MedicalResearch.com: Medical Research Exclusive Interviews July 9 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 9 2015
For Informational Purposes Only: Not for Specific Medical Advice.

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Low Testosterone Linked To Obesity and Depression In Men
MedicalResearch.com Interview with:
Michael S. Irwig MD
Division of Endocrinology Medical Faculty Associates
George Washington University
• Medical Research: What is the background for this study? What are the main findings?
Response: Many factors are associated with lower testosterone levels and many men who
have their testosterone levels checked have non-specific depressive symptoms. The main
finding is a remarkably high rate of depression and depressive symptoms (56%) in men who
are referred for borderline testosterone levels. Other significant findings include a prevalence
of overweight and obesity higher than the general population
• .
• Medical Research: What should clinicians and patients take away from your report?
• Response: Symptoms of low testosterone overlap with many other conditions such as
depression. It is very important to assess for depression in men referred for borderline
testosterone levels.
Read the rest of the interviews on MedicalResearch.com
Content NOT an endorsement of efficacy and NOT intended as specific medical advice.

Low Testosterone Linked To Obesity and Depression In Men
Michael S. Irwig MD
Division of Endocrinology Medical Faculty Associates
George Washington University
• Medical Research: What recommendations do you have for future research as a result of
this study?
• Response: I recommend more research on how different mental health conditions can
impact testosterone levels.
• Citation:
• Westley, C. J., Amdur, R. L. and Irwig, M. S. (2015), High Rates of Depression and Depressive
Symptoms among Men Referred for Borderline Testosterone Levels. Journal of Sexual
Medicine. doi: 10.1111/jsm.12937

Diabetes Medication Reduced Weight and Improved Metabolic Parameters in Obese Patients
Dr. F. Xavier Pi–Sunyer MD
Division of Endocrinology and Obesity Research Center
Columbia University, New York
Dr. Pi-Sunye: In a large randomized trial, the drug Liraglutide was compared to placebo in
overweight and obese non-diabetic volunteers. Over 52 weeks, in combination with diet and
increased physical activity, Liraglutide lowered body weight by 8.4 kg as compared to 2.8 kg
in placebo. 63% vs 27% lost at least 5% of baseline weight, 33% vs 10% lost more than 10% of
baseline weight.
Medical Research: What are the implications of this report?
• Dr. Pi-Sunye: This medication adds to the armamentarium physicians will have in helping
overweight and obese patients lose weight and maintain it off.

Diabetes Medication Reduced Weight and Improved Metabolic Parameters in Obese Patients
Dr. F. Xavier Pi–Sunyer MD
Division of Endocrinology and Obesity Research Center
Columbia University, New York
• Medical Research: What is the take home message?
• Dr. Pi-Sunye: Liraglutide can lower weight, improve cardiovascular risk factors and improve
quality of life. It can also reduce the progression to type 2 diabetes from prediabetes.
this study?
• Dr. Pi-Sunye: I think it would be an advance if an oral analogue to this medication could be
developed.
• Citation:
• A Randomized, Controlled Trial of 3.0 mg of Liraglutide in Weight Management
• Xavier Pi-Sunyer, M.D., Arne Astrup, M.D., D.M.Sc., Ken Fujioka, M.D., Frank Greenway, M.D.,
Alfredo Halpern, M.D., Michel Krempf, M.D., Ph.D., David C.W. Lau, M.D., Ph.D., Carel W. le
Roux, F.R.C.P., Ph.D., Rafael Violante Ortiz, M.D., Christine Bjørn Jensen, M.D., Ph.D., and John
P.H. Wilding, D.M. for the SCALE Obesity and Prediabetes NN8022-1839 Study Group
• N Engl J Med 2015; 373:11-22
July 2, 2015 DOI: 10.1056/NEJMoa1411892

Warming Climate May Not Reduce Winter Mortality
Prof. Patrick L Kinney Ph.D.
Professor of Environmental Health Sciences and
Director, Columbia Climate and Health Program Mailman School of Public Health
Columbia University, New York, NY
• Medical Research: What is the background for this study?
Dr. Kinney: Many previous assessments have concluded that climate change will lead to large
reductions in winter mortality.
• Medical Research: What are the main findings?
Dr. Kinney: We carried out analyses that contradict this conclusion. We argue that climate
change won’t have much impact one way or the other on winter mortality.

Warming Climate May Not Reduce Winter Mortality
Prof. Patrick L Kinney Ph.D.
Professor of Environmental Health Sciences and
Director, Columbia Climate and Health Program Mailman School of Public Health
Columbia University, New York, NY
•
Medical Research: What should clinicians and patients take away from your report?
• Dr. Kinney: I don’t think we can expect marked changes in the current annual cycle of disease
and deaths (higher in winter, lower in other seasons).
this study?
• Response: Most useful would be analyses of data over long time periods in multiple
locations.
• Citation:
• Winter season mortality: will climate warming bring benefits?
• Patrick L Kinney et al 2015 Environ. Res. Lett. 10 064016
doi:10.1088/1748-9326/10/6/064016

Celiac Disease Implies Higher Risk of Other Autoimmune Diseases
Louise Emilsson, MD PhD, Postdoc
Primary Care Research unit
Vårdcentralen Värmlands Nysäter and Institute of Health and Society
University of Oslo
• MedicalResearch: What is the background for this study?
• Dr. Emilsson: Genetics is considered an important factor in the development of celiac disease
and other autoimmune diseases. For e.g. the prevalence of celiac disease is about 10% in
first-degree relatives of celiac patients compared to about 1% in the general population.
Several earlier genome-wide association study (GWAS) studies have established shared
genetic features also in-between different autoimmune diseases, however, very little is
known about the risk of developing other autoimmune diseases in relatives of celiac patients.
Therefore we assessed the risk of several other non-celiac autoimmune diseases (Crohn’s
disease, type 1 diabetes mellitus, hypothyroidism, hyperthyroidism, psoriasis, rheumatoid
arthritis, sarcoidosis, systemic lupus erythematosus or ulcerative colitis) in all first degree
relatives and spouses of Swedish celiac patients.

University of Oslo
• MedicalResearch: What should clinicians and patients take away from your report?
• Dr. Emilsson: Clinicians could benefit from knowing that the genetic predisposition for celiac
disease in celiac first-degree relative also implies a higher risk of other autoimmune diseases.
For the patients the most important message is that it seems that both genetic and
environmental factors contribute to development of autoimmune diseases.

University of Oslo
• MedicalResearch: What are the main findings?
• Dr. Emilsson: The main finding is that both first-degree relatives (+28%) and spouses (+20%)
are at increased risk of other autoimmune diseases. There are several plausible explanations
for these findings. One is of course that individuals with celiac disease and their first-degree
relatives share a genetic autoimmune predisposition, another potential explanation involves
shared environment (relevant for both first-degree relatives and spouses) but finally we
cannot rule out that a certain degree of increased awareness of signs and symptoms in both
first-degree relatives and spouses might lead to more examinations and thereby diagnoses
(so-called ascertainment bias). Probably all these mechanisms contributed to the finding.

University of Oslo
• MedicalResearch: What recommendations do you have for future research as a result of
this study?
• Dr. Emilsson: The findings open up for future research on which shared environmental
factors confer an increased risk of autoimmune diseases. Such knowledge would of course be
of high clinical importance if they also mean that prevention is possible. It would also be
interesting to see if future GWAS studies on shared genetics in-between celiac disease and
systemic lupus erythematosus would yield some new loci of shared genetic traits.
• Citation:
• Louise Emilsson, Cisca Wijmenga, Joseph A. Murray, Jonas F. Ludvigsson. Autoimmune
Disease in First-Degree Relatives and Spouses of Individuals With Celiac Disease. Clinical
Gastroenterology and Hepatology, 2015; 13 (7): 1271 DOI: 10.1016/j.cgh.2015.01.026

Evidence of Value of Orphan Drugs Inconsistent
Igho Onakpoya MD MSc Clarendon Scholar
University of Oxford
Centre for Evidence-Based Medicine
Nuffield Department of Primary Care Health Sciences
Oxford UK
• MedicalResearch: What is the background for this study? What are the main findings?
• Dr. Onakpoya: Several orphan drugs have been approved for use in Europe. However, the
drugs are costly, and evidence for their clinical effectiveness are often sparse at the time of
their approval.
• We found inconsistencies in the quality of the evidence for approved orphan drugs. We could
not identify a clear mechanism through which their prices drugs are determined. In addition,
the costs of the branded drugs are much higher than their generic or unlicensed versions.

