MedicalResearch.com: Medical Research Interviews June 24 2014

MedicalResearch.com
Exclusive Interviews with Medical Research and
Health Care Researchers from Major and Specialty Medical
Research Journals and Meetings
Editor: Marie Benz, MD
info@medicalresearch.com
July 24 2014
For Informational Purposes Only: Not for Specific Medical Advice.

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Multiple Sclerosis: Clinical Features and MRI Changes of Decision-Making Difficulties
MedicalResearch.com Interview with: Dr Nils Muhlert
Wellcome Trust ISSF Research Fellow
School of Psychology
Cardiff University
• Medical Research: What are the main findings of the study?
• Dr. Muhlert: Decision making impairments are known to occur in people with multiple sclerosis (MS), and are important, given they can
contribute to employment status, treatment compliance and function in everyday life. Studies by Kleeberg, Simioni and others have
demonstrated that decision-making impairments can occur early in the course of multiple sclerosis and get worse as the disease
progresses. Questions however remain over whether these impairments are linked to more general cognitive difficulties, differences
between multiple sclerosis subtypes, and their relationship with MRI changes.
• We assessed decision-making and examined MRI changes in a relatively large sample of people with multiple sclerosis (N = 105) and
healthy controls (N = 43). All participants performed the Cambridge Gambling Task, which independently measures risk-taking,
impulsivity, deliberation and risk adjustment, and underwent an MRI scan including T1-weighted and diffusion MRI sequences.
• We demonstrate that people with multiple sclerosis experience difficulties with risk adjustment (gauging risk and adapting accordingly)
and in the speed of making decisions but not in impulsivity. These problems were seen in those classified as having cognitive
impairment and those not (i.e. cognitively unimpaired). We found that decision-making impairments were twice as common in people
with relapsing-remitting and primary progressive MS than healthy controls, and almost four times as common in people with secondary
progressive multiple sclerosis. In addition, decision making impairments in multiple sclerosis were linked to MRI changes in regions
previously linked to decision-making in other conditions, including fronto-striatal and hippocampal regions. These findings offer insight
into the precise decision-making difficulties experienced by people with multiple sclerosis, the relative prevalences in different subtypes
of the disease and the pathological processes that may underlie them.
•
Medical Research: Were any of the findings unexpected?
• Dr. Muhlert: To examine diffusion changes on MRI we used a novel technique, called diffusion orientational complexity (DOC). This
examines the number of different orientations in which water molecules diffuse within each voxel. In white matter tracts, where there
is often one dominant diffusion direction, DOC is low. In cortical grey matter, diffusion is likely to be multi-directional due to the
presence of neurons and neurites, and so DOC is higher. The direction of DOC changes in people with multiple sclerosis differed
between regions – being significantly decreased in cortical grey matter but significantly increased in the hippocampus, relative to
healthy controls. This is plausible given histopathology, in which reduced cortical diffusion may be caused by processes including
cortical demyelination, neurite transection and neuronal loss in the normally complex and multi-layered architecture of cortical grey
matter. In contrast, increased hippocampal DOC in multiple sclerosis may result from a reduction in the dominance of diffusion along its
axis. However a combined MRI-histopathology study is required to elucidate the relationship of pathological processes in multiple
sclerosis grey matter with changes in DOC.
Read the rest of the interview on MedicalResearch.com
Content Not Intended as Specific Medical Advice

Multiple Sclerosis: Clinical Features and MRI Changes of Decision-Making Difficulties
MedicalResearch.com Interview with: Dr Nils Muhlert
Wellcome Trust ISSF Research Fellow
School of Psychology
Cardiff University
• Medical Research: What should clinicians and patients take away from your report?
• Dr. Muhlert: Greater awareness of decision-making difficulties in people with MS may be
prudent given its implications for employment, social situations and quality of life.
Understanding how these impairments relate to clinical features or MRI changes may help to
improve our knowledge of why such difficulties develop and what may be done to reduce
them.
• Medical Research: What recommendations do you have for future research as a result of
this study?
• Dr. Muhlert: Future longitudinal studies can examine whether it is possible to predict
whether certain people with multiple sclerosis are more likely to develop decision-making
impairments. Understanding of the clinical or MRI features that may predict these problems
could lead to earlier interventions to minimise or even prevent the establishment of decision-
making impairments in people with MS.
• Citation:
• The grey matter correlates of impaired decision-making in multiple sclerosis
• Nils Muhlert, Varun Sethi, Lisa Cipolotti, Hamied Haroon, Geoff J M Parker, Tarek Yousry,
Claudia Wheeler-Kingshott,
• David Miller, Maria Ron, Declan Chard
• J Neurol Neurosurg Psychiatry jnnp-2014-308169Published Online First: 8 July 2014
doi:10.1136/jnnp-2014-308169

Chronic Inflammation Associated With Increased Risk of Diabetes and Heart Disease
MedicalResearch.com Interview with: Dr Alex Dregan
Lecturer in Translational Epidemiology and Public Health,
Division of Primary Care and Public Health Research
King’s College London, London
Dr. Dregan: Our study showed that chronic inflammation was associated with increased risk
of developing cardiovascular disease, specifically type II diabetes and coronary heart disease.
The risk of cardiovascular disease increased with the severity of inflammatory disorders. In
addition, inflammation also increased the risk of multiple morbidity (two or
more cardiovascular diseases).
•
• Dr. Dregan: Currently the evidence for the role of inflammation in cardiovascular disease is
limited to single disease single inflammatory disorder. Very limited evidence exists about the
risk of cardiovascular disease in less common inflammatory disorders (e.g.
vasculitis, ulcerative colitis). Our study indicated an across the board association
between inflammatory disorder and several cardiovascular diseases.

Chronic Inflammation Associated With Increased Risk of Diabetes and Heart Disease
MedicalResearch.com Interview with: Dr Alex Dregan
Lecturer in Translational Epidemiology and Public Health,
Division of Primary Care and Public Health Research
King’s College London, London
• Dr. Dregan: Current management guidelines tend to be generally condition specific. It may
be desirable to have a lower threshold for starting preventive medical interventions in most
chronic inflammatory conditions. Also, in inflammatory patients a higher CRP
threshold should be used to identify patients at increased risk of cardiovascular disease.
this study?
• Dr. Dregan: Greater focus should be placed on understanding the mechanisms through which
inflammatory disorders increase the risk of cardiovascular disease in different population
groups (e.g. men and women, old and young people). The impact of different anti-
inflammatory medication on the risk for cardiovascular disease is another important area for
future research.
• Citation:
• Chronic Inflammatory Disorders and Risk of Type 2 Diabetes Mellitus, Coronary Heart
Disease, and Stroke: A Population-Based Cohort Study
• Alex Dregan, Judith Charlton, Phil Chowienczyk, and Martin C. Gulliford
• Circulation. 2014;CIRCULATIONAHA.114.009990published online before print June 26 2014,
doi:10.1161/CIRCULATIONAHA.114.009990

Breast Cancer: Does Tamoxifen Affect Cognitive Function in Postmenopausal Women?
MedicalResearch.com Interview with:
Florien Boel MSc VU University Medical Center
Department of Medical Psychology
Amsterdam, The Netherlands
• Answer: In postmenopausal breast cancer patients, endocrine therapy is widely used, and
often for many years on end. Endocrine therapy is thought to have an effect on cognitive
functioning, but previous studies have not yet accounted for the possible influence of the
diagnosis of cancer and subsequent anxiety, depression or fatigue on cognitive performance.
In addition, the cognitive effects of endocrine therapy after long-term use are still mostly
unknown.
• Therefore, we compared cognitive functioning of postmenopausal breast cancer patients
who underwent surgery and/or radiotherapy (N=43) with the cognitive performance of
women who also received adjuvant endocrine therapy (tamoxifen) (N=20) and a group of
healthy matched individuals (N=44). In accordance with the literature, we found that
especially cognitive domains that rely heavily on verbal abilities (verbal memory and fluency)
seem to be at risk for deterioration during long-term treatment (~2.5 years) with tamoxifen.
• Answer: Yes, we found that participants in the adjuvant tamoxifen group had worse fluency
scores than healthy controls, but not when compared with the surgery and/or radiotherapy
group. We had expected that the adjuvant tamoxifen group would also perform worse than
this cancer control group. Perhaps future studies, preferably including larger sample sizes,
may be able to investigate this further.

