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

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Precision Antibodies Target Defective Protein in Alzheimer’s and Parkinson’s Model
MedicalResearch.com Interview with:
Fernando Goni, PhD MS
Adjunct associate professor
Department of Neurology, Center for Cognitive Neurology NYU School of Medicine
NYU Langone Medical Center
• Medical Research: What is the background for this study? What are the main findings?
Dr. Goni: It has been established that most neurodegenerative diseases including
Alzheimer’s, Lewy Body and other dementias, Parkinson’s and prion diseases develop and
progress along similar paths. In each disease, a particular protein undergoes a change in its
shape from a soluble, physiologically functional protein to a protein that has lost the ability to
perform its required tasks in the brain, starting off a chain reaction of binding to each other
with little control. These aggregates become toxic to brain cells.
• We raised antibodies in mice against the common beta-sheet structures present in toxic
oligomers of many neurodegenerative diseases including amyloid and tau in Alzheimer’s;
oligomeric forms of prions and oligomerized alpha-synuclein in Parkinson‘s. From that
response, we produced monoclonal antibodies of the same characteristics.
• At least three of the monoclonals recognize pathological structures in histological samples of
human brains from Alzheimer’s disease, Parkinson’s disease and GSS (human prionosis). They
also recognized in vitro the oligomeric forms particular for each disease.
• In old animals of a mouse model of Alzheimer’s, that already had pathology, the monoclonal
antibodies could rescue behavior and reduced significantly the oligomers of Tau and Abeta.
Read the rest of the interviews on MedicalResearch.com
Content NOT an endorsement of efficacy and NOT intended as specific medical advice.

Precision Antibodies Target Defective Protein in Alzheimer’s and Parkinson’s Model
Fernando Goni, PhD MS
Adjunct associate professor
Department of Neurology, Center for Cognitive Neurology NYU School of Medicine
NYU Langone Medical Center
• Medical Research: What should clinicians and patients take away from your report?
• Dr. Goni: It is extremely important to select the right target to attack and be careful to
develop the most suitable strategy to minimize side effects.
• Medical Research: What recommendations do you have for future research as a result of
this study?
• Dr. Goni: We are actively pursuing a therapeutic strategy that might be a disease-modifying
approach for many neurodegenerative diseases. Still, we have to be cautious before
transferring the monoclonal antibodies to the human version. If confirmed, we could be close
to planning clinical trials; all these efforts require a lot of time and support.
• Citation: Abstract presented at the Alzheimer’s Association International Conference 2015
• Monoclonal Antibodies that Recognize Oligomeric Tau and Aβ, also Recognize Pathological
Structures in Parkinson’s disease Human Brains

Younger Black Men With Breast Cancer Have Higher Mortality Rate
Helmneh Sineshaw, MD, MPH
Senior Epidemiologist, Health Services Researcher
American Cancer Society, Inc
Atlanta, GA 30303
Dr. Sineshaw: Male breast cancer is a rare disease, and its incidence rate is increasing. Younger
black men have a higher breast cancer incidence than their white counterparts. Although
black/white disparities in treatment receipt and survival among women with breast cancer have
been widely documented in the literature, there have been few similar studies in men with breast
cancer. Previous studies were based on smaller sample size, older databases, or using data from
elderly patients.

Atlanta, GA 30303
• MedicalResearch: What are the main findings?
• Dr. Sineshaw: Treatment receipt for black and white men diagnosed with early-stage breast
cancer was remarkably similar in both younger and older age groups. However, younger
blacks had a 76% higher risk of death than younger whites, which was significantly reduced
after adjustment for insurance and income. In contrast, older black men did not have
significant excess risk of death compared with their white counterparts.

Atlanta, GA 30303
• MedicalResearch: What should clinicians and patients take away from your report?
• Dr. Sineshaw: Although no significant difference in receipt of treatment among younger black
and white men for early-stage breast cancer, younger blacks had a higher risk of death.
Physicians may play a significant role in making sure their younger black patients receive and
complete the required standard treatment. Physicians as well as patients may need to look
for opportunities that could improve receipt of optimal treatment and adherence to
treatment.
• MedicalResearch: What recommendations do you have for future research as a result of
this study?
Dr. Sineshaw: Future research should focus on how we can better address barriers in access
to optimal care and equal outcomes for all men with breast cancer.
• Citation:
• Black/White Disparities in Receipt of Treatment and Survival Among Men With Early-Stage
Breast Cancer
• Helmneh M. Sineshaw, Rachel A. Freedman, Elizabeth M. Ward, W. Dana Flanders, and
Ahmedin Jemal
• JCO JCO.2014.60.5584; published online on May 4, 2015;

Angelina Jolie’s Announcement Encouraged Some Patients’ To Get Tested For Breast Cancer
Kami Kosenko PhD
Department of Communication
North Carolina State University
Medical Research: What is the background for this study? What are the main findings?
Dr. Kosenko: In May 2013, Angelina Jolie revealed that she had had a genetic test that revealed a
BRCA1 gene mutation and, as a result, had had a preventive double mastectomy. Although the
announcement was met with widespread interest and support, some worried that that her story
would prompt unnecessary genetic tests and requests for prophylactic surgeries. These concerns
served as the basis for a Time magazine article, entitled “The Angelina Effect,” in which the
authors hypothesized that her story would have a profound impact on the general public.
Anecdotal evidence supports Time magazine’s hypothesis, but we lack empirical tests of the
Angelina effect. So, we designed a study to how Angelina’s announcement affected women’s
intentions to engage in genetic testing for BRCA1.

Kami Kosenko PhD
• Medical Research: What are the main findings?
Dr. Kosenko: We found that the vast majority of individuals surveyed had heard about
Angelina’s announcement and that her story had a greater impact on individuals who
identified with Angelina or thought of her as a friend. Also, we found that one’s family history
of cancer, alone, did not motivate one’s intention to get tested but that, for women with
affected family members and a perceived friendship with Jolie, Angelina’s announcement
strengthened their intentions to get tested.
• Dr. Kosenko: Celebrity illness stories have both reach and impact, which suggests that a
celebrity’s star power could be harnessed for health promotion efforts. In addition, celebrity
health crises can serve as a cue to action for the general public.

Kami Kosenko PhD
this study?
• Dr. Kosenko: Some worry that celebrity health crises garner attention and funding for some
diseases and not others; however, we know little about the actual impact of celebrities on
health policy and funding. This warrants additional study. Also, our study, which was
conducted in the month following Jolie’s announcement, focused on individuals’ intentions to
get tested, not actual testing behavior. Further tests of Time magazine’s hypothesis need to
attend to the story’s effects on actual testing behavior.
• Citation:
• Kami A. Kosenko, Andrew Binder, Ryan Hurley. Celebrity Influence and Identification: A Test of
the Angelina Effect. Journal of Health Communication, 2015; 150720075912008 DOI:
10.1080/10810730.2015.1064498

No Difference in PCI Stent Surgery Mortality Performed With/Without Surgical Support
Dr Scot Garg FRCP PhD (Hons) FESC
Cardiology Department, Royal Blackburn Hospital
United Kingdom.
Medical Research: What is the background for this study?
Dr. Garg: In contrast to other countries, in particular the United States, the UK has seen a vast
expansion in the number of PCI centres operating without on-site surgical support. Part of the
reason for this is that outcome data from these centres are from modest populations at short-
term follow-up; consequently the ACC/AHA have failed to give delivery of PCI in centres without
surgical back-up a strong endorsement. The study was ultimately driven therefore to show
whether any differences existed in mortality between patients having PCI in centres with- and
without surgical support at long-term follow-up in large unselected population cohort.