Oxford UK
• Dr. Onakpoya: Because of inconsistencies in the evidence regarding the benefit-to-harm
balance of orphan medicines, coupled with their high prices, clinicians and patients should
assess whether the orphan drugs provide real value for money before making a decision
about their use for a medical condition.

Oxford UK
this study?
• Dr. Onakpoya: We need more clinical trials to assess the benefits and harms of orphan drugs,
especially for those which currently have low levels of evidence. Systematic reviews of some
orphan medicines are outdated, and these need to be updated since further clinical trial
results have become available. Furthermore, research aimed at providing a standard,
transparent and robust mechanism for determining the prices of orphan drugs is imperative.
• Citation:
• Effectiveness, safety and costs of orphan drugs: an evidence-based review
Igho J Onakpoya, Elizabeth A Spencer, Matthew J Thompson, Carl J Heneghan
• BMJ Open 2015;5:6 e007199 doi:10.1136/bmjopen-2014-007199

Omega-3 fatty Acid Supplementation May Benefit Mild Cognitive Impairment
Milan Fiala, M.D.
Research Professor, UCLA Department of Surgery
Los Angeles, CA
Medical Research: What is the background for this study? What are the main findings?
Dr. Fiala: Omega-3 fatty acid supplementation is well-known to public for its health benefits in
cardiovascular diseases and putative benefits against “Minor Cognitive Impairment” reported in
other studies . This study shows that omega-3 protected against oxidation and resveratrol
improves the immune system against amyloid-beta in the brain, probably by increasing its
clearance from the brain by the immune system. Overall the patients taking the drink seemed to
preserve their memory better for up to 2 years than expected based on previous studies.
However, our study was small and not controlled by a placebo, which may present a bias.

Milan Fiala, M.D.
Los Angeles, CA
• Dr. Fiala: Omega-3 supplementation with the Smartfish drink used in the study has objective
beneficial effect on the immune system important in prevention of Minor Cognitive
Impairment. However, personal problems may interfere with the immune system response
including infections, surgeries, GI intolerance, non-compliance, and personal issues like being
unable to travel with omega-3 drink ( 200 ml per day). The best responses were in ApoE3/E3
patients. Some ApoE4/E3 genotype patients have good response to the drink, whereas other
ApoE4 do not respond.

Milan Fiala, M.D.
Los Angeles, CA
this study?
• Dr. Fiala: Omega-3 fatty acid supplementation has benefits in Minor Cognitive Impairment
patients but not in patients with Alzheimer dementia, thus must be started early. Our flow
cytometric test of amyloid-beta phagocytosis can identify the patients who have defective
immunity against amyloid-beta and need omega-3 supplementation.
• Minor Cognitive Impairment is a human disease related to defective immune system against
amyloid-beta. Minor Cognitive Impairment must be investigated in human immune system of
human patients, which have specific biochemical defects not observed in animal models.
Therapy of Minor Cognitive Impairment needs to be individually applied and immunologically
monitored.
• This study was supported in part by Smartfish, Oslo, Norway.
• Citation:
• Fiala, R. C. Halder, B. Sagong, O. Ross, J. Sayre, V. Porter, D. E. Bredesen. –3 Supplementation
increases amyloid- phagocytosis and resolvin D1 in patients with minor cognitive
impairment. The FASEB Journal, 2015; DOI: 10.1096/fj.14-264218

No Definitive Biomarker Predicts Cancer Response To Radiation Therapy
Dr Ananya Choudhury
Consultant and Honorary Senior Clinical Lecturer, Clinical Oncology
The Christie NHS Foundation Trust, Wilmslow Road
Withington, Manchester, UK
Response: Although more than half of newly diagnosed cancer patients are treated with
radiotherapy, it is still not possible to select patients who will respond and tolerate
radiotherapy compared to those who do not. There has been a lot of work done to try and
isolate intrinsic biomarkers which will identify either radio-responsive or radio-resistant
disease. We have undertaken a systematic view summarising the evidence for biomarkers as
predictors of radiotherapy.
• Despite identifying more than 500 references during a systematic literature search, we found
only twelve studies which fulfilled our inclusion criteria. Important exclusion criteria included
pre-clinical studies, studies with no control population and a sample size of less than 100
patients.
• Only 10 biomarkers were identified as having been evaluated for their radiotherapy-specific
predictive value in over 100 patients in a clinical setting, highlighting that despite a rich
literature there were few high quality studies suitable for inclusion. The most extensively
studied radiotherapy predictive biomarkers were the radiosensitivity index and MRE11;
however, neither has been evaluated in a randomised controlled trial.

Dr Ananya Choudhury
• Response: Although these biomarkers show promise there is not enough evidence to justify
their use in routine practice. Further validation is needed before biomarkers can fulfil their
potential and predict treatment outcomes for large numbers of patients.

Dr Ananya Choudhury
this study?
• Response: Robust research following the REMARK guidelines such as the importance of
including a detailed assay method should be undertaken using where possible tissue
collected from large clinical trials. The biomarker should be validated in multiple independent
cohorts before being tested in a biomarker-driven phase III study.
• Citation:
• Biomarkers of Tumour Radiosensitivity and Predicting Benefit from Radiotherapy
Forker LJ, Choudhury A, Kiltie AE.
• Clin Oncol (R Coll Radiol). 2015 Jun 25. pii: S0936-6555(15)00235-6. doi:
10.1016/j.clon.2015.06.002.
[Epub ahead of print

Medicare’s Inconsistent Drug Coverage Policies Can Impede Access To New Technologies
Joshua P. Cohen Ph.D
Research Associate Professor
Tufts Center for the Study of Drug Development
Boston, Massachusetts
Dr. Cohen: Florbetapir 18F was the first radioactive diagnostic agent approved by the US
Food and Drug Administration for positron emission tomography imaging of the brain to
evaluate amyloid â neuritic plaque density.
• Dr. Cohen: Medicare has restricted coverage of florbetapir in the US, whereas conspicuously
the UK NHS decided to reimburse the radiopharmaceutical. Note, the British NHS is generally
more restrictive with regard to coverage of new technologies than the Centers for Medicare
and Medicaid Services. Historically Medicare has rejected coverage of 25% of diagnostics
approved by the FDA, but covers all FDA approved drugs administered in the physician’s
office. Furthermore, Medicare has subjected labeled use of diagnostics, including a half-
dozen Alzheimer’s diagnostics, to its coverage with evidence development program while not
subjecting any labeled uses of drugs to coverage with evidence development. In sum,
diagnostics are subject to a level of scrutiny by Medicare that is rarely given Medicare Part B
drugs (physician-administered).