Florien Boel MSc VU University Medical Center
Department of Medical Psychology
• Medical Research: What should readers take away from your report?
• Answer: With this study, we aimed to provide additional insight into the potential long-term effects
of different breast cancer treatments on cognitive functioning. As we included a group of patients
who only underwent surgery and/or radiotherapy and a group of healthy controls, we could
account for the mental and physical influences of the diagnosis and treatment of breast cancer
while examining cognitive performance. While cognitive domains relying on verbal abilities, e.g.,
verbal memory and fluency, seem to be at particular risk for deterioration during treatment with
tamoxifen, further preclinical and clinical research is needed to guide the development of
intervention strategies aimed to prevent or diminish cognitive symptoms.
• Medical Research: What recommendations do you have for future research as a result of this
study?
• Answer: Basic research into the mechanisms underlying the long-term cognitive effects of
endocrine treatments and imaging studies on the neural substrate of observed cognitive problems
are needed. In addition, to gain further knowledge on the long-term cognitive effects of endocrine
treatments and the causal relationships between cognitive sequelae of endocrine treatments, we
highly recommend that future studies incorporate a longitudinal study design.
• Citation:
• Cognitive functioning during long-term tamoxifen treatment in postmenopausal women with breast
cancer.
Boele FW1, Schilder CM, de Roode ML, Deijen JB, Schagen SB.
Menopause. 2014 Jun 23. [Epub ahead of print]

More Kids Killed on ATVs than Bikes
MedicalResearch.com Interview with: Charles A. Jennissen, MD
Department of Emergency Medicine
University of Iowa Carver College of Medicine
Iowa City, IA 52242
• MedicalResearch: Why did you perform this study?
• Dr. Jennissen: More youth 15 years and younger in the United States are killed in all-terrain
vehicle (ATV) crashes than on bicycles. Since 2001, children represent nearly 30% of all ATV-
related injuries and 20% of all ATV-related deaths. Although previous studies have shown
children to have high exposure to ATVs, these studies have been mostly limited to select rural
and agricultural groups. With this study, we wanted to investigate the epidemiology of ATV
use and safety-related behaviors among a large cross-sectional sample of adolescents.
MedicalResearch: How was the study performed?
• Dr. Jennissen: Prior to an in-classroom ATV safety education program, we administered a
survey to 4,684 students aged 11 to 16 years at 30 schools across Iowa.

Iowa City, IA 52242
• MedicalResearch: What are the main findings of the study?
Dr. Jennissen: Overall, 77% of the students had been on an ATV, with 38% of those riding daily or
weekly. Among ATV riders, 57% had been in a crash (defined as having rolled over, hit something, or fallen
off the ATV) . Most riders engaged in risky behaviors, including riding with passengers (92%), on public
roads (81%), or without a helmet (64%). Almost 60% reported engaging in all 3 unsafe behaviors; only 2%
reported that they engaged in none. Multivariable modeling revealed male youth, students riding
daily/weekly, and those reporting both riding on public roads and with passengers were 1.61, 3.73, and
3.24 times more likely to report a crash, respectively.
• MedicalResearch: Were any of the findings unexpected?
• Dr. Jennissen: Probably the biggest surprise was the high percentage of ATV exposed students who had
experienced a crash. Although many children do experience ATV-related injuries and deaths, our study
suggests that a lot of youth are experiencing ATV mishaps without the consequences of significant
injury. Of course, not experiencing a serious consequence from a crash is a good thing. However, I worry
that such events may lead to an increased sense of invulnerability in the adolescent mind and lead to even
greater risk taking activity, rather than being a “wake-up call” for practicing safer riding behaviors.
• The high ATV exposure was not really a big surprise to us, but what was a bit unexpected was that the
percentage exposed to ATVs did not vary much between students in school districts in areas federally-
designated as being isolated rural vs. rural vs. urban. Granted, our study population did not include
densely populated metropolitan school districts. However, Iowa’s pediatric ATV mortality rate is
comparable to or lower than that of 21 other states, suggesting Iowa is not unique regarding ATV use. In
addition, all states, even those with large metropolitan areas, have rural and suburban populations. In
fact, the top ten states in number of pediatric ATV fatalities includes California, Texas, Pennsylvania,
Florida, and New York. Therefore, ATV exposure beyond our state’s somewhat more rural communities
should not be discounted.

Iowa City, IA 52242
• MedicalResearch: What should clinicians and patients take away from your report?
• Dr. Jennissen: A large percentage of youth are riding ATVs, practicing unsafe behaviors, and experiencing crashes. Primary
care clinicians should determine whether their patients are exposed to ATVs and if so, should strongly consider injury
prevention counseling. ATV use meets key criteria for guidance importance: high severity and frequency of injury, availability
of environmental strategies to prevent injury, and evidence that the strategies are effective. Even children from urban
localities could be exposed, particularly those from suburban acreages or who visit rural areas. In fact, non-rural youth may
be at even greater risk of crash and injury if they lack ATV riding experience.
• An American Academy of Pediatrics policy statement recommends that no child younger than 16 years of age ride an ATV.
Although we support this recommendation, it is unlikely to be an effective message for many families. If youth are going to
ride ATVs, they should do so as safely as possible. This includes always wearing a helmet and using other protective
equipment, staying off public roads, no passengers (unless designated seats), never riding an adult-size machine, getting
safety training (preferably a hands-on certification course), limiting vehicle speed, and no alcohol or drug use. Routine
counseling by clinicians could greatly increase the number of adolescents receiving ATV safety education and potentially
decrease the number of pediatric ATV-related deaths and injuries. Of course, it is important for parents to be models of safe
ATV use, and strictly enforce safe riding behaviors in their children.
• MedicalResearch: What recommendations do you have for future research as a result of this study?
• Dr. Jennissen: More study is needed to determine the most effective methods for increasing ATV safety knowledge,
improving safe riding behaviors, and decreasing ATV-related injuries and deaths. This includes evaluating safety education
programs, such as we are presently doing in our school-based education program called STARs (Safety Tips for ATV Riders).
Among anticipatory guidance interventions, safety counseling is supported by the best evidence, but ATV injury prevention
counseling by clinicians has not yet been studied.
• Citation:
• A School-Based Study of Adolescent All-Terrain Vehicle Exposure, Safety Behaviors, and Crash Experience
Charles A. Jennissen, Karisa K. Harland, Kristel Wetjen, Jeffrey Peck, Pam Hoogerwerf, and Gerene M. Denning
Ann Fam Med July/August 2014 12:310-316; doi:10.1370/afm.1663