United Kingdom.
Medical Research: What are the main findings?
Dr. Garg: The study included the largest population of patients treated in centres without off-site
surgical support (n=119,036) and main findings were that following multi-variate adjustment
there were no differences in mortality for patients treated at centres with- or without surgical
support at 30-days, 1-year or 5-year follow-up irrespective of whether patients were treated for
stable angina, NSTEMI or STEMI. Furthermore, similar results were seen in a sensitivity analysis of
a propensity matched cohort of 74,001 patients.

United Kingdom.
• Dr. Garg: These data should provide reassurance to clinicians and patients. For clinicians it
shows that performing PCI in centres without surgical support is safe, and not associated with
an additional mortality hazard. Importantly the population studied was unrestricted including
complex patients with multi-vessel disease, chronic total occlusions, left main stem lesions
and bypass graft cases. These data show that the location of where the PCI is performed is
not important, however this does not remove the importance of ensuring an appropriate
forum is in place, such as Heart Team conference, to guarantee that the most appropriate
mode of revascularization is being selected. These data should help reassure patients that
having their PCI in a local hospital which does not have on-site surgery, does not mean that
they are having a risker procedure or one that is associated with poor outcomes.

United Kingdom.
this study?
• Dr. Garg: We would hope that the study would prompt researchers in other countries to
report outcomes from centres without on-site surgical support from their national registries
with expectation that this will better inform as to whether any specific patients benefit from
procedures performed at centres at which on-site surgical support is available. We would also
hope that the data can be used to support a stronger recommendation from the ACC/AHA for
performing PCI in centres with off-site surgical support.
• Citation:
• Garg S, Anderson SG, Oldroyd K, et al. Outcomes of percutaneous coronary intervention
performed at offsite versus onsite surgical centers in the United Kingdom. J Am Coll Cardiol
2015; 66:363-372. Abstract

Bystander CPR Programs Can Save Lives After Cardiac Arrest
Carolina Malta Hansen, M.D
Duke Clinical Research Institute
• Dr. Hansen: Approximately 300,000 persons in the United States suffer an out-of-hospital
cardiac arrest every year and under 10% survive. Cardiopulmonary resuscitation (CPR) and
defibrillation within the first few minutes of cardiac arrest can increase the chance of survival
from under 10% to over 50%. In 2010, the HeartRescue program in North Carolina initiated
statewide multifaceted interventions to improve care and outcomes for cardiac arrest
patients in North Carolina. The project included public training programs in defibrillators and
compression-only CPR at schools, hospitals and major events such as the N.C. State Fair, plus
additional instruction for EMS and other emergency workers on optimal care for patients in
cardiac arrest.

We found that following these four years of initiatives to improve care and outcomes for cardiac
arrest patients, the proportion of patients who received bystander CPR and first responder
defibrillation increased by more than 25% to approximately 50%, the combination of bystander
CPR and first responder defibrillation increased from 14% to 23%. Survival with favorable
neurologic outcome increased from 7% to 10% and this increase was only observed among
patients who received bystander CPR. Finally, we found that compared to patients who received
CPR and defibrillation by emergency medical services (EMS), patients who received bystander
and/or first responder CPR, defibrillation, or both, were more likely to survive. The combination
of bystander CPR and bystander defibrillation was associated with the best survival rates but
remained low during the study period with no increase over time.

• Dr. Hansen: Early intervention is paramount to increase the chance of surviving a cardiac
arrest and people (trained and untrained) should not hesitate to immediately start CPR and
use an automated external defibrillator (AED), if they suspect a cardiac arrest. Ordinary
people should know that their intervention is decisive to increase the chance of survival and
can’t do any harm. Also, our results suggest that strengthening first responder programs in
addition to encouraging bystander CPR is likely to improve survival. Finally, this program
shows that state and national programs to improve care of cardiac arrest, with a focus on the
community and emergency medical response, can save more lives.

this study?
• Dr. Hansen: Future research should study how we can increase bystander AED use, which is
still very low and did not increase during the study period. Future studies should also
examined whether the observed improvements have been consistent across gender, race
and socioeconomic status or whether certain groups are in disadvantage and need targeted
efforts.
• Citation:
• Malta Hansen C, Kragholm K, Pearson DA, et al. Association of Bystander and First-Responder
Intervention With Survival After Out-of-Hospital Cardiac Arrest in North Carolina, 2010-2013.
JAMA. 2015;314(3):255-264. doi:10.1001/jama.2015.7938.

High Risk Plaques Account for Only Half of Acute Coronary Events
Dr. Jagat Narula MD, PhD
Associate Dean For Global Affairs
Professor Medicine, Cardiology and Radiology
Mt. Sinai Hospital, NY
Dr. Narula: The cardiovascular diseases remain number one cause of mortality in men and
women and in high as well as middle and low income countries. It is important that we identify
those who are likely to die of preventable causes. Identification of the vulnerable plaques that are
likely to result in acute events has been an interesting focus of investigators, and numerous
intravascular imaging and noninvasive imaging strategies have been employed. CT angiography
has offered fairly attractive accuracy. We were the first to establish the features of high-risk
plaques (Motoyama, Narula JACC 2007) and their short-term prognostic implications (Motoyama,
Narula JACC 2009). In this new paper in a large population we present intermediate- to long-term
follow-up that critically analyzes the role of plaque characterization and puts it in perspective.
Should we keep chasing plaques or should we treat the patient? Does the answer lie in high risk
plaque busting or prevention be the mainstay?

From the previous studies from us and others we have known that computed tomography
angiography (CTA)-based plaque characteristics identify high-risk plaque (HRP) that predict short-
term risk of acute coronary syndrome (ACS). We in this study wanted to evaluate whether plaque
characteristics by CTA would predict intermediate- to long-term likelihood of acute events. The
presence of high-risk plaque characteristics were evaluated in more than 3000 patients
undergoing CTA and plaque progression (PP) in additional 450 patients who had two CTA one year
apart. We recorded fatal and nonfatal acute events and outcomes during follow-up: mean about
4 years and maximum up to 10 years. Acute Coronary Syndrome occurred in about 40 of ~300
(16%) with high risk plaque and 40 (less than 1.5%) of the remaining patients with non high risk
plaques. In patients with serial CTA, plaque progression also was an independent predictor of
ACS, with HRP (27%) and without HRP (10%) compared with patients without plaque progression
(0.3%).

• Dr. Narula: CTA-based characteristics of high risk plaques were independent predictors of
Acute Coronary Syndrome. However, the cumulative number of ACS patients with HRP was
similar to patients without HRP. Although Acute Coronary Syndrome incidence was 10-fold
lower in non high risk plaques, the cumulative number of patients developing ACS was similar
to those with high risk plaques; because the number of patients with non high risk plaques
was 10-fold higher.
• Although it is feasible to identify high-risk plaques and these plaques do result in adverse
events, our focus must remain on the patient and risk factors. If we only focus on plaque
characteristics we would miss out on 50% of events. Prevention remains the key.

this study?
• Dr. Narula: Plaque characterization should be commonly adapted while interpreting CT
angiography, and we must not only be limited to the results of plaque induced luminal
stenosis. Although fairly large, further confirmation of results in different cohorts would
strengthen data. It is Important that we have better automation for plaque analysis.
Noninvasive FFR assessment would complement the area of high-risk plaques further.
However, it is fairly convincing that our emphasis must remain on the diffuse disease process
and prevention rather than a plaque-based approach.
• Citation:
• Motoyama S, Ito H, Sarai M, et al. Plaque Characterization by Coronary Computed
Tomography Angiography and the Likelihood of Acute Coronary Events in Mid-Term Follow-
Up. J Am Coll Cardiol. 2015;66(4):337-346. doi:10.1016/j.jacc.2015.05.069.