Medicare’s Inconsistent Drug Coverage Policies Can Impede Access To New Technologies
Joshua P. Cohen Ph.D
Tufts Center for the Study of Drug Development
Boston, Massachusetts
• Dr. Cohen: From a clinical and policymaker perspective, Medicare’s inconsistency can impede
patient access to important new technologies, such as florbetapir. Medicare should be more
consistent in terms of the level of scrutiny given diagnostics and drugs. In addition,
measurement of benefits of diagnostics such as florbetapir should be broader than patient
outcomes. In the absence of Alzheimer’s treatments that confer significant benefits,
florbetapir’s impact will be measured with respect to its ability to rule out Alzheimer’s, which
in turn will influence a patient’s treatment pathways.
this study?
• Response: A prudent approach would be for the Centers of Medicare and Medicaid Services
to provide all Medicare beneficiaries with access to florbetapir.
• Citation:
• Cohen Joshua P, Dong Jinghui, Lu Christine Y, Chakravarthy Ranjana. Restricting access to
florbetapir: Medicare coverage criteria for diagnostics and drugs are inconsistent 2015; 351
:h3333

Women With Epilepsy At Much High Risk Of Death During Delivery
Sarah C. MacDonald, BS
Harvard T. H. Chan School of Public Health
MedicalResearch: What is the background for this study? What are the main
findings?Response: Approximately 0.3-0.5% of all pregnancies are in women with epilepsy. While
individual studies have suggested that women with epilepsy may be at increased risk for certain
adverse outcomes in pregnancy, the risks have not been well quantified in large population based
samples. We addressed this issue using a large retrospective sample of delivery hospitalizations
from across the United States.The main findings were that women with epilepsy had a more than
10 fold increased risk of death during their delivery hospitalization as compared to the risk in
women without epilepsy (80 deaths per 100,000 women with epilepsy vs. 6 deaths per 100,000
in women without epilepsy). We also found that women with epilepsy were at increased risk for a
cesarean delivery, prolonged hospital stay, preeclampsia, preterm labor, stillbirth and other
adverse outcomes.

• Response: The findings from our work suggest that women with epilepsy are at a higher risk
for many adverse outcomes during their delivery admission in hospital. While this is only one
study, our work suggests that pregnancies in women with epilepsy may be high risk and that
these patients may be best treated by physicians who are comfortable caring for these
complex patients. While the relative risk of death in women with epilepsy was quite high, it is
important to note that maternal death during delivery is still very rare, with only
approximately 80 deaths for every 100,000 women with epilepsy.

this study?
• Response: Our study was not designed to determine particular causes for the increased risks
in women with epilepsy. Therefore further research is needed to understand why women
with epilepsy are at a higher risk for adverse outcomes during delivery. Future research is
also needed to determine the benefits of particular interventions. One possible route of
improvement could be in triaging women with epilepsy to higher risk centers and following
them closely throughout gestation and post-delivery.
• Citation:
• MacDonald SC, et al “Mortality and morbidity during delivery hospitalization among pregnant
women with epilepsy in the United States” JAMA Neurology 2015; DOI:
10.1001/jamaneurol.2015.1017

Rosacea May Be Linked To Skin and Thyroid Cancer
Wen-Qing Li Ph.D
Department of Dermatology Warren Alpert Medical School
Department of Epidemiology, School of Public Health,
Brown University, Providence, RI
Response: Rosacea is a chronic inflammatory cutaneous disorder and may be an end-organ
response in a systemic disorder. We systemically examined the association between personal
history of rosacea and risk of cancer based on 75088 whites in the Nurses’ Health Study
II, during a follow-up of 20 years.
Response: We suggest possible associations between personal history of rosacea and an
increased risk of thyroid cancer and Basal Cell Cancer. Analyses did not find significant
associations for other individual cancer types.

Rosacea May Be Linked To Skin and Thyroid Cancer
Wen-Qing Li Ph.D
Department of Dermatology Warren Alpert Medical School
Department of Epidemiology, School of Public Health,
Brown University, Providence, RI
• Response: We provide evidence demonstrating that rosacea may represent a systemic
disorder beyond a skin condition. Pending further replication of our findings from other
studies, clinicians would be suggested to closely follow up their Rosacea cases for potential
malignant outcomes. Frequent physical examinations would also be suggested for patients.
this study?
• Response: Further studies are required to replicate our findings in other
populations, particularly those of women and non-Caucasians. It would be critical to explore
the potential heterogeneities for the association with cancer in different subtypes of
rosacea. Studies are warranted to explore the underlying mechanisms for our findings.
• Citation:
• Personal history of rosacea and risk of incident cancer among women in the US
• W-Q Li, M Zhang, F W Danby, J Han and A A Qureshi
British Journal of Cancer advance online publication 23 June 2015; doi: 10.1038/bjc.2015.217

Key Study Shifts Focus To Smooth Muscle Cells In Atherosclerotic Heart Disease
Dr. Gary K Owens Ph.D
Robert M. Berne Cardiovascular Research Center
University of Virginia, Charlottesville, Virginia
Medical Research: What is the background for this study?
Dr. Owens: The leading cause of death in the USA and worldwide is cardiovascular disease with
many of the clinical consequences including heart attacks (myocardial infarctions) and strokes
being secondary consequences of atherosclerosis, commonly referred to as hardening of the
arteries. Importantly, a heart attack is not caused by gradual narrowing of a large coronary artery
by the atherosclerotic plaque, but rather is caused by acute rupture of a plaque that results in a
catastrophic thrombotic event that can completely occlude a major coronary artery shutting off
blood supply to a major heart region. Similarly, rupture of a plaque can result in formation of a
thrombus that breaks off and circulates to a cerebral vessel where it can occlude blood flow to a
brain region leading to a stroke. As such, it is critical to understand the mechanisms that regulate
the stability of plaques, and the likelihood of plaque rupture.

The general dogma among clinicians and cardiovascular researchers has been that
atherosclerotic plaques that have an abundance of macrophages and macrophage-derived foam
cells relative to smooth muscle cells (SMC), the cells that normally line all of your blood vessels,
are less stable and more prone to rupture with subsequent clinical consequences. However, the
evidence for this is based on use of methods that are unreliable in identifying which cells within
the plaque are truly derived from macrophages versus SMC, and even more importantly, what
mechanisms regulate phenotypic transitions of these cells that are critical in the pathogenesis of
this disease. Indeed, results of studies in cultured smooth muscle cells and macrophages have
shown that each cell can express markers of the other cell type in response to stimuli likely to be
present within advanced atherosclerotic lesions while down-regulating expression of their typical
cell selective markers. As such, previous studies in the field have likely mis-identified which cell is
which in many cases.

The goals of our studies were to clearly identify which cells within advanced atherosclerotic
lesions are derived from SMC, to determine the various phenotypes exhibited by these cells and
their functional role in lesion pathogenesis, and to determine what regulates these phenotypic
transitions.

Medical Research: What are the main findings?
Dr. Owens: Using a rigorous SMC-specific lineage tracing mouse developed by our lab, we
determined that >80% of SMC within advanced atherosclerotic lesions of ApoE knockout
hyperlipidemic mice cannot be identified using typical SMC markers such as SM alpha-actin
(SMaA), the marker used in virtually all previous studies in the field. Moreover, we observed that
approximately 1/3 of cells within lesions that express macrophage markers are of SMC not
myeloid origin and that SMC-derived lesion cells that are negative for SMaA also express markers
of mesenchymal stem cells and/or myofibroblasts. Importantly, using a novel single cell
epigenetic SMC lineage tracing method previously developed by our lab, we also showed that
transition of smooth muscle cells to macrophage-like cells also is highly prevalent within
advanced human coronary artery atherosclerotic lesions comprising about 20% of cells previously
thought to be macrophages.

Finally, we show that SMC specific knockout of the stem cell pluripotency gene Klf4 did not result
in a change in the number of smooth muscle cells within lesions but resulted in these cells
undergoing transition to a phenotype that was atheroprotective as evidenced by lesions that
were much smaller in size, that contained far fewer SMC-derived macrophage-like cells, and
which exhibited multiple indices of increased plaque stability including a thickened fibrous cap. As
such, loss of one gene, Klf4, in one cell type, SMC, had a rather profound positive impact on the
pathogenesis of atherosclerosis.