Post-Concussion Symptoms Mimic Post Traumatic Stress Syndrome
Emmanuel Lagarde
Director of Research at INSERM, France
• Dr. Lagarde: Concussion accounts for more than 90 percent of all traumatic brain injuries, although little is
known about prognosis for the injury. The symptoms cited as potentially being part of post concussion
syndrome fall into three areas: cognitive, somatic and emotional. But the interpretation of symptoms after
concussion should also take into account that injuries are often sustained during psychologically
distressing events which can lead to Posttraumatic Stress Disorder.
•
• Dr. Lagarde: Yes, as we were expecting to observe long term (3-month) symptoms following brain injury,
but few were found to be specific : most of them were as frequent among patients with other injuries.
• Dr. Lagarde: It seems as if there is little evidence of the existence of a specific syndrome following mild
traumatic brain injury. However, patients who experienced a concussion are at risk of another well-known
syndrome called Posttraumatic Stress Disorder, which is associated with the distressing event that led to
the injury.
Medical Research: What recommendations do you have for future research as a result of this study?
• Dr. Lagarde: The classification system of symptoms following mild brain injury should be revisited as our
results are challenging the very relevance of the DSM-V post concussion syndrome.
• Citation:
• Lagarde E, Salmi L, Holm LW, et al. Association of Symptoms Following Mild Traumatic Brain Injury With
Posttraumatic Stress Disorder vs Postconcussion Syndrome. JAMA Psychiatry. Published online July 16,
2014. doi:10.1001/jamapsychiatry.2014.666.
•

Processesed Red Meat Linked To Higher Risk Of Heart Failure
Dr inz. Joanna Kaluza Department of Human Nutrition
Warsaw University of Life Sciences – SGGW
Warsaw POLAND
• Response: The most important finding of my study is the fact that processed red meat
consumption, but not unprocessed red meat, increases a risk of Heart Failure incidence and Heart
Failure mortality.
• Medical Research: Were any of the findings unexpected?
• Response: Our findings are in accordance with the previously reported positive associations
between processed red meat consumption and risk of other cardiovascular diseases and cancer so
when we started to analyze data we expected to receive such results.
• Response: To prevent risk of heart failure and other cardiovascular disease, people should reduce
consumption of red meat to the minimum and avoid consumption of processed meat, include to
the diet more fruit, vegetables, whole grain products as well as focus on higher fish consumption.
Moreover, we should not forget about being active every day.
study?
• Response: Our results should be confirm by other studies: conducted among other populations
with different levels of red meat consumption (we have studied men with low to moderate red
meat consumption), among women, and other ethnic groups and age groups.
• Citation:
• Processed and Unprocessed Red Meat Consumption and Risk of Heart Failure: A Prospective Study
of Men

Niacin Pill Did Not Reduce Heart Attacks or Strokes, but Did Increase Side Effects
Professor Jane Armitage Professor of Clinical Trials and Epidemiology
Clinical Trial Service Unit, Oxford Cardiovascular Science
Oxford, United Kingdom
• Prof. Armitage: The study showed that adding extended release niacin with laropiprant (to
reduce the flushing) to standard treatment including statins in people with heart disease or
strokes did not improve their outcome or reduce the risk of recurrent heart attacks or
strokes.
• Prof. Armitage: Yes, we had hoped that niacin would reduce the risk of heart attack and
strokes because of its effects on both good and bad cholesterol and we did not show this. But
the most unexpected result was that niacin caused many more side-effects than we
expected. We already knew that niacin caused skin, gastrointestinal (tummy) problems and
worsened diabetes control but these effects were more serious than we anticipated and it
caused excess infections and major bleeding.

Niacin Pill Did Not Reduce Heart Attacks or Strokes, but Did Increase Side Effects
Professor Jane Armitage Professor of Clinical Trials and Epidemiology
Clinical Trial Service Unit, Oxford Cardiovascular Science
Oxford, United Kingdom
• Prof. Armitage: There is no evidence that niacin is doing any good and a lot of evidence that
it is causing a range of different side-effects. Doctors and patients need to know this and
consider whether it should be stopped if people are taking it or whether it is appropriate to
start it.
this study?
• Prof. Armitage: We still need to find treatments to help people who remain at risk of heart
attacks and strokes despite current management. The results of this study don’t alter the
need to continue research into LDL-lowering and HDL raising treatments.
• Citation:
• Effects of Extended-Release Niacin with Laropiprant in High-Risk Patients
• The HPS2-THRIVE Collaborative Group
• N Engl J Med 2014; 371:203-212July 17, 2014DOI: 10.1056/NEJMoa1300955

Stroke History Raises Risks of Non-Cardiac Surgery
Mads E. Jørgensen, M.B.
University of Copenhagen, Denmark
• Answer: We included all patients undergoing non-cardiac surgery in 2005-2011, which were
then categorized by time elapsed between stroke and surgery. Patients with a very recent
stroke, i.e. less than 3 months prior to surgery, had a significant 14 times higher relative risk
of 30-day MACE following surgery, compared with patients without prior stroke. Patients with
a more distant stroke had a 2-5 fold higher risk of MACE following surgery, and still
significantly higher than risks in patients without prior stroke.
An additional model including time between stroke and surgery as a continuous measure
showed a steep decrease in risks of perioperative MACE during the first 9 months. After 9
months, an increase in time between stroke and surgery did not further reduce the risks. The
results for 30-day all-cause mortality showed similar patterns, although estimates were not
as dramatic as for 30-day MACE.
• When analyzing the MACE components individually, we found that recurrent strokes were
the main contributor to the high risk of MACE. A history of stroke any time prior to surgery
was associated with a 16 fold increased relative risk of recurrent stroke, compared with
patients without prior stroke.
• We also performed analyses stratified by surgery risk as low- (OR for stroke anytime, 3.97;
95% CI, 2.79-5.66), intermediate- (OR for stroke anytime, 4.46; 95% CI, 2.87-5.13) and high-
risk (OR for stroke anytime, 1.98; 95% CI, 1.20-3.27), which were somewhat challenged in
power. However, results indicated that stroke associated relative risk was at least as high in
low and intermediate-risk surgery as in high risk surgery.

•
• Answer: The analyses stratified by surgery risk showed that surgeries traditionally categorized as
low-risk and intermediate-risk surgeries were demonstrated to be associated with at least the same
relative risk of perioperative MACE as high-risk surgeries, were unexpected. Further, these analyses
also showed that patients with a stroke less than 3 months prior to surgery were at particularly high
risk of perioperative MACE, as seen in our main analyses.
• Do to relatively small sample sizes in these analyses, findings do need to be confirmed, but the
message that no surgery is small enough to be considered safe in this group of patients, is an
important message of our study
• Answer: We believe that our message of a markedly increased risk in patients with very recent
strokes, and a steep decrease in risk towards 9-month may help guiding clinicians in the decision
making process. Thus, our clear opinion is that the advantages of surgery in patients with a recent
stroke must be balanced with the very high risks of perioperative adverse events and that each
patient should be carefully considered and evaluated independently. Further, we must keep in mind
that competing risks might weigh in and although these analyses were comprehensively adjusted
and only elective surgeries were included, residual confounding is always a risk in these studies.

this study?
• Answer: At the moment, we believe that these results are the most complete and reliable
ones available, and though they should be considered in the preparation of future
perioperative guidelines.
• Also, we would like to take the chance to encourage future prospective clinical trials
evaluating the potential for optimizing the treatment of patients with a recent stroke, where
postponing the surgery beyond the suggested 9 month limit, is not an option.
• Citation:
• Time Elapsed After Ischemic Stroke and Risk of Adverse Cardiovascular Events and Mortality
Following Elective Noncardiac Surgery
• Mads E. Jørgensen MB, Christian Torp-Pedersen MD, DSc, Gunnar H. Gislason MD, PhD, Per
Føge Jensen MD, PhD, MHM, Siv Mari Berger MB, Christine Benn Christiansen MD, Charlotte
Overgaard MSc, PhD, Michelle D. Schmiegelow MD, Charlotte Andersson MD, PhD
• JAMA. 2014;312(3):269-277. doi:10.1001/jama.2014.8165

