MedicalResearch.com: Medical Research Exclusive Interviews March 24 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
March 24 2015
For Informational Purposes Only: Not for Specific Medical Advice.

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Understanding Leader Cells In Cell Migration
MedicalResearch.com Interview with:
Dr. Pak Kin Wong Ph.D.
Aerospace& Mechanical Engineering Department Biomedical Engineering and Bio5 Institute
The University of Arizona
• Response: Collective cell migration is central to various (patho)physiological processes, such as
tissue development, regeneration, and cancer metastasis. At the onset of the process, a subset of
cells acquires distinct leader cell phenotypes in the initially homogeneous population and leads the
migration. However, how leader cells are initiated among the initial homogeneous population and
how leader cell density is regulated during collective migration remain unknown. In this study, we
demonstrate the formation of leader cells is regulated dynamically by Dll4 signaling through Notch1
and cellular stress near the leading edge. Our finding provides a molecular basis for the stochastic
emergence of leader cells, a process originally considered random.
• Medical Research: What should clinicians and patients take away from your report?
• Response: Our findings demonstrate the importance of cell-cell coordination and
mechanoregulation in various physiological and pathological processes. The results will have
important implication in various tissue development, regeneration and disease conditions. For
instance, regulating leader cells may lead to novel strategies in engineering tissue constructs,
improve the treatment of non-healing diabetic wounds, and develop novel drug targets for
inhibiting cancer metastasis. In fact, we are currently expanding the work to regulate capillary
morphogenesis, a key requirement in tissue engineering, diabetic wounding and cancer metastasis.
• Citation:
• Notch1–Dll4 signalling and mechanical force regulate leader cell formation during collective cell
migration
Reza Riahi, Jian Sun, Shue Wang, Min Long, Donna D. Zhang & Pak Kin Wong
• Nature Communications 6,Article number: 6556 doi:10.1038/ncomms7556
Published 13 March 2015
Read the rest of the interviews on MedicalResearch.com
Content NOT an endorsement of efficacy and NOT intended as specific medical advice.

Clinicians’ Race and Social Biases Did Not Affect Patient Clinical Care
Dr. Adil Haider, MD, MPH
Kessler Director of the Center for Surgery and Public Health (CSPH)
at Brigham and Women’s Hospital
• Medical Research: What is the background for this study?
• Response: Disparities in the quality of care received by minority and low-income patients
have been reported for years across multiple medical conditions, types of care, and
institutions.
• To determine whether clinicians’ unconscious race and/or social class biases correlated with a
lower quality of care for minority patients and those of lower socioeconomic status, my
colleagues and I conducted a web-based survey among 215 physicians at an academic, level
one trauma center. Participants were asked to review eight clinical vignettes, and then
respond to three questions about management of care after each. Following their response,
a test known as an Implicit Association Test (IAT Test) was used to assess any unconscious
preferences.
• Medical Research: What are the main findings?
• Response: We found that race and class biases, as measured by response time to a
standardized Implicit Association Test, had no relationship to the way that patients were
clinically treated.
• Whether the lack of association found between implicit bias and decision making in this
study represents a true lack of association or the failure of clinical vignettes to capture the
nuances of how implicit biases translate into management decisions remains unclear. Existing
biases might influence the quality of care received by minority patients and those of lower
socioeconomic status in real-life clinical encounters.

• Response: Clinicians should be aware of their own implicit biases, to the extent that it’s
possible, and seek to understand the way that these biases may affect our everyday practice.
One way that we’ve attempted to account for biases is by creating surgical checklists and
other mechanisms to ensure that the care we provide each patient is the same. These
findings could support the effectiveness of these mechanisms, at least in this setting, and
could point to larger systemic factors (insurance, access to care, etc.) as the root cause of
disparities in surgical care.
• Patients should rest assured knowing that researchers are doing our best to understand what
existing unconscious race and social class biases exist, how they affect clinical decision
making, and what can be done to eliminate surgical disparities. Our focus is on providing
research that can then result in policies and procedures to ensure that every patient receives
the best, most person-centered care possible.

• Medical Research: What recommendations do you have for future research as a result of
this study?
• Response: Further research using data from actual clinical interactions is warranted to clarify
the effect of clinician implicit bias on the provision of health care and outcomes.
• Citation:
• Haider AH, Schneider EB, Sriram NN, et al. Unconscious Race and Social Class Bias Among
Acute Care Surgical Clinicians and Clinical Treatment Decisions. JAMA Surg. Published online
March 18, 2015. doi:10.1001/jamasurg.2014.4038.

Successful Long Term Weight Loss May Hinge On Increasing Exercise, Decreasing Alcohol
Sirpa Soini, MHC, researcher
Department of General Practice and Primary Health Care
University of Helsinki
Response: Short-term weight loss is often successful, but he obtained results
are difficult to maintain. Therefore, a study focusing on obese people who successfully lost weight,
with special emphasis upon methods applied and background factors,
is of major importance. Many people are successful in losing weight by
themselves without taking part in any organized group activity. The
knowledge about their success and the methods applied does not usually
reach the health care personnel and is one reason why it is difficult
to get reliable information about those who are successful in losing
weight.
• Medical Research: What is the background for this study? What are the main findings?
• Response: People who were successful in long-term weight loss have a much
healthier lifestyle than the general Finnish population. successful
weight loss is possible in all socio-economic groups. We observed that
long-term results can be achieved despite several previous attempts,
and the majority (68.7%) had previous weight loss attempts in their
history. Compared with the general Finnish population the participants
smoked less (P=0.009), used less alcohol (P≤0.001), and were
physically more active (P≤0.001).
• A total of 158 participants (100 women and 58 men) were included in
the final analyses. The mean age was 44 years,
average BMI before weight loss 35.9 kg/m2 and after weight loss 26.1
kg/m2, average weight loss was 26.5% or 32.4 kg.

Successful Long Term Weight Loss May Hinge On Increasing Exercise, Decreasing Alcohol
Sirpa Soini, MHC, researcher
Department of General Practice and Primary Health Care
University of Helsinki
• Response: People who want achieve long-term weight loss successfully should
decrease alcohol consumption and increase physical activity including
both leisure-time and commuting exercise. Smoking cessation is an
important part of a healthier life style, in this study 40% of
participants had stopped smoked and still succeed in weight loss.
Despite previous unsuccessful attempts people should be encouraged to
try again. There is no one-size fits all methods for successful weight
loss.
this study?
• Response: More in depth analysis focusing upon genetic factors and personality
factors in order to identify what method is most appropriate for whom
should be undertaken.
• Citation:
• Lifestyle-related factors associated with successful weight loss
• Soini S1, Mustajoki P, Eriksson JG.
Ann Med. 2015 Mar 9:1-6. [Epub ahead of print]

Antipsychotic Medications Linked To Higher Mortality In Dementia Patients
Donovan Maust, MD, MS
Assistant Professor of Psychiatry University of Michigan
Research Scientist, Center for Clinical Management Research VA Ann Arbor Healthcare System
Medical Research: What is the background for this study? What are the main findings?
Dr. Maust: From a recent government report, we known that about 1/3 of older adults with
dementia in nursing homes and about 14% of those in the community have been prescribed an
antipsychotic. While providers focus on what benefit the treatment they offer, it is important to
also be aware of the potential harms, particularly when it is death. Prior estimates came from
relatively short studies and showed a 1% increase. This paper finds that, over 180 days, the
increased mortality comparing antipsychotic users to matched non-users is about 2 to 5 times
higher.

• Dr. Maust:
• 1. The decision to prescribe an antipsychotic is associated with higher risk of mortality for
patients with dementia than previously described.
• Among antipsychotics, the risk of use compared to non-use is lowest for quetiapine and
highest for haloperidol.
• Among the atypical antipsychotics, high-dose use (e.g., risperidone >2.5mg/day) is associated
with 3.5% higher mortality than low-dose use (0.13-1.00mg/day). [Please note: this may also
be true for haloperidol, but the dose analysis was limited to the atypical antipsychotics.]

this study?
• Dr. Maust: We would like to learn more about how antipsychotic prescribing practice has
changed over the past decade. Perhaps more importantly, we would like to explore payment
strategies that will allow non-pharmacological interventions to be used more widely in
clinical practice.
• Citation:
• Maust DT, Kim H, Seyfried LS, et al. Antipsychotics, Other Psychotropics, and the Risk of
Death in Patients With Dementia: Number Needed to Harm. JAMA Psychiatry. Published
online March 18, 2015. doi:10.1001/jamapsychiatry.2014.3018.

