme B is abundant in DLE. Given DLE is often induced and/or
promoted by sunlight and involves scarring, hair loss, microvascular damage and other
features where we know Granzyme B plays a role, we believe there is a high liklihood that we
could modify/reduce the formation of scarring in these patients. viDA is anticipating clinical
trials to commence by the end of 2016.

this study?
• Dr. Granville: Obviously avoidance of sunlight is the best way to prevent skin aging/damage,
but sometimes it is unavoidable. Likewise, we also have evidence that repetitive exposure to
smoking can induce the expression of Granzyme B. Our future research is focused on further
validating Granzyme B as a therapeutic target and developing drugs to prevent skin damage
and restore skin (and other tissue) integrity.
• Citation:
• Parkinson, L. G., Toro, A., Zhao, H., Brown, K., Tebbutt, S. J. and Granville, D. J. (2014),
Granzyme B mediates both direct and indirect cleavage of extracellular matrix in skin after
chronic low-dose ultraviolet light irradiation. Aging Cell. doi: 10.1111/acel.12298

Structure of EV-D68 Common Respiratory Virus Delineated
Michael G. Rossmann PhD
Hanley Professor of Biological Sciences Hockmeyer Hall of Structural Biology
Purdue University, West Lafayette IN
Dr. Rossmann: My laboratory has long been interested in the structure of viruses and especially of
Picornaviruses (e.g. EV-D68). We published the first 3D, near atomic resolution map of any animal
virus in 1985. That was of Human Rhino (common cold) virus serotype 14. We then went on to
show where and how the virus would bind to cellular receptors and also how certain small capsid
binding compounds inhibited the viral infectivity. The latter was a collaboration first with the
Sterling Winthrop company and later with ViroPharma. Thus our work on EV-D68 is a direct
continuation of my interest in picornaviruses.
• Dr. Rossmann: The pleconaril compound (or derivatives of it) that we (in collaboration with
ViroPharma) developed against common cold viruses is likely to be an effective inhibitor of EV-D68,
the causative agent of childhood respiratory sickness.
study?
• Dr. Rossmann: Structural and functional analyses of recent isolates of the virus.
• Citation:
• Structure and inhibition of EV-D68, a virus that causes respiratory illness in children
Yue Liu, Ju Sheng, Andrei Fokine, Geng Meng, Woong-Hee Shin, Feng Long, Richard J. Kuhn, Daisuke
Kihara, and Michael G. Rossmann
Science 2 January 2015: 347 (6217), 71-74. [DOI:10.1126/science.1261962]

Risk of Breast Cancer in Women With Atypical Hyperplasia Better Defined
Dr. Lynn C. Hartmann MD
Professor of Oncology, Mayo Clinic
Associate Director for Education of the Mayo Clinic Cancer Center.
Dr. Hartmann: Women with atypical hyperplasia of the breast – which is defined via breast
biopsy that was done to evaluate findings on a mammogram or a palpable concern – have
been considered a “high risk” group of women, but the extent of their risk has not been
clearly defined. As a consequence, practice guidelines for high-risk women (eg for screening
MRI) do not include them. Mayo Clinic has developed a cohort of women with atypical
hyperplasia who have been followed long-term for later breast cancers and we show that
their risk of developing breast cancer is about 30% at 25 years of follow-up. This same level
of risk was confirmed in the other large cohort of women with atypical hyperplasia, based at
Vanderbilt University (Nashville Breast Cohort). This level of risk meets the current criterion
for screening MRI and should also encourage the use of anti-estrogen drugs, such as
tamoxifen, which have already been shown to be efficacious in this population of women.

• Dr. Hartmann: There are about 100,000 US women each year diagnosed with atypical hyperplasia
via breast biopsy. Although strictly speaking, atypical hyperplasia is a benign finding, it is associated
with a sizable risk of a later breast cancer. Physicians from numerous disciplines care for women
with high-risk benign breast issues, including gynecologists, family physicians, internists, surgeons
and oncologists. These practitioners, and the patients themselves, need information about the
absolute risk of breast cancer occurring over time after a diagnosis of atypical hyperplasia. This
information is provided in the NEJM report. Also, current guidelines should be updated to include
this high-risk population and specifics about their absolute risk, and that the risk level qualifies
these patients for screening MRI.
• Moreover, from the standpoint of risk reduction, four previously conducted breast cancer
prevention trials included women with atypical hyperplasia. These trials used hormonal therapies
(anti-estrogens) and showed that, in women with atypical hyperplasia, the use of such medications
could lower the risk of a later breast cancer by 50% or more. Yet, other research has shown that
women are quite reluctant to take such medications, primarily because of fear of side effects. In
the NEJM report, we detail specific numbers of side effects that actually occurred in women who
used these anti-estrogens (as opposed to the number of side effects seen in women taking placebo)
and show that most of the side effects occurred quite uncommonly. Thus, we hope that the
combination of information provided in this report on (i) actual risks of breast cancer and (ii) actual
risks of side effects will help patients and practitioners make informed decisions on the best
treatment approaches for women with atypical hyperplasia.