Study Uses Dental Stem Cells To Promote Retinal Regeneration After Eye Injury
MedicalResearch.com Interview with: Ben Mead
Molecular Neuroscience Group
Neurotrauma and Neurodegeneration Section
School of Clinical and Experimental Medicine University of Birmingham, Birmingham
• Answer: Traumatic and neurodegenerative disease of the retina lead to an irreversible loss of
retinal ganglion cells (RGC) which are the neuronal cells located in the inner retina that transmit
visual signals to the brain. Thus RGC injury results in visual defects which can ultimately progress
into permanent blindness. One promising therapeutic approach is the use of stem cells as a source
of replacement for lost retinal cells. However a theory has emerged suggesting that stem cells can
act through the secretion of signalling molecules (growth factors). One stem cell that has recently
shown great promise for neuronal repair are dental pulp stem cells (DPSC), which are multipotent
stem cells easily isolated from adult teeth, including third molars (Mead et al 2013, 2014).
• In our research, we transplanted either dental pulp stem cells or the more widely studied bone
marrow-derived mesenchymal stem cell (BMSC) into the vitreous chamber of the eye after optic
nerve crush (Mead et al 2013). The main finding of this study was that DPSC, to a significantly
greater degree than BMSC, promoted the survival of injured RGC and the regeneration of their
axons. We also showed that the mechanism of action was not through differentiation and
replacement of cells but was actually paracrine mediated, i.e. through DPSC-derived growth factors
(Mead et al, 2013, 2014).
Answer: Transplantation of mesenchymal stem cells (such as BMSC and DPSC) into other sites of
the body is short lived and the cells are cleared very quickly. The eye is an immunoprivileged
environment and migration of cells is limited. We found that the cells survived for 21 days in the
eye and did not engraft or migrate into any tissues. We also found that, due to the neural crest
origin of the DPSC, their neurotrophic secretory profile was more pronounced than BMSC,
explaining why DPSC were more neuroprotective and axogenic for injured RGC in vitro and in vivo.

Study Uses Dental Stem Cells To Promote Retinal Regeneration After Eye Injury
MedicalResearch.com Interview with: Ben Mead
Molecular Neuroscience Group
Neurotrauma and Neurodegeneration Section
School of Clinical and Experimental Medicine University of Birmingham, Birmingham
• Answer: Stem cells show great promise in treating a variety of neurological conditions,
including traumatic and neurodegenerative diseases of the eye. However, their mechanism of
action is not restricted to cell replacement and could be used therapeutically as a paracrine-
mediated therapy (Mead et al., 2014). Finally, stem cell therapy using ethically unhindered
cells such as the easily isolated BMSC and DPSC is showing promise as a future treatment for
the retina.
this study?
• Answer: The study warrants further investigation into the mechanisms of how different stem
cells work to promote neuroprotection and axogenesis. It also highlights how stem cells from
different sources in the body can have differing efficacy and highlights the need to test
different stem cells to ensure the most appropriate cell is taken forward to clinical trials.
• Citation:
• Mead B, Logan A, Berry M, Leadbeater W, Scheven BA (2013) Intravitreally transplanted
dental pulp stem cells promote neuroprotection and axon regeneration of retinal ganglion
cells after optic nerve injury. Invest Ophthalmol Vis Sci 54:7544-7556.
Mead B, Logan A, Berry M, Leadbeater W, Scheven BA (2014) Dental pulp stem cells, a
paracrine-mediated therapy for the retina. Neural Regeneration Research 9: 577-578.

Localized Prostate Cancer: Study Finds Primary Androgen Deprivation Therapy Not Associated With Survival Benefit
MedicalResearch.com Interview with: Grace Lu-Yao PhD, MPH Professor of Medicine
Robert Wood Johnson Medical School
Rutgers, The State University of New Jersey
Rutgers Cancer Institute of New Jersey New Brunswick, NJ 08903-2681
• Dr. Lu-Yao: Primary ADT (ie., use of androgen deprivation as an alternative to surgery, radiation or
conservative management for the initial management of prostate cancer) is not associated with
improved overall or disease specific survival.
• Dr. Lu-Yao: In our last report, primary androgen deprivation therapy was associated with a
borderline survival benefit for patients with high grade Gleason 8-10 disease; however, the effect is
no longer evident and it does not seem that any set of patients benefits from this treatment.
• Dr. Lu-Yao: Primary androgen deprivation therapy is not effective in improving survival among
elderly patients with localized prostate cancer. Given the side effects associated with the treatment,
the risks of the treatment are likely to outweigh any potential benefit for older patients (>65 years
of age) with low-risk disease.
study?
• Dr. Lu-Yao: A randomized study designed specifically to answer this question would be the best way
to confirm the results.
• Citation:
• Lu-Yao GL, Albertsen PC, Moore DF, et al. Fifteen-Year Survival Outcomes Following Primary
Androgen-Deprivation Therapy for Localized Prostate Cancer. JAMA Intern Med. Published online
July 14, 2014. doi:10.1001/jamainternmed.2014.3028.

Study Probes Hormonal Pathway in Skin That Influences Melanoma Risk
MedicalResearch.com Interview with: John D’Orazio, M.D., Ph.D.
Drury Pediatric Research Endowed Chair
Associate Professor, Univ. KY College of Medicine Pediatric Hematology-Oncology The Markey Cancer Center
Lexington, KY 40536-0096
• Medical Research: What is the background for this study?
• Dr. D’Orazio: Malignant melanoma is the deadliest of skin cancers, and it’s incidence has increased
enormously over the last several decades. In the 1930’s only one in every fifteen hundred Americans
would get melanoma in his/her lifetime. Now it’s one in fifty or sixty. Plus, it often affects young adults in
the prime of their lives. Altogether, nearly 10,000 Americans die of melanoma every year. However, risk is
not equally shared. Fair-skinned people who tend to burn rather than tan from sun exposure have a much
higher risk than dark skinned people. On the surface, it would appear that the amount of melanin in the
skin would be the only determinant of melanoma risk but the truth is more complex. Our lab has been
interested in a particular hormonal pathway in the skin that directly influences melanoma risk. When UV
radiation (sunlight) hits the skin, it causes damage to the cells of the skin. Cells respond to this damage to
protect themselves against further injury. One way in which they do this is by turning on a hormone called
melanocyte stimulating hormone, abbreviated “MSH”. Made by keratinocytes, the most abundant cells in
the epidermis, MSH is directly responsible for ramping up melanin production by melanocytes, the cells
that make the pigment in the skin that gives us a tan. This pigment called melanin acts as natural
sunscreen and blocks UV radiation from penetrating into the skin. This is very important because people
who can tan are in a much safer state the next time they get sun exposure. Because they have more
melanin in the skin, the UV won’t cause as much damage. The key is to realize that UV causes mutations
in melanocytes, and with enough damage to the DNA, melanocytes can turn cancerous and become
melanomas. People who have the melanoma-prone, “can’t tan” skin type often have problems in this
MSH hormonal pathway. Specifically, they have inherited problems with the receptor on melanocytes that
binds to MSH and makes the cells make more pigment. This protein, called the melanocortin 1 receptor
(or “MC1R”), is the way that melanocytes sense that the skin has been injured and needs more melanin. If
the MC1R won’t signal, then melanocytes just sit there and can’t be induced to make more melanin
pigment. Surely this is a major reason why people with MC1R signaling defects are at high risk of
melanomas.