Blacks are Significantly Younger Than Whites At Time of Cardiac Arrest
Dr. Sumeet Chugh MD
Pauline and Harold Price Professor of Cardiac Electrophysiology
Associate director of the Cedars-Sinai Heart Institute
Response: Research studies performed in the past 2 decades suggest that there is a higher
burden of sudden cardiac arrest in black americans compared to whites. However there are no
studies that explore the reasons for this phenomenon. Our study confirmed that these
observations hold true in the current era. There are two additional novel findings. Firstly, we
uncovered the disturbing fact that blacks are significantly younger than whites at the time of their
cardiac arrest. The majority of blacks are under the age of 65 and the majority of whites were
over 65. Furthermore, blacks who suffered sudden cardiac arrest were more likely to have
diabetes, high blood pressure and chronic kidney disease.

Dr. Sumeet Chugh MD
• Response: This initial study indicates that there may be unique clinical differences between
blacks and whites who suffer sudden cardiac arrest. In the past we assumed that reduction in
coronary disease would also reduce burden of sudden cardiac arrest. While more research is
needed, it is possible that effective prevention of sudden cardiac arrest in blacks may require
treatment of diabetes, hypertension and kidney disease. The nature of sudden cardiac arrest
prevention may be different in blacks vs. Whites.

Dr. Sumeet Chugh MD
this study?
• Response: Significant further research is needed that also compares these subjects to blacks
and whites who have not suffered sudden cardiac arrest. We need to further understand the
specific reasons for these unique clinical differences.
• Citation:
• Kyndaron Reinier, Gregory A. Nichols, Adriana Huertas-Vazquez, Audrey Uy-Evanado, Carmen
Teodorescu, Eric C. Stecker, Karen Gunson, Jonathan Jui, Sumeet S. Chugh. Distinctive Clinical
Profile of Blacks versus Whites Presenting with Sudden Cardiac Arrest. Circulation, 2015;
CIRCULATIONAHA.115.015673 DOI: 10.1161/CIRCULATIONAHA.115.015673

Elevation of Both apoB and nonHDL-C Imply Greater Atherosclerosis Risk in Type 1 Diabetes
Petter Bjornstad, MD
Fellow in Pediatric Diabetes & Endocrinology
Children’s Hospital Colorado & Barbara Davis Center for Childhood Diabetes
Aurora, CO 80045
• MedicalResearch: What is the background for this study?
• Dr. Bjornstad: Apolipoprotein B (apoB) and non-high density lipoprotein-cholesterol
(nonHDL-C) have been proposed to be superior indicators of cardiovascular (CV) risk than
total cholesterol and/or low density lipoprotein-cholesterol (LDL-C). Some authors argue that
while nonHDL-C and apoB correlate, they are not necessarily interchangeable, and may in
fact provide unique information about cardiovascular risk. However, there are insufficient
data on the concordance between apoB and nonHDL-C in adults with type 1 diabetes mellitus
(DM) across a wide range of risk factors for cardiovascular disease.

Aurora, CO 80045
• Dr. Bjornstad: Adults with type 1 diabetes and elevated apoB (≥90mg/dL) and nonHDL-C
(≥130mg/dL) had greater odds of coronary artery calcification progression compared to
adults with type 1 diabetes and normal apoB and nonHDL-C (OR: 1.90, 95% CI 1.15-3.15), and
compared to adults with type 1 diabetes with elevated apoB alone (OR: 2.86, 95% CI 1.43-
5.74) adjusting for age, sex, duration, HbA1c and statins. We also obtained similar results
with elevated apoB and nonHDL-C defined as ≥ the cohort means. Accordingly, we concluded
that elevated apoB and nonHDL-C carry a greater risk of atherosclerosis than elevated apoB
in the absence of elevated nonHDL-C in adults with type 1 diabetes.

Aurora, CO 80045
• Dr. Bjornstad: Although nonHDL-C and apoB correlate and elevated categories of each
measure are concordant, our data show that a significant proportion of adults with type 1
diabetes had elevated apoB in the absence of elevated nonHDL-C, a lipid profile that was
associated with lower risk of atherosclerosis than elevated apoB and elevated nonHDL-C. In
other words, our data suggest that apoB and nonHDL-C should be viewed as complementary
rather than competitive indices of CVD risk in type 1 diabetes.

Aurora, CO 80045
this study?
• Dr. Bjornstad: Our 6-year follow-up may have been insufficient to fully examine progression
of coronary artery calcification in a cohort of relatively young adults with type 1 diabetes and
fairly favorable lipid profiles. For that reason, further research should examine the
longitudinal relationships of apoB and nonHDL-C with atherosclerosis and CV events over a
longer time in adults with type 1 diabetes.
• Citation:
• Relation of Combined Non-High Density Lipoprotein-Cholesterol and Apolipoprotein B with
Atherosclerosis in Adults with Type 1 Diabetes Mellitus
• Bjornstad, Petter et al. American Journal of Cardiology
• DOI: http://dx.doi.org/10.1016/j.amjcard.2015.07.020

Prenatal Factors and Unhealthy Lifestyle Contribute To Risk of Type 2 Diabetes
Lu Qi, MD, PhD, FAHA
Assistant Professor of Medicine Harvard Medical School
Assistant Professor of Nutrition HarvardSchool of Public Health
Dr. Lu Qi: Most previous studies focus on the effects of either lifestyle or prenatal
malnutrition on diabetes risk; no study has assess these two types of risk factors in
combination.
• Dr. Lu Qi: Adulthood lifestyle and prenatal environment such as nutrition are equally
important, and should be considered simultaneously in prevention of diabetes.

Prenatal Factors and Unhealthy Lifestyle Contribute To Risk of Type 2 Diabetes
Lu Qi, MD, PhD, FAHA
Assistant Professor of Medicine Harvard Medical School
Assistant Professor of Nutrition HarvardSchool of Public Health
this study?
• Dr. Lu Qi: To further investigate the potential mechanisms underlying the interactions
between prenatal developmental risk and adulthood exposure to unhealthy lifestyle.
• Citation:
• Li Yanping, Ley Sylvia H, Tobias Deirdre K, Chiuve Stephanie E, VanderWeele Tyler J, Rich-
Edwards Janet W et al. Birth weight and later life adherence to unhealthy lifestyles in
predicting type 2 diabetes: prospective cohort study 2015; 351 :h3672

Prolonged Standing Associated With Musculoskeletal Disorders and Health Problems
Maria-Gabriela Garcia Ph.D candidate
Sensory-Motor Systems Lab, ETH Zurich Zurich, Switzerland and
Dr. B.J. Martin
University of Michigan, Ann Arbor
Response: Many workers are required to stand for prolong periods of time at their workplace.
Several investigations have associated prolonged standing with back pain, and musculoskeletal
disorders. The accumulation of muscle fatigue is assumed to lead to such disorders. However,
the long-lasting effects of fatigue in the lower limbs induced by prolonged standing work have
received little attention. Our main findings indicate that 5 hours of standing work including
regular seated rest breaks lead to a significant long-term fatigue in the lower leg muscles. The
objective measures showed that the effects persisted at least 30 min after a seated recovery
period while they were not subjectively perceived. Thus, subjective evaluations may not be
sensitive to the long-term effects of fatigue. In addition, fatigue was not observed after 2 hours
of standing work.