this study?
• Dr. Hartmann: First, women with atypical hyperplasia should be included in future
prospective trials of novel imaging strategies (they were not included in trials of MRI, which
had been limited to women with hereditary risk).
• Second, efforts should continue to predict which women with atypical hyperplasia are at
highest risk, especially in the first 5-10 years after their biopsy, so they can be cared for
optimally. Our research team, and others, continue to study the underlying molecular
pathways that drive the progression from atypical hyperplasia to cancer; identifying such
processes would not only aid in risk prediction but also identify driving pathways that could
be blocked pharmaceutically.
• Citation:
Lynn C. Hartmann, Amy C. Degnim, Richard J. Santen, William D. Dupont, Karthik Ghosh.
Atypical Hyperplasia of the Breast — Risk Assessment and Management Options. New
England Journal of Medicine, 2015; 372 (1): 78 DOI: 10.1056/NEJMsr1407164

COPD: Most Hospital Readmissions Not Due To COPD
Tina Shah, MD University of Chicago Medicine
Department of Pulmonary and Critical Care
University of Chicago
• Dr. Shah: The reason why we undertook this study is to better understand the Medicare
COPD population that falls under the purview of the CMS Hospital Readmissions Reduction
Program (HRRP). This program places up to a 3% penalty on all Medicare revenues for
hospitals that take care of beneficiaries should a hospital exceed its “expected readmission
rate.” Previously 30 day readmissions after index admissions for congestive heart failure,
acute myocardial infarction and pneumonia fell subject to the HRRP. As of October 2014,
COPD has been added to the list, despite minimal evidence to guide hospitals in how to curb
COPD readmissions. The goal of this research was to provide an epidemiological background
for this population and identify trends as a hypothesis generating first step to predict who is
most likely to be readmitted and to identify targets for successful future interventions on this
group. Our study population is unique in that we longitudinally look at about 1/2 of all
Medicare admissions for COPD exacerbations, using the CMS guideline definition which is
based on discharge ICD-9 codes. As described in previous literature, there is a large
discrepancy between identification of COPD by provider versus coding algorithm, however
since the Hospital Readmissions Reduction Program is based on discharge coding it is
important to examine this particular group.

COPD: Most Hospital Readmissions Not Due To COPD
Tina Shah, MD University of Chicago Medicine
Department of Pulmonary and Critical Care
University of Chicago
• Dr. Shah: Our paper has 3 main findings:
• First, Although COPD was the leading cause of rehospitalization within 30 days of an initial index
admission, the majority of readmissions were not due to COPD and include a wide array of reasons.
• Second, patients who used post-acute care, including home care and skilled nursing facilities were
readmitted for different reasons than those who were discharged to home.
• Third, patients who were readmitted were likely to be dually eligible for Medicare and Medicaid,
posing the potential for a disproportionately high penalty on hospitals who care for a large
percentage of patients who are generally sicker, poorer and have less community access to health
resources. This finding adds to the growing concern in other literature about the lack of
standardization by socioeconomic status in the current penalty.
• The application of this study’s findings for clinicians and patients is a better understanding of the
patient related factors including dual eligibility status that are associated with a higher risk of
readmission and to take a closer look at the use and appropriate triage of patients to levels of care
upon discharge. Our study highlights a need for research looking into the role of post acute care on
readmissions, a next area of investigation that our research group is undertaking.
• Citation:
• Understanding why copd patients get readmitted: a large national study to delineate the medicare
population for the readmissions penalty expansion
• Published online December 24, 2014.
Shah T, Churpek MM, Coca Perraillon M, Konetzka R.
• doi:10.1378/chest.14-2181.

