MedicalResearch.com - Medical Research Interviews Week in Review

MedicalResearch.com
Exclusive Interviews with Medical Research and
Health Care Researchers
Editor: Marie Benz, MD
info@medicalresearch.com
February 22 2014
For Informational Purposes Only: Not for Specific Medical Advice.

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Maternal Influenza and Offspring Bipolar Disorder
MedicalResearch.com Interview with:
Alan S. Brown, M.D., M.P.H.
Professor of Clinical Psychiatry and Clinical Epidemiology College of Physicians and Surgeons of Columbia University Director
Unit in Birth Cohort Studies Division of Epidemiology New York State Psychiatric Institute New York, NY

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MedicalResearch.com: What are the main findings of the study?
Dr. Brown: We found that a mother’s exposure to influenza during pregnancy, documented by antibodies
in her serum, increased the risk of bipolar disorder with psychotic symptoms in her offspring. We did not
show a relationship between influenza and bipolar disorder not accompanied by psychosis.
MedicalResearch.com: Were any of the findings unexpected?
Dr. Brown: We had expected to find a relationship between influenza and bipolar disorder without
psychotic symptoms based on my previous study; however, influenza was assessed differently between
the two studies. And my lab previously showed that prenatal influenza increased the risk of schizophrenia,
so the findings of our current study were consistent with an effect of prenatal influenza on psychosis in
general, rather than on a particular type of psychotic disorder.
MedicalResearch.com: What should clinicians and patients take away from your report?
Dr. Brown: The study provides support for influenza vaccinations in women planning a pregnancy and to
consider vaccination while pregnant as recommended by several health organizations.
MedicalResearch.com: What recommendations do you have for future research as a result of this study?
Dr. Brown: We wish to replicate the finding in other samples and examine the pathway by which maternal
influenza and other inflammatory insults alter fetal brain development to lead to psychosis outcomes.
Citation:
Serological Documentation of Maternal Influenza Exposure and Bipolar Disorder in Adult Offspring
Sarah E. Canetta, Ph.D.; Yuanyuan Bao, M.S.; Mary Dawn T. Co, M.D.; Francis A. Ennis, M.D.; John Cruz,
B.S.; Masanori Terajima, M.D., Ph.D.; Ling Shen, Ph.D.; Christoph Kellendonk, Ph.D.; Catherine A. Schaefer,
Ph.D.; Alan S. Brown, M.D., M.P.H.
Am J Psychiatry 2014;:. doi:10.1176/appi.ajp.2013.13070943

Read the rest of the interview on MedicalResearch.com

COPD: Risk from Chinese WaterPipe Smoking
Chunxue Bai, MD & PhD
Director, Shanghai Respiratory Research Institute
Professor of Medicine, Chairman, Shanghai Leading academic discipline Chair, Chinese Alliance against Lung Cancer
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Dr. Bai: Recently, we found a dilemma phenomenon that the incidence of chronic obstructive pulmonary disease (COPD) and lung cancer has
remained high in southwest China despite the 1976 National Stove Improvement Program for indoor air quality.
However, little information is known to the public about a regional endemic related to Chinese waterpipe smoking, which is different from the Arabic
waterpipe. The Chinese waterpipe has been traditionally misconceived as less harmful for three reasons:
(1) no charcoal was used in contrast to the Arabic waterpipe,
(2) tobacco smoke passed through the water as opposed to cigarette smoking and
(3) smoking through a large volume waterpipe could “improve lung function.”
In our study, we provide robust results that the large volume Chinese waterpipe use and exposure are associated with the elevated prevalence of
COPD, which have been identified by epidemiologic, physiologic, radiology, and toxicologic findings for the first time.
Dr. Bai: Noted is the five individuals in our study who were tested and confirmed as having lung cancer by computed tomography (CT) and pathology
evaluations:
3 CWS (lung adenocarcinoma)
1 CWPS (lung adenocarcinoma) and
1 CS (lung squamous cell carcinoma). It will cause our attention and strengthen the monitoring of lung cancer.
Dr. Bai: The Chinese waterpipe has been mistaken as less harmful. Our study has provided evidence confirming this misconception. Exposure to
active and passive Chinese waterpipe smoke may be a significant risk factor for developing COPD. The damage from Chinese waterpipe use and
exposure are worse than cigarette. Our results highlight smoking cessation in Chinese waterpipe users is as important as in other tobacco products in
preventive intervention of COPD.
Dr. Bai: In addition to Chinese waterpipe use and exposure are associated with COPD; the PM2.5 from the Chinese waterpipe smoke was twice as
high as from cigarette smoke. Our results also predict the prevalence of COPD will be increased by long-term exposure to high concentrations of
PM2.5, which will bring a huge economic and social burden to the globe and calls for more research to be directed toward preventive measures and
efforts.
Citation:
Chinese waterpipe smoking and the risk of chronic obstructive pulmonary disease
She J, Yang P, Wang Y, et al.
Published online February 20, 2014.
doi:10.1378/chest.13-1499.
Chest. 2014. doi:10.1378/chest.13-1499


Atrial Fibrillation: Ablation Found Superior to Conventional Drug Therapy
Carlos A. Morillo, MD, FRCPC, FACC, FHRS, FESC Professor Department of Medicine, Cardiology Division
Program Director Cardiac Electrophysiology and Autonomic Physiology Fellowship ,Hamilton, ON, Canada

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Carlos A. Morillo, MD, FRCPC, FACC, FHRS, FESC 
Professor Department of Medicine, Cardiology Division
Program Director Cardiac Electrophysiology and Autonomic Physiology Fellowship ,Hamilton, ON, Canada
Dr. Morillo: The main findings were that Ablation of atrial fibrillation was superior to conventional antiarrythmic drug
therapy in patients with Paroxysmal atrial fibrillation that had not been treated with Antiarrhythmic medications. Ablation
extended the time to first recurrence of atrial fibrillation within the 2 year follow-up of the study and significantly reduced
the recurrence of repeated episodes of AF.
Dr. Morillo: Not really many studies have shown that ablation is better than medications but in patients that have previously
failed Antiarrhythmic drug treatment. We were expecting a greater effect of ablation but still documented a 44% relative
risk reduction in recurrence of AF.
Dr. Morillo: This study provides further support to offering ablation as first line treatment of Atrial fibrillation in young
patients with paroxysmal atrial fibrillation that have not received Antiarrhythmic drugs previously. The procedure is not free
of risks and this procedure should be performed in centres with experience managing patients with atrial fibrillation.
Citation:
Radiofrequency Ablation vs Antiarrhythmic Drugs as First-Line Treatment of Paroxysmal Atrial Fibrillation (RAAFT-2)A
Randomized Trial
Morillo CA, Verma A, Connolly SJ, et al. Radiofrequency Ablation vs Antiarrhythmic Drugs as First-Line Treatment of
Paroxysmal Atrial Fibrillation (RAAFT-2): A Randomized Trial. JAMA. 2014;311(7):692-700. doi:10.1001/jama.2014.467.


Colon Cancer Patients Have Less Diverse Gut Bacteria
MedicalResearch.com Interview with: Jiyoung Ahn, PhD
Assistant Professor of Epidemiology Department of Population Health
NYU School of Medicine New York, NY 10016
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Dr. Ahn: Before we did our research, it was suspected that gut bacteria were related to colorectal cancer. We, for the first
time, found colorectal cancer patients have a different gut bacteria composition than healthy subjects.
Dr. Ahn: Not really. Humans host trillions of gut bacteria that help in digestion and other normal functions. The diverse
types of bacteria are important to carry out these activities. A decrease in diversity may indicate a lack of balance in the
complex bacterial population. Our research shows that subjects with colon cancer have a less diverse population of
gut bacteria. It will take more research to determine if this decreased diversity leads to colon cancer or is a response to
having the disease.
Dr. Ahn: This research, although in an early stage, is pointing to the possibility that gut microbes are involved in colon cancer
development. If this is correct, the research could open up new ways to protect from this serious disease. Beyond our
research program, it remains important now to maintain a healthy diet and follow physician recommendations for screening
for the early detection of colon cancer.
Dr. Ahn: Our group is working on diet and lifestyle factors determining gut microbe profile. For example, dietary factors,
such as dietary fruit and vegetable and bean intakes, rich sources of dietary fiber, and obesity are suspected factors.
Citation:
Human Gut Microbiome and Risk for Colorectal Cancer
Jiyoung Ahn, Rashmi Sinha, Zhiheng Pei, Christine Dominianni, Jing Wu, Jianxin Shi, James J. Goedert, Richard B. Hayes, and
Liying Yang
Human Gut Microbiome and Risk of Colorectal Cancer JNCI J Natl Cancer Inst djt300 doi:10.1093/jnci/djt300 first published
online December 6, 2013


After Ear Tubes: Eardrops Found Superior to Oral Antibiotics for Ear Discharge
Dr. T. M. A van Dongen, MD Univ Med Ctr Utrecht
Julius Ctr Hlth Sci & Primary Care, Dept Epidemiol
Utrecht, Netherlands.

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Answer: We performed a pragmatic trial, in which we randomly assigned 230 children who had acute
tympanostomy-tube otorrhea to receive antibiotic-glucocorticoid eardrops, oral antibiotics or to undergo
initial observation. The primary outcome of our study was the presence of ear discharge, 2 weeks after
study-group assignment. We also looked at, among others, the duration of the initial otorrhea episode and
the total number of days of otorrhea and the number of otorrhea recurrences during 6 months of followup. We found that antibiotic–glucocorticoid eardrops were superior to oral antibiotics and initial
observation for all outcomes.