Dr. B.J. Martin
• Response: Anyone expose to a prolonged standing work should be aware of the health
implications it could have. Prolonged standing has been associated with several
musculoskeletal disorders and health problems such us low back pain, varicose veins,
arthrosis, among others. Standing over a 2 hour period might be demanding for the
musculoskeletal system even in young persons. Furthermore, 5 min seated breaks and a
lunch break do not appear sufficient to prevent the development of fatigue of long duration.
We do not recommend seating only as an alternative to standing as prolonged seating
present also major issues (e.g., reduced metabolism, back pain, etc….).

Dr. B.J. Martin
this study?
• Response: Future research should consider evaluating prolong standing with objective
measures sensitive to long term fatigue and avoid reliance on self reported fatigue or
discomfort. Furthermore, the evaluation of intervention methods such as “antifatigue mats”
should also consider objective measurements sensitive to long term fatigue effects. Current
mat designs do not appear to mitigate these effects of fatigue, as shown by some studies,
including one of our own studies. Hence other designs should be tested. It may be very
important to investigate the effects of alternatives such as seat-stand or seating- standing
periods as well as. It should be noted that most seat-stand chairs do not allow complete
relaxation of leg muscles. We are also currently expending our study to quantify the benefit
of other alternatives.
• Citation:
• Long-Term Muscle Fatigue After Standing Work
• Garcia MG1, Läubli T2, Martin BJ3.
• um Factors. 2015 Jun 5. pii: 0018720815590293. [Epub ahead of print]

Oral Anticoagulation Medications Have Led To More Patients Treated For Atrial Fibrillation
Geoffrey Barnes, MD, MSc
Clinical Lecturer
Cardiovascular Medicine and Vascular Medicine
University of Michigan Health System
• Dr. Barnes: While warfarin has been the primary oral anticoagulant used for over 60 years, a
new class of anticoagulants known as ‘direct oral anticoagulants’ (including dabigatran,
rivaroxaban and apixaban) have been introduced within the last 5 years. These newer
medications were developed to be easier for patients and physicians to use. While early data
suggested quick adoption of these medications, there had not been a nation-wide
assessment of their use and how specific diseases influenced the use of specific oral
anticoagulants.
• Using a national sample of office visits, we generated national estimates of oral anticoagulant
use for patients between 2009 and 2014. The primary finding is that total number of office
visits where an anticoagulant was used increased from 2.05 million to 2.83 million between
2009 and 2014, largely driven by a rapid increase in the use of the direct oral anticoagulant
medications. Specifically among patient visits for atrial fibrillation, the total number of visits
where an oral anticoagulant was used increased from 52% to 67%. This is important because
there has long been concern about “under treatment” of atrial fibrillation and the risk of
stroke for patients who do not receive anticoagulation. This study suggests that the direct
oral anticoagulants may be helping to protect more patients with atrial fibrillation from
strokes.

Clinical Lecturer
• Dr. Barnes: This study suggests that clinicians are more frequently using oral anticoagulants
for their atrial fibrillation patients. However, there are still a significant number of office
visits where atrial fibrillation patients are not receiving any oral anticoagulants. We need to
find ways to improve the use of anticoagulants for atrial fibrillation patients to help prevent
life-threatening strokes.
• The study also provides reassurance to providers that there is widespread and rapid adoption
of the first three direct oral anticoagulants (dabigatran, rivaroxaban and apixaban). This class
of medications now represents ~40% of all office visits where an oral anticoagulant was used.

Clinical Lecturer
this study?
• Dr. Barnes: Future studies will need to understand how and why patients and providers
select specific oral anticoagulants. Studies will also need to focus on strategies to further
improve the use of oral anticoagulants for atrial fibrillation patients. Lastly, we will need to
explore how the trend of increasing direct oral anticoagulant use continues in the future and
the economic impact it has on healthcare spending.
• Citation:
• National Trends in Ambulatory Oral Anticoagulant Use
• Barnes, Geoffrey D. et al. Published Online: July 02, 2015
• The American Journal of Medicine
• DOI: http://dx.doi.org/10.1016/j.amjmed.2015.05.044

No Association Between Kidney Stones and Osteoporosis or Fractures in Women
Monique Bethel, MD
Subspecialty Service, Department of Veterans Affairs Medical Center,
Department of Medicine, Section of Rheumatology Georgia Regents University
Augusta, GA
• Dr. Bethel: Osteoporosis and kidney stones share several risk factors, including elevated
calcium in the urine (hypercalciuria), low potassium intake, and possibly, diets high in sodium.
Accordingly, several studies have shown a significant relationship between kidney stones and
osteoporosis in men. However, it is unclear if this relationship is also true for women.
Previous studies examining this association have been small and inconclusive. With the
Women’s Health Initiative, we had data available from approximately 150,000
postmenopausal women in the US. Using this database, we were able to study the
relationship between kidney stones and changes in bone mineral density and fractures.

Monique Bethel, MD
Augusta, GA
• relationship between kidney stones and changes in bone mineral density and fractures.
• Dr. Bethel: We found no association between the presence of kidney stones and changes in
bone mineral density over time at the hip, lumbar spine, or the whole body. Also, there was
no association between the presence of kidney stones and fractures. We also found that 14%
of women who had a history of kidney stones upon entering the studies had another one
occur during the course of the study (approximately 8 years).

Monique Bethel, MD
Augusta, GA
•
MedicalResearch: What should clinicians and patients take away from your report?
• Dr. Bethel: The bottom line is that unlike what we see in men, kidney stones do not increase
the risk for osteoporosis or fractures in postmenopausal women. However, women with a
kidney stone are at significant risk for another stone, therefore, clinicians should advise these
patients on risk reduction measures to prevent future kidney stones.

Monique Bethel, MD
Augusta, GA
this study?
• Dr. Bethel: Our findings only relate to postmenopausal women; in premenopausal females an
association may exist. Additionally, the urine calcium levels of WHI participants was not
available, and in the subset of women with kidney stones and hypercalciuria an association
may exist. Future studies may be able to address these questions.
• Citation:
• J Bone Miner Res. 2015 May 19. doi: 10.1002/jbmr.2553. [Epub ahead of print]
• Urinary Tract Stones and Osteoporosis: Findings From the Women’s Health Initiative.
• Carbone LD1,2, Hovey KM3, Andrews CA4, Thomas F5, Sorensen MD6,7, Crandall CJ8, Watts NB9,
Bethel M1,2, Johnson KC5.

Investigational Drug Shows Promise In Treating Marburg Hemorrhagic Fever
Alison E. Heald, M.D
Harborview Medical Center
Seattle, WA 98104
• MedicalResearch: What is the background for this study? What are the main findings?
• Dr. Heald: Marburg virus causes a very serious, potentially fatal infection in humans for which
there is currently no licensed or approved treatments or vaccines. We demonstrated that
AVI-7288, an investigational drug specifically directed against Marburg virus, is effective in
preventing death in monkeys exposed to Marburg virus in an experimental model, and that
AVI-7288 raises no safety concerns in parameters measured in the healthy human volunteers
dosed at or above the estimated efficacious dose. Importantly, taken together, these results
have allowed us to predict a dose that could be expected to protect humans exposed to
Marburg virus.

Seattle, WA 98104
• Dr. Heald: Developing new drugs for treatment of uncommon, lethal infectious diseases is
difficult, since it’s unethical to deliberately give the infectious agent to humans to test
promising drugs, and it’s difficult to conduct field studies for an infection that occurs
infrequently. This report bridges between efficacy studies in monkeys and safety studies in
humans, demonstrating that AVI-7288 holds promise as a potential therapeutic for Marburg
hemorrhagic fever.