Sustained Weight Loss Improves Arial Fibrillation Control
Dr Rajeev Kumar Pathak MBBS, FRACP
Cardiologist and Electrophysiology Fellow Centre for Heart Rhythm Disorders | University of Adelaide
Cardiovascular Investigation Unit | Royal Adelaide Hospital Adelaide Australia
Response: Obesity and atrial fibrillation (AF) are dual epidemics that frequently coexist.
Weight-loss reduces atrial fibrillation burden; however, whether this is sustained, has a dose
effect or is influenced by weight-fluctuation is not known. In this study we evaluated
the long-term impact of weight-loss and weight-fluctuation on rhythm control in obese
individuals with atrial fibrillation.
• Response:
• Sustained weight loss is associated with dose dependent reduction in atrial fibrillation burden
and maintenance of sinus rhythm.
• >5% Weight fluctuation dampens the benefit conferred by weight loss.
• A dedicated clinic improves patient engagement, promoting treatment adherence,
preventing weight regain and fluctuation.

Sustained Weight Loss Improves Arial Fibrillation Control
Dr Rajeev Kumar Pathak MBBS, FRACP
Cardiologist and Electrophysiology Fellow Centre for Heart Rhythm Disorders | University of Adelaide
Cardiovascular Investigation Unit | Royal Adelaide Hospital Adelaide Australia
this study?
• Response: A randomised clinical trial is already underway looking at the impact of goal
directed risk factor management on atrial fibrillation burden and ablation. Mechanistic
studies look at the the impact of weight loss on blood pressure, diabetes mellitus and Lipid
profile will be some of the useful studies which should follow.
• Citation:
• Prashanthan Sanders et al. Long-Term Effect of Goal Directed Weight Management in an
Atrial Fibrillation Cohort: A Long-term Follow-Up StudY (LEGACY Study). JACC, March 2015
DOI: 10.1016/j.jacc.2015.03.002

Large Study Evaluates Predictors of Long Term PCI Outcomes
Prof. Ran Kornowski, M.D, FACC, FESC
Chairman – Division of Cardiology, Rabin Medical Center
Petah-Tikva, Israel
• MedicalResearch: What is the background for this study?
• Prof. Kornowski: Over the years, the PCI procedure went-through many progresses. Among
those are some angioplasty techniques, generalize use of stents and drug eluting stents, and
adjuvant novel antithrombotic therapy. Unmistakably, these were associated with an overall
improved PCI outcome. As many of the data on PCIs’ adverse outcomes predictors come from
predates studies, we sought to update this matter.
• MedicalResearch: What are the main findings?
• Prof. Kornowski: This study confirms the influence of advanced age, diabetes-mellitus
and urgent settings (i.e. acute coronary syndromes) on PCI long term outcome. However, we
found that their effect extent is modest while supplementary predictors such as anemia
(even mild), chronic kidney injury and echocardiographic findings of left ventricular
dysfunction have a greater effect on contemporary PCI prognosis.

Large Study Evaluates Predictors of Long Term PCI Outcomes
Prof. Ran Kornowski, M.D, FACC, FESC
Chairman – Division of Cardiology, Rabin Medical Center
Petah-Tikva, Israel
• MedicalResearch: What should clinicians and patients take away from your report?
• Prof. Kornowski: Risk stratification of PCI patients should take account of LV dysfunction,
chronic kidney injury and anemia (even mild), as these factors have stronger association with
adverse outcome than older age and urgent PCI settings. Contemporary drug eluting
stents may provide a sustained benefit and should be used whenever possible.
• Citation:
• Predictors of Long Term Outcomes in 11,441 Consecutive Patients Following Percutaneous
Coronary Interventions
• Landes, Uri et al.
• American Journal of Cardiology , Volume 115 , Issue 7 , 855 – 859

Women With Low Vitamin D More Likely To Report Depression
David C.R. Kerr Ph.D.
Sch of Psychological Science Associate Professor
College of Liberal Arts Oregon State University
Dr. Kerr: Many people assume we already know that low levels of vitamin D contribute to
depression, especially in winter. However, studies have not found consistent evidence for
this, and most studies have focused on people in late life or with serious medical conditions.
We focused on apparently healthy young women living in the Pacific Northwest. We found
that women with low blood levels of vitamin D were more likely to report clinically significant
depressive symptoms. This link existed even when we considered other factors that might
explain both problems, such as diet, obesity, and time of year.
• Dr. Kerr: Healthy young women are nonetheless at risk for depression and vitamin D
deficiency. In our study, women of color and women who did not take a vitamin supplement
commonly showed vitamin D insufficiency, especially in Winter. Given the established
negative consequences of vitamin D deficiency for longterm physical health, supplementation
seems warranted whether or not our findings on depression are supported in future
research.

Women With Low Vitamin D More Likely To Report Depression
David C.R. Kerr Ph.D.
Sch of Psychological Science Associate Professor
College of Liberal Arts Oregon State University
this study?
• Dr. Kerr: A clinical trial of vitamin D supplementation directed at preventing or reducing
symptoms in at-risk young women would offer a more conclusive test of these questions.
• Citation:
• Associations between vitamin D levels and depressive symptoms in healthy young adult
women
• David C.R. Kerr, David T. Zava, Walter T. Piper, Sarina R. Saturn, Balz Frei, Adrian F. Gombart
• Received: September 3, 2014; Received in revised form: February 20, 2015; Accepted:
February 25, 2015; Published Online: March 06, 2015
• DOI: http://dx.doi.org/10.1016/j.psychres.2015.02.016

German Study Suggests CT Screening For Lung Cancer Has Unresolved Questions
Prof. Dr. Nikolaus Becker
Epidemiologisches Krebsregister Baden-Württemberg
Deutsches Krebsforschungszentrum Heidelberg Germany
Prof. Becker: Lung cancer is the leading cause of cancer death in our Western countries as well as
worldwide. One reason is that it is clinically diagnosed mostly in an advanced stage with a poor
five-year survival of less than 10%. Diagnosed at an early stage, more than 70% would survive 5
years. For low dose-multislice CT (MSCT) indications exist that it is able to detect lung cancers
early. As every newly upcoming screening tool, it has to be carefully analyzed whether it is really
able to decrease the mortality from lung cancers and at which costs in terms of undesired side
effects such as false-positive findings and overdiagnosis. Our results indicate that spontaneous
MSCT screening with changing doctors might be ineffective due to many false-positive alarms; if
screening then within an organizational framework.

• Prof. Becker: Currently, there are several randomized trials running in Europe and the USA
from which interesting results have already been published. It appears nevertheless too early
for a decision in favour of lung cancer screening in high risk populations since many
important questions remain unresolved. Reduction of lung cancer mortality has been shown
from one study (NLST) but not from others. Overdiagnosis is an important issue which can
directly only be resolved with studies comparing low dose-multislice CT with no intervention
as the European studies are designed. Their results should be waited for until decisions are
taken. Clinicians should inform interested patients in detail about the currently existing
uncertainties and the risks of self-initiated screening diagnostics.

this study?
• Prof. Becker: The running studies should be continued. It is highly interesting whether the
reduction of lung cancer mortality persists in the NLST or is followed by an increase above
background incidence indicating to a postponement of lung cancer death by screening. It is
important to see the results on lung cancer mortality from the other studies, and what can
they contribute to the issue of overdiagnosis. Newly established studies should approach the
screening interval which has only addressed so far by NELSON (the Netherlands and Belgium)
and MILD (Italy). Even appropriate and efficient structures for an organized screening should
be investigated in advance of a broad roll-out.
• Citation:
• Randomised study on early detection of lung cancer with MSCT in Germany: results of the
first 3 years of follow-up after randomisation.
• Becker N1, Motsch E, Gross ML, Eigentopf A, Heussel CP, Dienemann H, Schnabel PA,
Eichinger M, Optazaite DE, Puderbach M, Wielpütz M, Kauczor HU, Tremper J, Delorme S.
• J Thorac Oncol. 2015 Mar 16. [Epub ahead of print]