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Answer: Since acute tympanostomy-tube otorrhea, like acute otitis media, can be self-limiting, initial
observation was thought by some to be a good alternative for antibiotic treatment. We are the first
to compare the effectiveness of oral or topical treatment with initial observation. Approximately one in
two children managed by initial observation still had otorrhea at 2 weeks and initial observation resulted
in more days with otorrhea in the following months than did topical or oral antibiotics. So our results
actually suggest that initial observation is not an adequate management strategy in such children.
Answer:
· Standard patient information usually advises parents to contact a physician when their child’s
symptoms of tube otorrhea persist for more than a week. At that stage, so when parents contact a
physician, recommendations from clinical practice guidelines vary widely: some advise physicians to
manage with oral antibiotics or more observation, while others suggest prescribing antibiotic
eardrops. We recommend updating current patient information and clinical practice guidelines. Our
results show it’s best to inform parents to contact a physician when otorrhea occurs, rather than waiting
for a week or more to see if otorrhea abates without treatment. In addition, we recommend physicians to
treat these children with eardrops shortly after onset of symptoms.

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After Ear Tubes: Eardrops Found Superior to Oral Antibiotics for Ear Discharge
Dr. T. M. A van Dongen, MD Univ Med Ctr Utrecht
Julius Ctr Hlth Sci & Primary Care, Dept Epidemiol
Utrecht, Netherlands.

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MedicalResearch.com: What recommendations do you have for future research as a result of this
study?
Answer: For many years, the use of topical antibiotics in children with acute tympanostomy-tube
otorrhea has been questioned for their presumed inability to reach the middle ear. In vivo studies
in children with a ‘clean’ ear canal and patent tympanostomy tube as well as in vitro studies
reported low rates of spontaneous penetration of eardrops into the middle ear. These studies
raised even more doubt about eardrops reaching the middle ear in children with active tube
otorrhea. Yet our study of children with middle ear fluid visibly draining through the tympanostomy
tube into the ear canal showed that eardrops were highly effective, indicating that its active
components do reach the site of infection. As such, one could therefore question whether
antibiotic(-glucocorticoid) eardrops may also be effective in children without tubes who develop
acute otitis media and present with spontaneous otorrhea. So far, this has not been evaluated in a
randomized clinical trial, presumably based upon the same rationale, i.e. that the eardrops would
not reach the infected middle ear. Since topical treatment is usually well tolerated, causes no
systemic side effects and is less likely to cause antimicrobial resistance as compared to oral
antibiotics, a trial of the effectiveness of topical antibiotics versus oral antibiotics in children with
acute otitis media presenting with spontaneous otorrhea seems warranted.
Citation:
A Trial of Treatment for Acute Otorrhea in Children with Tympanostomy Tubes
hijs M.A. van Dongen, M.D., Geert J.M.G. van der Heijden, Ph.D., Roderick P. Venekamp, M.D.,
Ph.D., Maroeska M. Rovers, Ph.D., and Anne G.M. Schilder, M.D., Ph.D.
N Engl J Med 2014; 370:723-733
February 20, 2014DOI: 10.1056/NEJMoa1301630


Glioblastoma: Avastin Did Not Improve Survival or Symptoms
Minesh P. Mehta, M.B., Ch.B. F.A.S.T.R.O.
Professor of Radiation Oncology, University of Maryland School of Medicine
Radiation oncologist, University of Maryland Marlene and Stewart Greenebaum Cancer Center

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Dr. Mehta: RTOG 0825 was a clinical trial evaluating whether the addition of a novel drug that inhibits
tumor vascular growth, bevacizumab, to the standard of care for glioblastoma, an aggressive brain tumor,
would prolong survival. Patients were allocated randomly to one of two different treatment regimens –
the standard of care, which includes radiotherapy and a drug known as temozolomide, or another regimen
of radiation, temozolomide and bevacizumab. The trial design was double-blinded, and therefore, on one
arm patients received the bevacizumab, whereas on the other arm they received a placebo. The survival
on both arms was equivalent, and therefore it was fairly concluded that bevacizumab failed to prolong
survival when given initially as part of treatment for glioblastoma.
Freedom from progression, referred to as progression-free survival was also measured on this trial, and
although bevacizumab appeared to lengthen progression-free survival, this level of benefit did not meet
the pre-defined goals, and is therefore regarded as statistically not demonstrating an improvement.
Additional endpoints included outcomes reported by the patient, including the burden of symptoms, and
the impact of these on the quality of life, as well as effects on the brain, known as neurocognitive
changes. Bevacizumab did not improve these endpoints either.

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Dr. Mehta: This trial was based on an earlier trial in which patients with recurrent glioblastoma were
treated with bevacizumab. In that trial, progression of disease was delayed, and tumor shrinkage on brain
MRI scans was noted, resulting in FDA approval for use in recurrent glioblastoma. Based on those results,
as well as the known biology of this tumor, there was good expectation that a survival benefit would be
observed. Failure to observe that was somewhat unexpected and truly disappointing.


Glioblastoma: Avastin Did Not Improve Survival or Symptoms
Minesh P. Mehta, M.B., Ch.B. F.A.S.T.R.O.
Professor of Radiation Oncology, University of Maryland School of Medicine
Radiation oncologist, University of Maryland Marlene and Stewart Greenebaum Cancer Center

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Dr. Mehta: This agent bevacizumab is known to help several patients with recurrent glioblastoma,
and the results of this trial should not detract from that; patients and physicians need to keep this
in mind and recognize that the drug has value in the recurrent setting. Upfront use cannot be
supported in terms of improving duration of survival.
study?
Dr. Mehta: improved, but in that trial, the patient-reported outcomes were more favorable for the
bevacizumab arm. Therefore, the collective data from both trials regarding these endpoints are
expected to be analyzed in greater detail. Further, it is possible that certain subsets of patients
might have benefited from the agent, and specific molecular evaluation of individual patients’
tumors is ongoing to tease this out.
Citation:
A Randomized Trial of Bevacizumab for Newly Diagnosed Glioblastoma
Mark R. Gilbert, M.D., James J. Dignam, Ph.D., Terri S. Armstrong, Ph.D., A.N.P.-B.C., Jeffrey S. Wefel,
Ph.D., Deborah T. Blumenthal, M.D., Michael A. Vogelbaum, M.D., Ph.D., Howard Colman, M.D.,
Ph.D., Arnab Chakravarti, M.D., Stephanie Pugh, Ph.D., Minhee Won, M.A., Robert Jeraj, Ph.D., Paul
D. Brown, M.D., Kurt A. Jaeckle, M.D., David Schiff, M.D., Volker W. Stieber, M.D., David G.
Brachman, M.D., Maria Werner-Wasik, M.D., Ivo W. Tremont-Lukats, M.D., Erik P. Sulman, M.D.,
Kenneth D. Aldape, M.D., Walter J. Curran, Jr., M.D., and Minesh P. Mehta, M.D.
N Engl J Med 2014; 370:699-708
February 20, 2014DOI: 10.1056/NEJMoa1308573


Breast Cancer Brain Metastasis: Genomic and Epigenomic Analysis
Bodour Salhia, PhD Assistant Professor Integrated Cancer Genomics Division
Translational Genomics Research Institute
Phoenix, Arizona, 85004

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Dr. Salhia: Our study identified novel rare genomic and epigenomic events underlying breast cancer metastasis to brain. We
demonstrated that we could molecularly subtype breast cancer brain metastasis the same way we can subtype primary
breast cancer. From this analysis we found that the Luminal B subtype was the most common subtype in our cohort,
followed by Her2+/ER- enriched tumors and Basal-like tumors. Each of these subtypes displayed genetic and epigenetic
features reminiscent of primary breast cancer. We demonstrated that these tumors have a strong predilection to grow by
activating pathways involved in G2/M cell cycle progression, whereas, many genes involved in cell migration were
epigenetically silenced. Broad amplification of chromosome 8q was common, which resulted in the upregulation of
important genes.
Dr. Salhia: Certainly, gain of 8q has been previously described for breast cancer and has been associated with disease
progression and poor patient prognosis. What was surprising to us was the amplification of the cMYC oncogene on 8q
without concomitant expression. If we assume that the 8q locus is important in the development of brain metastasis, this
data suggests that other genes on 8q (not cMYC) may be driving metastasis to brain.
Dr. Salhia: This is an important study that integrated multiple genomic datasets to determine underlying molecular
characteristics of brain metastasis. Survival with brain metastasis remains quite poor. So we want patients to walk away with
a sense of hope, as we get closer to finding better ways to treat this disease.
Dr. Salhia: Breast cancer brain metastasis is a really significant problem and a huge unmet need. We now want to dig deeper
and uncover more specific genomic links and study new ways to treat these patients so we can dramatically improve
outcomes.
Citation:
Integrated Genomic and Epigenomic Analysis of Breast Cancer Brain Metastasis
Bodour Salhia, Jeff Kiefer, Julianna T. D. Ross, Raghu Metapally, Rae Anne Martinez, Kyle N. Johnson, Danielle M. DiPerna,
Kimberly M. Paquette, Sungwon Jung, Sara Nasser, Garrick Wallstrom, Waibhav Tembe, Angela Baker, John Carpten, Jim
Resau, Timothy Ryken, Zita Sibenaller, Emanuel F. Petricoin, Lance A. Liotta, Ramesh K. Ramanathan, Michael E. Berens,
Nhan L. Tran Research Article | published 29 Jan 2014 | PLOS ONE


Promising Approach to Treat Non-Alcoholic Fatty Liver Disease and Visceral Obesity
MedicalResearch.com Interview with: Norbert Stefan, MD
Heisenberg Professorship for Clinical and Experimental Diabetology
Department of Internal Medicine IV
University Hospital Tübingen Tübingen, Germany

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Dr. Stefan: Currently there is little evidence for an effective and safe pharmacological
treatment of nonalcoholic fatty liver disease (NAFLD). Based on the fact that inhibition of
11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), the enzyme, that converts inactive
cortisone into active cortisol in metabolic tissues such as liver and adipose, was found to be
effective to improve lipid metabolism in animals, we hypothesized that inhibition of 11βHSD1 may also prove to be effective to decrease liver fat content in patients with NAFLD. In
our 12 week trial in 82 patients with NAFLD, inhibition of 11β-HSD1 with RO5093151 resulted
in a 14 % decrease of liver fat content and in a resolution of NAFLD in 20 % of the patients.
This was accompanied by a decrease of liver enzymes. Furthermore, inhibition of 11β-HSD1
brought about a reduction of body weight and total body- and visceral adipose tissue mass,
while insulin sensitivity did not change. In agreement with findings from other trials, also in
our study 11β-HSD1 inhibition was well tolerated and safe.
Dr. Stefan: These findings were not unexpected. High 11β-HSD1 activity in metabolic tissues
as the liver and adipose tissue is known to be closely related to features of the Cushing’s
disease. Thus, the observed decrease in liver fat content and visceral adipose tissue mass was
in agreement with the expected mode of action of a compound that specifically inhibits 11βHSD1 activity. This supports the hypothesis that targeting 11β-HSD1 is a promising approach
to treat NAFLD and visceral obesity.