• Medical Research: What are the main findings of this report?
• Dr. D’Orazio: Our findings build on this observation. We and others have realized that besides stimulating
melanocytes to make more pigment, the MSH-MC1R hormonal signaling axis also allows melanocytes to
be better able to deal with UV damage to DNA. Using a unique and genetically-defined mouse model, we
showed that MC1R defects result in delayed clearance of UV DNA damage in the skin. We also found that
MC1R signaling was able to accelerate repair of UV DNA damage in human melanocytes. The reason why
this is important is that the longer UV damage persists, the more likely it will cause actual mutations in
melanocytes.
• Therefore, individuals who have inherited a problem with MC1R have a multi-pronged problem with UV
radiation.
• First, they don’t make enough melanin pigment (so they have less natural “sunblock” in the skin and more
UV light can get through to the sensitive layers of the epidermis where melanocytes reside).
• Second, they have a sub-optimal way of dealing with DNA damage caused by UV, so over time their
melanocytes will accumulate more mutations from UV than others who can repair the damage better
because of a “good” MSH-MC1R signaling axis.
• We uncovered a critical molecular link that explains how MC1R signaling impacts DNA repair pathways in
melanocytes. Specifically, we confirmed that MC1R signaling increases cAMP second messenger in the
cytoplasm, which in turn activates cAMP-dependent protein kinase (also called PKA). The new finding is
that PKA then adds a phosphate group to a critical cellular protein called ATR (“ataxia and rad3-related”),
known to be recruited after cellular injury. ATR is classically thought of as a global damage-response
protein. It is a serine/threonine kinase which classically phosphorylates Chk1 protein to cause cells to stop
proliferating, allowing them to survey and repair DNA damage before replication can proceed (minimizing
mutation risk). Our findings highlight a new role for ATR. Once phosphorylated by PKA (downstream of
MC1R signaling), ATR associates with a protein called XPA, the rate-limiting factor in the nucleotide
excision repair pathway, which is a major way cells rid themselves of UV-induced DNA damage.

• Dr. D’Orazio: Yes. PKA-mediated phosphorylation of ATR activates ATR in a unique
way. Instead of causing a cell cycle arrest, phosphorylation of the Serine 435 residue of ATR
promotes recruitment of the nucleotide excision repair pathway to sites of UV-induced DNA
damage. In this way, melanocytes can efficiently rid themselves of UV damage that might
otherwise cause permanent mutations and malignant degeneration.
• Dr. D’Orazio: Our work really deals with melanoma prevention. By understanding how
melanocytes protect themselves against UV damage, we hope to be able to develop new
ways of “rescuing” these pathways in people who have inherited problems with the MC1R
and would otherwise be UV-sensitive and melanoma-prone.
• We now know how MC1R signaling protects melanocytes against mutations and therefore
against turning into melanoma. There are at least two important translational implications
from these findings:
• 1. It is possible that inherited mutations in ATR (specifically at Ser435) might increase
lifetime melanoma risk (as MC1R mutations are known to do).
• 2. It might be possible to pharmacologically modify melanoma risk. We hope to use this
newly-found knowledge in developing new and effective therapies to help people lower their
melanoma risk and make tanning safer.

study?
• Dr. D’Orazio: This work is quite basic in nature at this stage. Part of what we did in the paper was to
see how some very common MC1R mutations found in actual humans respond to UV damage. We
confirmed that certain MC1R mutations (the exact same ones that are associated with tendency to
burn rather than tan after sun exposure and the exact same ones that predict up to a four-fold
increased lifetime risk of melanoma) cannot activate the ATR pathway we discovered and so
accumulate mutations at a much higher level than normal. This explains why melanomas run in
families and how MC1R mutations (very common in fair-skinned, UV-sensitive people) predispose
to melanoma. Most people know their UV tendencies and about how much UV they can handle
without getting burned, but one implication of our work is that if someone knew that he or she
carried an MC1R (or ATR) mutation that blunted their ability to fix UV damage in the skin, they
should certainly practice vigorous sun safety and stay out of tanning beds as well.
• Our current research builds on this novel observation, further delineating how melanocytes protect
themselves and the skin in general against the dangers of UV radiation.
• Citation:
• Stuart G. Jarrett, Erin M. Wolf Horrell, Perry A. Christian, Jillian C. Vanover, Mary C. Boulanger, Yue
Zou, John A. D’Orazio. PKA-Mediated Phosphorylation of ATR Promotes Recruitment of XPA to UV-
Induced DNA Damage. Molecular Cell, 2014; 54 (6): 999 DOI: 10.1016/j.molcel.2014.05.030
•

Testicular Cancer Incidence Rises In Young Hispanic Americans
MedicalResearch.com Interview with
Rebecca H. Johnson, MD
Assistant Professor, Clinical Genetics University of Washington
Seattle, Washington
• Dr. Johnson: We observed that, over the past two decades, there has been an increase in the
incidence of testicular cancer in Hispanic American adolescents and young adults (AYAs) between
15 and 39 years of age. This increase is seen in both major subtypes of testicular cancer and affects
Hispanic AYA patients with all stages of disease at the time of diagnosis. No comparable increase
was observed in non-Hispanic white AYA,s or in older American men regardless of Hispanic
ethnicity. Between 1992 and 2010, the incidence of testicular cancer in AYA Hispanics has
increased 58% in contrast to just 7% in non-Hispanic white AYAs.
• Dr. Johnson: Hispanic Americans comprise the fastest growing ethnic group in the United States.
Until only recently, cancer incidence data for this population has been too sparse to accurately
analyze testicular cancer trends among Hispanic men. Our study presents novel evidence of a
significant trend in cancer incidence among Hispanics.
• Testicular cancer strikes non-Hispanic white men more commonly than other ethnic groups. The
incidence of testicular cancer in non-Hispanic white men is known to have increased in the 1980s
and then to have leveled off since the early 1990’s. In contrast, the incidence of testicular cancer in
Hispanic white men has been increasing steadily since 1992. If these current trends continue, the
rate of testicular cancer among Hispanic Americans will outpace that of non-Hispanic white men by
the end of our current decade. This would be the first time that the testicular cancer rate in an
ethnic minority group has surpassed that of non-Hispanic whites.

Testicular Cancer Incidence Rises In Young Hispanic Americans
MedicalResearch.com Interview with
Rebecca H. Johnson, MD
Assistant Professor, Clinical Genetics University of Washington
Seattle, Washington
• Medical Research What should clinicians and patients take away from your report?
• Dr. Johnson: The increasing rate of testicular cancer in AYA Hispanic males, combined with the rapid
expansion of the Hispanic population in the United States, is projected to have a measurable impact on
the United States healthcare system. Clinicians should keep in mind that testicular cancer is not solely a
disease of non-Hispanic white men but is increasingly a disease of Hispanic men as well. Hispanic
Americans are the fastest growing population in the United States. Due to the combination of increasing
population as well as rising testicular cancer incidence in Hispanics, clinicians treating testicular cancer will
be seeing more and more patients of Hispanic heritage. Men or women of any age or ethnicity should
remember that if they detect an unexplained lump or bump on their body, they should see their doctor
promptly.
• Medical Research Medical Research: What recommendations do you have for future research as a result
of this study?
• Dr. Johnson: This study reports a novel trend in cancer incidence but does not assess the causes of the
trend. Future studies should corroborate these findings in other countries that have substantial Hispanic
populations. Subsequent research should also investigate the etiology of the increase in cancer incidence
in Hispanic AYAs. The cause of the increase may be multifactorial. Testicular cancer risk in Hispanic white
AYAs may potentially be mediated by nutritional factors such as adult height. Greater adult height is a
known risk factor for testicular cancer, and adult height has increased rapidly in the US Hispanic white
population over the past several decades. Changing patterns of modifiable lifestyle choices such as the
reported increase in marijuana use among Hispanic adolescents may also affect testicular cancer
incidence.
• Citation:
Increase in testicular germ cell tumor incidence among Hispanic adolescents and young adults in the
United States.”
• Chien, F. L., Schwartz, S. M. and Johnson, R. H. (2014), Increase in testicular germ cell tumor incidence
among Hispanic adolescents and young adults in the United States. Cancer. doi: 10.1002/cncr.28684