• Dr. Owens: Taken together, results of our studies indicate that smooth muscle cells-derived
cells play a much more important role in atherosclerosis pathogenesis than has generally
been appreciated but that SMC-derived lesion cells can exhibit detrimental as well as
beneficial properties depending on the nature of their phenotypic transitions. Results also
clearly establish that most previous studies of atherosclerosis have mis-identified many of
the SMC and macrophages within lesions of both man and animal models, as well as the
extent to which these cells contribute to formation of foam cells and plaque stability.

this study?
• Dr. Owens: Our results clearly establish that use of conventional markers of smooth muscle
cells and macrophages are insufficient for identifying these cell types within lesions. Future
studies need to be much more careful in interpreting results if the experimental approach
does not include rigorous lineage tracing.
• However, of greatest significance, studies are the first to our knowledge to demonstrate that
therapeutic targeting of smooth muscle cells within lesions represents a viable means of
enhancing plaque stability to reduce the probability of plaque rupture with possible
myocardial infarction or stroke. That is, can we identify therapeutic agents that induce SMC
to undergo changes in phenotype that are beneficial in promoting stability of advanced
atherosclerosis plaques?

• This represents a paradigm shift for the atherosclerosis field since therapies to date have
largely been focused on drugs such as statins that control blood lipids which do modestly
reduce disease prevalence and/or anti-inflammatory strategies targeting macrophages and
other immune cells which have largely failed, including a number of recent $500M+ clinical
trials that showed either no significant benefit or detrimental effects. A key goal for the
future is to identify the factors and mechanisms that can promote beneficial changes in
smooth muscle cells phenotype that can either augment or replace these more conventional
anti-atherosclerotic therapies.
• Citation:
• KLF4-dependent phenotypic modulation of smooth muscle cells has a key role in
atherosclerotic plaque pathogenesis
• Nature Medicine 21,628–637(2015) doi:10.1038/nm.3866Received
• 05 February 2015 Accepted 22 April 2015 Published online18 May 2015
• Laura S Shankman, Delphine Gomez,Olga A Cherepanova Morgan Salmon,
• Gabriel F Alencar,Ryan M Haskins,Pamela Swiatlowska,Alexandra A C Newman,
• Elizabeth S Greene,Adam C Straub,Brant Isakson,Gwendalyn J Randolph
• & Gary K Owens

Cognitive Behavioral Therapy May Help Many Patients With Insomnia
Jason Ong, Ph.D., CBSM
Associate Professor, Department of Behavioral Sciences
Director, Behavioral Sleep Medicine Training Program
Rush University Medical Center
Response: Insomnia is a very common sleep problem that was previously thought to be
related to another medical or psychiatric condition. Evidence now supports the notion that
insomnia can emerge as a disorder distinct from the comorbid condition. In this study, we
evaluated the effectiveness of cognitive behavioral therapy for insomnia (CBT-I), the most
widely used nonpharmacologic treatment for insomnia, in the context of medical and
psychiatric comorbidities.
• We conducted a systematic review and meta-analysis of 37 studies and found that 36% of
patients who received cognitive behavioral therapy for insomnia were in remission at post-
treatment compared to 17% who received a control or comparison condition. CBT-I had
medium to large effects for improving sleep quality and reducing the amount of time awake
in bed. Positive findings were also found on the comorbid condition, with greater
improvements in psychiatric conditions compared to medical conditions.

• Response: Patients who experience sleep disturbances should discuss their sleep problems
with their doctors. Clinicians should regularly assess for sleep disturbances in the context of
comorbid medical and psychiatric conditions and they should be aware that cognitive
behavioral therapy for insomnia is an effective treatment option.

this study?
• Response: Future studies should examined more precisely the impact of treating sleep
disturbances on the comorbid condition. This would help improve the understanding of the
relationship between sleep and overall health. In addition, research on dissemination and
implementation of cognitive behavioral therapy for insomnia is needed to find more efficient
and effective ways to deliver cognitive behavioral therapy for insomnia to patients with
insomnia. Currently, there is an insufficient number of CBT-I providers to meet the demands
of the numerous people with insomnia.
• Citation:
• Wu JQ, Appleman ER, Salazar RD, Ong JC. Cognitive Behavioral Therapy for Insomnia
Comorbid With Psychiatric and Medical Conditions: A Meta-analysis. JAMA Intern Med.
Published online July 06, 2015. doi:10.1001/jamainternmed.2015.3006.

Benzoyl Peroxide May Reduce Risk of P.acnes Infection After Surgery
Paul M. Sethi, MD
Orthopaedic & Neurosurgery Specialists
Greenwich, CT
• MedicalResearch: What is the background for this study?
• Dr. Sethi: Propionibacterium acnes is one of the most significant pathogens in shoulder
surgery; the cost of a single infection after shoulder arthroplasty may be upwards $50,000.
Residual P. acnes may be found on the skin 29% of the time immediately after surgical skin
preparation and in 70% of dermal biopsy specimens. Identifying more ideal skin preparation
may help reduce the risk of infection.
• MedicalResearch: What is the purpose of this study?
• Dr. Sethi: The purpose of this study was to evaluate the ability of topical benzoyl peroxide
(BPO) cream, along with chlorhexidine skin preparation, to reduce the chance of identifying
residual bacteria after skin preparation. Our hypothesis was that adding topical benzoyl
peroxide to our skin preparation would reduce the number of positive P. acnes cultures
identified during surgery.

Paul M. Sethi, MD
Greenwich, CT
• MedicalResearch: What are the main findings?
• Dr. Sethi: This study demonstrates that adding topical benzoyl peroxide (BPO) cream to
current skin preparation reduces the rate at which residual P. acnes is identified. When
topical BPO cream is used 48 hours before shoulder surgery, there was no significant
detectable difference in the rate of positive cultures between a control air swab and
surgically obtained samples. Our findings are important as recent studies have demonstrated
a 36% to 70% increased risk above controls for having a positive P. acnes culture.

Paul M. Sethi, MD
Greenwich, CT
• Dr. Sethi: Benzoyl Peroxide (BPO) along with current surgical preparation reduced the risk of
P. acnes. Application of BPO is an effective way to reduce P. acnes on skin at the beginning
and, importantly at the end of surgical procedure. This may result in a lower risk for
postoperative infection. This is a safe and effective adjunct to help decrease the risk for post-
operative infection after shoulder surgery.

Paul M. Sethi, MD
Greenwich, CT
this study?
• Dr. Sethi: We plan on a multi-center longitudinal study to determine if this new skin
preparation will reduce the actual rate of infection in shoulder arthroplasty across a broad
group of patients. This is very exciting as this is a simple, safe and in expensive way to reduce
post-operative infection, a potentially devastating problem.
• Citation:
• Efficacy of topical benzoyl peroxide on the reduction of Propionibacterium acnes during
shoulder surgery
• James R. Sabetta, MD Vishal P. Rana, BS Katherine B. Vadasdi, MD R. Timothy Greene, MD
James G. Cunningham, MD Seth R. Miller, MD, Paul M. Sethi, MD
• Journal of Shoulder and Elbow Surgery
• Volume 24, Issue 7, July 2015, Pages 995–1004

Modest Lifestyle Changes May Markedly Reduce Heart Failure Risk
Liana C. Del Gobbo, PhD
Postdoctoral Research Fellow
Friedman School of Nutrition Science & Policy
Tufts University Boston MA
Dr. Del Gobbo: Heart failure most commonly develops in adults over 65 years old- the most
rapidly growing portion of the US population. The condition greatly reduces the quality of life
of older adults. Heart failure is the leading cause of hospitalizations in the US among those on
Medicare, and is associated with large health care costs. Prevention is key for reducing the
burden of this disease.
• A detailed analysis of factors that might help prevent heart failure, such as a person’s pattern
of eating (as well as individual foods), in addition to other lifestyle factors (eg. smoking,
physical activity, etc), had not been previously examined all together, in the same study.
• To get a fuller picture of how to prevent this condition, this study examined the relative
importance of dietary habits and other lifestyle factors for development of heart failure.
• Our paper shows that older adults can cut their risk in half by adhering to a few healthy
lifestyle factors, including moderate physical activity, modest alcohol consumption (eg. more
than one drink/week, but not more than 1-2 drinks/day), not smoking, and maintaining a
healthy weight.