Promising Approach to Treat Non-Alcoholic Fatty Liver Disease and Visceral Obesity
MedicalResearch.com Interview with: Norbert Stefan, MD
Heisenberg Professorship for Clinical and Experimental Diabetology
Department of Internal Medicine IV
University Hospital Tübingen Tübingen, Germany

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Dr. Stefan: Our trial was a phase 1b study. Currently there is no approved drug available that
inhibits 11β-HSD1 activity. However, our findings are encouraging in that in more advanced phases
such a pharmacological concept may prove to be effective in larger studies.
study?
Dr. Stefan: Further clinical studies are now needed to evaluate whether longer term 11β-HSD1
inhibition might be more effective to reduce liver fat content in NAFLD, and whether it may have
beneficial effects in non-alcoholic steatohepatitis. In addition, such trials should further explore
whether 11β-HSD1 inhibition may qualify as a pharmacological treatment option for obesity.
Citation:
Inhibition of 11β-HSD1 with RO5093151 for non-alcoholic fatty liver disease: a multicentre,
randomised, double-blind, placebo-controlled trial
Prof Norbert Stefan MD,Markus Ramsauer PhD,Paul Jordan PhD,Bettina Nowotny MD,Konstantinos
Kantartzis MD,Jürgen Machann PhD,Jong-Hee Hwang PhD,Peter Nowotny PhD,Sabine Kahl
MD,Jürgen Harreiter MD,Silke Hornemann MD,Prof Arun J Sanyal MD,Prof Paul M Stewart MD,Prof
Andreas F Pfeiffer MD,Prof Alexandra Kautzky-Willer MD,Prof Michael Roden MD,Prof Hans-Ulrich
Häring MD,Sabine Fürst-Recktenwald MD
The Lancet Diabetes & Endocrinology – 17 February 2014
DOI: 10.1016/S2213-8587(13)70170-0


Many Pregnant Women Have Not Taken Folic Acid to Reduce Neural Tube Defects
MedicalResearch.com Interview with: Prof. Nicholas J. Wald
Wolfson Institute of Preventive Medicine
Barts and the London School of Medicine and Dentistry Queen Mary University of London
London, United Kingdom

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Prof Wald: The percentage of women who become pregnant without having taken folic acid supplements
to reduce the risk of a neural tube defect declined from a relatively low proportion (35%) to an even lower
one (31%) between 1999 and 2012.
Moreover such use of folic acid in some groups of the population is much lower for example 17% in AfroCaribbean women and 6% in women aged under 20.
Prof Wald: Only about half of women who had already had a neural tube defect pregnancy took folic acid
supplements prior to their current pregnancy – a group at much higher risk
Prof Wald: The main takeaway message is directed to public health authorities and governments rather
than clinicians or patients.
The main message for clinicians and patients is that many women who have already had a neural tube
defect pregnancy are not receiving folic acid supplements before pregnancy and these should be routinely
offered and prescribed to all such women.
Prof Wald: The message of this paper is not further research, but further action needed.
Citation:
Prevention of Neural Tube Defects: A Cross-Sectional Study of the Uptake of Folic Acid Supplementation in
Nearly Half a Million Women
Jonathan P. Bestwick, Wayne J. Huttly, Joan K. Morris, Nicholas J. Wald Research Article | published 19 Feb
2014 | PLOS ONE 10.1371/journal.pone.0089354


Increased Sitting Time Linked to Disability
MedicalResearch.com Interview with: Dorothy D Dunlop, PhD
Professor, Medicine-Rheumatology
Center for Healthcare Studies – Institute for Public Health and Medicine and Preventive Medicine
Northwestern University Feinberg School of Medicine

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Dr. Dunlop: We know being active, especially doing moderate activity like taking a brisk walk, is good for health. We know a
sedentary lifestyle leads to health problems. What we do not know is whether or not those are two ways of looking at the
same question. Does being sedentary like sitting just reflect insufficient activity OR is sedentary time is a separate and
distinct risk factor for health problems. Our physical activity research group looked at national US data from the National
Health and Nutrition Examination Survey. This is an important study because they monitored physical activity using an
accelerometer. We found sedentary behavior such as sitting was its own separate risk factor for disability.
Dr. Dunlop: We were impressed at the strength and consistency of the relationship between sedentary time and disability.
Dr. Dunlop: “There are two messages here.
First, being physically active is very important. It is well documented that recommended levels of moderate activity reduces
the risk for disability.
Second, being sedentary is a separate and important risk factor. People should focus on both. Be as active as possible. And
for people who spend a large portion of their day sitting, it is beneficial to find opportunities to replace some of that sitting
with other activities. The bottom line is to stay active and reduce sitting
Dr. Dunlop: Because our study examined data collected at one point in time, it does not determine sedentary behavior
causes disability. It does draw our attention to the fact sedentary behavior is a problem. Future studies need to look at the
relationship of sedentary time and the subsequent development of disability.
Citation:
Sedentary Time in U.S. Older Adults Associated With Disability in Activities of Daily Living Independent of Physical Activity
JPAH In Press
Authors: Dorothy Dunlop1, Jing Song1, Emily Arnston2, Pamela Semanik3, Jungwha Lee4, Rowland Chang4, and Jennifer M.
Hootman5
Acceptance Date: November 12, 2013
DOI: http://dx.doi.org/10.1123/jpah.2013-0311


Blood Clot Risk Elevated for 12 Weeks After Childbirth
Dr.Hooman Kamel MD
Department of Neurology and the Brain and Mind Research Institute
Weill Cornell Medical College in New York City.

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Dr. Kamel: The risk of thrombotic events remains higher than normal for twice as long after
childbirth as previously thought. However, the absolute risk in any given patient is low, especially
after the first 6 weeks.

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Dr. Kamel: Our hypothesis was that the risk of thrombotic events would be higher than normal
beyond 6 weeks, and that is indeed what we found.
Dr. Kamel: Patients and providers should be aware that thrombotic risk remains elevated until 12
weeks after delivery, so that any symptoms of possible thrombosis (e.g., shortness of breath, chest
pain, leg swelling or pain, sudden neurological symptoms) are evaluated appropriately.
study?
Dr. Kamel: Our findings suggest that future studies should evaluate the risks and benefits of
extended postpartum prophylactic therapy in high-risk women (e.g., those with prior thrombosis).
Citation:
Risk of Thrombosis Remains Elevated for 12 Weeks After Labor and Delivery
American Stroke Association 2014 Meeting Report: ISC abstract: Abstract: 216

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Advanced Cervical Cancer: Adding Avastin to Chemotherapy Prolonged Survival
Krishnansu S. Tewari, MD, FACOG, FACS| Professor & Director of Research
Principal Investigator – The Gynecologic Oncology Group at UC Irvine, Division of Gynecologic Oncology
University of California, Irvine Medical Center Orange, CA 92868

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Dr. Tewari: The main findings of this study were that the addition of bevacizumab to chemotherapy resulted in a significantly
improved survival of 3.7 months in a population of patients that have very limited options. This improvement in overall
survival was not accompanied by any significant deterioration in quality of life and serious side effects were limited to 3% to
8% of the study population.
Dr. Tewari: The findings were not unexpected. We have known for decades that angiogenesis (ie., the formation of new
blood vessels between the cancer and the patient) is an important process in cervical cancer. Angiogenesis allows the cancer
to obtain nutrients to supports its growth. We now have a drug that can block angiogenesis and we were very pleased to
learn that using this drug resulted in improved survival for these patients.
Dr. Tewari: We may have identified a therapeutic mechanism through which we can now improve survival in this population
of patients to allow them to obtain further benefits from newer drugs currently being studied such as other inhibitors of
angiogenesis, immunologic therapies, etc. Previously, advanced cervical cancer was a disease in which patients rarely could
tolerate multiple lines of chemotherapy (unlike ovarian and breast cancers which can be made into chronic diseases with
patients receiving many lines of therapy for many years). Now, with bevacizumab we may be on the cusp of being able to
convert this disease into a more chronic one that doesn’t kill patients so quickly.
Dr. Tewari: First thing that needs to be done is to get the drug approved by the US FDA so that patients in greatest need can
benefit from this therapy. Then we need to study other types of anti-angiogenesis therapy and immunologic therapy in this
population of patients – many such trials are already underway.
Citation:
Improved Survival with Bevacizumab in Advanced Cervical Cancer
Krishnansu S. Tewari, M.D., Michael W. Sill, Ph.D., Harry J. Long, III, M.D., Richard T. Penson, M.D., Helen Huang, M.S., Lois M.
Ramondetta, M.D., Lisa M. Landrum, M.D., Ana Oaknin, M.D., Thomas J. Reid, M.D., Mario M. Leitao, M.D., Helen E. Michael,
M.D., and Bradley J. Monk, M.D.
N Engl J Med 2014; 370:734-743February 20, 2014DOI: 10.1056/NEJMoa1309748


Good Sleep Habits for Children: Early Consistent Bedtime, No Evening TV
MedicalResearch.com Interview with: Dr Abi Fisher PhD
Senior Researcher, Cancer Research UK
Health Behaviour Research Centre
University College London

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Dr. Fisher: Getting sufficient sleep at night is essential to the health and development of young children.
Before the age of 5 years, children who regularly sleep less than 11 hours a night are at an increased risk
of poor health, so understanding the factors that determine short sleep is very important. Some key
factors were related to shorter sleep in our study, including being from ethnic minority backgrounds, lower
socioeconomic groups and watching more than an hour of television in the evening. Whilst these factors
have been related to childhood sleep in previous studies, ours was the first to show that the effects of
these variables on children’s sleep may be operating through a later bedtime.