Auditory Hallucinations Surprising Varied, Complex and Physical
Dr Angela Woods
Associate Editor, BMJ Medical Humanities Journal Senior Lecturer in Medical Humanities
Deputy Director, Centre for Medical Humanities
Durham University
• Dr. Woods: We’ve known for a long time that hearing voices, or auditory hallucinations, is
reported by people with a wide range of psychiatric diagnoses as well as by those who have
no diagnosis. 5–15 per cent of adults will hear voices at some point during their lives – in
circumstances that may be related to spiritual experiences, bereavement, trauma, sensory
deprivation or impairment, as well as mental and emotional distress. However, what we
know about voices clinically and empirically comes from a small handful of studies, typically
conducted in mental health settings with patients with a diagnosis of schizophrenia using
quantitative scales and measures. Our study asked people to describe, in their own words,
what it is like to hear voices. We designed an open-ended online questionnaire which was
completed by 153 people with a range of diagnoses, including 26 who had never had a
psychiatric diagnosis.
• Our study found that a large majority of participants described hearing multiple voices (81%)
with characterful qualities (70%). While fear, anxiety, depression and stress were often
associated with voices, 31% of participants reported positive and 32% neutral emotions. To
our surprise less than half the participants reported hearing literally auditory voices; 45%
reported either thought-like or mixed experiences. Perhaps the most startling finding
concerned the physicality of voices. Bodily sensations while hearing voices were reported by
66% of participants – these included feelings of tingling, numbness, burning, pressure, and a
sense of being distanced or disconnected from the body.

Dr Angela Woods
Durham University
• Dr. Woods: The significance of our research lies in its commitment to understanding the
experience of voice-hearers. Auditory hallucinations are much more complex and varied that
is frequently recognised. It’s important not to make assumptions about voice-hearing,
especially not ones based on diagnostic status; instead, we need to ask people about their
experiences and the ways they understand and make sense of them. A large majority of
people hear multiple voices, and many also hear positive and neutral voices, so our
understanding of hearing voices will be limited if we focus only on dominant or negative
voices.

Dr Angela Woods
Durham University
this study?
• Dr. Woods: We hope that future research into the experience of voice-hearing will also be
open to mixed-methods approaches and to working with voice-hearers in the design and
conduct of research. More work needs to be done to explore the experience of hearing
voices systematically and in cross-diagnostic and non-clinical groups. A greater
understanding of the complexity and variety of that experience could lead to the
identification of sub-types of auditory hallucination, and this has implications for the
therapeutic management of distressing voices and for the design of future clinical,
phenomenological and neuroscientific studies of voice-hearing.
• Citation:
• Experiences of hearing voices: analysis of a novel phenomenological survey
• Angela Woods, Nev Jones, Ben Alderson-Day, Felicity Callard, Charles Fernyhoug
Lancet Psychiatry 2015 Published Online March 11, 2015
• http://dx.doi.org/10.1016/S2215-0366(15)00006-

Healthy Diet and Physical Activity Vital For Cardiovascular Health of Kids
MedicalResearch.com Interview with: Donald M Lloyd-Jones, MD/ScM
Senior Associate Dean for Clinical and Translational Research, Chair, Department of Preventive Medicine
Director, Northwestern University Clinical and Translational Sciences Institute (NUCATS) Eileen M. Foell Professor
Professor in Preventive Medicine-Epidemiology and Medicine-Cardiology
Northwestern University Feinberg School of Medicine
• MedicalResearch: What is the background for this study? What are the main findings?
• Dr. Lloyd-Jones: Previous studies have examined the associations of cardiovascular health, as
defined by the American Heart Association, with outcomes in younger and middle-aged
adults. Prior studies have also examined the status (i.e., prevalence) of cardiovascular health
in adults across the age spectrum, and in adolescents ages 12-19 years. However, no study to
date has examined the status of cardiovascular health in children under 12 years of age, so
we sought to define it in detail using nationally-representative data.
• Overall, although we have inadequate surveillance systems to monitor cardiovascular health
optimally in our youngest children, this study shows that there are concerning signals that
they are losing the intrinsic cardiovascular health they are born with, even well before age 12
years. The implications for loss of cardiovascular health before adulthood have been well
established, with earlier onset of cardiovascular diseases, cancer and other diseases, earlier
mortality, lower quality of life and many other adverse consequences.

• MedicalResearch: What should patients and clinicians take away from this report?
• Dr. Lloyd-Jones: It seems to me that the takeaway for parents, patients, clinicians, and for our
society as a whole, is that we must make every effort to preserve cardiovascular health by
establishing healthy habits in our kids right from the start. This includes providing access and
encouraging eating a healthy diet high in fruits and vegetables, with lean proteins and limited
processed foods and starches. It also means making sure children establish a pattern of
physical activity. Together, these two areas of behavior can mean that children avoid
unhealthy weight gain and the attendant changes in blood pressure, blood lipids and blood
sugar that follow.

• MedicalResearch: What future research do you recommend as a result of this work?
• Dr. Lloyd-Jones: Future work should focus on improving surveillance of cardiovascular health
beginning at the youngest ages, especially for vulnerable populations.
• Citation:
• Ning H, Labarthe DR, Shay CM, et al. Status of Cardiovascular Health in US Children Up to 11
Years of Age – The National Health and Nutrition Examination Surveys 2003–2010.
Circulation: Cardiovascular Quality and Outcomes. Published online March 17 2015

Toxins In Vapor From Electronic Cigarettes Can Travel Far
Jonathan Thornburg, PhD
Director, Exposure and Aerosol Technology RTI International
Research Triangle Park, NC
• MedicalResearch: What is the background for this study? What are the main findings?
• Dr. Thornburg: RTI wants to improve the human condition by protecting public health from
exposure to contaminants. That includes secondhand exposure to electronic cigarette vapors.
RTI realized that most research has focused on the electronic cigarette user, not on
secondhand exposure. Our research created a simulated lung in our laboratory to produce
representative electronic cigarette aerosol that a user would exhale so we could measure the
aerosol size distribution and chemical composition. Those two parameters are critical
characteristics for understanding the physical and chemical properties of the aerosol as it
disperses in the environment to produce the airborne concentrations that determine
someone’s secondhand exposure. Our main findings were:
• The aerosol particles exhaled by a user are smaller than 1000 nm, with median size between
100 and 200 nm. The aerosol size distribution varies with the type of e-liquid used.
• The aerosol is made of water, glycerin/propylene glycol, nicotine, artificial flavors, and
preservatives
• Artificial flavors identified were ethyl maltol, 2-methyl naphthalene and 2-tert-butyl-p-cresol
present.
• BHA and BHT preservatives were present.
• Dosimetry modeling determined that more than 50% of the electronic cigarette emissions
were exhaled by the user, potentially leading to secondhand exposure.

• MedicalResearch: What should clinicians and patients take away from your report?
• Dr. Thornburg: That exhaled electronic cigarette vapors contain particles of small size that
can travel far distances within buildings and outdoors. They travel much farther than the
point where the “white cloud” exhaled by the user disappears. The size of these
particles, less than 1000 nm, will penetrate the alveolar region of a person’s lungs. The
particles contain flavorings and preservatives that are “generally regarded as safe” as a food
additive. No one knows how safe these chemicals are if they are inhaled

• MedicalResearch: What recommendations do you have for future research as a result of
this study?
• Dr. Thornburg: Future research should incorporate an integrated program that synergistically
addresses
1) characterization of the physical and chemical properties of the electronic cigarette
emissions,
2) the toxicity of the emissions,
3) secondhand exposure measurements, and 4) acute respiratory changes, such as asthma,
that result from inhaling electronic cigarette emissions.
• CITATION:
• Jonathan Thornburg, Quentin Malloy, Seung-Hyun Cho, William Studabaker, and Youn Ok Lee.
Exhaled Electronic Cigarette Emissions: What’s Your Secondhand Exposure? RTI Press,
March 2015 DOI: 10.3768/rtipress.2015.rb.0008.1503

Abnormal Nocturnal Blood Pressure In Young Adults May Lead To Later Cognitive Impairments
Yuichiro Yano MD
Dept of Preventive Medicine,
Northwestern University, Chicago
Response: Previous research has suggested that nocturnal blood pressure (blood pressure
during sleep) is more predictive of cardiovascular events than daytime blood pressure.
However, the effect of nocturnal blood pressure on cognitive function in midlife, especially
for young adults, has not been studied before.
• The long-term clinical significance of the findings is that nocturnal blood pressure
measurements in younger adults could be potentially useful to identify those who may be at
risk for developing lower cognitive function in midlife.
•
Medical Research: What should clinicians and patients take away from your report?
• Response: Study results suggest that collecting data on ambulatory blood pressure
monitoring in addition to office blood pressure monitoring seems to be a very important
strategy to identify people who are at risk for developing low cognitive executive function in
the future.