Seattle, WA 98104
this study?
• Dr. Heald: Additional studies of the safety of AVI-7288 need to be conducted in humans, and
additional studies of AVI-7288 need to be completed in monkeys to determine its efficacy
after longer delays in treatment and after inoculation with other variants of Marburg virus.
• Citation:
• AVI-7288 for Marburg Virus in Nonhuman Primates and Humans
• Alison E. Heald, M.D., Jay S. Charleston, Ph.D., Patrick L. Iversen, Ph.D., Travis K. Warren,
Ph.D., Jay B. Saoud, Ph.D., Mohamed Al-Ibrahim, M.B., Ch.B., Jay Wells, B.S., Kelly L. Warfield,
Ph.D., Dana L. Swenson, Ph.D., Lisa S. Welch, B.S., Peter Sazani, Ph.D., Michael Wong, M.D.,
Diane Berry, Ph.D., Edward M. Kaye, M.D., and Sina Bavari, Ph.D.
• N Engl J Med 2015; 373:339-348
• July 23, 2015 DOI: 10.1056/NEJMoa141034

Change in PAP Smear Guidelines Unintentionally Means Fewer Chlamydia Tests
Allison Ursu, MD
Department of Family Medicine
University of Michigan Medical School
Ann Arbor
Dr. Ursu: This study was the result of a trend I noticed in clinical practice when in 2009 ACOG
recommended that screening for cervical cancer =not begin until age 21 and it seemed that
chlamydia screening could be easily missed. When a PAP test is done for cervical cancer
screening it is very easy to send another swab for chlamydia screening. Our main findings are two
years after the 2009 guideline change the rates of PAP tests decreased significantly which was
appropriate but there was an unintended consequence of a significant decrease in chlamydia
screening despite no change to the recommendation of chlamydia screening for females age 16-
24.

Allison Ursu, MD
Ann Arbor
• Dr. Ursu: For clinicians: after my study several departments at the University of Michigan
(Family Medicine, Internal Medicine, OBGYN, Pediatrics and the University Health Service)
formed a task force to identify barriers to chlamydia screening and improve
our institution’s screening rates. About 1 year ago we implemented an outpatient based
protocol to capture all eligible 16-24 year old women that relies on a team based approach
and a clinical decision support tool in our EMR. These changes have significantly improved
our rates of screening.
• For patients: chlamydia is the most common sexually transmitted infection, usually has no
symptoms, and can cause serious health problems . It is easily tested for by a urine test and is
easily cured with antibiotics.

Allison Ursu, MD
Ann Arbor
this study?
• Dr. Ursu: It would be interesting to know if chlamydia screening decreased in women aged
21-24 after the guideline change as they are having less frequent PAP testing. We are
currently assessing whether our novel approach to screening will lead to more screening,
decreased rates of chlamydia transmission and decreased rates complications from
chlamydia like pelvic inflammatory disease.
• Citation:
• Annals Journal Club: Impact of Cervical Cancer Screening Guidelines on Screening for
Chlamydia
Allison Ursu, Ananda Sen, and Mack Ruffin
Ann Fam Med July/August 2015 13:361-363; doi:10.1370/afm.1811

Study Evaluates Cannabis For Pain From Diabetic Neuropathy
Mark S. Wallace MD
Department of Anesthesiology
School of Medicine
University of California, San Diego, California
Dr. Wallace: The study was funded by the center for medicinal cannabis research at the
University of California San Diego. The center was funded by the state of California. The center
was the first to fund a series of double-blind randomized controlled trials with inhaled cannabis
for neuropathic pain. My trial is the first in diabetic peripheral neuropathy pain which is one of
the most prevalent pain syndromes in our society with limited treatments. We found a dose
dependent reduction in pain. However there was also a dose dependent increase in euphoria
and sedation which may limit clinical use. Effects on neurocognitive functioning were minimal.

Mark S. Wallace MD
School of Medicine
• Dr. Wallace: This was a single dose study and results should be interpreted with caution. This
study used cannabis that was high in tetrahydrocannabinol (THC) and low in cannabidiol
(CBD). Therefore, it showed that THC can provide pain relief with minimal effects on
neurocognitive functioning. However, euphoria and sedation may limit use.

Mark S. Wallace MD
School of Medicine
this study?
• Dr. Wallace: We need more long-term chronic delivery studies with cannabis to determine
long-term efficacy and safety. The sedation from THC may be beneficial for sleep as many
chronic pain patients suffer from sleep disturbance with very limited options. THC may prove
a very valuable treatment and further studies are needed. We also need more studies using
CBD which has no psychoactive effects but appears to have many medicinal uses.
• Citation:
• J Pain. 2015 Jul;16(7):616-27. doi: 10.1016/j.jpain.2015.03.008. Epub 2015 Apr 3.
• Efficacy of Inhaled Cannabis on Painful Diabetic Neuropathy.
• Wallace MS1, Marcotte TD2, Umlauf A2, Gouaux B2, Atkinson JH3.

Compliance With Guidelines Not Linked To Outcomes in Traumatic Brain Injury
Aaron J. Dawes, MD
Fellow, VA/RWJF Clinical Scholars Program
Division of Health Services Research, University of California Los Angeles
Los Angeles, CA 90024
Dr. Dawes: In the fall of 2013, we formed the Los Angeles County Trauma Consortium, building
upon a prior administrative relationship between LA County’s 14 trauma centers. We added
health research researchers from UCLA and USC, and shifted the focus of the group from
logistical issues to quality improvement. As a first project, our hospitals wanted to know if there
was any variation in how traumatic brain injury patients are cared for across the county.
Traumatic brain injury accounts for over 1/3 of all injury-related deaths in the U.S. and is the
number one reason for ambulance transport to a trauma center in LA County.

Aaron J. Dawes, MD
•
• When we looked at the data, we found widespread variation in both how these patients were
cared for at different hospitals and what happened to them as a result of that care. After
adjusting for important differences in patient mix, we found that mortality rates varied by
hospital from roughly 25% to 55%. As we tried to explain this variation, we looked into how
often hospitals complied with two evidence-based guidelines from the Brain Trauma
Foundation, hoping that we could eventually develop an intervention to boost compliance
with these recommended care practices. While compliance rates varied even more widely
than mortality—from 10 to 65% for intracranial pressure monitoring and 7 to 76% for
craniotomy—they did not appear to be associated with risk-adjusted mortality rates. Put
simply, we found no connection between how often hospitals complied with the guidelines
and how likely their patients were to survive.

Aaron J. Dawes, MD
• Dr. Dawes: Two things. First, despite efforts from organizations like the Brain Trauma
Foundation, the clinical care of patients with severe traumatic brain injury is still variable,
even within a single regional trauma system. Overall less than 50% of severe traumatic brain
injury patients in our county received two recommend care processes. On the one hand, this
means that we have a lot of room to improve, but, on the other, learning where we need to
improve an important first step. We really believe that the best way to improve quality is to
come together as a trauma system, to share data and to share practices, which is what we’re
doing with the Consortium.
• Second, the lack of an association between compliance and mortality suggests that these
particular metrics should not be used to judge a hospital’s quality. Part of this may be
because the metrics themselves are rather blunt: both look only at whether or not a
procedure is done, not how that procedure is done, what other treatments are used, and
how additional information from these procedures is used to direct care. We believe in
evidence-based medicine and in the use of guidelines to help guide care, however, our study
suggests that certain metrics just don’t tell you enough about hospital quality. We need to
develop and utilize better measurement strategies to help hospitals improve.