Cholera Bacteria Kills Neighbors To Acquire Antibiotic Resistance Genes
Melanie Blokesch PhD Assistant Professor (tenure-track)
Laboratory of Molecular MicrobiologyGlobal Health Institute, School of Life Sciences
Swiss Federal Institute of Technology Lausanne (EPFL) Lausanne Switzerland
• Dr. Blokesch: We have been studying the cholera-causing bacterium Vibrio cholerae for many years
in my laboratory. Our main focus has always been on elucidating how this pathogen acquires new
genetic material that allows it to evolve. This is often accomplished through a mechanism known as
horizontal gene transfer (HGT). There are three main modes of horizontal gene transfer in bacteria
and the one we are primarily interested in is called natural competence for transformation. When
the bacterium enters the state of natural competence it can take up free genetic material from its
surrounding and in case it recombines this new material into its own genome the bacterium is
considered to be naturally transformed. Notably, natural competence/transformation was first
described in 1928 by Fred Griffith, who showed that transformation can render harmless bacteria
pathogenic. These early experiments can be considered a milestone in molecular biology as it later
led to the discovery of DNA as the carrier of genetic information.
Dr. Blokesch: The main finding of our study is that the pathogen V. cholerae does not solely rely on
free DNA floating around but that it actively kills neighbouring bacteria followed by the uptake of
their DNA. Indeed, we were able to show that the two processes – killing of other bacteria and DNA
uptake – are co-regulated by the same proteins within the bacterial cell. We also used imaging
techniques to visualize the killing of other bacteria by V. cholerae, followed by the release of their
genetic material, which the predator then pulled into its own cell. We further quantified these HGT
events by following the transfer of an antibiotic resistance gene from the killed bacterium to the
predatory V. cholerae cell. Notably, the spread of antibiotic resistances is a major health concern
and HGT is a major driver of it.

• Dr. Blokesch: There is still a long way to go until we fully understand this process and can act
accordingly. However, another important finding of our study was that the killing device (and
the DNA uptake machinery) was triggered by a natural polysaccharide, chitin, which is the
most abundant polymer in aquatic environments (e.g, it makes up the shell/exoskeleton of
small crustaceans). Indeed, V. cholerae is a natural inhabitant of such environments and is
therefore primarily transmitted to humans by contaminated water. It is tempting to speculate
that the bacterium’s association with chitinous surfaces followed by the production of the
killing device could render the bacteria more pathogenic when ingested by humans as it
could kill the protective commensal bacteria in the human gut. Therefore, filtration methods
that remove larger (chitinous) particles might be a good way to at least partially protect
people from cholera infections. Indeed, such filtration studies have been performed by Rita
Colwell (University of Maryland) and her collaborators in rural villages of Bangladesh. The
scientists reported that folding sari cloth a few times followed by the filtration of water
through them could remove V. cholerae bacteria attached to particles and significantly lower
the number of cholera patients in this endemic area.

this study?
• Dr. Blokesch: There is so much we don’t know yet about the causative agent of cholera even
though the disease itself has been extensively studied over the last 100 years. Thus, in the
future we and probably also others will focus on elucidating the environmental lifestyle of
the pathogen. This will allow us to acquire new insights into cholera transmission and to
better understand how an innocuous aquatic bacterium evolved towards being a dangerous
human pathogen.
• Citation:
• The type VI secretion system of Vibrio cholerae fosters horizontal gene transfer
Sandrine Borgeaud, Lisa C. Metzger, Tiziana Scrignari, Melanie Blokesch
Science 2 January 2015:
Vol. 347 no. 6217 pp. 63-67
DOI: 10.1126/science.126006