HIV: Self Testing Increased Number of Adults Starting Treatment
Dr Peter MacPherson MBChB PhD Wellcome Trust Clinical Research Fellow
Liverpool School of Tropical Medicine Department of Clinical Sciences Liverpool School of Tropical Medicine
Pembroke Place, Liverpool L3 5QA
• Dr. MacPherson: In 2012, an estimated 35 million individuals were infected with the human
immunodeficiency virus (HIV) worldwide. Antiretroviral therapy (ART) substantially reduces the risk
of HIV transmission as well as greatly reducing illness and death, raising hopes that high uptake
of annual HIV testing and early initiation of ART could improve HIV prevention as well
as care. Achieving high coverage of HIV testing and treatment is a major challenge however, with
low rates of HIV testing and poor linkage into HIV care.
• Self-testing for HIV infection (defined as individuals performing and interpreting their HIV test in
private) is a novel approach that has seen high acceptance in Malawi and the United States, and is a
process that could overcome barriers to conventional facility-based and community-based
HIV testing, which lack privacy and convenience. However, no studies in high HIV prevalence
settings have investigated linkage into HIV care after HIV self-testing.
• Among 16,6660 adults in Blantyre, Malawi offered HIV self-testing, optional home initiation of HIV
care (including two-weeks of ART for those eligible) compared with standard HIV care resulted in a
substantial and significant increase in the proportion of adults initiating antiretroviral therapy.
• HIV self-testing was also extremely popular, with 58% of the adult population self-testing with just
6-months.
• To our knowledge, this is the first study to investigate a comprehensive home-based HIV testing,
eligibility assessment and treatment initiation strategy.
• Dr. MacPherson: At a time when universal test and treat approaches to controlling the HIV
epidemic are being considered, home initiation of HIV care shows high promise as a simple strategy
to improve uptake of ART when HIV self-testing is carried out at home. HIV self-testing has high
potential to improve access to convenient and confidential HIV testing.

HIV: Self Testing Increased Number of Adults Starting Treatment
Dr Peter MacPherson MBChB PhD Wellcome Trust Clinical Research Fellow
Liverpool School of Tropical Medicine Department of Clinical Sciences Liverpool School of Tropical Medicine
Pembroke Place, Liverpool L3 5QA
this study?
• Dr. MacPherson: HIV self-testing was implemented through neighborhood volunteers living
close to participants. Home initiation of HIV care was a highly feasible option in this situation
and may not apply to other models of HIV self-testing delivery. Other models for encouraging
linkage may need to be developed and ideally directly compared for effectiveness.
• Although rates of loss from ART by 6-months were not significantly different between home
and facility group ART initiators, future studies should examine cynical outcomes over longer
periods of follow-up.
• Citation:
• Effect of Optional Home Initiation of HIV Care Following HIV Self-testing on Antiretroviral
Therapy Initiation Among Adults in MalawiA Randomized Clinical Trial
• MacPherson P, Lalloo DG, Webb EL, et al. Effect of Optional Home Initiation of HIV Care
Following HIV Self-testing on Antiretroviral Therapy Initiation Among Adults in Malawi: A
Randomized Clinical Trial. JAMA. 2014;312(4):372-379. doi:10.1001/jama.2014.6493.

Stroke: Homocysteine Associated With Atherosclerosis of Cerebral Vessels
Sang-Beom Jeon, MD, PhD
From the Department of Neurology Asan Medical Center
University of Ulsan College of Medicine Seoul, Republic of Korea.
• Dr. Sang-Beom Jeon: In this MRI study of 825 stroke patients, we demonstrated that high plasma concentrations of
homocysteine, also known as hyperhomocysteinemia, were associated with small-vessel disease (lacunar infarcts and
leukoaraiosis) and large-vessel atherosclerosis of cerebral arteries.
• Dr. Sang-Beom Jeon: Hyperhomocysteinemia was related to the atherosclerosis of extracranial arteries, but not to the
atherosclerosis of intracranial arteries. In multiple logistic regression analysis, however, hyperhomocysteinemia was not
related to the atherosclerosis of extracranial arteries.
• Dr. Sang-Beom Jeon: Severe clinical trials failed to show a beneficial effect of B vitamin therapy on the development of
stroke. However, the ingestion of B vitamins (folate, vitamin B6, and vitamin B12) may decrease the incidence of stroke,
because
• 1) B vitamins can lower plasma concentrations of homocysteine,
2) the main outcomes of previous clinical trials consisted of stroke with sudden neurologic deficits, but small-vessel disease
may cause an insidious cognitive decline, and 3) short follow-up durations (<5 years) of previous clinical trials may also be
insufficient to observe anti-atherosclerosis effects of homocysteine-lowering treatment.
• Medical Research: What recommendations do you have for future research as a result of this study?
• Dr. Sang-Beom Jeon: Future studies evaluating the benefits of homocysteine-lowering therapy need to include the extent of
small-vessel disease and large-vessel atherosclerosis of cerebral arteries.
•
• Citation:
• Homocysteine, small-vessel disease, and atherosclerosis
• An MRI study of 825 stroke patients
• Sang-Beom Jeon, MD, PhD, Dong-Wha Kang, MD, PhD, Jong S. Kim, MD, PhD and Sun U. Kwon, MD, PhD
• Published online before print July 16, 2014, doi: 10.1212/WNL.0000000000000720
Neurology10.1212/WNL.0000000000000720
•

Death Rate From HIV-AIDS Continues to Drop
Dr. Colette Smith: PhD
Research Department of Infection and Population Health
University College London, London, UK
• Dr. Smith: We followed a group of approximately 45,000 HIV-positive people from Europe,
USA and Australia between 1999 to 2011. We found that the death rate approximately halved
over the 12-year study period. For every 1,000 people, around 18 died per year in 1999-
2001, reducing to 9 deaths per year in 2009-2011.
• We also studied what people died of. We found that the death rate from AIDS and from liver
disease decreased by around two-thirds. Deaths from heart disease approximately halved.
However, the rate of cancer deaths (excluding cancers that are classified as AIDS events)
remained constant over time.
• One in three deaths were caused by AIDS in 1999 to 2011, and this decreased to one in five
deaths in the last two years of the study. However, even in recent years it was the joint most
common cause of death. The proportion of deaths from cancer increased over time. One in
ten deaths were from cancer in 1999 to 2001, and this increased to one in five deaths in 2009
to 2011. By the end of the study it was the joint-most common cause of death.

• Dr. Smith: Although the rate of death from AIDS decreased substantially over the study
period, it was surprising that it remained the joint-most common cause of death. It was also
disappointing that the rate of cancer deaths had not improved over time.
• Dr. Smith: It is very encouraging that death rates are continuing to decrease among HIV-
positive people. It shows how effective antiretroviral treatment has been and continues to
be.
• It is likely that HIV-positive people are at an increased risk of non-AIDS diseases, including
liver disease, heart disease and cancer. Reasons for this may include side-effects of the
antiretroviral treatment, lifestyle factors (e.g. smoking is more common among HIV-positive
people compared to national averages), or HIV infection itself increasing risk. Our study
suggests that HIV-positive people and their clinicians have successfully reduced the
frequency of deaths from these other diseases, with the exception of cancer.
• Disappointingly, we found AIDS was still the most common cause of death. We must make
every effort to ensure that HIV-positive people are able to keep taking their medication
regularly so they can experience the benefits of treatment. We must also increase our efforts
to ensure that people who are unaware that they have HIV are tested, so they can receive
care and treatment in a timely manner.