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Dr. Fisher: These findings are important as they can be used to give parents, caregivers and health
professionals constructive advice on how to improve child sleep; an emphasis on an early and consistent
bedtime could help promote healthy sleep. Parents should also be encouraged not to allow evening
television viewing.
Dr. Fisher: Our study was observational, so randomised controlled trials should be carried out with short
sleeping children and their families, to determine whether introducing earlier bedtimes do indeed
improve sleep length and quality and improve health outcomes.
Citation:
Predictors of Shorter Sleep in Early Childhood
Laura McDonald, Jane Wardle, Clare H. Llewellyn, Cornelia H.M. van Jaarsveld, Abigail Fisher
Sleep Medicine – 10 February 2014 (10.1016/j.sleep.2014.01.005)


Pediatric Oncology: Radiation Free Imaging Test as Alternative to PET/CT Scans
MedicalResearch.com: Interview with:
Dr Heike Daldrup-Link
Associate Professor of Radiology
Stanford University School of Medicine, Palo Alto

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Answer: We use magnetic resonance imaging, a technology based on magnetic fields rather than
radiotracers or x-rays. The underlying technology is not new – it has been used for tumor staging
for many years. This is an advantage as MR scanners are available in nearly every major Children’s
Hospital where children with cancer are treated. What is new about our approach is that we
combined anatomical and functional images, similar to current approaches that use radiotracers
and CT (PET/CT): We first acquired scans that showed the anatomy of the patient very well and we
then acquired scans that depict tumors as bright spots with little or no background information. We
did that by using an iron supplement as a contrast agent: The iron supplement can be detected by
the MRI magnet and improved tumor detection and vessel delineation MR scans. We then fused
the anatomical scans with the tumor scans.

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One could compare this to highlighting roads and points of interests (the tumors) simultaneously on
a geographic map. Previous MR imaging approaches have either shown the point of interest very
well or the anatomical map, but not both. By fusing MR scans that highlight the tumor with MR
scans that provide a very detailed anatomical map of the body, we created radiation-free images
that shows us very clearly, where tumors are in relation to anatomical landmarks.
Our radiation free WB-DW MR imaging technique detected 158 of 174 malignant tumors and FDGPET/CT detected 163 of 174 malignant tumors. The resultant sensitivities, specificities, and
diagnostic accuracies were all excellent, with values above 90%, and were not significantly different
between the two imaging modalities. Tumour staging results also showed very good agreement
between both imaging modalities with a κ of 0.93. At the same time, the associated radiation
exposure could be reduced from about 12.5 mSv for the PET scans to zero for the WB-DW scans.
Both exams required roughly the same time between tracer injection and end of scan and the
estimated exam costs were comparable.

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Answer: Accurate staging of malignant tumors in children and adolescents is critical, as the
presence and location of tumor manifestations throughout the body determines therapy
management and prognosis. However, several human population studies have shown that
exposure to ionizing radiation above doses of about 50-100 mSv increases the risk for development
of secondary cancers later in life. This is especially concerning for young patients because they are
more susceptible to the effects of radiation than older patients and they live long enough to
encounter secondary cancers later in live.
We demonstrate that it is possible to provide sensitive tumor staging of children with malignant
tumors by using a completely radiation free imaging test as an alternative to PET/CT scans. Maybe,
one could compare this to replacing conventional light bulbs with LED lights, which eliminate
unwanted heat production. Just as we want light only for our lamps, we want tumor detection only
without associated side effects from radiation. Current imaging techniques do not meet our high
standards of patient care without side effects. Creating a potential risk of inducing new cancers
with our diagnostic imaging tests is not acceptable. Our new radiation-free imaging test provides a
solution for this problem. The next step will be to prove our findings in larger patient populations,
beyond our single center. We are currently planning a multi-institutional initiative of six major
Children’s hospital in the US, who want to compare the value of whole body MRI and PET/CT for
staging of Hodgkins lymphoma. And we were recently also contacted by centers in Europe who
want to join in. This could potentially evolve into a truly global initiative that could make this
imaging test widely available. Our ultimate goal is to provide global access to tumor staging tests
with substantially reduced or eliminated radiation exposure.



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MedicalResearch.com: What recommendations do you have for future research as a result
of this study?
Answer: We evaluated the value of our new imaging test for the initial diagnosis of tumors in
pediatric patients. Further studies have to show if this imaging test is also useful for
evaluation of a response of the detected tumors to treatment. Such studies are also under
way. There are new technological developments that combine radiotracer based imaging
studies with our MRI technique. Those imaging tests still have a substantially reduced
radiation exposure compared to classical PET/CT scans, but may provide additional
information compared to our radiation free scan. Future studies will have to show, which
patients will benefit most from a completely radiation-free whole body imaging test, as
described in our article, versus new ULD (ultra low dose) PET/MR imaging tests. This is a
major focus of our future multi-institutional research efforts.
Citation:
Published online February 19, 2014 http://dx.doi.org/10.1016/S1470-2045(14)70021-X1
Christopher Klenk, Rakhee Gawande, Lebriz Uslu, Aman Khurana, Deqiang Qiu, Andrew
Quon, Jessica Donig, Jarrett Rosenberg,
Sandra Luna-Fineman, Michael Moseley, Heike E Daldrup-Link. Ionising radiation-free wholebody MRI versus ¹⁸F-fluorodeoxyglucose PET/CT scans for children and young adults with
cancer: a prospective, non-randomised, single-centre study
Lancet (2014) doi.org/10.1016/S1470-2045(


Mesh Hernia Repairs Associated with Fewer Recurrences
Mike K.Liang, MD,
Department of Surgery, The University of Texas Health
Sciences Center, Lyndon B. Johnson Hospital,Houston, TX 7702

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Dr. Liang: Compared to suture repair, mesh repair of primary ventral hernias (umbilical, epigastric, spigelian, lumbar), the
most common type of ventral hernias, is associated with fewer hernia recurrence but slightly more seromas and surgical site
infections.
Dr. Liang: In current practice, many surgeons continue to repair primary ventral hernias with suture repair only believing
that they can obtain the same outcomes. This study reinforces the concept that even for small hernias, mesh reinforcement
is associated with improved long term outcomes at a slightly increased risk of more short term adverse events.
Dr. Liang:
Clinicians: meta-analysis is not to answer questions but rather to frame questions properly. Further prospective
randomized controlled trials are needed to properly assess the best role of mesh and suture repair of primary ventral
hernias.
Patients: in most situations, mesh repair of primary hernias improve long term outcomes with slight increase in more short
term adverse events.
Dr. Liang:
More high quality prospective randomized controlled trials are needed to asses the role of mesh versus suture repair of
primary ventral hernias.
Given the current evidence, use of mesh in most primary hernias will yield better long term outcomes with a slight increase
in short term complications.
Citation:
Comparison of Outcomes of Synthetic Mesh vs Suture Repair of Elective Primary Ventral Herniorrhaphy
A Systematic Review and Meta-analysis
Nguyen MT, Berger RL, Hicks SC, et al. Comparison of Outcomes of Synthetic Mesh vs Suture Repair of Elective Primary
Ventral Herniorrhaphy: A Systematic Review and Meta-analysis. JAMA Surg. 2014;():. doi:10.1001/jamasurg.2013.5014.


Carcinogens in Food Packaging
Dr. Jane Muncke PhD Managing Director
Food Packaging Forum Foundation
Zurich, Switzerland

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MedicalResearch.com: What are the main conclusions from your work?
Answer: Food packaging is a relevant, but still under-recognized source of chemical
contamination in foods. Everybody is exposed to these chemicals on a daily basis, but we
have very little understanding of the actual health effects caused by this chronic exposure
source. We propose that epidemiological research tackles chemical exposures from food
packaging as a new and highly relevant exposure source. Epidemiologist have played crucial
roles in advancing understanding of health issues, for example cardiovascular disease caused
by fine particulate air pollution. Through their work they have encouraged toxicologists to ask
different questions, thereby supporting the generation of critical knowledge and, essentially,
enabling prevention.

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MedicalResearch.com: Which insights were most unexpected to you?
Answer: We were surprised to find known carcinogens being authorized for the use in food
contact materials. As such, the FDA lists asbestos fiber as indirect food additive for the use in
rubbers intended for food contact applications. This means that its use is, at least in theory,
completely legal in the US. Another chemical of concern is formaldehyde, a known human
carcinogen which is used as monomer in melamine formaldehyde tableware. Formaldehyde
is also a non-intentionally added substance leaching from plastic soda bottles. Considering
how many people consume beverages from such containers on a daily basis we have to
assume that exposures to formaldehyde at low levels affect the entire population.