Healthy Lifestyle, Not Supplements, Linked to Longevity
Annlia Paganini Hill PhD
Project Scientist Biostatistician and Epidemiologist
Department of Neurology, School of Medicine University of California, Irvine, Irvine, California
• Response: Free radicals are formed when one exercises and when the body converts food to
energy. Environmental sources (e.g. smoke, air pollution, sunlight) also expose the body to free
radicals. Free radicals can cause “oxidative stress” and damage cells. Oxidative stress is thought to
play a role in a variety of diseases: cancer, cardiovascular disease, diabetes, Alzheimer’s disease,
Parkinson’s disease, cataracts, and age-related macular degeneration.
• Antioxidants are man-made or natural substances that may prevent or delay some types of cell
damage. Antioxidants are found in many foods and are also available as dietary supplements.
Vegetables and fruits are rich sources of antioxidants. There is good scientific evidence that eating a
diet with lots of vegetables and fruits is healthful and lowers risks of certain diseases. However, it is
unclear whether this is because of the antioxidants, something else in these foods, other foods in
people’s diet, or other lifestyle choices.
• While antioxidants have been shown to counteract oxidative stress in cells and animal
studies, whether consuming large amounts of antioxidant supplements benefits human health is
debated. Given the continued use of vitamin supplements by a large proportion of the population
and the presumed safety of antioxidant supplementation, we assessed the relationship between
antioxidant vitamin intake and all-cause mortality in older adults.
• We examined these associations using data from the Leisure World Cohort Study, a study of nearly
14,000 residents of a California retirement community. In the early 1980s, participants (median
age, 74 years) reported details on use of vitamin supplements and dietary intake of foods
containing vitamins A and C. During followup (1981-2013), over 93% of participants had died
(median age at death, 88 years).

• Response: Previously, we had found that a number of factors were associated with lower risk
of death in our cohort — not smoking, physical activity, moderate alcohol consumption,
caffeine intake, ideal body mass index (neither too fat nor too thin), and no history of high
blood pressure, angina, heart attack, stroke, diabetes, rheumatoid arthritis, or cancer .
• Neither dietary nor supplemental intake of vitamins A, C or E were significantly associated
with reduced mortality in this study once these other lifestyle behaviors and disease
conditions were taken into account.
• In Leisure World Cohort and in the general population, health-promoting habits often cluster;
e.g. those who take vitamin supplements often exercise, do not smoke, and are not obese.
Thus, these factors explain the observed association between longevity and vitamin
supplements in our and previous studies.

• Response: Antioxidant supplements should not be used to replace a nutritionally adequate
diet. A healthful diet characterized by high amounts of fruits and vegetables, whole grains,
and fish should be recommended to avoid nutritional deficiencies and to prevent chronic
disease.
• Additionally, other studies have shown that high-dose antioxidant supplements may even be
harmful (increased risks of prostate cancer, hemorrhagic stroke, and lung cancer in smokers).
And because antioxidant supplement may interact with other medications, use of
supplements should be discussed with a health care provider.
• Citation:
• Antioxidant Vitamin Intake and Mortality: The Leisure World Cohort Study.
• Paganini-Hill A, Kawas CH, Corrada MM.
Am J Epidemiol. 2014 Dec 29. pii: kwu294. [Epub ahead of print]

Adenocarcinoma of Lung May Spread Through Airways
MedicalResearch.com Interview with: Joao R. Inacio, MD
Cardiothoracic Radiologist Director Visiting Professor Program
Assistant Professor of Radiology, University of Ottawa
Medical Imaging, The Ottawa Hospital Ottawa, ON
Dr. Inacio: Lung cancer is the most common and most lethal cancer worldwide. Its prognosis
remains poor with a 5-year survival rate of 6–18%. Adenocarcinoma has surpassed squamous
cell carcinoma as the leading histologic type. The presence of metastases carries the worst
prognosis in lung cancer and is the most important in determining staging and management.
Hematogenous spread (i.e., carried by blood) is the most common mechanism of
intrapulmonary metastasis. Cumulative evidence suggests that intrapulmonary aerogenous
spread may exist and is under recognized.
• Deriving from our clinical experience, we performed a literature review that supports the
hypothesis that lung cancer, particularly adenocarcinoma, may spread through the airways.
With aerogenous metastases, it has been postulated that cancer cells growing along the
alveolar septa at the primary site detach from the basal membrane, spread through the
airways and re-attach and grow along alveolar septa away from the primary focus.
• Radiology-pathology correlation studies, using Chest Computed Tomography (CT), have
documented the radiological evolution from focal adenocarcinoma to multifocal airspace
disease and demonstrated cytologic and histologic findings supportive of aerogenous spread.