this study?
• Dr. Smith: Unfortunately, we do not currently have a cure for HIV, and it seems likely that
people will have to take antiretroviral drugs for life. We believe that it is important to
continue to monitor death rates in HIV-positive people. This is to ensure that the
antiretrovirals remain effective over decades of treatment. We are also not yet sure whether
decades of antiretroviral treatment will lead to unexpected side-effects. Therefore, we must
continue to investigate what HIV-positive people die of, to pick up these potential side-effects
as quickly as possible.
• Citation:
• Trends in underlying causes of death in people with HIV from 1999 to 2011 (D:A:D): a
multicohort collaboration
• Dr Colette J Smith PhD,Lene Ryom PhD,Prof Rainer Weber MD,Philippe Morlat PhD,Prof
Christian Pradier MD,Prof Peter Reiss PhD,Justyna D Kowalska PhD,Stephane de Wit PhD,Prof
Matthew Law PhD,Prof Wafaa el Sadr MD,Ole Kirk DMSc,Nina Friis-Moller DMSc,Antonella
d’Arminio Monforte MD,Prof Andrew N Phillips PhD,Prof Caroline A Sabin PhD,Prof Jens D
Lundgren DMSc,for the D:A:D Study Group
The Lancet – 19 July 2014 ( Vol. 384, Issue 9939, Pages 241-248 )
DOI: 10.1016/S0140-6736(14)60604-8

Antiretroviral Medications Used Pre-Pregnancy in HIV Discordant Couples
Jared Baeten, MD PhD
Professor, Departments of Global Health and Medicine Adjunct Professor, Department of Epidemiology
University of Washington Seattle, WA 98104
• Dr. Baeten: Among heterosexual African couples in which the male was HIV positive and the
female was not, receipt of antiretroviral pre-exposure preventive (PrEP) therapy did not
result in significant differences in pregnancy incidence, birth outcomes, and infant growth
compared to females who received placebo.
• Dr. Baeten: None of the findings were unexpected. However, the results are new – this is
the first study to assess systematically the safety of PrEP when used in the periconception
period.

Antiretroviral Medications Used Pre-Pregnancy in HIV Discordant Couples
Jared Baeten, MD PhD
Professor, Departments of Global Health and Medicine Adjunct Professor, Department of Epidemiology
University of Washington Seattle, WA 98104
• Dr. Baeten: In implementation of antiretroviral pre-exposure preventive as an HIV prevention strategy for
heterosexual populations, pregnancies will occur. Safe and effective HIV prevention options for women
that do not require negotiations for safe sex and do not interfere with conception and pregnancy
outcomes are a priority, and PrEP provides one such option. Our findings provide additional evidence to
support the use of periconception administration of antiretroviral PrEP for HIV-uninfected women in both
high and low income populations, along with other strategies such as antiretroviral treatment of their HIV-
infected partners and limiting unprotected sex to peak fertility periods to reduce the risk of sexual
transmission of HIV. These results should be discussed with HIV uninfected women receiving PrEP who are
considering becoming pregnant.
• Medical Research: What recommendations do you have for future research as a result of this study?
• Dr. Baeten: Additional research will be needed to assess the safety of PrEP when used throughout
pregnancy. In addition, for some of the outcomes in our study, including pregnancy loss, preterm birth,
congenital anomalies, and infant mortality, confidence intervals were wide (suggesting uncertainty in the
result), and more study will continue to be needed.
• Citation:
• Pregnancy Incidence and Outcomes Among Women Receiving Preexposure Prophylaxis for HIV Prevention:
A Randomized Clinical Trial
• Nelly R. Mugo MBChB, MPH, Ting Hong MD, PhD, Connie Celum MD, MPH, Deborah Donnell PhD,
Elizabeth A. Bukusi MBChB, PhD, Grace John-Stewart MD, PhD, Jonathan Wangisi MBChB, Edwin Were
MBChB, MPH, Renee Heffron MPH, PhD, Lynn T. Matthews MD, MPH, Susan Morrison MD, MPH, Kenneth
Ngure PhD, Jared M. Baeten MD, PhD
• JAMA. 2014;312(4):362-371. doi:10.1001/jama.2014.8735
•

Safety and Efficacy of Acupuncture for Knee Arthritis Pain
Ling Zhao Ph. D. Associate Professor
College of Acupuncture-Tuina,
Shanghai University of Traditional Chinese Medicine, China
• Dr. Zhao: In our study, we found that a 6-week course of moxibustion treatment (i.e., a modality of
traditional acupuncture using burning moxa to warm and stimulate the acupoint) significantly
reduced pain and improved function in patients with knee osteoarthritis compared to a credible
placebo control. Our findings suggest that this ancient modality might be a useful adjunctive
treatment for knee osteoarthritis. We also found that our sham device is credible for a double-blind
randomized clinical trial assessing this traditional treatment modality.
• Dr. Zhao: Yes, there were several unexpected findings:
• First of all, we were pleased that the dropout rate in our trial was relatively low (10% by the end of
the trial) and the patient compliance to the treatment was high. This was probably due to the fact
that the study was conducted in the local communities which were close to the patients’ residence.
• Secondly, we thought most of Chinese had experience with moxibustion and worried that they
might be able to tell the difference between the real vs sham moxibustion. To our surprise, these
patients were successfully blinded to the group assignment and were not able to tell which group
they were assigned to. This might be due to the fact that the sham moxi device not only appears
identical to the real device, it also actually produces heat sensation (40.9°C, vs 49.8°C from real
device),
• and finally, we noticed that the pain and function had further improved after the end of 6-week
treatment indicating the moxibustion may have a long lasting effect for the treatment of knee
osteoarthritis..

Safety and Efficacy of Acupuncture for Knee Arthritis Pain
Ling Zhao Ph. D. Associate Professor
College of Acupuncture-Tuina,
Shanghai University of Traditional Chinese Medicine, China
• Dr. Zhao: Our findings suggest that traditional moxibustion is a safe, effective, easy-to-use
therapy that can be a useful adjunct to conventional medicine for alleviating pain and
improving function in patients with knee osteoarthritis.
this study?
• Dr. Zhao: Although positive, our study was a small scaled clinical trial. The findings of our
study provided us useful information for designing a future larger trial. Based on the results
of this trial, a larger randomized, double-blinded, placebo-controlled, multi-centered clinical
trial is warranted to confirm and generalize our findings.
• Citation:
• Effectiveness of moxibustion treatment as adjunctive therapy in osteoarthritis of the knee: a
randomized, double-blinded, placebo-controlled clinical trial
• Ling Zhao, Ke Cheng, Lizhen Wang, Fan Wu, Haiping Deng, Ming Tan, Lixing Lao and Xueyong
Shen1
• Arthritis Research & Therapy 2014, 16:R133 doi:10.1186/ar4590

Chronic Kidney Disease Patients Receiving Less ESA Therapy For Anemia
Dennis J. Cotter President
Medical Technology and Practice Patterns Institute, Inc.
Bethesda, MD 20816
• Answer: This is the first study to document anemia management practice patterns among predialysis CKD
patients before and after publication of TREAT. Using a retrospective observational design based on a large
US health plan database with over 1.2 million claims for predialysis CKD stage 3 and 4 patients, we report
4 main study findings.
• 1) For CKD stage 3 patients, the proportion prescribed ESA therapy declined from 17% pre-TREAT to 11%
post-TREAT (a 38% decline) and for CKD stage 4 patients, from 34% to 27% (a 22% decline).
• 2) Prescribing of ESA therapy was declining even before TREAT, but the decline accelerated in the post-
TREAT period.
• 3) ESA prescribing declined after TREAT regardless of anemia status; among patients with hemoglobin <10
g/dL, only 25% of stage 3 and 33% of stage 4 CKD were prescribed ESAs two years after TREAT, a notable
50% decline.
• 4) After adjusting for all covariates, the probability of prescribing ESAs was 35% less during a two year
period after vs. before TREAT publication.
• Answer: Our finding that cancer patients were 42% more likely to receive ESA therapy compared to
noncancer patients both before and after TREAT was unanticipated given the stringent restrictions on ESA
use among cancer patients.
We speculate that:
• 1) Cancer CKD patients have more severe anemia compared to their noncancer counterparts; and
• 2) Use of CKD diagnoses by oncologists were perhaps used to justify ESA therapy given that CMS restricted
ESA reimbursement for cancer patients in 2007. After this time oncologists had a marked increase in
prescribing ESA using the CKD diagnoses, and marked decrease in using their previously acceptable cancer
diagnoses.