Carcinogens in Food Packaging
Dr. Jane Muncke PhD Managing Director
Food Packaging Forum Foundation
Zurich, Switzerland

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Answer: As a consumer, we can make choices to eat as many fresh, unprocessed, organic and, if
possible, unpackaged foods as possible—a recommendation many doctors most likely make
already. Furthermore, it is essential to avoid potentially harmful chemical exposures especially
during pregnancy, for example arising from increased chemical leaching into hot foods. However,
our influence as consumers is unfortunately limited, because we do not know how foods were
stored or processed before they reach the stores. And, we do not always have a choice what kind of
foods we eat, due to availability, time or budget restrictions. What we need most therefore are
chemical regulations that are informed by the most current scientific understanding, with
prevention of chronic diseases as main target.
MedicalResearch.com: What recommendations do you have for future research as a result of your
work?
Answer: We hope to inspire epidemiologists to integrate knowledge about chemical exposures
from food packaging in their studies. Such exposures are a relatively discrete and measurable route
of exposure that would lend itself for amending existing methods, like food frequency
questionnaires, dietary intake records or 24h recalls. Ideally, such efforts would be supplemented
by biomonitoring for specific target compounds. Consumer behavior at home may be another
interesting area of research, i.e. understanding in what container types foods are stored and
reheated.
Citation:
Food packaging and migration of food contact materials: will epidemiologists
rise to the neotoxic challenge?
JOURNAL OF EPIDEMIOLOGY AND COMMUNITY HEALTH
Published Feb 19 2014


Online Physician Rating Sites: Public Awareness and Participation Increasing
MedicalResearch.com Interview with: Dr. David Hanauer, MD
Associate Professor, University of Michigan Medical School
1500 East Medical Center Drive
Ann Arbor, MI 48109-5940

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MedicalResearch.com: What are the main findings of the study
Dr. Hanauer: From my perspective, the primary findings were that 65% of the general public is now aware of physician rating
web sites and among those who are aware, about 36% had used them in the prior year. Awareness and usage seems to be
rapidly increasing compared to what has been reported in prior studies from just a few years ago. We also found that
patients consider word of mouth recommendations (from family/friends) to be almost twice as important as ratings sites
are.
Dr. Hanauer: I was surprised that the public was truly using these online rating sites to make decisions. In our study, among
those who had sought online physician ratings in the prior year, 35% had chosen a doctor based on good ratings and 37%
had avoided a doctor based on bad ratings. This is important to because the implications of using these sites are potentially
much larger than using similar rating sites for standard consumer goods and services (choosing a movie to watch, for
example).
One thing that wasn’t surprising is how few people actually leave ratings themselves. In our study, 5% of the public had left
a rating about a physician. We know from prior work that one of the biggest concerns about such sites is that, because so
few people leave ratings, it is hard for people to make judgements about how accurate or representative the ratings are.
Dr. Hanauer: Clinicians should be aware that the public is actually using these sites more and more to make decisions so the
information on them could impact whether or not the next potential patient chooses to see them or not. Many clinicians
have long been resistant to such ratings, but they seem to be here to stay, and may even be proliferating. It seems as if there
are an increasing number of online rating sites for clinicians these days.
However, from the patient perspective it is important to realize that there isn’t much (if any) regulation of the sites, and it is
hard to know how trustworthy many of them are. For example, even for the few (potentially non-represenative) ratings
about a physician on a site, can we even know if the rating was real, or what factors it was based on? This may be why
patients are still seeking input from family and friends more than rating sites.


Online Physician Rating Sites: Public Awareness and Participation Increasing
MedicalResearch.com Interview with: Dr. David Hanauer, MD
Associate Professor, University of Michigan Medical School
1500 East Medical Center Drive
Ann Arbor, MI 48109-5940

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MedicalResearch.com: What recommendations do you have for future research as a result
of this study?
Dr. Hanauer: Given that ratings sites are likely not going away, I think in the future it will be
important to understand how to make the sites more reliable so that both clinicians and
patients can feel that at least the data are trustworthy. I think it will be important to better
understand what patients would like to see in ratings sites, and what clinicians think are
reasonable measures to include. Finding the right balance will be tricky.
Another very important aspect to consider is what actually should go into defining a “good”
clinician rating? While some may seem obvious (bedside manners, skills, etc), others may be
more controversial (decor of the waiting room, for example). Right now there is no
consensus, and as a result different rating sites often measure different things. So a potential
healthcare “consumer” may develop a different perspective depending on which site(s)
he/she visited.
Citation:
Hanauer DA, Zheng K, Singer D, Gebremariam A, Davis M. Public Awareness, Perception, and
Use of Online Physician Rating Sites. JAMA. (In Press)


Pulmonary Fibrosis: High Resolution CT Diagnosis
MedicalResearch.com Interview with: Ganesh Raghu, M.D.,FCCP, FACP
Professor of Medicine & Lab Medicine (Adjunct)
Division of Pulmonary & Critical Care Medicine University of Washington(UW)
Director,CENTER for Interstitial Lung Disease (ILD),UW Medicine, ILD, Sarcoid and Pulmonary Fibrosis Program
Co-Director, Scleroderma Clinic, UW Medical center(UWMC) Seattle, WA 98195

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Dr. Raghu: In a subgroup of patients with typical clinical features of Idiopathic pulmonary fibrosis ( IPF) , further evaluation
by a thorough evlauation by regional experts experienced in management of idiopathic pulmonary fibrosis and related
diseases may lead to a diagnosis of idiopathic pulmonary fibrosis without the need for surgical lung biopsy if the HRCT
features have a Possible-UIP pattern AND if there are no suspicion for environmental factors or collagen vascular diseases to
explain the pulmonary fibrosis .

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Dr. Raghu:
The HRCT pattern of Inconsistent- UIP does not exclude UIP in surgical lung biopsy
Dr. Raghu:
General clinicians and confronted patients must familiarise themselves with clinical manifestations of Interstitial lung
diseases , Idiopathic interstitial pneumonias and Idiopathic pulmonary fibrosis( IPF )
These findings MUST not be extrapolated to the interpretation of HRCT pattern of possible UIP by general /community
physicians and general radiologists
Prompt referral to regional experts, experienced with management of ILD for an accurate diagnosis.
Dr. Raghu: Ascertain sensitivity and specificity of the possible-UIP pattern in consecutive patients evalutated for ILD /
idiopathic interstitial pneumonia
Citation:

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Diagnosis of idiopathic pulmonary fibrosis with high-resolution CT in patients with little or no radiological evidence of
honeycombing: secondary analysis of a randomised, controlled trial
Ganesh Raghu, David Lynch, J David Godwin, Richard Webb, Thomas V Colby, Kevin O Leslie, Juergen Behr, Kevin K Brown,
James J Egan,
Kevin R Flaherty, Fernando J Martinez, Athol U Wells, Lixin Shao, Huafeng Zhou, Patricia S Pedersen, Rohit Sood, A Bruce
Montgomery, Thomas G O’Riordan

TAVR vs Surgical Aortic Valve Replacement for Aortic Stenosis with LV Dysfunction
Sammy Elmariah, MD, MPH
Massachusetts General Hospital
Boston, MA
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Dr. Elmariah: Within the randomized PARTNER I trial, we evaluated the effect of left ventricular (LV) dysfunction on clinical outcomes
after transcatheter and surgical aortic valve replacement (TAVR and SAVR, respectively) and the impact of valve replacement technique
on recovery of LV function. We found that LV dysfunction, defined as an LV ejection fraction < 50%, had no impact on 30-day and 1-year
mortality after either TAVR or SAVR. In those with baseline LV dysfunction, marked improvement in LV ejection fraction was observed
within 30-days of valve replacement in approximately half of patients, with an equivalent degree of improvement observed after TAVR
and SAVR. Permanent pacemaker at study entry, low mean aortic valve gradient, and high LV ejection fraction were associated with
reduced odds of LV functional recovery after valve replacement.
Dr. Elmariah: Yes, we found that patients with LV dysfunction that did not demonstrate improvement in LV function within 30-days of
TAVR possessed an increased risk of death at 1-year follow-up. Surprisingly, lack of early LV functional improvement did not influence
clinical outcomes after SAVR. The reason for this discrepancy is not readily apparent, although we suspect that injury of the LV during
transapical TAVR, paravalvular aortic regurgitation, and conduction abnormalities after TAVR may be involved.
MedicalResearch.com: What should clinicians and patients take away from this study?
Dr. Elmariah: Our findings highlight the beneficial impact of aortic valve replacement in patients with aortic stenosis and LV dysfunction
and demonstrate that TAVR should be considered a feasible alternative to SAVR regardless of the presence of LV systolic dysfunction.
MedicalResearch.com: What further research do you recommend as a result of your study?
Dr. Elmariah: Further efforts are needed to identify the reasons responsible for poor clinical outcomes in patients with persistent LV
dysfunction after TAVR. If in fact LV injury during transapical TAVR is found to mediate this observation, alternative approaches may
prove to be beneficial in patients with LV dysfunction undergoing TAVR.
Citation:
Outcomes of Transcatheter and Surgical Aortic Valve Replacement in High-Risk Patients With Aortic Stenosis and Left Ventricular
Dysfunction: Results From the Placement of Aortic Transcatheter Valves (PARTNER) Trial (Cohort A)
Sammy Elmariah, Igor F. Palacios, Thomas McAndrew, Irene Hueter, Ignacio Inglessis, Joshua N. Baker, Susheel Kodali, Martin B. Leon,
Lars Svensson, Philippe Pibarot, Pamela S. Douglas, William F. Fearon, Ajay J. Kirtane, Hersh S. Maniar, and Jonathan J. Passeri
Circ Cardiovasc Interv. 2013;CIRCINTERVENTIONS.113.000650published online before print November 12 2013,
doi:10.1161/CIRCINTERVENTIONS.113.000650


Pre-Op Vitamin D and Infection Risk Following Gastric Bypass Surgery
Sadeq A. Quraishi, MD, MHA
Massachusetts General Hospital, Harvard Medical School
Boston, Massachusetts