Abnormal Nocturnal Blood Pressure In Young Adults May Lead To Later Cognitive Impairments
Yuichiro Yano MD
Dept of Preventive Medicine,
Northwestern University, Chicago
this study?
• Response: Understanding the underlying pathways (e.g., vascular dysfunction, brain atrophy,
or impaired brain integrity) between higher nocturnal blood pressure and cognitive
dysfunction, using brain MRI is important.
• From our data, whether abnormal nocturnal blood pressure in young adults is simply markers
of concurrent pathophysiology (if so, what pathophysiology ?) or related in a causal pathway
to pathogenesis in cognitive dysfunction remains uncertain. Further research is warranted,
exploring whether improving nocturnal blood pressure abnormalities in young adults can
prevent lower cognitive function in those middle-aged or over.
• Citation:
• Nocturnal Blood Pressure in Young Adults and Cognitive Function in Midlife: The CARDIA
Study
• Yuichiro Yano, Hongyan Ning, Paul Muntner, Jared Reis, David Calhoun, Anthony Viera,
Deborah Levine, Jacobs David, Daichi Shimbo, Kiang Liu, Philip Greenland, and Donald Lloyd-
Jones
• Circulation. 2014;130:A11968
• Email *

Melanoma: Targeting Macrophages Increases BRAF Inhibitors’ Effectiveness
Russel E. Kaufman, MD President Emeritus
Professor, Molecular and Cellular Oncogenesis Program
Molecular and Cellular Oncogenesis Program The Wistar Institute
Response: Targeted therapies in cancer were hailed as a “magic bullet” because of their ability to
act upon the mutations responsible for cancer while leaving nearby healthy cells alone. Using an
approach like this, it would make sense that therapies designed to target mutations of
BRAFV600E/K could be effective for melanoma, since that gene is mutated in about half of all cases of
the disease.
• However, we’ve learned over time that these targeted therapies simply aren’t as effective as we
had hoped they would be. In the case of these BRAF inhibitors, while patients do live slightly longer,
they eventually relapse within months of treatment. We wanted to know why this was happening.
• We decided to look at macrophages, which are the most abundant inflammatory cells in
melanoma. The more macrophages present in a patient with melanoma, the worse his or her
outcome will be. They’ve been linked to cancer progression, but before this study, no one had really
looked at the role they may play in the resistance to treatment with BRAF inhibitors.
• We found that BRAF inhibitors activate the mitogen-activated protein kinase (MAPK) pathway in
macrophages. When this pathway is activated, it leads to the production of vascular endothelial
growth factor (VEGF), a signaling protein closely associated with angiogenesis. The VEGF produced
in the macrophages is able to activate the MAPK pathway in melanoma cells, thereby stimulating
the growth of cancer cells.
• Taking these findings one step further, we discovered that when we blocked the MAPK pathway or
VEGF signaling, we appeared to reverse macrophage-mediated resistance. When we targeted
macrophages, we were able to increase the antitumor activity of BRAF inhibitors in mouse and
human models.

• Response: This is just one explanation for how patients who are treated with BRAF inhibitors
eventually become resistant to the targeted therapy. We believed that focusing on
macrophages would provide us with a reasonable explanation for why this is happening, and
it did, but there are many, many off-target effects caused by targeted therapies that we don’t
yet understand. There really needs to be a comprehensive study that explores all of the
different ways in which targeted therapies can affect a patient or cause different cancer-
causing pathways to become activated.

this study?
• Response: It’s possible that therapy can be improved by targeting the macrophages
themselves, since this stimulated the antitumor activity of BRAF inhibitors. However, since
macrophages are the culprit behind this one form of BRAF inhibitor resistance, we might also
want to consider designing new BRAF inhibitors that do not activate macrophages.
• Citation:
• BRAF Inhibition Stimulates Melanoma-Associated Macrophages to Drive Tumor Growth
• Tao Wang, Min Xiao, Yingbin Ge, Clemens Krepler, Eric Belser, Alfonso Lopez-Coral, Xaiowei
Xu, Gao Zhang, Rikka Azuma, Qin Liu, Rui Liu, Ling Li, Ravi K Amaravadi, Wei Xu, Giorgos C
Karakousis, Tara C Gangadhar, Lynn M. Schuchter, Melissa Lieu, Sanika Khare, Molly B
Halloran, Meenhard Herlyn, and Russel E. Kaufman
• Clin Cancer Res clincanres.1554.2014; Published Online First January 23, 2015;
doi:10.1158/1078-0432.CCR-14-1554

Rate At Which Genetic Code Read May Offer New Drug Targets
Jeff Coller, PhD Associate professor
Division of General Medical Science
Associate director, The Center for RNA Molecular Biology, Case Western Reserve University School of Medicine
• MedicalResearch: What is the background of this study?
• Dr. Coller: There are a diverse number of half-lives for any individual messenger RNA (mRNA).
The range of those half-lives is from seconds to hours. What the field has wanted to know for
30 years is how those rates are regulated, and there has been considerable anecdotal and
real evidence that sequences in untranslated regions (UTRs) could regulate decay, but it
doesn’t explain all of the half-lives that are observed for all messages. In addition, we have
known mRNAs that are translated better are more stable than mRNAs that are translated
poorly, so those pieces together led to the discovery.
•
MedicalResearch: What are the main findings of the study?
• Dr. Coller: We can explain a large number of mRNA half-lives based on codon usage. We
found that every codon within the genetic code is not created equal. The degeneracy in the
genetic code is not only there because of the mathematics, but it is also there because it sets
speed limits for the ribosome. So some codons are read faster than others. The rate at which
those codons are read is cumulative across the entire span of the message and ultimately
affects the overall level of protein and feeds back into mRNA decay. Codon composition sets
a speed limit for translation rate, and that affects protein expression and mRNA decay rate.
Those are the fundamental findings.

• MedicalResearch: What can clinicians take away from this report?
• Dr. Coller: Now that we recognize that protein synthesis rate is determined by codon
composition, which is a novel finding, there may be disease states that activate at that level.
For example, it would be possible to have a disease state where the rate of protein synthesis
was changed, but wouldn’t be observed as a mutation within that particular gene. The
machinery that sets that rate of translation could be altered, and that may have profound
implications to medicine. This opens a whole new category of potential targets for drugs, as
well as where disease states will arise.

• MedicalResearch: What are the recommendations for future research?
• Dr. Coller: What will have to be determined will be whether the rates of protein synthesis
change in disease states. Our study shows that the rate of protein synthesis is determined by
the levels of transfer RNAs (tRNA). What we will have to determine is whether there are
disease states where tRNA concentrations have changed within the cell. In addition, can we
target the machinery that sets the rate of translation in order to alleviate a disease state?
That will be the future research — how codon optimality relates to human health. My lab will
investigate extensively how speed limits are controlled in human cells and different cell types
and in different disease states. In the scientific community in general, lots of researchers will
conduct their own investigations into the rate of at which codons are read.
• Citation:
• Codon optimality is a major determinant of mRNA stability
Presnyak, Vladimir et al.
• Cell , Volume 160 , Issue 6 , 1111 – 1124

Both Clindamycin and Trimethoprim–Sulfamethoxazole Effective For Uncomplicated Skin Infections
Loren G. Miller, M.D., M.P.H.
Los Angeles Biomedical Research Institute
(LA BioMed) Infectious Disease Specialist
• Dr. Miller: Skin and skin structure infections are extremely common reasons for persons
to seek medical care in the U.S., accounting for approximately 14.2 million
outpatient visits in 2005, the latest year for which statistics are
available, and 850,000 hospital admissions. Until this study was completed,
the most effective approach to outpatient antibiotic treatment of
uncomplicated skin infections in the era of community-acquired
methicillin-resistant Staphylococcus aureus (MRSA) was unclear. Prior to
this research, there were no data on which antibiotics were best for
treatment of these common skin infections.