• Dr. Del Gobbo: The take-home message is encouraging- older adults can make simple
changes to reduce their heart failure risk, such as not smoking, engaging in moderate physical
activity, and maintaining a healthy weight.
• Our findings hold true for adults of both sexes, for older and younger seniors, and whether or
not adults have pre-existing cardiovascular disease, diabetes, or are on hypertensive
medications. For adults with chronic diseases, check with your doctor before starting or
changing your exercise program.

this study?
• Dr. Del Gobbo: We need to look into specific dietary determinants, such as sodium, and
physical activity type, duration, and frequency in future studies and trials for heart failure
prevention among older adults.
• We need to better understand and integrate the determinants and relative contribution of
lifestyle and other risk factors for heart failure beyond the scope of this work, including
congenital defects, cardiomyopathies, drugs and/or toxins, renal dysfunction, and genetic risk
predictors.
• Citation:
• Del Gobbo LC, Kalantarian S, Imamura F, et al. Contribution of Major Lifestyle Risk Factors for
Incident Heart Failure in Older Adults: The Cardiovascular Health Study. JCHF. 2015;3(7):520-
528. doi:10.1016/j.jchf.2015.02.009.

Autoimmune Antibodies Can Lead To EKG Abnormalities and Ventricular Arrhythmias
Mohamed Boutjdir, PhD, FAHA
Director of the Cardiovascular Research Program VA New York Harbor Healthcare System
Professor, Depts of Medicine, Cell Biology and Pharmacology, State University of New York Downstate Medical Center and
NYU School of Medicine, New York, NY
Dr. Boutjdir: Patients with autoimmune diseases including Sjogren’s syndrome, systemic
lupus erythematosus and other connective tissue diseases who are seropositive for anti-
SSA/Ro antibodies may present with corrected QTc prolongation on the surface ECG. This QTc
prolongation can be arrhythmogenic and lead to Torsades de Pointes fatal arrhythmia.
• In our study, we established for the first time an animal model for this autoimmune
associated QTc prolongation that is reminiscent of the clinical long QT2 syndrome. We
also demonstrated the functional and molecular mechanisms by which the presence of the
anti-SSA/Ro antibodies causes QTc prolongation by a direct cross-reactivity and then block of
the hERG channel (Human ether-a-go-go-related gene). This hERG channel is responsible for
cardiac repolarization and its inhibition causes QTc prolongation. We were able to pinpoint to
the target epitope at the extracellular pore forming loop between segment 5 and segment 6
of the hERG channel.

• Dr. Boutjdir: QT prolongation has been attributed to either a congenital origin resulting from
ion channel mutations or an acquired origin generally resulting from QT-prolonging drugs.
Patients with QTc prolongation are prone to complex ventricular arrhythmias, including
Torsade de Pointes, syncope, and sudden death. Here, we propose a novel form of acquired
QT prolongation of autoimmune origin induced by anti-SSA/Ro antibodies. QTc prolongation
associated with anti-SSA/Ro antibodies per se may confer an increased risk for developing
ventricular arrhythmias and represents an additional risk factor for patients with drug-
induced or congenital QTc prolongation.
• The finding from the present study supports the recommendations that adult patients with
anti-Ro antibodies may benefit from routine ECG screening for QTc prolongation and that
those already identified with anti-Ro antibodies associated QTc prolongation should receive
counseling, including education about avoiding drugs and other conditions known to prolong
the QT interval.

this study?
• Dr. Boutjdir: Large multicenter clinical trials with thousands of patients with autoimmune
diseases are warranted to confirm or infirm whether the anti-SSA/Ro antibodies are
associated with QTc prolongation and under which circumstances.
Similarly, the molecular mechanisms underlying the absence of QTc prolongation
in certain cohorts of patients despite the presence of anti-SSA/Ro antibodies need
be elucidated.
• Citation:
• Yue, M. Castrichini, U. Srivastava, F. Fabris, K. Shah, Z. Li, Y. Qu, N. El-Sherif, Z. Zhou, C.
January, M. M. Hussain, X.-C. Jiang, E. A. Sobie, M. Wahren-Herlenius, M. Chahine, P.-L.
Capecchi, F. Laghi-Pasini, P.-E. Lazzerini, M. Boutjdir. Pathogenesis of the Novel Autoimmune-
Associated Long QT Syndrome. Circulation, 2015; DOI:
10.1161/CIRCULATIONAHA.115.009800

Brown Fat Transplants May One Day Cure Type I Diabetes
Subhadra Gunawardana DVM, Ph.D
Department of Molecular Physiology & Biophysics Vanderbilt University Medical Center
Nashville, TN 37232
Response: For many years the general consensus has been that insulin replacement is essential
for treating type 1 diabetes. Recent studies increasingly show that extra-pancreatic hormones,
particularly those arising from adipose tissue, can compensate for insulin, or entirely replace the
function of insulin under appropriate circumstances. Our work on mouse models show that type
1 diabetes can be effectively reversed without insulin, through subcutaneous transplantation of
embryonic brown adipose tissue (BAT). BAT transplantation leads to replenishment of recipients’
white adipose tissue; dramatic decrease of inflammation; secretion of a number of beneficial
adipokines; and fast and long-lasting euglycemia. Insulin-independent glucose homeostasis is
established physiologically, through a combination of endogenously generated hormones arising
from the transplant and/or newly-replenished white adipose tissue.

Nashville, TN 37232
• Response: If translated to human patients, this approach could provide a cure for type 1
diabetes that does not require regular exogenous administration of insulin or any other
compound, and would thus avoid the many inherent difficulties with such therapies.

Nashville, TN 37232
this study?
• Response: The ability to reverse diabetes without insulin is unique to embryonic/fetal brown
adipose tissue. Transplantation of adult adipose tissue has failed to achieve the same results
so far. Identifying the specific embryonic factors mediating these functions would help mimic
the results with adult adipose tissue, which would greatly improve the practicality of this
approach.
• Citation:
• Insulin-independent reversal of type 1 diabetes in nonobese diabetic mice with brown
adipose tissue transplant
• Subhadra C. Gunawardana , David W. Piston
• American Journal of Physiology – Endocrinology and Metabolism Published 15 June 2015 Vol.
308 no. 12, E1043-E1055 DOI: 10.1152/ajpendo.00570.2014

Endocrine Therapies for Young Breast Cancer Patients Can Cause Abrupt Menopause Symptoms
Dr. Jürg Bernhard Ph.D.
International Breast Cancer Study Group Coordinating Center and Bern University Hospital, Inselspital, Bern, Switzerland
Response: In the combined analysis of the SOFT and TEXT trials, the aromatase inhibitor
exemestane was more effective than tamoxifen in preventing breast cancer recurrence in
young women (premenopausal) who also receive ovarian function suppression (OFS) as
adjuvant (post-surgery) treatment for hormone-sensitive early breast cancer, providing a new
treatment option for these women. These trials were conducted by the International Breast
Cancer Study Group (IBCSG) and involved more than 4700 patients of over 500 centers in 27
countries. Now we present patient-reported quality of life outcomes from these trials.
• In the TEXT and SOFT trials, patients assigned exemestane+OFS reported more detrimental
effects of bone or joint pain, vaginal dryness, greater loss of sexual interest and difficulties
becoming aroused, while patients assigned tamoxifen+OFS were more affected by hot flushes
and sweats. Global quality of life domains (mood, ability to cope and physical well-being)
were similar between the randomized treatment groups.