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Dr. Quraishi: Our retrospective study suggests that there is an association between pre-operative 25-hydroxyvitamin D
[25(OH)D] levels and the risk of hospital-acquired infections after gastric bypass surgery. In particular, patients with 25(OH)D
levels <30 ng/ml before surgery were almost 4 times more likely to develop a surgical site infection within 30 days of surgery
than patients with pre-operative 25(OH)D levels at 30 ng/ml or higher.
Dr. Quraishi: While the findings themselves are not surprising, given our emerging understanding of how vitamin D status
affects immune function, the magnitude of this association is rather surprising. We did select a patient cohort at high risk for
low 25(OH)D levels and high risk for hospital-acquired infections. As such, further studies are needed to extend our work, to
assess the generalizability of our findings to all surgical patients, and to test whether vitamin D supplementation can
influence the risk of developing hospital-acquired infections.
Dr. Quraishi: We believe that 25(OH)D optimization before surgery is a promising strategy for supporting immune health
through the perioperative setting. Active research in this area by our group and others will help us to better understand
whether vitamin D supplementation is indeed helpful, and if so, how much to take and when to take it.
Dr. Quraishi: Observational research (such as this study) helps us to generate more questions and provides a rationale to
further pursue an idea – it does not address the issue of causality. To answer the question of whether vitamin D
supplementation can reduce the risk of hospital-acquired infections, well-designed, placebo-controlled clinical trials are the
next step.
Citation:
Association Between Preoperative 25-Hydroxyvitamin D Level and Hospital-Acquired Infections Following Roux-en-Y Gastric
Bypass Surgery.
Quraishi SA, Bittner EA, Blum L, Hutter MM, Camargo CA Jr.
JAMA Surg. 2013 Nov 27. doi: 10.1001/jamasurg.2013.3176. [Epub ahead of print]


Alzheimer’s: Celexa Reduced Agitation, Has Modest Cognitive, Cardiac Side Effects
MedicalResearch.com Interview with: Anton P. Porsteinsson M.D.
William B. and Sheila Konar Professor of Psychiatry
Director, Alzheimer’s Disease Care, Research and Education Program (AD-CARE)
University of Rochester School of Medicine and Dentistry Rochester, N.Y. 14620
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Dr. Porsteinsson: Identifying drugs outside the antipsychotic class with targeted anti-agitation effects that provide greater benefit or
lower risk among patients with Alzheimer’s disease is a research priority. Citalopram, a selective serotonin reuptake inhibitor (SSRI), is
frequently used in older individualsand has been suggested as an alternative to antipsychotic drugs for agitation and aggression in
dementia. Among 186 patients with probable Alzheimer’s disease and agitation receiving psychosocial intervention, the addition of
citalopram compared with placebo robustly and significantly reduced agitation and caregiver distress, but modest cognitive and cardiac
adverse effects of citalopram may limit its practical application at the 30 mg/d dose studied in this trial. There are insufficient data on
efficacy for agitation at lower doses of citalopram.
Dr. Porsteinsson: Three quarters of the way through the study, the Food and Drug Administration (FDA) issued an advisory regarding
dose-dependent risk of QT prolongation with citalopram therapy that subsequently came under scrutiny. We added ECG monitoring
and QT interval prolongation was seen in the citalopram group similar to what had been described in the advisory for a younger
population and our findings validate the FDA’s action. Furthermore, an unexpected modest cognitive decline was seen in the
citalopram group compared to placebo over 9 weeks with no difference in spontaneously reported somnolence or confusion.
Dr. Porsteinsson: Neuropsychiatric symptoms occur in a majority of patients with Alzheimer’s disease. Agitation is common, persistent,
difficult to treat, costly, and associated with severe adverse consequences for patients and caregivers. Psychological, environmental
and pharmacologic therapies have proven inadequate. Antipsychotics continue to be widely used for agitation, despite serious safety
concerns, including increased mortality, and uncertain efficacy. The takeaway message is that there are very limited options for the
treatment of this tremendously distressing and difficult to treat behavioral disruption. If non-pharmacological intervention is not
beneficial, judicious use of citalopram appears to have a role in managing agitation in patients with Alzheimer’s disease but generally
the dose should not surpass 20 mg/d.
Dr. Porsteinsson: Given potentially concerning side effects of citalopram at 30 mg/d, further investigation is needed to determine
whether a smaller dose will be as effective.
Citation:
Porsteinsson AP, Drye LT, Pollock BG, et al. Effect of Citalopram on Agitation in Alzheimer Disease: The CitAD Randomized Clinical Trial.
JAMA. 2014;311(7):682-691. doi:10.1001/jama.2014.93.


Expanded Health Insurance: Hospital Services Use by Young Adults with Behavioral Diagnoses
Ellen R. Meara
Associate Professor of The Dartmouth Institute
Adjunct Associate Professor in Economics & Nelson A. Rockefeller Center for Public Policy, Dartmouth College

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MedicalResearch.com: What are the main findings of this study?
Answer: When insurance coverage for young adults rose by over 15 percentage points following Massachusetts’ 2006 health
reform, use of inpatient care for mental illness and substance use disorders fell and emergency department visits for these
conditions grew more slowly for 19 to 25 year olds in Massachusetts relative to other states. Also, their care was much more
likely to be paid for by private or public insurance insurers.
MedicalResearch.com: Where any of the findings surprising?
Answer: Because treatment for mental illness and substance use disorders has been more responsive to the price patients
face, compared with treatment of physical conditions, some policymakers have feared that expanding insurance coverage
would lead to rapid growth in spending on treatment of mental illness and substance use disorders, especially in expensive
hospital settings. We found that, in Massachusetts, a group with high need for treatment of mental illness and substance
abuse, young adults, did not increase use of hospital care compared with other states after 2006.
MedicalResearch.com: What should patients and providers take take away from your study?
Answer: Takeaway for clinicians and patients – with expanded insurance coverage, when young adults do need hospital
based care, the financial burden to patients and providers is lower.
MedicalResearch.com: What future research do you recommend as a result of your report?
Answer: We need better data on care in outpatient settings, since we cannot distinguish whether lower use of hospital care
in Massachusetts reflects access to effective outpatient care, or some other trend that limited use of hospital care after
health reform
Citation:
Use of Hospital-Based Services Among Young Adults
With Behavioral Health Diagnoses Before and After Health
Insurance Expansions
Ellen R. Meara, Dartmouth College, Ezra Golberstein, University of Minnesota, Rebecca Zaha, The Dartmouth Institute for
Health Policy and Clinical Practice, Shelly F. Greenfield, McLean Hospital, William R. Beardslee, Harvard University and Susan
H. Busch, Yale University
Presented at Association for Public Policy Analysis and Management


Target: Stroke Program Improved Stroke Treatment Time and Outcomes
Gregg C Fonarow, UCLA Medical Ctr, Los Angeles, CA;
Director, Ahmanson-UCLA Cardiomyopathy Center
Professor, Department of Medicine Associate Chief, Cardiology
David Geffen School of Medicine

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Dr. Fonarow: The study examined data from hospitals that have adopted the American Heart
Association/ American Stroke Association’s national quality initiative, Target: Stroke. The
primary aim of Target: Stroke is to increase the number of stroke patients treated with tPA for
acute ischemic stroke within 60 minutes or less after hospital arrival. The study demonstrated
that patients received stroke therapy significantly faster in hospitals that participated in
Target: Stroke. Between 2010 and 2013, the time between hospital arrival and use of tPA
(door-to-needle time) dropped by 15 minutes, from 74 to 59 minutes, in hospitals that
participated in Target: Stroke. This study found that the percentage of patients treated within
the recommended timeframe increased from less than one-third before Target: Stroke to
more than half afterwards. The Target: Stroke program goal of 50 percent or more of patients
having door-to-needle times within 60 minutes was successfully achieved. Faster treatment
was associated with improved patient outcomes and fewer complications, including death.

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Dr. Fonarow: It was surprising that the quality improvement intervention was so successful in
all types of patients including young and older, men and women, white, black, and Hispanic
patients as well as those with greater and lesser stroke severity.


Target: Stroke Program Improved Stroke Treatment Time and Outcomes
Gregg C Fonarow, UCLA Medical Ctr, Los Angeles, CA;
Director, Ahmanson-UCLA Cardiomyopathy Center
Professor, Department of Medicine Associate Chief, Cardiology
David Geffen School of Medicine

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Dr. Fonarow:
Target: Stroke was successful. The timeliness of tPA administration improved substantially after initiation
of the multidimensional AHA/ASA Target: Stroke quality initiative. The proportion of patients with door-toneedle times ≤60 minutes increased from 29.6% to 53.3%. There was also a more than 4-fold increase in
the annual rate of improvement in patients with door-to-needle time ≤60 minutes. This improvement was
accompanied by lower in-hospital mortality, symptomatic intracranial hemorrhage, and overall tPA
complications with more patients able to be discharged to home.
Dr. Fonarow: These findings further reinforce the importance and clinical benefits of faster administration
of intravenous tPA. By showing that the timeliness of tPA administration can be improved at the national
level, these findings also support further expansion of the Target: Stroke initiative. Future studies should
evaluate hospital and systems factors associated with the greatest improvement in performance.
Citation:
International Stroke Conference 2014: Abstract LB 12
Title: Improving Door-to-Needle Times in Acute Ischemic Stroke: Principal Results from the Target: Stroke
Initiative
Authors: Gregg C Fonarow, UCLA Medical Ctr, Los Angeles, CA; Xin Zhao, Duke Clinical Res Inst, Durham,
NC; Eric E. Smith, Univ of Calgary, Calgary, AB, Canada; Jeffrey L. Saver, UCLA Neurology, Los Angeles, CA;
Mathew J. Reeves, Michigan State Univ, East Lansing, MI; Deepak L. Bhatt, Brigham and Women’s Hosp,
Boston, MA; Ying Xian, Adrian Hernandez, Eric D. Peterson, Duke Clinical Res Inst, Durham, NC; Lee H.
Swhwamm, Massachusetts General Hosp, Boston, MA