• Dr. Miller: Two antibiotics frequently prescribed to treat serious skin infections –
clindamycin and trimethoprim sulfamethoxazole (TMP-SMX) – had similar rates
of success in curing uncomplicated infections in outpatients. They also had
similar rates of side effects.
• To conduct the study, we recruited outpatients from emergency departments,
clinics and other healthcare facilities associated with Los Angeles County’s
Harbor-UCLA Medical Center, University of Chicago Medical Center, San
Francisco General Hospital and Vanderbilt University Medical Center from May
2009 to August 2011. We studied 524 adults and children with uncomplicated
skin infections who had cellulitis, abscesses of 5 centimeters or more or
both. In the multicenter, double blind, randomized clinical trial, 264
received clindamycin and 260 received TMP-SMX. We followed the outpatients
for a month after their treatment.
• We found similar outcomes for both groups – 80.3% of the outpatients who
received clindamycin and 77.7% of the outpatients in the group that received
TMP-SMX were cured within seven to 10 days after the end of their treatment.
• These are not considered significant differences, so our evaluation is that
these two commonly prescribed antibiotics for serious skin infections are
similarly effective in treating uncomplicated skin infections in children
and adults who have few or no major co-existing conditions.

• Dr. Miller: In areas of where MRSA is a common cause of skin infections, which is all of
the United States and many parts of the world, either clindamycin or TMP-SMX
can be used to treat outpatients with uncomplicated skin infections,
regardless if the infection is cellulitis, abscess, or both.
this study?
• Dr. Miller: Studies of other generic antibiotics for uncomplicated skin infections, such
as doxycycline, are warranted given some patients may not be able to take
these medications or local patterns of antimicrobial resistance may make
some of these therapies not useful.
• Citation:
• Clindamycin versus Trimethoprim–Sulfamethoxazole for Uncomplicated Skin Infections
• Loren G. Miller, M.D., M.P.H., Robert S. Daum, M.D., C.M., C. Buddy Creech, M.D., M.P.H.,
David Young, M.D., Michele D. Downing, R.N., M.S.N., Samantha J. Eells, M.P.H., Stephanie
Pettibone, B.S., Rebecca J. Hoagland, M.S., and Henry F. Chambers, M.D. for the DMID 07-
0051 Team
• N Engl J Med 2015; 372:1093-1103
• March 19, 2015 DOI: 10.1056/NEJMoa1403789

Most Kidney Failure Patients Around World Die Without Access to Dialysis
Prof Vlado Perkovic MBBS PhD FASN FRACP
George Institute for Global Health
University of Sydney Sydney Australia
Prof. Perkovic: There has been much discussion about the large number of people with
kidney disease around the world- more than 10% of the population in most countries- but
the current number of people with kidney failure had not been clearly defined.
• We therefore systematically collected information on the number of people with kidney
failure around the world and found that 2.6 million people were receiving treatment for
kidney failure in 2010, almost 80% of whom were undergoing dialysis while the others had
received a kidney transplant. We then noticed very large differences in the number of people
receiving treatment in different regions and countries, so used mathematical modeling to
calculate the number of people who should be receiving treatment for kidney failure. The
results of this analysis suggested there should be between 5 and 10 million people receiving
treatment for kidney failure, suggesting that between half and three-quarters of people with
kidney failure around the world died without access to dialysis, as a result of the high cost of
dialysis treatment that is not affordable for many people around the world. These people are
doomed to die of kidney failure, a condition for which we have had an effective treatment for
over 50 years.

Most Kidney Failure Patients Around World Die Without Access to Dialysis
Prof Vlado Perkovic MBBS PhD FASN FRACP
George Institute for Global Health
University of Sydney Sydney Australia
• Prof. Perkovic: The number of people with kidney failure is large and growing rapidly. We
need to pay much more attention to prevention of kidney failure, by controlling blood
pressure, diabetes and other conditions that we know to be risk factors for kidney failure.
this study?
• Prof. Perkovic: Firstly, we need cheaper forms of dialysis so that this old, established
treatment is available to all of those people who need it. To achieve this, we have partnered
with the International Society of Nephrology and the Asia-Pacific Society of Nephrology to
establish a prize aiming to encourage people to develop affordable dialysis technologies. The
winner will win US$100,000.
• Citation:
• Worldwide access to treatment for end-stage kidney disease: a systematic review
• Thaminda Liyanage, MBBS† Toshiharu Ninomiya, PhD†, Prof Vivekanand Jha, DM, Prof Bruce
Neal, PhD, Halle Marie Patrice, MD, Ikechi Okpechi, PhD, Prof Ming-hui Zhao, PhD, Jicheng Lv,
PhD, Prof Amit X Garg, PhD, John Knight, MBA, Prof Anthony Rodgers, PhD, Martin Gallagher,
PhD, Sradha Kotwal, MD, Prof Alan Cass, PhD, Prof Vlado Perkovic, PhD
• DOI: http://dx.doi.org/10.1016/S0140-6736(14)61601-
• The Lancet: Published Online: 13 March 2015

Low Dose Seizure Medication May Benefit Early Alzheimer’s Disease
Arnold Bakker, Ph.D. Assistant Professor Division of Psychiatric Neuroimaging
Department of Psychiatry and Behavioral Sciences
The Johns Hopkins University School of Medicine
Baltimore, MD 21287
Dr. Bakker: Patients who are at increased risk for developing dementia due to Alzheimer’s
disease show hyperactivity in an area of the brain called the hippocampus, which is critically
important for memory function. This study investigated the functional significance of this
hyperactivity and determined if, similar to animal studies, treatment with low dose
levetiracetam would reduce this increased activation and improve memory function in these
patients. Results showed that this overactivity is a dysfunctional condition that contributes to
the memory impairment such that treatment with very low doses of levetiracetam both
reduces this overactivity and improves memory function in these patients.
• Dr. Bakker: Low dose Levetiracetam treatment potentially confers benefit to patients in the
earliest symptomatic stages of Alzheimer’s disease, prior to the clinical presentation of
dementia, but more studies are needed before recommendations can be made for patient
treatment.

Low Dose Seizure Medication May Benefit Early Alzheimer’s Disease
Arnold Bakker, Ph.D. Assistant Professor Division of Psychiatric Neuroimaging
Department of Psychiatry and Behavioral Sciences
The Johns Hopkins University School of Medicine
Baltimore, MD 21287
this study?
• Dr. Bakker: The findings from this study are very promising and point to a role for low dose
levetiracetam as a therapeutic in the pre-dementia stage of Alzheimer’s disease. Next a
phase 3 clinical trial, registered with the FDA, is planned to further assess the efficacy assess
the efficacy in preserving cognition and memory and assess its potential to delay the
progression to the clinical stage of Alzheimer’s disease. The sponsor for that trial will be
AgeneBio, Inc,, which is a biopharmaceutical company founded out of Johns Hopkins
technology transfer.
• Citation:
• Response of the medial temporal lobe network in amnestic mild cognitive impairment to
therapeutic intervention assessed by fMRI and memory task performance
• Arnold Bakkera, , , Marilyn S. Albert bGregory Kraussb, Caroline L. Specka, Michela Gallagherc
• NeuroImage: Clinical Volume 7, 2015, Pages 688–698

Human Brains Age Less Than Previously Thought
Kamen Tsvetanov, PhD
Centre for Speech, Language and the Brain Department of Psychology University of Cambridge
Downing Street Cambridge, United Kingdom
• Brain areas with rich blood supply lower their vascular reactivity with ageing
• Dr. Tsvetanov: Older brains may be more similar to younger brains than previously thought!
In our study we have shown that changes in the aging brain previously observed using
functional magnetic resonance imaging (fMRI) – one of the standard ways of measuring brain
activity – may be due to changes in our blood vessels, rather than changes in the activity of
our nerve cells, our neurons. Given the large number of fMRI studies used to assess the aging
brain, this has important consequences for understanding how the brain changes with age
and it challenges current theories of ageing.