• Response: From a quality of life perspective, there is no strong indication favoring either
exemestane+OFS or tamoxifen+OFS. The different side effects of the two treatments should
be considered with each patient, to determine how these symptoms might affect her
individually, especially considering the better disease control for one of the treatments.

this study?
• Response: Endocrine treatments for premenopausal women can cause menopausal
symptoms earlier in their lives than natural menopause, and often more abruptly. These two
treatments both cause treatment-induced menopausal symptoms. An early recognition of
the impact these symptoms is essential for patient care. Some of the menopausal symptoms
can be lessened by a multidisciplinary approach, but there is also a need to develop more
safe and effective treatments for menopausal symptoms.
• Citation:
• Patient-reported outcomes with adjuvant exemestane versus tamoxifen in premenopausal
women with early breast cancer undergoing ovarian suppression (TEXT and SOFT): a
combined analysis of two phase 3 randomised trials
• Dr Jürg Bernhard, PhD,Weixiu Luo, MD,Karin Ribi, PhD,Marco Colleoni, MD,Harold J Burstein,
MD,Carlo Tondini, MD,Graziella Pinotti, MD,Simon Spazzapan, MD,Thomas Ruhstaller,
MD,Fabio Puglisi, MD,Lorenzo Pavesi, MD,Vani Parmar, MBBS,Meredith M Regan, ScD,Olivia
Pagani, MD,Gini F Fleming, MD,Prudence A Francis, MD,Karen N Price, BS Alan S Coates,
MD,Richard D Gelber, PhD,Aron Goldhirsch, MD Barbara A Walley, MD
• Lancet Oncology Volume 16, No. 7, p848–858, July 2015
• DOI: http://dx.doi.org/10.1016/S1470-2045(15)00049-2

Hormonal and Reproductive Factors Influence Uterine Cancer Risk in Lynch Syndrome
Aung Ko Win, MBBS MPH PhD Research Fellow
NHMRC Early Career Clinical Research Fellow
Centre for Epidemiology and Biostatistics
Melbourne School of Population and Global Health
Response: About 2-5% of uterine cancer are associated with an underlying genetic condition
mainly Lynch syndrome. Lynch syndrome is caused by a mutation in one of the mismatch
repair genes. At least 1 in 1000 people in the population have a mutation that causes Lynch
syndrome and these people have a very high risk of cancers mainly bowel and uterine
cancers. One in three women with a mutation in one of the mismatch repair genes are likely
to develop a uterine cancer in their lifetime. The only way to reduce the risk of uterine cancer
for these women is to remove the uterus. There is no current recommendation for screening
method to detect uterine cancer early. Almost nothing is known about if and how lifestyle
factors and hormonal factors can modify their risk of uterine cancer.
• By studying 1128 women with a mutation that causes Lynch syndrome who were recruited
from Australia, New Zealand, Canada and the USA, we found that later age at first menstrual
cycle, having one or more live births, and using hormonal contraceptive use for one year or
longer were associated with a lower risk of uterine cancer.

• Response: For women with a Lynch syndrome mutation, some reproductive and hormonal
factors are associated with a lower risk of uterine cancer. The directions and strengths of
associations are similar to those for women from the general population. If replicated,
women with a Lynch syndrome mutation may be counseled like the general population in
regard to hormonal influences on uterine cancer risk.

this study?
• Response: It is important to conduct further research on the role of lifestyle and hormonal
factors in the development of uterine cancer in women with a Lynch syndrome mutation.
Identifying modifiers of cancer risks for people with a Lynch syndrome mutation is important
for them to reduce their cancer risks.
• Citation:
• Seyedeh Ghazaleh Dashti, Rowena Chau, Driss Ait Ouakrim, Daniel D. Buchanan, Mark
Clendenning, Joanne P. Young, Ingrid M. Winship, Julie Arnold, Dennis J. Ahnen, Robert W.
Haile, Graham Casey, Steven Gallinger, Stephen N. Thibodeau, Noralane M. Lindor, Loïc Le
Marchand, Polly A. Newcomb, John D. Potter, John A. Baron, John L. Hopper, Mark A. Jenkins,
Aung Ko Win. Female Hormonal Factors and the Risk of Endometrial Cancer in Lynch
Syndrome. JAMA, 2015; 314 (1): 61 DOI: 10.1001/jama.2015.6789

Aspirin and Ibuprofen May Reduce Bowel Cancer Risk in Lynch Syndrome
Aung Ko Win, MBBS MPH PhD
Research Fellow
Response: At least 1 in 1,000 people in the population have a mutation in one of the
mismatch repair genes that causes Lynch syndrome. These people have a very high risk of
bowel cancer (colorectal cancer): if nothing is done, about half would develop the
disease. The main risk reduction method for these people is to have regular colonoscopy
screening every year. Almost nothing is known whether or not lifestyle factors and
medications can modify the risk of bowel cancer for people with Lynch syndrome.
• A study was conducted to investigate the associations between aspirin and ibuprofen intake
and the risk of bowel cancer, by studying 1,858 people with Lynch syndrome who were
recruited into the Colon Cancer Family Registry from Australia, New Zealand, Canada and the
USA. This is the largest study to date investigating the associations between aspirin,
ibuprofen and bowel cancer risk for people with Lynch syndrome.

Research Fellow
• Response: People with Lynch syndrome who took aspirin regularly have half the risk of
developing bowel cancer compared with people who did not take aspirin. People with Lynch
syndrome who took ibuprofen regularly, another nonsteroidal anti-inflammatory drug, were
about 60% less likely to develop bowel cancer compared with people who did not take
ibuprofen. These associations were seen in both men and women.

Research Fellow
• Response: For people with Lynch syndrome, chemoprevention by taking aspirin and
ibuprofen might be effective in reducing their risk of bowel cancer.
this study?
• Response: Further studies are needed to help determine the optimal dose, duration and
timing of taking aspirin and ibuprofen to recommend for people with Lynch syndrome.
• Citation:
• Driss Ait Ouakrim, Seyedeh Ghazaleh Dashti, Rowena Chau, Daniel D. Buchanan, Mark
Clendenning, Christophe Rosty, Ingrid M. Winship, Joanne P. Young, Graham G. Giles, Barbara
Leggett, Finlay A. Macrae, Dennis J. Ahnen, Graham Casey, Steven Gallinger, Robert W. Haile,
Loïc Le Marchand, Stephen N. Thibodeau, Noralane M. Lindor, Polly A. Newcomb, John D.
Potter, John A. Baron, John L. Hopper, Mark A. Jenkins, and Aung Ko Win
• Aspirin, Ibuprofen, and the Risk of Colorectal Cancer in Lynch Syndrome JNCI J Natl Cancer
Inst (2015) 107 (9): djv170 doi:10.1093/jnci/djv170 First published online June 24, 2015 (11
pages)

Residents Participation In Neurosurgery Did Not 30-Day Outcomes
Judy Huang, M.D. Professor of Neurosurgery
Program Director, Neurosurgery Residency Program
Fellowship Director, Cerebrovascular Neurosurgery
Johns Hopkins Hospital
Dr. Huang: Residents are medical school graduates who are in training programs working
alongside and under supervision of more senior physicians, known as attendings. Patients are
sometimes wary of having residents assist in their operations, but an analysis of 16,098 brain and
spine surgeries performed across the United States finds that resident participation does not
raise patient risks for postoperative complications or death.