• Dr. Inacio: The putative occurrence of intrapulmonary aerogenous metastasis of lung cancer
has staging, management, and prognostic implications.
• This phenomenon has been described in primary lung adenocarcinoma, particularly those
with invasive mucinous, papillary and micro-papillary subtypes.
• There are CT features that are suggestive of aerogenous spread, specifically persistent
centrilobular nodules and branching opacities (tree-in-bud nodules). Nodules tend to be
clustered and invariably grow on serial imaging, in some cases progressing to confluent
airspace disease. When these features are found remote from a dominant lung lesion proven
to be an adenocarcinoma, and/or in patients with a prior history of treated lung
adenocarcinoma, intrapulmonary aerogenous spread should be suspected.
• Importantly, aerogenous metastases must be distinguished from multiple synchronous
lesions in the spectrum of lung adenocarcinoma. A multidisciplinary approach, including
clinicians, radiologists, thoracic surgeons, pathologists and geneticists is required to guide
diagnosis and treatment in these cases. Genomic profiling may be beneficial in the future to
prove monoclonality when aerogenous metastases are suspected.

this study?
• Dr. Inacio: There is a need for prospective studies combining imaging, pathology and
molecular studies to confirm the presence of this phenomenon and elucidate its impact on
the prognosis of lung cancer patients.
• Future therapies might attempt to address some of the unique aspects of aerogenous
dissemination. For instance, drugs targeting mechanisms involved in cancer cell shedding,
anchorage-independent survival, and re-attachment in distant alveoli may hold promise. One
could hypothesize inhalational therapy as a potential treatment to target the intra-alveolar
nature of aerogenous metastases. K-Ras mutations and infiltration of tumor tissue by
macrophages and neutrophils have been implicated in the pathogenesis of mucinous
adenocarcinoma and aerogenous metastases. Pharmacologic agents modulating K-Ras
activation and tumor-associated leukocyte interaction could prove beneficial in the
prevention of aerogenous spread.
• Citation:
• Anand Gaikwad, Carolina A. Souza, Joao R. Inacio, Ashish Gupta, Harmanjatinder S. Sekhon,
Jean M. Seely, Carole Dennie, Marcio M. Gomes. Aerogenous Metastases: A Potential Game
Changer in the Diagnosis and Management of Primary Lung Adenocarcinoma. American
Journal of Roentgenology, 2014; 203 (6): W570 DOI: 10.2214/AJR.13.12088

Y Chromosome Mutation Can Lead To Sex Reversal and Cancer
Michael A. Weiss, MD, PhD and Joseph Racca
Case Western Reserve School of Medicine in Cleveland, Ohio.
Response: The function of the gene responsible for male differentiation, sex-determining region of the Y
chromosome (SRY), was first demonstrated in transgenic mouse models by P. Koopman, R. Lovell-Badge
and colleagues in the early 1990s. These findings were corroborated by identification of mutations in
human SRY that are associated with human sex reversal: XY, 46 gonadal dysgenesis leading to somatic sex
reversal (Swyer’s Syndrome). Such mutations may occur spontaneously in spermatogenesis or be
inherited. The characterization of the molecular defects associated with these mutations has unmasked
novel biological and biochemical activities of SRY. More broadly, such studies have also increased our
understanding of an entire family of related transcription factors (Sry-box related; SOX), which broadly
function in metazoan development (from worms, fish and flies to mammals). Within human SRY, the
majority of clinical mutations occur in the region of the protein responsible for specific DNA binding and
DNA bending, the primary molecular actions of SRY at target genes. Our study bridges structure (i.e.,
protein folding and stability) and function (i.e., transcriptional activation of target genes and related cell-
biological processes such as trafficking and proteosomal degradation).
• In our current study, we highlighted the importance of a structural scaffold in human SRY, specifically a key
single amino acid that buttresses the unique L-shape structure of this domain. The mutation of interest
represents a “perfect storm” leading to deleterious effects on multiple activities, including specific DNA
binding, cellular localization, and both protein and cellular stability (lifetime), among other properties,
together leading to sex reversal and cancer (gonadoblastoma) in the proband patient. Our integrated
multi-disciplinary approach allowed us to characterize these various facets of SRY in the context of its
biological site of action: the pre-Sertoli cell in an embryonic gonadal ridge just prior to its morphological
differentiation into a testis. We are grateful to Prof. Patricia K. Donahoe (Harvard Medical School and the
Massachusetts General Hospital), who generously provided this micro-dissected pre-Sertoli cell line.