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Blood Pressure Damage to Blood Vessels Detectable In Retinal Blood Vessel Thickening
Maria Lorenza Muiesan
Department of Clinical and Experimental Sciences
University of Brescia, Internal Medicine
Brescia, Italy.
Dr. Muisean: An increase in the ratio of retinal arteries wall thickness to lumen diameter may serve as an in-vivo parameter of
microvascular damage. We conducted a study that examined the relationship between changes in retinal arterioles wall thickness/
lumen diameter and several measures of blood pressure, including clinic brachial blood pressure, 24 hours brachial blood pressure and
central aortic blood pressure. We found that the an increase of wall-to-lumen ratio of retinal arterioles was most closely related to 24
hours blood pressure.
We also confirmed previous finding of our group, showing that changes in retinal arterioles were significantly associated with an
increase in aortic stiffness, an index of macrovascular damage, further supporting the concept that microvasculature and
macrovasculature are strongly interrelated.
Dr. Muisean: Some previous results, obtained with measurements of clinic blood pressure and of central aortic pressure by pulse wave
analysis, found a closer relationship with aortic central blood pressure.
Our findings indicate that 24 hours pressure load may be a stronger determinant of microvasculature changes than a single
measurement of aortic central pressure.
Dr. Muisean: The evaluation of the arterioles in the fundus oculi by Scanner Doppler Laser Flowmetry is a noninvasive and easily
repeatable procedure and shows that retinal arterioles changes are related to 24 hours blood pressure load as well as to non-invasive
measures of aortic stiffness.
Dr. Muisean: New technologies, presently under clinical evaluation, may help in the future to noninvasively assess microvascular
structural alterations and to better stratify CV risk of hypertensive patients with consequent optimization of treatment. The wider use
of a noninvasive approach for the stratification of risk in the majority of hypertensive patients may be proposed, since microvascular
structure may represent an intermediate endpoint in the evaluation of the effects of antihypertensive treatment.
Citation:
Relationship of Wall-to-Lumen Ratio of Retinal Arterioles With Clinic and 24-Hour Blood Pressure , Massimo Salvetti, Claudia Agabiti
Rosei, Anna Paini, Carlo Aggiusti, Anna Cancarini, Sarah Duse, Francesco Semeraro, Damiano Rizzoni, Enrico Agabiti Rosei, and Maria
Lorenza Muiesan
Hypertension. 2014;HYPERTENSIONAHA.113.03004published online before print February 10 2014,
doi:10.1161/HYPERTENSIONAHA.113.03004


Alcohol Toxic to Placenta During Pregnancy
MedicalResearch.com: Interview with: Sylvia Lui
Tommy’s Maternal and Fetal Health Research Centre
The University of Manchester
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Answer: The research shows women who drink alcohol at moderate or heavy levels in the early stages of their pregnancy might damage the growth and function of
their placenta – the organ responsible for supplying everything that a developing infant needs until birth
Answer: Yes, as we did not expect the strong effect on placental function. The results add weight to existing research in this area - that alcohol has negatively effects
pregnancy or fetal development, but previous studies have used the upper limits of alcohol concentration, and at levels that would not be found in the human body.
Our results show that the damage caused by alcohol may start with an abnormally developing placenta, and that it can happen very early on in pregnancy – perhaps
before a woman knows she is pregnant – in the very early weeks and at drinking levels as found in an average population.
The aim of this project was to investigate and provide clarity on the effects of alcohol at low, moderate and ‘binge’ levels, on the developing placenta and hence
pregnancy and the baby.
Answer: It can often be a few weeks before a woman discovers she’s pregnant, and this research shows that moderate drinking during those vital first weeks can
have a big impact on the development of the baby. Low levels had no effect and perhaps awareness of alcohol units should be a key factor in educating women about
their pregnancy. However research shows that it is difficult for people to judge how much they are drinking according to the recommended daily units, and are often
incorrect. It is also recognised that alcohol is one of the most well-known, and most avoidable, toxin in pregnancy.
Many pregnancies are unplanned, but for those actively planning a family this research raises questions about whether women should consider their alcohol intake
even before they fall pregnant.
Answer: Our main focus in this study was the effect on placental growth and placental taurine transport, as they are major contributors towards fetal development.
Future studies on other placental functions that are known to be indicators of a healthy pregnancy, such as hormone production, would further show how alcohol
and acetaldehyde impacts pregnancy. Changes in hormone levels are known to change maternal metabolism, hence a successful pregnancy and fetal well-being.
Future research would also include alcohol and acetaldehyde’s effects on placental barrier function. The placenta is a barrier in preventing unwanted substances
crossing from mother to baby. Though alcohol and acetaldehyde freely crosses the placenta to the baby, how they affect the placenta’s ability to acts as a barrier
against other toxins is unknown.
On a broader scale, future investigations would include possible preventative therapies such as diet supplements. Studies in animals have shown that folic acid is
protective against effects of alcohol. Extra taurine intake, after alcohol, has been shown to decrease brain lesions in animal models. Further work is required to
investigate whether supplementation, through the mother, has any side effects, or can improve pregnancy outcomes where there may have been alcohol exposure.
There are many questions to be still answered, but the placenta is a valuable means to investigate pregnancy-related problems due to its crucial role in a healthy
pregnancy.
Citation:
Detrimental effects of ethanol and its metabolite, acetaldehyde, on first trimester human placental cell turnover and function.” S. Lui, R.L. Jones, N.J. Robinson, S.L.
Greenwood, J.D. Aplin, C.L. Tower was published on 4 February in PLoS One


TAVR for Aortic Stenosis: Improvement in Quality of Life
Caroline A. Kim, MD, MS;
Beth Israel Deaconess Medical Center
Boston, MA 02215.

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Dr. Kim: We conducted a systematic review of 62 studies that examined functional status and
quality of life in patients who underwent transcatheter aortic valve replacement (AVR) for
their symptomatic severe aortic valve stenosis. In 11,205 patients who underwent TAVR, a
clinically meaningful improvement was seen in physical functional measures and diseasespecific quality of life measures, whereas improvement in psychological measures or more
general health measures were modest and inconsistent. Given the dismal prognosis of
severe aortic stenosis treated conservatively, it was clear that transcatheter AVR improved
functional status and quality of life. However, there was insufficient evidence that compares
these patient-centered outcomes between transcatheter AVR and surgical AVR.
Dr. Kim: The majority of studies had major methodological limitations that did not allow
accurate estimation of overall benefits of transcatheter AVR. Although many patients with
severe aortic stenosis may place a higher value on improving the quality of life than
prolonging survival, we were surprised to learn that most research only focused on
procedural success or mortality; very few studies compared transcatheter AVR and surgical
AVR. In most studies, measures of functional status and quality of life other than the New
York Heart Association functional class were seldom studied. Furthermore, it was evident
that some patients did not benefit from transcatheter AVR.

TAVR for Aortic Stenosis: Improvement in Quality of Life
Caroline A. Kim, MD, MS;
Beth Israel Deaconess Medical Center
Boston, MA 02215.

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Dr. Kim: Here are the take-home points from our work:
1) Transcatheter AVR improves survival, physical function, and some measures of quality of life
compared with conservative treatment.
2) However, these observed benefits of transcatheter AVR were not observed from all patients
treated with transcatheter AVR. Some did not receive any meaningful benefits.
3) The functional and quality-of-life benefits of transcatheter AVR compared with surgical AVR
remain to be examined. Previous research showed similar survival rates.
4) Until more evidence accrues, clinicians and patients should weight potential risks and benefits of
the two procedures, individuals’ risk factors for complications (medical comorbidities and frailty)
and life expectancy, to select patients who are most likely to benefit. This point is not directly
supported from our work, but it is a general statement based on current evidence.
study?
Dr. Kim: We call for more prospective studies that compare functional status and quality of life
between transcatheter AVR and surgical AVR to better inform clinicians and patients in making
treatment decisions for symptomatic severe aortic stenosis. More research is needed to develop
an algorithm that identifies those who are more likely to benefit from transcatheter AVR than
surgical AVR.
Citation:
Caroline A. Kim, Suraj P. Rasania, Jonathan Afilalo, Jeffrey J. Popma, Lewis A. Lipsitz, Dae Hyun Kim;
Functional Status and Quality of Life After Transcatheter Aortic Valve Replacement
A Systematic Review. Annals of Internal Medicine. 2014 Feb;160(4):243-254.


Stroke: Intracranial Atherosclerosis as a Major Risk Factor
M. Arfan Ikram, MD, PhD
Departments of Radiology, Epidemiology, and Neurology Erasmus Medical Center,
Rotterdam, the Netherlands

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Dr. Ikram: The main finding of the study, carried out within the Rotterdam Study and led by drs.
Daniel Bos and Arfan Ikram (both from the Erasmus Medical Center Rotterdam, the Netherlands),
was that intracranial atherosclerosis is a major risk factor for stroke in the Western (white)
population. Traditionally, intracranial atherosclerosis has not been considered of major importance
to stroke risk in Western populations. In contrast, most research on intracranial atherosclerosis
originates from Asian and African populations, where is was actually recognized as the most
important risk factor of stroke. Our study demonstrates that also in the Western population
intracranial atherosclerosis is a major risk factor for stroke and should get more focus in clinical
practice. Moreover, our findings indicate that its contribution to the proportion of all strokes is
greater than that of atherosclerosis in other vessel beds that are further away from the brain.

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Dr. Ikram: Our hypothesis was that atherosclerosis that is located in the vasculature directly
supplying the brain would have more influence on the development of stroke compared to
locations further away from the brain (such as heart or aorta). This was in conjunction with the
second hypothesis that intracranial atherosclerosis would be a major risk factor of stroke in
Western populations too. In that sense, our finding that intracranial atherosclerosis was indeed a
strong risk factor for stroke, was not entirely unexpected. However, the magnitude of the
association was larger than we anticipated. Especially, the finding that the association between
intracranial atherosclerosis and stroke firmly remained after adjustment for the presence of
atherosclerosis in the carotid bifurcation, aortic arch and the coronary arteries, emphasizes the
importance of intracranial atherosclerosis.