Human Brains Age Less Than Previously Thought
Kamen Tsvetanov, PhD
Centre for Speech, Language and the Brain Department of Psychology University of Cambridge
Downing Street Cambridge, United Kingdom
• Dr. Tsvetanov: The study addresses fMRI issues of measuring neural activity indirectly
through changes in regional blood flow. Without careful correction for age differences in
vascular reactivity, differences in fMRI signals can be erroneously regarded as neuronal
differences. The unique combination of an impressive multimodal data set across 335 healthy
volunteers over the lifespan, as part of the CamCAN project (www.cam-can.com), allowed my
colleagues and I to validate a method for correction, which is suitable for fMRI studies of
aging. Our findings clearly show that without such correction methods, fMRI studies of the
effects of age on cognition may misinterpret effect of age as a neurocognitive, rather than
neurovascular, phenomena.

Despite High Risk Of Stroke, Some Atrial Fibrillation Patients Not Adequately Anticoagulated
Jonathan L. Halperin, M.D.
The Robert and Harriet Heilbrunn Professor of Medicine
Mount Sinai School of Medicine
Dr. Halperin: The two analyses come from the GLORIA-AF Registry Program, a global,
prospective, observational study supported by Boehringer Ingelheim, which is designed to
characterize the population of newly diagnosed patients with non-valvular atrial fibrillation
(NVAF) at risk for stroke, and to study patterns, predictors and outcomes of different
treatment regimens for stroke risk reduction in non-valvular atrial fibrillation patients. The
data is based on treatment trends in 3,415 patients who entered the registry from November
2011 to February 2014 in North America. All patients had a recent diagnosis of NVAF, and
86.2 percent had a CHA2DS2-VASc score of 2 or higher.
• Results from the first analysis demonstrated that patients with the paroxysmal (occasional)
form of non-valvular atrial fibrillation and at a high risk for stroke (CHA2DS2-VASc score of 2 or
higher) were given an anticoagulant medication less often than those with persistent or
permanent forms of NVAF, and a CHA2DS2-VASc score of 2 or higher. This pattern runs
counter to NVAF guidelines calling for patients to receive oral anticoagulant therapy based on
their risk of stroke, rather than the type of atrial fibrillation.
• In the second analysis, researchers found that despite high stroke risk, a considerable number
of patients receive only aspirin or no medication.

• Dr. Halperin: The two analyses suggest that despite available new treatment options for non-
valvular atrial fibrillation, some patients at high risk of stroke are undertreated or receive no
treatment. While clinical guidelines call for patients to receive antithrombotic therapy based
on their risk of stroke or thromboembolism and bleeding, rather than the type of atrial
fibrillation, the results of these analyses showed that 21.9 percent of patients with new-
onset paroxysmal NVAF and a CHA2DS2-VASc score of 2 or higher were not given an oral
anticoagulant medication, compared to 12.4 percent and 11.2 percent of those diagnosed
with persistent or permanent NVAF, respectively, and a CHA2DS2-VASc score of 2 or higher.
• Patients with NVAF should discuss with their physician which treatment is right for them.

this study?
• Dr. Halperin: Ongoing studies of factors that contribute to prescribing patterns for NVAF
patients, like GLORIA-AF, provide valuable information about the use of available treatments
in clinical practice. I encourage more such research that examines the use of antithrombotic
treatment for NVAF patients in daily clinical.
• Citation:
• Halperin JL, Huisman M, Diener H-C, et al. Patterns of newly detected atrial fibrillation and
antithrombotic treatment in North America (GLORIA-AF Phase II). Abstract No./Poster No:
1246-124, Presented at: the American College of Cardiology 64th Annual Scientific Session
(ACC.15), March 14-16, 2015, San Diego, CA – available at:
http://www.abstractsonline.com/pp8/#!/3658/presentation/36041

Both Stenting and Bypass Surgery Reasonable For 2+ Blocked Coronary Arteries
Sripal Bangalore, MD, MHA, FACC, FAHA, FSCAI
Director of Research, Cardiac Catheterization Laboratory, Director, Cardiovascular Outcomes Group,
Associate Professor of Medicine, New York University School of Medicine,
New York, NY 10016
Dr. Bangalore: Prior studies have shown a mortality benefit of bypass surgery over stenting.
But these studies compared bypass surgery with older generation stents which are no longer
used. We used data from the New York state registry of patients who underwent stenting or
bypass surgery for 2 or more blockages of coronary arteries. With data from over 18,000
patients we found that there was no difference between stenting and bypass surgery for long
term mortality. In addition we found that both procedures have trade offs. Bypass surgery
has upfront risk of death and stroke whereas PCI has long term risk of needing a repeat
procedure. In addition, in patients who underwent incomplete revascularization, there was
increase in myocardial infarction with PCI.
• Dr. Bangalore: Both PCI and bypass surgery are reasonable options for patients with 2 or
more blockages of coronary arteries. The decision as to which one to choose should be based
on weighing the upfront risk of death and stroke with bypass surgery versus the long term
risk of needing a repeat procedure with PCI. Both the patients anatomy and preference
should be taken into consideration.

Both Stenting and Bypass Surgery Reasonable For 2+ Blocked Coronary Arteries
Sripal Bangalore, MD, MHA, FACC, FAHA, FSCAI
Director of Research, Cardiac Catheterization Laboratory, Director, Cardiovascular Outcomes Group,
Associate Professor of Medicine, New York University School of Medicine,
New York, NY 10016
this study?
• Dr. Bangalore: We need large clinical trials that are well powered to address this question
• Citation:
Presented at the 2015 ACC in San Diego March 2015 and published in NEJM:
• Everolimus-Eluting Stents or Bypass Surgery for Multivessel Coronary Disease
• March 16, 2015 Bangalore S., Guo Y., Samadashvili Z., et al.
10.1056/NEJMoa1412168

More Neurosurgeons Will Be Needed As Population Ages
MedicalResearch.com Interview with: Uzma Samadani, MD, PhD
Chief of Neurosurgery, New York Harbor Health Care System
Assistant Professor, Departments of Neurosurgery, Psychiatry, Neuroscience and Physiology
Co-Director, Steven and Alexandra Cohen Veterans Center
NYU Langone Medical Center
Response: The purpose of this study was to determine the current and future incidence of chronic
subdural hemorrhage in the United States civilian and Veterans’ Administration populations. It’s
main findings are that, as the population ages, the incidence of subdural hemorrhage is increasing.
• Response: Clinicians and patients need to be aware that the need for neurosurgical and
rehabilitation care for people with chronic subdural hemorrhage is increasing as the population
ages. They need to work with their politicians and other leadership to ensure that adequate
resources are in place for the future. They also need to recognize that research on mechanisms to
prevent brain atrophy are critical to slowing this trend of increasing incidence of subdural
hemorrhage. Support for such research is extremely important.
• Medical Research: What recommendations do you have for future research as a result of this
study?
• Response: Training of increased numbers of neurosurgeons will likely be necessary as the US
population ages.
• Citation:
• Actual and projected incidence rates for chronic subdural hematomas in United States Veterans
Administration and civilian populations
david balser, bs, sameer Farooq,talha mehmood, md, marleen reyes, ba, and uzma samadani, md,
phd
Journal of Neurosurgery Posted online on March 20, 2015.

Diet Soda Linked To Increased Belly Fat and Waist Size
Helen P. Hazuda, Ph.D. Professor of Medicine
Division of Nephrology Department of Medicine
University of Texas Health Science Center at San Antonio San Antonio, TX
Dr. Hazuda: The long-term effects of diet soda consumption on health outcomes is unclear, and
studies in both humans and animals have raised concerns about their potentially harmful health
effects including weight gain and increased cardiometabolic risk. Most human studies have focused
on middle-aged or younger adults, rather than focusing specifically on people 65 years and older, a
rapidly growing segment of the U.S. population that has a disproportionately high burden of
cardiometabolic disease and associated healthcare costs. Therefore, our study examined
prospectively the association between diet soda intake and long-term change in waist
circumference in a biethnic cohort of older (65+ years) Mexican American and European American
participants in the San Antonio Longitudinal Study of Aging (SALSA).
• SALSA included a baseline examination (1992 – 1996) and three follow-up examinations (2000-
2001, 2001-2003, and 2003-2004). The total follow-up period averaged 9.4 years. Diet soda intake,
waist circumference (WC), height and weight were measured at each examination along with
sociodemographic factors, leisure physical activity, diabetes mellitus, smoking, and length of follow-
up.
• The main finding is that over the total 9.4-year SALSA follow-up period and after adjustment for
multiple potential confounders, daily diet soda users (1+ diet sodas/day) experienced an increase
in waist circumference of 3.2 inches, while occasional diet soda users (>.05 < 1 diet soda/day)
experienced a waist circumference increase of 1.8 inches, and nonusers of diet soda experienced a
WC increase of 0.8 inches. Thus, there was a striking dose-response relationship between chronic
diet soda intake and long-term increases in waist circumference.