• Response: Mutations in SRY associated with sex reversal may coincide with the formation of
gonadoblastoma, pediatric malignancy containing a solid mass of undifferentiated cells types.
• Although patients harboring mutations in SRY may exhibit a continuum of phenotypes, all XY
sex-reversed females are sterile. The XY gonads are intra-abdominal, scarred and prone to
cancer. On microscopic examination, such gonads lack differentiated features of either testes
or ovaries. In childhood, such patients will otherwise grow normally as girls. At the onset of
puberty, however, the XY child will not begin to have periods (“primary amenorrhea”); pubic
hair and breast development is typically within the normal range.
• An important aspect of this study is the use of an integrated approach to probe the molecular
functions of SRY. Due to the location of this mutation (within the DNA-binding domain), it
might have been annotated as simply a DNA binding defect. Such a domain-based annotation
would have missed the “perfect storm” of perturbations to the cellular biochemistry of the
protein and general biophysical importance of the general aromatic-buttress motif in the
overall SOX family of transcription factors. Our integrated and multi-disciplinary approach
revealed multiple facets of structure and function. The editors of The Journal of Biological
Chemistry highlighted this study as a “Paper of the Week” in light of such beautiful facets: the
findings highlight the utility of clinical mutations as key “experiment of nature” to probe the
subtle inter-relation of structure, function and phenotype that underlies developmental gene
regulation.

this study?
• Response: As previously mentioned, this location of this mutation is within the DNA binding
and bending region of human SRY and this region also harbors the majority of sex reversal
mutations. What this particular mutation taught was that these mutations are “nature-
designed” probes for structure-functions studies. Furthermore, we have undertaken studies
of inherited mutations to study how subtle defects in SRY can lead to two different
developmental outcomes. Our ongoing studies of candidate SRY mutations are providing
molecular insights into mechanistic details of how this protein functions as a switch in
development. Also, our over-arching general concepts will (with regard to specific DNA
binding and bending and conserved cellular functions), as we believe, relate to the entire
family of related transcription factors.
• Citation:
• Structure-Function Relationships in Human Testis-determining Factor SRY: AN AROMATIC
BUTTRESS UNDERLIES THE SPECIFIC DNA-BENDING SURFACE OF A HIGH MOBILITY GROUP
(HMG) BOX
Joseph D. Racca, Yen-Shan Chen, James D. Maloy, Nalinda Wickramasinghe, Nelson B. Phillips,
and Michael A. Weiss Biol. Chem. 2014 289: 32410-32429. First Published on September 24,
2014, doi:10.1074/jbc.M114.597526

Whole Grains Linked To Lower Cardiac and Overall Mortality
MedicalResearch.com Interview with: Qi Sun, MD ScD
Assistant Professor of Medicine Channing Division of Network Medicine
Brigham and Women’s Hospital and Harvard Medical School, Assistant Professor, Department of Nutrition
Harvard School of Public Health Boston, MA 02115
Dr. Sun: While we know whole grains are beneficial for reducing the risk of some major chronic
diseases, such as heart disease and diabetes, evidence regarding whether whole grains are also
able to lower mortality is sparse. We therefore want to answer this important research question in
the current analysis. Using data collected from two prospective cohort studies consisted of more
than 100 thousand US men and women, we found that whole grain intake was significantly
associated with lower total mortality and lower cardiovascular mortality, but not cancer mortality.
For every serving (28 grams) of whole grain intake per day, the total mortality is reduced by 5% and
cardiovascular mortality by 9%.
• Dr. Sun: Whole grains should be recommended to replace refined carbohydrate, such as white
bread, white rice, and sugar-sweetened beverages, to help lower the risk of developing heart
disease, diabetes, and premature death.
study?
• Dr. Sun: Future research may focus on understanding the mechanisms, especially the active
ingredients in whole grains, that account for the beneficial effects of whole grains. In addition, we
need to understand whether whole grain consumption can especially benefit people with certain
characteristics, including genetic susceptibility and other risk profiles.
• Citation:
• Wu H, Flint AJ, Qi Q, et al. Association Between Dietary Whole Grain Intake and Risk of Mortality:
Two Large Prospective Studies in US Men and Women. JAMA Intern Med. Published online January
05, 2015. doi:10.1001/jamainternmed.2014.6283.