Stroke: Intracranial Atherosclerosis as a Major Risk Factor
M. Arfan Ikram, MD, PhD
Departments of Radiology, Epidemiology, and Neurology Erasmus Medical Center,
Rotterdam, the Netherlands

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Dr. Ikram: Over the past decades, there has not been much attention for intracranial atherosclerosis as
cause of stroke in the Western (white) population. With the current study we demonstrated that from
different important sites where atherosclerosis frequently occurs (carotid bifurcation, aorta, coronary
arteries), the presence and amount of intracranial atherosclerosis seems to be the most important with
regard to strokes. In other words, intracranial atherosclerosis is an underestimated risk factor for stroke
and deserves significantly more attention in current practice.
Dr. Ikram: The next step in research should include the investigation of the predictive value of intracranial
carotid artery calcification for stroke. To a certain extent there is some analogy with the coronary arteries
and coronary events, especially myocardial infarction. Compared to the extensive research that has been
performed in this field, it is evident that much research is still to be done to assess the value of intracranial
atherosclerosis as a potential predictor of stroke. The coronary calcium score for example, has proven
added value in the prediction of acute cardiac disease beyond the Framingham risk score profile.
Additionally, more research is needed on prevention and treatment of intracranial atherosclerosis. In
recent years, there have been some clinical trials specifically targeting intracranial atherosclerosis in stroke
patients, but have not been entirely conclusive. Further research should also focus on preventing
intracranial atherosclerosis in healthy populations.
Citation:
Intracranial Carotid Artery Atherosclerosis and the Risk of Stroke in Whites: The Rotterdam Study
Daniel Bos MD, PhD, Marileen L. P. Portegies MD, Aad van der Lugt MD, PhD, Michiel J. Bos MD, PhD, Peter
J. Koudstaal MD, PhD, Albert Hofman MD, PhD, Gabriel P. Krestin MD, PhD, Oscar H. Franco MD, PhD,
Meike W. Vernooij MD, PhD, M. Arfan Ikram MD, PhD
JAMA Neurol. 2014;71(4):-. doi:10.1001/jamaneurol.2013.6223


Obesity: Linked to Genetics of Appetite and Satiety
Dr Clare Llewellyn PhD Cpsychol Lecturer in Behavioural Obesity Research
Health Behaviour Research Centre
Department of Epidemiology and Public Health University College London, London

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Dr. Llewellyn:This study indicated that appetite – and, in particular, satiety sensitivity (how quickly
you feel full during eating, or how long you remain full after eating) – could be one of the
mechanisms through which ‘obesity genes’ influence body weight.
We know that body weight has a strong genetic basis, but the mechanisms through which ‘obesity
genes’ influence weight are largely unknown.
We showed that children with a higher genetic predisposition to obesity (estimated from a score
comprising 28 known obesity-related genes) not only had more body fat (a larger BMI and waist
circumference), but importantly they were also less sensitive to satiety.
Dr. Llewellyn: Children who demonstrate low satiety sensitivity are at greater risk of obesity. This
appetitive characteristic is something for parents and clinicians to be aware of.
Satiety sensitivity could be targeted for pharmacological and behavioural interventions, to prevent
or treat obesity. For example, children who demonstrate low satiety sensitivity could be taught
techniques to improve their fullness signals when eating, such as slowing their eating speed.
Another approach might be to provide better advice to parents and children about appropriate
portion sizes, and limiting ‘seconds’. Pharmaceutical companies could develop drugs that increase
satiety responsiveness to food.
Citation:
Satiety Mechanisms in Genetic Risk of Obesity
Clare H. Llewellyn PhD, Maciej Trzaskowski PhD, MSc, Cornelia H. M. van Jaarsveld PhD, Robert
Plomin PhD, Jane Wardle PhD
JAMA Pediatr. 2014;168(4):-. doi:10.1001/jamapediatrics.2013.4944


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COPD: Treatment with twice daily N-acetylcysteine 600 mg
MedicalResearch.com Interview with: Jinping Zheng MD FACCP
on behalf of Prof. Nanshan Zhong
Prof. Nanshan Zhong –Jinping Zheng, MD, FCCP Guangzhou Institute of Respiratory Disease
First Affiliated Hospital of Guangzhou Medical University
151 Yanjiang Rd. Guangzhou 510120, China

Answer: PANTHEON is the largest, evidence-based study of long-term treatment with N-acetylcysteine (NAC) in COPD
patients conducted to date. The main finding of this study is that 1-year of treatment with high dose NAC (600mg twice
daily) was effective at reducing exacerbations in patients with COPD, especially in the earlier stage [GOLD II (moderate) of
disease. NAC was well tolerated.
Answer: We expected but failed to demonstrate the improvement of the SGRQ total scores in COPD patients treated with
NAC, The low SGRQ was probably attributable to the low severity of COPD spirometric impairment.
Answer: Oral administration of NAC, an anti-oxidant and mucolytic medicine, is recommended as a valuable treatment for
prevention of progression in patients with COPD. The treatment strategy of NAC includes higher dose, longer term and
earlier (moderate severity) administraton.
Answer: Future studies are needed to explore efficacy in patients with mild COPD (GOLD I); We also recommend that the
thio-compound mucolytics (NAC or Carbocisteine) should be put in the list of routine management of COPD in COPD
guidelines such as GOLD (Global Initiative for Chronic Obstructive Lund Disease), owing to their similar efficacy comparing
with ICS/LABA, the characters of cheaper, safe and easier to handle (oral administration).
Citation:
Twice daily N-acetylcysteine 600 mg for exacerbations of chronic obstructive pulmonary disease (PANTHEON): a randomised,
double-blind placebo-controlled trial
Prof Jin-Ping Zheng MD,Prof Fu-Qiang Wen MD,Prof Chun-Xue Bai MD,Prof Huan-Ying Wan MD,Prof Jian Kang MD,Prof Ping
Chen MD,Prof Wan-Zhen Yao MD,Prof Li-Jun Ma MD,Xia Li MS,Luca Raiteri MD,Marco Sardina MD,Yi Gao MD,Bai-Song Wang
PhD,Prof Nan-Shan Zhong MD,on behalf of the PANTHEON study group
The Lancet Respiratory Medicine – 30 January 2014
DOI: 10.1016/S2213-2600(13)70286-8


Gene Modifies Response to Topiramate in Heavy Drinkers
MedicalResearch.com Interview with: Henry R. Kranzler, MD
Professor, Department of Psychiatry
Director of the Center for Studies of Addiction.
University of Pennsylvania Perelman School of Medicine, Philadelphia

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Dr. Kranzler: The study had two main findings:
First, topiramate, at a maximal dosage of 200 mg/day, which is lower than the 300 mg/day used in prior treatment trials,
substantially reduced the frequency of heavy drinking and increased the frequency of abstinent days more than placebo. The
lower dosage was well tolerated.
Second, a variant in a gene that encodes a receptor subunit that binds topiramate moderated the response to topiramate.
That is, C-allele homozygotes in the single nucleotide polymorphism rs2832407 in GRIK1, the gene encoding the GluK1
subunit of the kainate receptor, were the subgroup that accounted for the effects of topiramate on heavy drinking. This has
important implications for the personalized treatment of alcohol use disorder, in that 40% of people of European ancestry
have this genotype and, if confirmed, these findings would make it possible to screen people genetically to select an
effective treatment.
Dr. Kranzler: Although the moderating effect of rs2832407 was hypothesized beforehand, the magnitude of the effect was
surprisingly large.
Dr. Kranzler: Topiramate can be used to reduce heavy drinking in people whose goal is sensible drinking, rather than only
those with a goal of abstinence. This is consistent with prior studies. Although it requires replication before it can be widely
recommended, the finding of genetic moderation could make it possible to select patients for whom topiramate would be
the medication of choice to treat alcohol use disorder.
Dr. Kranzler: The findings of moderation require replication. We are planning a study in which patients are selected in
advance based on genotype and then treated with topiramate to validate our initial findings. I am also working with
investigators in Australia on a plan to replicate the findings there.
Citation:
Topiramate Treatment for Heavy Drinkers: Moderation by a GRIK1 Polymorphism
Henry R. Kranzler, M.D.; Jonathan Covault, M.D., Ph.D.; Richard Feinn, Ph.D.; Stephen Armeli, Ph.D.; Howard Tennen,
Ph.D.; Albert J. Arias, M.D.; Joel Gelernter, M.D.; Timothy Pond, M.P.H.; Cheryl Oncken, M.D., M.P.H.; Kyle M. Kampman,
M.D. Am J Psychiatry 2014;:. doi:10.1176/appi.ajp.2013.13081014


Type 2 Diabetes: Weight Gain Pattern Before Diagnosis
Dorte Vistisen
Senior researcher, MSc PhD 469 – Epidemiology
DK-2820 Gentofte Denmark

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Dr. Vistisen: Our study highlights the complexity of type 2 diabetes. We show that in most people the
development of type 2 diabetes is preceded by many years of overweight and not by massive weight gain.
Dr. Vistisen: We expected to find different patterns in obesity development, but we were surprised that
the majority of those developing diabetes had such a stable weight pattern in the overweight range in the
years preceding diabetes.
Dr. Vistisen: We hope this study will help clinicians to recognise that other factors than obesity is
important in prevention of type 2 diabetes. For instance physical inactivity, smoking, unhealthy diet, genes
and maybe environmental pollutants, possibly in interaction with slight overweight.
Dr. Vistisen: First of all, our results need to be confirmed in other studies including populations with a
different ethnic mix and younger populations. Secondly, researchers should move away from the “one-size
fits all” approach when studying risk factors for diabetes, because there are many different pathways
leading to this disease. A better understanding of this heterogeneity in diabetes development, especially
of the interplay between different risk factors, is needed.
Citation:
Patterns of Obesity Development before the Diagnosis of Type 2 Diabetes: The Whitehall II Cohort Study
Dorte Vistisen, Daniel R. Witte, Adam G. Tabák, Christian Herder, Eric J. Brunner, Mika Kivimäki, Kristine
Færch Published:
February 11, 2014
DOI: 10.1371/journal.pmed.1001602


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