• Dr. Hazuda: Waist circumference is an indicator of abdominal obesity, and large waist
circumference, an important component of metabolic syndrome, is associated with greater
cardiometabolic risk (i.e., risk of diabetes, cardiovascular disease, and stroke). The SALSA
study shows that increasing diet soda intake was associated with increasing abdominal
obesity, which may increase cardiometabolic risk in older adults. While our prospective
observational study does not prove that there is a causal link between chronic diet soda
intake and WC, together with accumulating evidence from both other human studies and
animal studies, findings from the SALSA study should heighten both patients’ and clinicians’
awareness of the potential harmful health effects of diet soda consumption.

this study?
• Dr. Hazuda: The most compelling evidence about possible adverse health effects of diet soda
intake may come from research that can identify both the health outcomes of chronic diet
soda intake and the mechanisms that link diet soda intake to these health
outcomes. Mechanisms such as the dysregulation of sweet taste as a predictor of caloric
consequences and a trigger for physiological responses that regulate energy balance; adverse
effects on beneficial microflora in the gut that play a major role in body weight
regulation;and adverse effects on leptin signaling that inhibits hunger and maintains energy
balance are being studied in animal models. More intense study of these and other possible
mechanisms in human populations is needed to support the accumulating findings from
observational studies such as SALSA about the adverse health effects of diet sodas on
cardiometabolic ris and other health outcomes.
• Citation:
• Diet Soda Intake Is Associated with Long-Term Increases in Waist Circumference in a Biethnic
Cohort of Older Adults: The San Antonio Longitudinal Study of Aging
• Sharon P.G. Fowler MPH, Ken Williams MS and Helen P. Hazuda PhD
• J Am Geriatr Soc 2015.

Apremilast -Otezla -May Be Cost Effective For Psoriasis Treatment
Steven R. Feldman, M.D., Ph.D.
Professor of Dermatology
Wake Forest Baptist Medical Center Winston-Salem, NC
Response: Results show that introducing apremilast into the treatment pathway prior to
biologics is cost-saving and confers a cost and quality of life benefit. Over 10 years, apremilast
was estimated to provide an additional 0.74 years (5.00 vs. 4.26 years) in which patients
achieved a 75% reduction from baseline in PASI score, compared to a pathway of biologics
only. It was also found to be less costly, mainly due to less time spent on more expensive
biologic therapy (costs reduced by $9,072.39 over 10 years).
• Response: Plaque psoriasis is a chronic disease for which there is no cure and patients may
require multiple therapies throughout their lifetime. Apremilast is a therapy with a different
risk/benefit profile compared to existing biologics, and for patients for whom it is considered
appropriate, is a valuable option.

Apremilast -Otezla -May Be Cost Effective For Psoriasis Treatment
Steven R. Feldman, M.D., Ph.D.
Professor of Dermatology
Wake Forest Baptist Medical Center Winston-Salem, NC
this study?
• Response: While the main assumptions of the economic evaluation were based on clinical
trial data, it would be useful to obtain real world data on the effectiveness and persistence of
apremilas
• Citation:
• American Academy of Dermatology March 2015
• Economic Evaluation of Apremilast in the Treatment of Moderate to Severe Psoriasis in the
United States
Authors: Tom Tencer, Zoe Clancy, Sandrine Cure, Vidya Damera, Steven Feldman, Frank Zhang

Topical Spironolactone May Limit Skin Thinning From Steroids
Nicolette Farman MD Ph.D. Directeur de recherche
Université Pierre et Marie Curie, Paris, France Centre de Recherche des Cordeliers
Paris, France
• Dr. Farman: I have been working for a long time on aldosterone, a steroid hormone
that enhances renal sodium transport, thus regulating blood pressure
levels. Importantly, excessive effects of the hormone can be blocked
by a pharmacological agent (a blocker of the receptor of the hormone): spironolactone. This drug has been
used for decades as an anti-hypertensive drug.
• We identified several tissues where the receptor for the hormone
(the mineralocorticoid receptor, MR) is expressed, in addition to
kidney cells. Unexpectedly we found the receptor to be present in the
human epidermis, but its role there was ignored. We designed first a
mouse model, and found that overexpression of the receptor leads to
thin and fragile skin in mice, as observed in glucocorticoid-treated
skin. We hypothetized that perhaps the glucocorticoids exhibit this
deleterious side-effect because they could bind to the mineralocorticoid receptor.
As a consequence, we argued that pharmacological blockade of the MR over
the skin should limit this side-effect.
• We used human skin explants in culture, and treated them with a
potent dermocorticoid (clobetasol) alone or together with
spironolactone. After 5 days in culture, we saw that spironolactone
could indeed limit the atrophy of the epidermis induced by the
dermocorticoid. Then a clinical trial was performed in healthy
volunteers, that confirmed the efficiency of topical spironolactone to
limit glucocorticoid-induced atrophy. Although the effect is not full
reversion, the benefit was there. This is why we propose now that this
approach could bring benefit to patients, if our results are confirmed
in patients with psoriasis or eczema, that receive a dermocorticoid
cream or gel.

Paris, France
• Dr. Farman: Our study is a first step; it is too early to use spironolactone now
to treat epidermal atrophy. We need to expand our knowledge with
inclusion of subjects with skin diseases (psoriasis or eczema) to
evaluate the benefit of adding spironolactone on top of the classical
glucocorticoid treatment, in well defined and controlled conditions
(new clinical trials). It will be also necessary to reformulate
spironolactone for cutaneous use, including toxicology and
pharmacodynamic studies. It is only after these mandatory steps that
clinical use of a spironolactone cream will be proposed, and with
limited specific applications in human diseases.

Paris, France
this study?
• Dr. Farman: Future research should identify the cellular mechanisms at the origin
of this potential benefit (fundamental research) and try to identify
those patients that should successfully benefit from this treatment.
• Citation:
• Topical Mineralocorticoid Receptor Blockade Limits Glucocorticoid-Induced Epidermal
Atrophy in human Skin.
• Maubec E1, Laouénan C2, Deschamps L3, Nguyen VT4, Scheer-Senyarich I5, Wackenheim-
Jacobs AC6, Steff M1, Duhamel S7, Tubiana S8, Brahimi N5, Leclerc-Mercier S9, Crickx B1, Perret
C7, Aractingi S10, Escoubet B11, Duval X8, Arnaud P12, Jaisser F7, Mentré F2, Farman N7.
• J Invest Dermatol. 2015 Feb 10. doi: 10.1038/jid.2015.44. [Epub ahead of print]

Acne: Potassium Monitoring May Not Be Necessary For Spironolactone Therapy
Dr. Arash Mostaghimi, MD, MPA Director of Dermatology Inpatient Service
Brigham and Women’s Hospital Boston, MA
Dr. Mostaghimi: Spironolactone, a generic drug that’s been used in the clinic since 1959, is
commonly prescribed for treating hormonal acne – acne that tends to affect the jaw line
most commonly around the time of the month when a woman gets her period. The US Food
and Drug Administration recommends frequent potassium monitoring in patients with heart
failure who are taking spironolactone as a diuretic and antihypertensive treatment, but it’s
been unclear if these guidelines should apply to healthy patients taking spironolactone for
the treatment of acne, and, if so, how frequently such patients should have their potassium
levels tested.
• My colleagues and I have found that for young, healthy women taking spironolactone to treat
hormonal acne, potassium monitoring is an unnecessary health care expense. For the
approximately 1,000 patients we studied, blood tests to monitor potassium levels did not
change the course of treatment, but the tests cumulatively totaled up to $80,000. We
suggest that routine potassium monitoring should no longer be recommended for this
patient population in order to improve the patient care experience, decrease unnecessary
office visits and reduce health care spending.