No Link Between HPV Vaccine and Multiple Sclerosis
Anders Hviid, M.Sc., Dr.Med.Sci.
Senior Investigator, Statens Serum Institut
• Medical Research: What is the background for this study?
Response: After the widespread introduction of HPV vaccination of adolescent girls, a number of
safety concerns have emerged. In this case, demyelinating diseases, including multiple sclerosis,
occurring after HPV vaccination has been reported in social media, news media and medical
journals.
• Response: In a study of almost 4 million Danish and Swedish women, we found no support for an
increased risk of multiple sclerosis or other demyelinating diseases following HPV vaccination.
• Response: In this the largest and most comprehensive study to date, there was no support for this
particular safety concern. The current evidence suggests that clinicians and patients should not fear
demyelinating diseases as a result of HPV vaccination.
study?
• Response: Vaccine safety issues continue to arise. To maintain professional and public trust in
routine immunization programs, it is important to address these issues in a timely manner with
high quality research.
• Citation:
• Langer-Gould A, Qian L, Tartof SY, et al. Vaccines and the Risk of Multiple Sclerosis and Other
Central Nervous System Demyelinating Diseases. JAMA Neurol. 2014;71(12):1506-1513.
doi:10.1001/jamaneurol.2014.2633.
•

Disruptive Gastrointestinal Problems Common In Infants and Toddlers
Miranda van Tilburg, PhD
Associate Professor of Medicine
University of North Carolina
Medical Research: What is the background for this study? What are the main findings?
Dr. van Tilburg: Functional gastrointestinal disorders are common in children, adolescents and
adults but little is known about the prevalence in infants and toddlers. Functional gastrointestinal
disorders in infancy include disorders such as regurgitation, colic, and dyschezia, while functional
gastrointestinal disorders in toddlers include functional constipation, functional diarrhea,
functional dyspepsia, cyclic vomiting, and rumination. Of these disorders only colic and
regurgitation have received much research attention. Prevalence, cause and consequences of
most functional gastrointestinal disorders in infants and toddlers are largely unknown. We set out
to determine the prevalence in the US by asking a representative sample of mothers to report on
their child’s symptoms. Our study found that 27% of infants and toddlers may suffer from a
functional gastrointestinal disorder. Among infants, regurgitation was the most common disorder
and among toddlers constipation. Despite functional gastrointestinal disorders generally being
more prevalent in older girls and adult women, no sex differences were found in this age group.
Toddlers who suffer from a functional gastrointestinal disorders had lower quality of life and
made more health care visits.

Disruptive Gastrointestinal Problems Common In Infants and Toddlers
Miranda van Tilburg, PhD
Associate Professor of Medicine
University of North Carolina
• Dr. van Tilburg: These findings indicate that functional gastrointestinal disorders affect more
than 1 in 4 infants and toddlers, making it one of the most common disorders in this age
group. These disorders have a measurable impact on quality of life and health care visits.
Studying these conditions may improve the lives of a significant number of children.
this study?
• Dr. van Tilburg: These conditions are largely neglected in the scientific literature. For
example in the past 15 year studies scientific publications on functional gastrointestinal
disorders in children and adolescents have increased rapidly and new discoveries have been
made about their causes, consequences and treatment. However, only a handful of studies
focus on these disorders in infants and children. The results of the current study indicate that
any study in these disorders will impact the lives of many children and their families. Given
the paucity in existing research, we need studies on all aspects of these disorders.
• Citation:
• Prevalence of Functional Gastrointestinal Disorders in Infants and Toddlers
Miranda A.L. van Tilburg, PhD Paul E. Hyman, MD Lynne Walker, PhD Audra Rouster, MD
Olafur S. Palsson, PhD Sung Min Kim, BA William E. Whitehead, PhD
The Journal of Pediatrics Available online 31 December 2014

Childhood Molluscum Contagiosum Can Last Up To Two Years
Jonathan Olsen
Institute of Primary Care and Public Health
Cardiff University Heath Park Cardiff
• MedicalResearch: What is the background for this study? What are the main findings?
• Response: Molluscum Contagiosum is a common skin condition in children which has a
prevalence of between 5.1% to 8% in children aged 14 years and under. Strikingly however,
there is little epidemiological evidence describing the natural history, transmission between
family members and impact upon quality of life of molluscum contagiosum. Our research
aimed to address this gap in evidence by conducting a prospective cohort study of UK
children recruited by clinical and self-referral using the validated Molluscum Contagiosum
Diagnostic Tool for Parents (MCDTP).
• We recruited 306 children during 2013 and showed that on average lesions will last for 12
months, however 30% still had lesions at 18 months and 13% still had lesions at 24 months.
Most children experienced only a small effect on their quality of life from the condition,
however 1 in 10 experienced a large or very large impact on their quality of life. The
condition was shown to be highly contagious with further transmission between children
living in the same household as an index case shown in 40%.