• Dr. Huang: An analysis of the data from 16,098 patients in American College of Surgeons
National Surgical Quality Improvement Program database who had undergone elective or
emergent neurosurgical procedures between 2006 and 2012 suggests that contributions of
residents had no effect on patients’ risks of postoperative complications or death within 30
days of the surgery.
• Overall, 15.8% of all patients had at least one postoperative complication. A complication
rate of 20.12% was found in the attending+resident group, while patients with an attending-
only surgeon had a statistically significantly lower complication rate at 11.70% (p < 0.001). In
the entire study population, 263 patients (1.63%) died within 30 days of surgery. Stratified by
operating surgeon status, 162 patients (2.07%) in the attending+resident group died versus
101 (1.22%) in the attending only group (p < 0.001). Regression analyses compared patients
who had resident participation to those with only attending surgeons, the referent group.
After adjustment for preoperative patient characteristics and comorbidities, multivariate
regression analysis demonstrated that patients with resident participation in their surgery
had the same odds of 30-day morbidity (OR = 1.05, 95% CI 0.94–1.17) and mortality (OR =
0.92, 95% CI 0.66–1.28) as their attending only counterparts.
• Cases with resident participation had higher rates of mortality and morbidity; however, these
cases also involved patients with more comorbidities initially. On multivariate analysis,
resident participation was not an independent risk factor for postoperative 30-day morbidity
or mortality following elective or emergent neurosurgical procedures.

this study?
• Dr. Huang: Further examination of the effect of resident participation in specific
neurosurgical procedures as well as in other surgical subspecialty fields would be of potential
interest to patients.
• Citation:
• Mohamad Bydon, Nicholas B. Abt, Rafael De la Garza-Ramos, Mohamed Macki, Timothy F.
Witham, Ziya L. Gokaslan, Ali Bydon, Judy Huang. Impact of resident participation on
morbidity and mortality in neurosurgical procedures: an analysis of 16,098 patients. Journal
of Neurosurgery, 2015; 122 (4): 955 DOI: 10.3171/2014.11.JNS14890

IVF: Single Cell Analysis Allows Extremely Early Prediction Of Embryo Abnormalities
Shawn L. Chavez, Ph.D
Assistant Scientist/Professor
Oregon National Primate Research Center
OHSU | Oregon Health & Science University
Dr. Chavez: This study builds upon a previous study also published in Nature Communications in
2012, which demonstrated that chromosomally normal and abnormal 4-cell human embryos can
be largely distinguished by combining the timing intervals of the first three cell divisions with the
presence or absence of a dynamic process called cellular fragmentation. The current study
further combines time-lapse imaging of embryo development and full chromosome analysis with
high throughout single-cell gene expression profiling to assess the chromosomal status of human
embryos up to the 8-cell stage.

Medical Research: What are the main findings?
Dr. Chavez: The key findings of this research were that by measuring the duration of the first cell
division, one can identify which embryos are chromosomally normal versus abnormal even
earlier in development. By examining gene expression at a single-cell level, we were able to
correlate the chromosomal make-up of an embryo to a subset of 12 genes that are activated
prior to the first cell division. These genes likely came from either the egg or sperm and can be
used to predict whether an embryo will be chromosomally normal or abnormal within the first 30
hours of development.

• Dr. Chavez: A big debate in the in vitro fertilization (IVF) community right now is whether
time-lapse imaging is actually beneficial and can replace pre-implantation screening
(PGS). Personally, I think that by combining these two techniques and now potentially
extending this to gene expression profiling, will provide the most comprehensive information
for both clinicians and patients in the decision of which embryo(s) to transfer. The main goal
of the prediction model was not to predict chromosomal abnormalities by itself, but to
identify cellular pathways and related molecules indicative of embryo viability in culture
medium or via other methods.

this study?
• Dr. Chavez: Although the predictive model has been tested on embryos from several
different patients and IVF clinics, it will likely be necessary to test the model on other embryo
cohorts in order to further substantiate our findings. Additional studies should also focus on
the 1-cell embryo as a potential source of biomarkers that can prospectively predict embryo
chromosomal status and obviously, this needs to be non-invasive at this stage of
development.
• Citation:
• Maria Vera-Rodriguez, Shawn L. Chavez, Carmen Rubio, Renee A. Reijo Pera, Carlos Simon.
Prediction model for aneuploidy in early human embryo development revealed by single-cell
analysis. Nature Communications, 2015; 6: 7601 DOI: 10.1038/ncomms8601

New Molecular Device Can Quickly Detect Dangerous Superbugs
Yingfu Li, PhD
Professor, Dept of Biochemistry and Biomedical Sciences and
Dept of Chemistry and Chemical Biology
McMaster University, Hamilton, Canada
Dr. Li: Simple, accurate and sensitive diagnostic tests are highly sought-after in modern
medicine. Take bacterial infection as an example. Many microbial pathogens pose serious
threats to public health and are responsible for many annual outbreaks that result in
numerous human illnesses and deaths. Early and accurate detection of specific pathogens
has long been recognized as a crucial strategy in the control of infectious diseases because
such a measure can provide timely care of patients, prevent potential outbreaks, and
minimize the impact of on-going epidemics. To detect the infection early, we need highly
sensitive tests.
• We have developed a molecular device made of DNA that can be turned on by a molecule of
choice, such as a biomarker for a disease. When it gets switched on, the system will undergo
massive signal amplification allowing for extremely sensitive detection of the target
molecule. The test has the best sensitivity ever reported for a detection system of this kind –
it is as much as 10,000 times more sensitive than other detection systems. The scientific
report can be found at http://onlinelibrary.wiley.com/doi/10.1002/anie.201503182/abstract

Yingfu Li, PhD
• Dr. Li: he test we have developed is very versatile and can be applied for various diseases. We
are in the process of developing several clinically useful tests that can be used to easily and
quickly identify dangerous superbugs including C. difficile and MRSA.

Yingfu Li, PhD
this study?
• Dr. Li: We wish to adapt this assay on paper, so as to create litmus paper-like sensors. These
simple devices would completely eliminate the need for lab instruments, allowing users—
family physicians, for example—to run the test.
• Citation:
• Meng Liu, Wenqing Zhang, Qiang Zhang, John D. Brennan, Yingfu Li. Biosensing by Tandem
Reactions of Structure Switching, Nucleolytic Digestion, and DNA Amplification of a DNA
Assembly. Angewandte Chemie International Edition, 2015; DOI: 10.1002/anie.201503182

PD-L1 and TILS Predict Resistance in BRAF-Treated Melanoma Patients
Mario Mandalà, MD
Department of Oncology and Haematology
Papa Giovanni XXIII Hospital
Bergamo, Italy
Dr. Mandalà: In addition to their established molecular mechanism of action, growing evidence
suggests that the therapeutic efficacy of BRAFi relies on additional factors that affect the tumor–
host interactions, including the enhancement of melanoma antigen expression and the increase
in immune response against tumor cells. Preclinical data show that oncogenic BRAF contributes
to immune evasion, and that targeting this mutation may increase the melanoma
immunogenicity. Data in vitro or from animal models propose PD-L1 as a potential mechanism
that favors BRAFi resistance through the modulation of host immune responses. However,
demonstration of this hypothesis in the clinical setting is lacking.

Mario Mandalà, MD
Bergamo, Italy
• Dr. Mandalà: In the present study, we have evaluated, in a homogeneous series of MMP
treated with BRAFi, the association of tumoral PD-L1 IHC expression and the density of TIMC
with RR, PFS and OS. Results provide the first proof-of-principle clinical evidence of
the predictive and prognostic relevance of PD-L1 IHC expression and density of immune cell
infiltration in BRAFV600 mutated MMP receiving BRAFi.

Mario Mandalà, MD
Bergamo, Italy
• Dr. Mandalà: The most striking finding of this study is that IHC PD-L1 overexpression,
together with the lack of TIMC in metastatic melanoma samples, are associated with
resistance and poor prognosis in MMP receiving BRAFi. A limitation of our study is that in our
patient cohort, no patient received BRAF and MEK inhibitors, which are now known to
improve RR, PFS and OS, as compared to BRAFi alone. Furthermore we did not evaluate the
immunophenotype of immune cell infiltration, and the absence of CD8 staining that has been
widely used in previous studies in association with PD-L1 expression and could give more
quantitative and reliable results regarding the immune infiltrate.