Aaron J. Dawes, MD
this study?
• Dr. Dawes: Our major work now has been to explain the variation that we found in risk-
adjusted mortality rates. If guideline compliance is not the answer—and our study suggests it
is not—then what is driving these differences? To do this, we have been meeting as a
Consortium to compare practices and are planning site visits where clinicians from different
hospitals actually watch and comment on how other trauma teams care for their patients.
We hope this will give us the information we need to try to better standardize care in ways
that actually improve clinical outcomes for all traumatically-injured patients in LA County.
• Citation: Dawes AJ, Sacks GD, Cryer H, et al. Compliance With Evidence-Based Guidelines and
Interhospital Variation in Mortality for Patients With Severe Traumatic Brain Injury. JAMA
Surg. Published online July 22, 2015. doi:10.1001/jamasurg.2015.1678.

Melanoma: Lymph Node Radiation After Lymphadenectomy Did Not Improve Survival
Michael A Henderson MBBS BMedSc MD FRACS
Professor of Surgery, University of Melbourne
Deputy Director Division of Cancer Surgery Head Skin and Melanoma Service
Division of Cancer Surgery
• Dr. Henderson: A number of retrospective reviews of adjuvant radiotherapy after
lymphadenectomy for patients at high risk of further lymph node field relapse had all
suggested that the risk of lymph node field relapse was reduced but there was controversy
about whether there was any impact on survival. In addition many clinicians were concerned
about the side effects of radiotherapy and in the absence of a proven survival benefit were
reluctant to recommend it. Previously a phase 2 trial of adjuvant radiotherapy conducted by
one of our co-authors Prof Bryan Burmiester confirmed that the morbidity of lymph node
field radiotherapy was limited and the risks of recurrence was reduced. On that basis the
current ANZMTG TROG randomised multicentre trial was initiated.

In summary this final report updates information on overall survival, lymph node field relapse etc
and provides information for the first time on long term toxicity of treatment, quality of life and
lymphedema. Adjuvant lymph node field radiotherapy for patients at high risk of further lymph
node field relapse reduces the risk of further lymph node field relapse by 50% but it has no effect
on survival. Although radiotherapy toxicity was common (3 in 4 patients), mostly involving skin
and subcutaneous tissue it was mild-to-moderate in severity and had little impact upon the
patient’s quality of life as measured by the FACT-G quality of life tool. Specific regional symptoms
were more common in the radiated group. Limb volume measurements confirmed a significant
but modest increase for patients receiving inguinal radiation (15%) but not for axillary radiation.

In the design of this trial, a decision was made to allow patients in the observation arm who
developed an isolated lymph node field relapse to be salvaged by surgery and or radiotherapy.
There were only two patients in the radiotherapy arm who developed an isolated lymph node
field relapse and both died of metastatic disease. In the observation arm 26 patients developed
an isolated lymph node field relapse and the majority (23) achieved lymph node field control with
a combination of surgery and or radiotherapy. The five-year survival FROM development of a
lymph node field relapse in this group was 34% which is comparable to the overall survival of the
entire cohort (42% five-year overall survival). This information whilst a subset analysis suggests
that if it would be reasonable in some patients to consider a policy of observation only, reserving
further surgery and or radiotherapy for a second relapse.

• Dr. Henderson: At this author’s institution, the Peter MacCallum Cancer Centre in Melbourne
Australia, we do not now routinely recommend adjuvant radiotherapy after
lymphadenectomy. Increasingly our preference is to recommend that patients consider
participating in one of the new generation of adjuvant therapy trials. The extraordinary
success of immune checkpoint inhibitors and targeted therapies in advanced disease gives
great hope for an effect in the adjuvant setting. It should be remembered that patients at
high risk of further lymph node field relapse after lymphadenectomy are also at high risk of
developing metastatic disease and dying of melanoma (42% five-year overall survival was
seen in this study).

This study provides information to allow patients and clinicians to understand the benefits and
risks of adjuvant radiotherapy and make a decision in the absence of a survival benefit as to
whether they will undergo radiotherapy. This study suggests that for those patients not entering
an adjuvant study observation is a realistic option. The lymph node field relapse rate is of course
higher in patients avoiding radiotherapy but the majority who do develop an isolated lymph node
field relapse can achieve lymph node field control with a survival comparable to patients in the
adjuvant radiotherapy arm with a combination of surgery and radiotherapy.

For some patients (and clinicians) the prospect of lymph node field relapse is unacceptable
regardless of the inconvenience of treatment and possible side effects. This study provides
patients and clinicians with information on the effectiveness of treatment and likely side effects
to aid in the decision process. For other patients where participation in an adjuvant trial is not
possible e.g. the elderly or unwell and a large tumor burden (extensive extra nodal extension of
tumor) radiotherapy may be considered and balanced against anticipated side effects and
morbidity.

this study?
• Dr. Henderson: This study was conceived and undertaken during a time when there were no
effective systemic treatments for melanoma. The spectacular success of targeted therapies
and immune checkpoint inhibitors has dramatically changed the treatment options for
patients with advanced melanoma and increasingly is likely to offer options for adjuvant
therapy of patients at high risk of both lymph node field relapse and distant relapse. The
details of these treatments is currently under intense investigation. The major benefit
therefore of this study was to identify a group of patients at high risk of lymph node field
relapse and describe their clinical course. This study has confirmed that adjuvant lymph node
field radiotherapy does not impact on survival and it is reasonable to consider a policy of
close observation. The long term toxicity of radiotherapy is modest and patents quality of life
is acceptable regardless of whether they received adjuvant radiotherapy or not.
• For the future the challenge will be to integrate all the therapeutic options to maximise
outcomes with minimal morbidity.
• Citation:
• Adjuvant lymph-node field radiotherapy versus observation only in patients with melanoma
at high risk of further lymph-node field relapse after lymphadenectomy (ANZMTG
01.02/TROG 02.01): 6-year follow-up of a phase 3, randomised controlled trial

Almost A Third of Adults With Heart Disease or Stroke Don’t Take Aspirin Regularly
Dr. Jing Fang Ph.D.
Epidemiologist
Center For Disease Control
• MedicalResearch: What is the background for this study? What are the main findings?
• Dr. Fang: Although the effectiveness of aspirin for secondary prevention (e.g. people who
already have coronary heart disease or have had an ischemic stroke) of cardiovascular
disease has been determined, its prevalence as a preventive measure has varied widely
across settings, data collection methods and U.S. states. As a result, we wanted to more
closely examine aspirin use among U.S. adults with a history of coronary heart disease or
stroke.
• To determine these findings, we analyzed data from the 2013 Behavioral Risk Factor
Surveillance System. Nearly 18,000 people from 20 states and the District of Columbia with a
self-reported history of coronary heart disease or stroke were included in the annual
telephone survey.

Dr. Jing Fang Ph.D.
Epidemiologist
• Overall, we found about 70 percent of U.S. adults with heart disease or stroke reported
regularly taking aspirin – meaning every day or every other day. Out of that group, nearly 94
percent said they take aspirin for heart attack prevention, about 80 percent linked it to stroke
prevention efforts, and approximately 76 percent said they use it for both heart attack and
stroke prevention. However, four percent of respondents with pre-existing cardiovascular
problems said they take aspirin for pain relief without awareness of its benefits for
cardiovascular disease.
• Aspirin use also differed by state and sociodemographic characteristics including gender,
race/ethnicity and age. In general, men, non-Hispanic whites, individuals aged 65 and older,
and people with at least two of four risk factors (hypertension, smoking, diabetes and high
cholesterol) are more likely to use aspirin than other groups. By state, aspirin use ranged
from 44 percent in Missouri to more than 71 percent in Mississippi.