• Dr. Mostaghimi: We hope that by presenting these data, we will begin to create a standard of
practice that best serves patients and helps physicians who may be ambivalent about
recommending these tests for otherwise healthy patients. The low rate of hyperkalemia that
we found in this patient population may encourage more health care professionals to
consider the use of this highly effective drug in their clinical practice.

this study?
• Dr. Mostaghimi: As we begin to consider the costs of care, it is important to systematically
re-evaluate our practices to make sure that our prescribing and monitoring practices provide
the greatest value possible. Future research needs to continue to challenge our assumptions
to make sure we provide the best care possible at the lowest possible price.
• Citation:
• Plovanich M, Weng Q, Mostaghimi A. Low Usefulness of Potassium Monitoring Among
Healthy Young Women Taking Spironolactone for Acne. JAMA Dermatol. Published online
March 22, 2015. doi:10.1001/jamadermatol.2015.34.

Trial of Current Dietary Guidelines Reduced Waistlines and Cardiovascular Risk Markers
Tom Sanders, PhD DSc
Emeritus Professor of Nutrition & Dietetics, Diabetes and Nutritional Sciences Division,
King’s College London London, UK
Dr. Sanders: Controversy surrounds the effectiveness of dietary guideline for cardiovascular disease
(CVD) prevention in healthy middle-aged and older men and women. These dietary guidelines are
similar in UK and other Western countries and focus on modifying the overall dietary pattern so that
food and nutrient targets are met. However, surprisingly the overall impact of changing the dietary
pattern has never been tested in a trial. We conducted a 12-wk controlled dietary trial in 165 healthy
non-smoking men and women (aged 40-70 years) to compare a diet conforming to current dietary
guidelines with a traditional nutritionally balance British diet on well established (blood pressure
measured by 24-h ambulatory monitoring and blood lipids) and newer predictors of cardiovascular
disease risk (measures of blood vessel functioning and stiffness, inflammation and the body’s sensitivity
to insulin). The dietary guideline targets were to reduce total and saturated fat intake to provide no
more than 35% and 10% of the food energy, to cut salt to below 6g/day, to meet the 5-a-day
recommendation for fruit and vegetables, to consume at least 1portions of oily fish a week (i.e.
mackerel, salmon, sardines), to obtain half of the cereal intake from wholegrains and to restrict intake
of non-milk extrinsic sugar to no more than 10% energy. Subjects were counseled by a dietitian and
provided with advice tailored to their individual food preferences and were provided with some foods
to assist them following the dietary advice. The control diet was a nutritionally balanced traditional
British diet without restriction on salt and sugar intake. It was based around refined cereals (white
bread, pasta, breakfast cereals, white rice) and potatoes with meat (red meat, meat products or
poultry), but with a limited intake of oily fish (less than once a month) and wholegrain
cereals. Participants allocated to control were supplied with a butter-based spread and a liquid
unhydrogenated vegetable oil (palm olein) that contained 40 % saturated fatty acids. They were advised
to consume three servings of full-fat dairy products (milk, yogurt and cheese), and at least one serving
of fruit and two servings of vegetables each day. Both groups were given advice to limit consumption of
confectionery, snack foods (chips, cake, cookies) and drink alcohol within safe limits.

• Food intake records showed few differences in micronutrient intakes between diets with the
exception of vitamin D where the intake and plasma 25-OH-vitamin D levels were greater on
the dietary guidelines diet owing to the higher intake of oily fish. The average body weight in
the group who followed the modified diet fell by 1.3 kg whilst that in the control group rose
by 0.6 kg after 12 weeks, resulting in an overall difference in weight of 1.9 kg between the
two groups; the equivalent difference in Body Mass Index (BMI) was 0.7 kg/m2 between the
groups. Waist circumference was 1.7 cm lower in the dietary guidelines group compared to
the control group.
• The drop-out rate was low, with 80 participants completing on the dietary guidelines diet and
82 on the control. Adherence to the dietary advice was confirmed both with dietary records
and by measuring specific biomarkers in the participants’ blood and urine. The latter
indicated an increase in potassium and fibre intake in the dietary group along with a drop in
sodium (salt) and saturated fat and added sugar intake. However, total sugar intake remained
unchanged owing to the increase in sugar intake from fruit.

The primary outcomes were changes in day-time systolic blood pressure, endothelial function
measured using the flow mediated dilation technique and total cholesterol: HDL cholesterol ratio.
All other outcomes were secondary or exploratory outcomes. Significant falls in systolic blood
pressure/diastolic blood pressure of 4.2/2.5 mm Hg for daytime and 2.9/1.9 mm Hg for night time
were measured in the dietary group compared with the control group; the average heart rate was
found to have lowered by 1.8 beats per minute. Causal mediated effects analysis based on
urinary sodium excretion indicated that sodium reduction explained 2.4 mm Hg (95% CI 1.0, 3.9)
of the fall in blood pressure There were no changes in endothelial dependent or endothelial
independent vasodilation but arterial stiffness measured as carotid to femoral pulse wave
velocity was 0. 29 m/sec lower on the dietary guidelines diet compared with the control diet.
Total cholesterol:HDL cholesterol ratio was 4% lower on the dietary guidelines diet compared to
the control low density lipoprotein and triglyceride concentrations were 10% and 9% lower
respectively. The reduction in LDL-C (0.30 mmol/L) was greater than that achieved in most
community based studies of dietary advice where the average reduction is 0.16 mmol/L but still
modest compared with what can be achieved with statins (1.0 mmol/L). Compared with the
control diet, the dietary guideline diet decreased low-grade inflammation (C-reactive protein). No
significant change was recorded in markers for 24-h insulin secretion or insulin sensitivity, which
predicts the risk of developing type 2 diabetes.

• Dr. Sanders: The strength of this study is in it size and the good evidence of compliance to the
dietary advice as well as multiple measurements of blood pressure using ambulatory monitoring.
Its findings apply to middle-aged and older people without existing health problems. This is
important because most heart attacks and strokes occur in those not identified as being at high risk.
The study shows that adherence to a dietary patterns consistent with current dietary guidelines,
which advocate a change in dietary pattern from the traditional British diet (high in saturated fat,
salt and sugar, low in fibre, oily fish and fruit and vegetables) would substantially lower that risk.
The control diet was a nutritionally balanced and not a “junk food” diet. Recently, there has been a
much controversy in the media regarded the dietary recommendations for saturated fat and salt
and much focus has shifted from these to the effects of sugar. Current dietary guidelines
recommend replacement of saturated and trans fatty acids with mainly monounsaturated fatty
acids and not refined carbohydrates. While the dietary guidelines diet possessed several
characteristics of a Mediterranean diet (plenty of fruit and vegetables and a high intake of
monounsaturated fatty acids), the latter is not necessarily low in salt and sugar or high in
wholegrains and fish. A particularly interesting observation was that the dietary guidelines diet
promoted the loss of small amounts of weight especially around the waist compared with those of
the control diet, which had the opposite effect. This could be seen could be seen a limitation to the
study but may be an unavoidable consequence of conforming to the dietary guidelines. While this
diet was well received by participants, it may be a greater challenge to bring about change in
groups who are less health conscious. In conclusion, selecting a diet consistent with current dietary
guidelines as compared to a traditional UK dietary pattern would be predicted on the basis of the
changes in BP and lipids, reduce risk of fatal and non-fatal CVD by 15% and 30% respectively in the
general population.

this study?
• Dr. Sanders: The main limitation of the study is that risk was estimated using surrogate
markers. However, randomized controlled trials with clinical endpoints in healthy participants
are unlikely to be conducted due, large numbers of participants required and the
practicalities of sustaining differences in dietary intake over several years. Although, this
study was able to show that the intake of added sugar was reduced, total sugar intake did not
change because of the increase in fruit consumption. In view of recent recommendation to
restrict the intake of sugar by WHO, further studies are needed to see if restrictions in total
sugar intake have any further benefits on CVD risk factors.
• Citation:
• How effective are current dietary guidelines for cardiovascular disease prevention in healthy
middle-aged and older men and women? A randomized controlled trial.
• Dianne P Reidlinger, Julia Darzi, Wendy L Hall, Paul T Seed, Philip J Chowienczyk, and Thomas
AB Sanders on behalf of the Cardiovascular disease risk REduction Study (CRESSIDA) study
investigators
• Am J Clin Nutr ajcn097352; First published online March 18, 2015.
doi:10.3945/ajcn.114.097352

MedicalResearch.com: Medical Research Exclusive Interviews March 24 2015

MedicalResearch.com: Medical Research Exclusive Interviews March 24 2015

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