Mario Mandalà, MD
Bergamo, Italy
this study?
• Dr. Mandalà: Since PD-L1 overexpressing melanoma patients are at higher risk of developing
early progression and worse outcome than those who are PD-L1 negative, a different strategy
should probably be pursued in these patients. Whether starting with anti PD-1 antibodies
may result in a better outcome should be evaluated in ad hoc designed studies, since PD-L1
positive melanomas with immune cell infiltration seem to benefit particularly from anti PD-1
antibodies
• Citation:
• Massi, D. Brusa, B. Merelli, C. Falcone, G. Xue, A. Carobbio, R. Nassini, G. Baroni, E. Tamborini,
L. Cattaneo, V. Audrito, S. Deaglio, and M. Mandalà
• The status of PD-L1 and tumor-infiltrating immune cells predict resistance and poor prognosis
in BRAFi-treated melanoma patients harboring mutant BRAFV600 Ann Oncol first published
online June 2, 2015 doi:10.1093/annonc/mdv255

Simultaneous Risk Factors Markedly Increase Heart Disease Death Rates
Dr Emanuele Di Angelantonio FESC FAHA
University Lecturer | University of Cambridge
Director | MPhil in Public Health
Response: Previous research as mainly focused on individual with one cardiometabolic condition
alone and, despite it could be expected that having more than one condition poses a greater risk,
this is the first study that is able to precisely quantify how much is worst. Furthermore, given that
the conditions we study (diabetes, heart attack, and stroke) share several risk factors, it could be
expected that the combination of these will not be multiplicative. We were somewhat surprised
to find that participants who had 1 condition had about twice the rate of death; 2 conditions,
about 4 times the rate of death; and all 3 conditions, about 8 times the rate of death.
We estimated that at the age of 60 years, men with any two of the cardiometabolic conditions
studied would on average have 12 years of reduced life expectancy, and men with all three
conditions would have 14 years of reduced life expectancy. For women at the age of 60 years, the
corresponding estimates were 13 years and 16 years. The figures were even more dramatic for
patients at a younger age. At the age of 40 years, men with all three cardiometabolic conditions
would on average have 23 years of reduced life expectancy; for women at the same age, the
corresponding estimate was 20 years.

• Response: These results are of main use for clinicians and policy makers, and emphasize for
example the importance of measures to prevent cardiovascular disease in people who
already have diabetes, and, conversely, to avert diabetes in people who already have
cardiovascular disease. However, at the same time, we must not lose sight of tackling these
serious conditions within the wider population.

this study?
• Response: Future research should focused on the wider issues of co-morbidities in an aging
population.
• Citation:
• The Emerging Risk Factors Collaboration. Association of Cardiometabolic Multimorbidity With
Mortality. JAMA. 2015;314(1):52-60. doi:10.1001/jama.2015.7008.
•
Dr Emanuele Di Angelantonio FESC FAHA, & University Lecturer | University of Cambridge
(2015). Simultaneous Risk Factors Markedly Increase Heart Disease Death Rates

New Generation Biologic Markedly Improved Psoriasis
Prof. Dr. med. Kristian Reich
DERMATOLOGIKUM HAMBURG
Hamburg
Prof. Reich: The Phase 2b X-PLORE study compared a new generation biologic therapy,
guselkumab – an inhibitor of IL–23, with the anti–tumor necrosis factor (TNF)–alpha agent
adalimumab (Humira®) and placebo in the treatment of moderate-to-severe plaque-type
psoriasis. It showed that up to 86 percent of patients treated with guselkumab achieved a
Physician’s Global Assessment (PGA) score of cleared psoriasis or minimal psoriasis at week 16,
the study’s primary endpoint. Interestingly, levels of efficacy were higher for several guselkumab
doses through week 16 when compared to adalimumab. Improvements with guselkumab
continued through week 40 with every eight- or twelve-week maintenance treatment.

Hamburg
• Prof. Reich: The Phase 2b guselkumab study shows that blockade of IL-23 resulted in
significant skin clearance, and provides important insights into the role of IL-23 in the
pathogenesis of psoriasis and the potential therapeutic benefit of guselkumab. IL-23 appears
to be a particularly attractive therapeutic target in psoriasis given the emerging profile of
guselkumab, in particular the combination of high levels of response with a very favorable
safety profile and an extremely convenient injection scheme. This is the desirable profile of a
new generation biologic therapy.

Hamburg
this study?
• Prof. Reich: As a dermatologist, I am particularly excited about the potential of guselkumab
and what this investigational therapy may mean for patients and the treatment of moderate
to severe plaque psoriasis in the future. Findings from the ongoing Phase 3 guselkumab
studies will provide even greater insights into the efficacy and safety profile of this novel
biologic.
• Citation:
• A Phase 2 Trial of Guselkumab versus Adalimumab for Plaque Psoriasis
• Kenneth B. Gordon, M.D., Kristina Callis Duffin, M.D., Robert Bissonnette, M.D., Jörg C. Prinz,
M.D., Yasmine Wasfi, M.D., Ph.D., Shu Li, Ph.D., Yaung-Kaung Shen, Ph.D., Philippe Szapary,
M.D., M.S.C.E., Bruce Randazzo, M.D., Ph.D., and Kristian Reich, M.D., Ph.D.
• N Engl J Med 2015; 373:136-144
• July 9, 2015
• DOI: 10.1056/NEJMoa1501646

Duration of Anticoagulation After Primary Pulmonary Embolism Clarified
Professor Francis Couturaud, MD, PhD
Department of Internal Medicine and Chest Diseases
University Hospital Center of Brest
Brest, France
Dr. Couturaud: Patients who have completed 3 to 6 months of anticoagulation for a first episode
of pulmonary embolism that was not provoked by a major transient risk factor, such as surgery or
prolonged immobilization, have a high risk of recurrent venous thromboembolism after stopping
anticoagulation. In this high-risk population, extending anticoagulation beyond 3 to 6 months is
associated with a major reduction in recurrences as long as the treatment is continued. However,
whether this benefit is maintained thereafter remains uncertain, as in most previous studies,
patients were not followed after treatment discontinuation. In addition, while extending
anticoagulation is very effective in preventing recurrent venous thromboembolism,
anticoagulation is also associated with an increased risk of bleeding. Therefore, in patients with a
first episode of unprovoked pulmonary embolism, the optimal duration of anticoagulation
remains uncertain.

Duration of Anticoagulation After Primary Pulmonary Embolism Clarified
Professor Francis Couturaud, MD, PhD
Department of Internal Medicine and Chest Diseases
University Hospital Center of Brest
Brest, France
• In the PADIS-PE multicenter, double-blind, randomized trial that included 371 patients with a
first episode of unprovoked pulmonary embolism initially treated during 6 months, we aimed
to evaluate the benefit and risk of an additional 18 months of warfarin therapy versus
placebo during the 18-month study treatment period and during an additional 2 years of
follow-up after study treatment discontinuation.
• The main findings are the followings: during the study treatment period, we found a 80%
reduction in the relative risk of recurrent venous thromboembolism or major bleeding,
mainly driven by the 90% risk reduction of recurrences; however, during the post-treatment
follow-up period of two years, the benefit was lost, and the risks of recurrent venous
thromboembolism and major bleeding were not different between the 2 groups. In addition,
recurrent venous thromboembolism occurred as pulmonary embolism in 80% of cases (8%
were fatal) and were unprovoked in 90% of cases.

MedicalResearch.com: Medical Research Exclusive Interviews July 9 2015

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