Dr. Jing Fang Ph.D.
Epidemiologist
• Dr. Fang: This study is meaningful because it helps to identify disparities in aspirin use for
secondary prevention. Public health practitioners and clinicians can use the data to target
resources and interventions in specific states or around eligible groups who report lower
aspirin use, such as women and minorities. As a result, doctors and patients can work
together on customized strategies aimed at preventing recurrent heart attacks and strokes.
• Nearly 800,000 Americans die each year from heart disease, stroke and other cardiovascular
diseases, accounting for one in every three deaths. Aspirin use is widely promoted as an
effective way to treat or prevent recurrent cardiovascular events in the U.S., and is a key
strategy in programs including Healthy People 2020 and Million Hearts®, a national initiative
aimed at preventing one million heart attacks and strokes by 2017.

Dr. Jing Fang Ph.D.
Epidemiologist
this study?
• Dr. Fang: Further work is needed to assess possible variation in aspirin use at subnational
levels and among different risk groups. It’s also important to identify how often patients and
their healthcare providers are discussing whether aspirin use is right for them.
• Citation:
• Use of Aspirin for Prevention of Recurrent Atherosclerotic Cardiovascular Disease Among
Adults — 20 States and the District of Columbia, 2013
• MMWR Weekly
• July 17, 2015 / 64(27);733-737

Lipid in Butter and Whole Fat Milk May Decrease Risk of Pre-Diabetes
Dr. Stephanie K. Venn-Watson
Doctor of Veterinary Medicine, MS
Director, Translational Medicine and Research Program
National Marine Mammal Foundation
Dr. Venn-Watson: Bottlenose dolphins, just like people, can develop a condition called
metabolic syndrome. In humans, metabolic syndrome is also called prediabetes, which affects
1 in every 3 adults in the U.S.
• Some human studies have suggested that eating a diet high in fish may lower the risk of
developing metabolic syndrome. Other similar studies, however, have had inconsistent
findings. To better understand how fish diets may be associated with dolphin metabolic
health, we compared 55 fatty acids among 49 dolphins and their dietary fish.
• We were surprised to find that the strongest predictor of lower, healthier insulin levels in
dolphins was a saturated fat called, heptadecanoic acid (or C17:0). When we provided a diet
higher in C17:0 to six dolphins over six months, their insulin, glucose, and triglycerides
normalized. We also saw an immediate decrease in ferritin, a protein which – at high levels –
may be a risk factor for metabolic syndrome.
• In addition to some fish, C17:0 is present in dairy fat, including whole fat milk and butter.
C17:0 was not present in nonfat dairy products. We hypothesize that movement towards
nonfat dairy foods may be lowering human C17:0 blood levels, which may be contributing to
the global rise in metabolic syndrome and type 2 diabetes.

• Dr. Venn-Watson: While this research is still in its early stages, our findings are consistent
with the growing body of science that not all fats are bad. In fact, some saturated fats may be
good. Clinicians and patients should closely monitor the American Dietary Guidelines (ADG)
for recommendations related to dietary cholesterol and fats. Just this year, the ADG softened
its recommendations to limit dietary cholesterol and some fats.

this study?
• Dr. Venn-Watson: To understand the relevance of our study to human health, we will be
collaborating with hospitals and other research institutions to assess C17:0 levels in a variety
of human populations with and without metabolic syndrome and type 2 diabetes.
• Citation:
• Stephanie K. Venn-Watson, Celeste Parry, Mark Baird, Sacha Stevenson, Kevin Carlin, Risa
Daniels, Cynthia R. Smith, Richard Jones, Randall S. Wells, Sam Ridgway, Eric D. Jensen.
Increased Dietary Intake of Saturated Fatty Acid Heptadecanoic Acid (C17:0) Associated with
Decreasing Ferritin and Alleviated Metabolic Syndrome in Dolphins. PLOS ONE, 2015; 10 (7):
e0132117 DOI: 10.1371/journal.pone.0132117

Menopausal Women Accumulate Fat…..Around Their Hearts
Samar R. El Khoudary, Ph.D., M.P.H.
Assistant professor
Graduate School of Public Health Department of Epidemiology
University of Pittsburgh
• Medical Research: What is the background for this study?
Response: Cardiovascular disease is the leading cause of death in women, and it increases
after age 50 – the average age when a woman is going through menopause. Weight gain in
women during and after menopause has long been attributed to aging, rather than
menopause itself. However, recent research identified changes in body fat composition and
distribution due to menopause-related hormonal fluctuations.
• No previous study had evaluated whether those changes in fat distribution during
menopause affect cardiovascular fat. Increased and excess fat around the heart and
vasculature can be more detrimental than abdominal fat, causing local inflammation and
leading to heart disease. Doubling certain types of cardiovascular fat can lead to a more than
50 percent increase in coronary events. My team and I investigated whether there may be a
link between menopause and cardiovascular fat using data from 456 women from Pittsburgh
and Chicago enrolled in the Study of Women’s Health Across the Nation (SWAN). The women
averaged about 51 years of age and were not on hormone replacement therapy.

Assistant professor
• Response: Our study is the first to find that late- and post-menopausal women have
significantly greater volumes of fat around their hearts than their pre-menopausal
counterparts. As concentrations of the sex hormone estradiol – the most potent estrogen –
declined during menopause, greater volumes of cardiovascular fat were found. The finding
held even after my colleagues and I took into account the effects of age, race, obesity,
physical activity, smoking, alcohol consumption, medication use and chronic diseases.

Assistant professor
• Response: There is mounting evidence that changes during menopause put women at
greater risk for heart disease. Doctors need to be aware of this and monitor their
menopausal patients for signs and symptoms of heart disease. And women should always
strive for a healthy lifestyle. They should discuss with their doctors the best diet and level of
physical activity to keep them healthy, particularly as they transition through menopause.

Assistant professor
this study?
• Response: Developing prevention strategies to reduce cardiovascular fat in women at midlife
may reduce their heart disease risk, especially knowing that the menopausal transition puts
women at risk for excess fat around their hearts. Previous studies suggest that reducing heart
fat is feasible through weight loss or weight management, but these studies only looked at
small numbers of people and there have been no clinical trials linking cardiovascular
outcomes with heart fat changes due to weight management interventions. Clearly there is a
need for larger scale studies to determine the best intervention strategies to help post-
menopausal women reduce fat near the heart.
• My team is also seeking more funds to evaluate whether cardiovascular fat volumes progress
over time in midlife women, and, if so, whether this progression will be associated with
greater evolution in atherosclerosis and more cardiovascular events in post-menopausal
women.
• Citation:
• Samar R. El Khoudary, Kelly J. Shields, Imke Janssen, Carrie Hanely, Matthew Budoff, Emma
Barinas-Mitchell, Susan A. Everson-Rose, Lynda H. Powell, Karen A. Matthews. Cardiovascular
Fat, Menopause and Sex Hormones in Women: The SWAN Cardiovascular Fat Ancillary Study.
The Journal of Clinical Endocrinology & Metabolism, 2015; JC.2015-2110 DOI:
10.1210/JC.2015-2110

Recessive Genes May Play Role in Coronary Artery Disease, Especially in Inbred Populations
Dr. Paraskevi Christofidou
Department of Cardiovascular Sciences, University of Leicester
NIHR Biomedical Research Unit in Cardiovascular Disease, Leicester UK
• Dr. Christofidou: Homozygosity arises when identical alleles are present on both
chromosomes. Runs of homozygosity (ROHs) are very long segments of uninterrupted
sequences of homozygous variants across the human genome. Runs of homozygosity
represent “re-union” of pieces from DNA from parents in their children. The two DNA copies
are identical because have been inherited from a common ancestor somewhere in the
distant past.
• Runs of homozygosity are recognized signature of recessive inheritance, because they allow
unmasking of recessive variants. Recessive variants only show their effect when present on
both chromosomes of an individual’s genome. Some of these ROHs may potentially harbor
variants that exert their pathological effects in the homozygous recessive state. This is
important because it helps us better understand the consequences of the recessive model of
inheritance in relation to complex diseases.