Childhood Molluscum Contagiosum Can Last Up To Two Years
Jonathan Olsen
Institute of Primary Care and Public Health
Cardiff University Heath Park Cardiff
• MedicalResearch: What should clinicians and patients take away from your report?
• Response: For most children molluscum contagiosum will have only a small effect on their quality
of life, however children with a greater number of lesions may experience a greater effect on their
quality of life. Parents should be aware that there is risk of transmission to other children living in
the household, however there is little evidence of whether steps can be taken to reduce this risk.
• The idea that molluscum contagiosum is always a benign, trivial illness needs to be challenged.
• MedicalResearch: What recommendations do you have for future research as a result of this
study?
• Response: We recommend that treatment should be considered for children with the condition, in
particular those experiencing a significant impact on their quality of life and with a more severe
episode of the disease (larger number of lesions).
• In first instances a well conducted treatment trial should be conducted to assess the effects of
therapeutic approaches.
• Citation:
• Time to resolution and effect on quality of life of molluscum contagiosum in children in the UK: a
prospective community cohort study
Jonathan R Olsen, MSc Prof John Gallacher, PhD, Prof Andrew Y Finlay, FRCP,
Prof Vincent Piguet, FRCP, Nick A Francis, MRCGP
• The Lancet Infectious Diseases Available online 23 December 2014

Bariatric Surgery Linked To Lower Long Term Mortality
David Arterburn, MD, MPH, FACP Associate Investigator
Group Health Research Institute Seattle, WA 98101 and
David L. Maciejewski PhD Center for Health Services Research in Primary Care
Durham VA Medical Center, Durham, North Carolina
• MedicalResearch.com: Why was this study needed?
• Response: There were several reasons to conduct this study. First, although complications
and death during and soon after bariatric surgery have progressively declined over the past
several decades, there is simply very little long-term evidence on the survival benefits of
bariatric surgery in Americans having surgical procedures that are being used today in routine
practice.
• Second, we felt that it was important to look at the impact of bariatric surgery among
veterans because they represent an older male cohort often with multiple medical
comorbidities, which is different from the typical bariatric patient in the United States, who is
often younger and female.
• MedicalResearch.com: How was your study conducted?
• Response: We conducted a retrospective observational study using high-quality data from
national Department of Veterans Affairs electronic databases and the VA Surgical Quality
Improvement Program. We identified veterans who underwent bariatric surgery in VA
medical centers from 2000 to 2011. Three quarters of them were men. We matched them to
control patients using an algorithm that included age, sex, VA geographic region, body mass
index (BMI), diabetes, and Diagnostic Cost Group. We then compared survival across bariatric
patients and matched controls using Kaplan-Meier estimators and stratified, adjusted Cox
proportional hazards analyses.

Bariatric Surgery Linked To Lower Long Term Mortality
David Arterburn, MD, MPH, FACP Associate Investigator
Group Health Research Institute Seattle, WA 98101 and
David L. Maciejewski PhD Center for Health Services Research in Primary Care
Durham VA Medical Center, Durham, North Carolina
• MedicalResearch.com: What were the main findings of your study?
• Response: This study had three important results:
• 1) Our analysis showed no significant association between bariatric surgery and death
from all causes in the first year of follow-up. In other words, having bariatric surgery was not
significantly related to a veteran’s chance of dying in the first year compared to not having
surgery.
• 2) We had an average follow-up of 6.9 years in the surgical group and 6.6 years in the
matched control group. After one to five years, adjusted analyses showed significantly lower
mortality in the patients who had surgery: 55% lower, with a hazard ratio of 0.45. The finding
was similar at 5 or more years, with a hazard ratio of 0.47. This means that bariatric surgery
was associated with lower long-term mortality – that is, better long-term survival among
veterans, which is consistent with limited non-VA research that has addressed this same
question.
• 3) Finally, we also found that the relationship between surgery and survival were similar
comparing men and women, patients with and without diagnosed diabetes, and patients
who had bariatric surgery before versus after year 2006.

MedicalResearch.com: Medical Research Exclusive Interviews January 7 2014

MedicalResearch.com: Medical Research Exclusive Interviews January 7 2014

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MedicalResearch.com: Medical Research Exclusive Interviews January 7 2014