• Coronary artery disease (CAD) is a terminal clinical manifestation of cardiovascular disease
and is the leading cause of death worldwide and is the UK’s single biggest killer. Nearly one in
six men and one in ten women die from CAD. Coronary artery disease is a complex,
multifactorial disorder originating from a complicated interplay of multiple genetic and
environmental factors.
• Contributions of ROHs to the genetic architecture of CAD are not known. The primary goal of
this project was a comprehensive analysis of association between genome-wide
homozygosity measures and CAD in individuals of white European ancestry. A secondary aim
was to explore the association of ROHs and gene expression in human monocytes and
macrophages.

• Dr. Christofidou: Our analysis of 24,320 individuals from 11 populations of white European
ethnicity revealed statistically significant differences in homozygosity levels between
individuals with Coronary artery disease and control subjects.
• On average, individuals with CAD had 0.63 ROHs more than control subjects. The average
total length of ROHs was approximately 1046.92 kb greater in individuals with CAD than
control subjects. We were able to qualify a measure of genome-wide homozygosity levels in
relation to CAD – an estimated 13% increase in CAD per 1 standard deviation increase in the
proportion of the autosomal genome covered by ROHs.
• Individual ROHs showed significant associations with monocyte and macrophage expression
of genes located nearby. These associations suggest that many ROHs might be signatures of
biologically active recessive variants with a potential to regulate transcription.

• Dr. Christofidou: This is the first study that examined whether genome-wide homozygosity
levels are a risk factor for Coronary artery disease in outbred populations and whether ROHs
might play a role in regulation of gene expression within cells of key importance to
atherosclerosis.
• Our findings are important because they provide evidence for an excess of ROHs as a
potential contributor to Coronary artery disease and therefore support a theory on the role
of recessive component in the genetic architecture of CAD that was overseen by previous
genome-wide studies.
• As the offspring of inbred populations may have lower mean health and fitness because of
the homozygous expression of detrimental recessive alleles, similar effects could operate
with the more numerous recessive variants influencing complex diseases in outbred
populations.

this study?
• Dr. Christofidou: Additional work is needed to unravel the exact synergistic role of multiple
recessive variants, homozygosity levels and their association to coronary artery disease.
• Citation:
• Am J Hum Genet. 2015 Jul 7. pii: S0002-9297(15)00237-2. doi: 10.1016/j.ajhg.2015.06.001.
[Epub ahead of print]
• Runs of Homozygosity: Association with Coronary Artery Disease and Gene Expression in
Monocytes and Macrophages.
• Christofidou P1, Nelson CP2, Nikpay M3, Qu L4, Li M4, Loley C5, Debiec R1, Braund PS1, Denniff
M1, Charchar FJ6, Arjo AR7, Trégouët DA7, Goodall AH2, Cambien F7, Ouwehand WH8, Roberts
R3, Schunkert H9, Hengstenberg C9, Reilly MP10, Erdmann J11, McPherson R3, König IR5,
Thompson JR12, Samani NJ2, Tomaszewski M13.

Comparison of Surgical Techniques For Abdominal Aortic Aneurysm Repair
Dr. Marc Schermerhorn, MD
Chief of Vascular and Endovascular Surgery
Beth Israel Deaconess Medical
Dr. Schermerhorn: Abdominal Aortic Aneurysm is common, about 4% of men over 60 and 1% of
women will have AAA, higher in smokers and those with family members with AAA.
Dr. Schermerhorn: Endovascular repair has substantially lower operative mortality and
complications and patients leave the hospital earlier and are more likely to go home rather than
rehab or a nursing home.
• The early survival advantage with endovascular repair fades over time and late survival is
similar. After endovascular repair more re-interventions to maintain the Abdominal Aortic
Aneurysm repair are needed while after open repair there are more complications related to the
abdominal incision.
• Importantly, late Abdominal Aortic Aneurysm rupture is more common after endovascular
repair. This highlights the need for more research to prevent late rupture and highlights the need
for patients to continue to undergo routine surveillance to detect problems that can potentially be
fixed with a minimally invasive treatment.
• Finally, endovascular results are improving over time.
• Citation:
• Marc L. Schermerhorn, M.D., Dominique B. Buck, M.D., A. James O’Malley, Ph.D., Thomas Curran,
M.D., John C. McCallum, M.D., Jeremy Darling, B.A., and Bruce E. Landon, M.D., M.B.A.
• N Engl J Med 2015; 373:328-338
July 23, 2015
DOI: 10.1056/NEJMoa1405778

Long Term Survival After Breast Cancer Diagnosis Has Increased For All Age Groups
Mitchell H. Gail, M.D., Ph.D. Senior Investigator Biostatistics Branch
Division of Cancer Epidemiology and Genetics
National Cancer Institute National Institutes of Health
Rockville MD 20850-9780
Dr. Gail: In the United States, breast cancer survival following diagnosis has been improving
since the 1970s. We wanted to understand what might explain these shifts, to fully
characterize the changes over time, and to explore whether tumor size and estrogen
receptor status could help explain the trends in age- and stage-specific breast cancer death
rates after diagnosis.
• We evaluated survival from breast cancer from the date of diagnosis of all women diagnosed
with invasive breast cancer in the US SEER Cancer Registries between 1973 and 2010. We
excluded women with ductal or lobular carcinoma in situ. We analyzed separate age groups
(<50, 50-69, 70+ years) and SEER stage of disease (local, regional, distant).

Dr. Gail: Between 1973 and 2010, breast cancer death rates after diagnosis in the United
States have fallen for each age group of women diagnosed with local or regional stage
disease, not only in the first five years after diagnosis, but also thereafter. For women under
age 70, rates also fell for women with distant disease.
• Changes in tumor size or estrogen-receptor status do not explain much of the improvement
among women under age 70 years, but do explain roughly half the improvement in 70+ year
old women in the first five years after diagnosis.

• Dr. Gail: There have been long-term favorable trends in breast cancer survival following
diagnosis. Women under age 70, who received more intensive treatment than older women,
seem to have benefited from such treatment, because their survival improvement was not
explained by changes in tumor size or estrogen-receptor status and because even younger
women with distant disease had improved survival. Some of the improvements in 70+ year
old women may be related to treatment and some to detection of smaller lesions and
improved care, indicated by a decreasing proportion with unknown estrogen-receptor status.
• Our study had some limitations. SEER does not provide detailed treatment data on breast
cancer patients; thus the argument in favor of treatment is indirect. Our study focused on
survival improvements within disease stage. Possible benefits from screening mammography
in shifting the stage distribution were not studied, but the stage distribution has been stable
since about 1990. Other unidentified changes in the nature of the tumors diagnosed within
stage may also have played a role.

MedicalResearch.com: Medical Research Exclusive Interviews July 24 2015

MedicalResearch.com: Medical Research Exclusive Interviews July 24 2015

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MedicalResearch.com: Medical Research Exclusive Interviews July 24 2015