Chronic Kidney Disease Patients Receiving Less ESA Therapy For Anemia
Dennis J. Cotter President
Medical Technology and Practice Patterns Institute, Inc.
Bethesda, MD 20816
• Medical Research What should clinicians and patients take away from your report?
• Answer: We conclude by saying, “Several clinical trials have raised important safety concerns
regarding ESA therapy among the CKD population. The most recent trial – the TREAT study –
appears to have accelerated the previous decline in physician prescribing of ESAs among stage 3
and 4 CKD patients.” In other words, the physicians observed in our study appeared to be
influenced by the TREAT authors who concluded that the risk of using ESA in CKD patients with
moderate anemia who were not undergoing dialysis “will outweigh the potential benefits.”
• Medical Research What recommendations do you have for future research as a result of this
study?
• Answer: Previous publications have indicated limited change in physician practice following the
publication of clinical trial findings, yet we found that TREAT resulted in significant declines in ESA
dosing. Perhaps future research could determine why trials like TREAT vs. other clinical findings
make a difference in clinical practice. For example, an FDA meeting highlighting TREAT results after
publication may have contributed to the dissemination and implementation of TREAT
recommendations.
• Citation:
• Erythropoiesis-Stimulating Agent Use Among Non–Dialysis-Dependent CKD Patients Before and
After the Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT) Using a Large US
Health Plan Database
• Thamer, Mae et al.
• American Journal of Kidney Diseases

Antibiotic Resistant Bacteria Increase in South East US Community Hospitals
Dr Joshua Thaden MD, PhD
Duke University Division of Infectious Diseases
Durham, North Carolina
• Dr. Thaden: The primary findings of the study are that
• The rate of detection of particularly antibiotic resistant bacteria — the carbapenem-resistant
Enterobacteriaceae (CRE) — has increased 5-fold in a set of community hospitals in the southeastern
United States, and that
• This increase is due to both changes in how we detect CRE and in increased endemicity (i.e., there are just
more CRE around).
• Dr. Thaden:
• First, the degree to which CRE detection increased was quite alarming. The five-fold increase in CRE
detection over a relatively short period (2008-2012) was unexpected, particularly in small, community
hospitals. We sometimes imagine that highly antibiotic resistant bacteria are primarily a problem at large,
tertiary medical centers, but as we illustrated in this study this is clearly not the case. Antibiotic resistance
is a major problem in the smaller, community hospitals as well, and we all need to remain vigilant.
• Second, the degree to which hospital microbiology laboratory practices affected CRE detection was also
quite surprising. There is a center called the Clinical and Laboratory and Standards Institute (CLSI) that
makes recommendations on how to detect bacteria such as CRE. In our study, only 20% (5 out of 25)
of hospitals had adopted the most recent CLSI guidelines regarding detection of CRE. We demonstrated
that adopting the newer guidelines is hugely important in making sure that all CRE are found. In hospitals
that adopted these guidelines, for example, we found that the CRE detection rate increased from 0.5 CRE
per 100,000 patient days before implementation of new CLSI guidelines, to 4.1 CRE per 100,000 patient
days after the guidelines were implemented. Thus, there are sure to be many CRE that are slipping
through the cracks in our surveillance net in those hospitals that have not yet adopted the new CLSI
carbapenem breakpoints.

• Dr. Thaden: There are several messages to glean from the study.
• First, the methods for detecting CRE need to improve. As noted above, only 20% of
community hospitals in our study had adopted the most recent CLSI guidelines regarding CRE
detection, and so there are many CRE that are slipping through our surveillance net. We
cannot control the spread of CRE if they remain undetected.
• Second, once detected, there needs to be a swift and centralized response. A hospital’s
infection control team and the state laboratory should be notified so that a plan can be
developed to prevent spread to other patients.
• Third, there is still a great amount of research that needs to be done in order to identify
effective strategies for slowing the spread of CRE and understanding the genetic basis for the
spread of carbapenem-resistance.

study?
• Dr. Thaden: Moving forward, one important area of research will be to examine the genetics of
carbapenem-resistance in bacteria from community hospitals. There are many different enzymes
and molecular mechanisms by which Enterobacteriaceae can become resistant to the carbapenem
antibiotics, and understanding how bacteria are generating and passing on carbapenem resistance
will be critical in understanding and controlling CRE. Another important area of research involves
the study of public health measures to prevent spread of CRE. The CDC has outlined some basic
strategies to decrease transmission, including hand hygiene, contact precautions, healthcare
personnel education, limitation of medical device use, patient and staff cohorting, laboratory
notification strategies, antimicrobial stewardship, and CRE active screening, though more research
is necessary determine the effectiveness of these and other interventions so that we can develop a
comprehensive and efficacious strategy for preventing the spread of CRE.
• Citation:
• Rising Rates of Carbapenem-Resistant Enterobacteriaceae in Community Hospitals: A Mixed-
Methods Review of Epidemiology and Microbiology Practices in a Network of Community Hospitals
in the Southeastern United States
• Joshua T. Thaden, MD, PhD,Sarah S. Lewis, MD, Kevin C. Hazen, PhD, Kirk Huslage, BSN, MSPH,
Vance G. Fowler Jr, MD, MHS,Rebekah W. Moehring, MD, MPH, Luke F. Chen, MBBS,
MPH,Constance D. Jones, RN, CIC,Zack S. Moore, MD, MPH, Daniel J. Sexton, MD, and Deverick J.
Anderson, MD, MPH
Infection Control and Hospital Epidemiol… Vol. 35, No. 8, August 2014

Vision Loss Still Significant Barrier To Employment
Pradeep Ramulu
Wilmer Eye Institute at John Hopkins
Baltimore, MD
• MedicalResearch What are the main findings of the study?
• Answer: The main finding is that people with vision loss, especially women and people with other
diseases such as diabetes, are much less likely to be working.
MedicalResearch Were any of the findings unexpected?
• Answer: One might have expected the result, but the magnitude of the result is unexpected, and
troubling from a societal perspective. Amongst women, for example, 63% worked if they had
normal vision, while only 25% worked if they were visually impaired.
• MedicalResearch What should clinicians and patients take away from your report?
• Answer: Keeping one’s vision is critical to keeping them working. If you lose your sight, your
prospects for employment likely diminish considerably.
• MedicalResearch What recommendations do you have for future research as a result of this
study?
• Answer: At a societal level, we really need to consider how to enable these individuals to join the
workforce. While doing so has costs, providing for a non-working adult is probably even more
costly. There is a need to understand barriers to employment, and to initiate and spread programs
which enable employment amongst this group.
• Citation:
• Association of Vision Loss and Work Status in the United States
Cheryl Sherrod, Kevin Frick, Pradeep Ramulu, and Clinical/ Epidemiologic Research
Invest. Ophthalmol. Vis. Sci. 54: E-Abstract 4543.

Elders Who Walk Out Of Necessity Rather Than Recreation Suffer More Falls
MedicalResearch.com: Interview with:
Dr. Wenjun Li , PhD
Health Statistics and Geography Lab Division of Preventive and Behavioral Medicine
University of Massachusetts Medical School, Worcester.
• Dr. Wenjun Li: Compared to those walking for recreational purposes only, older adults
walking for utilitarian purposes had higher risk for outdoor falls and fall-related injuries that
require medical attention.
• Dr. Wenjun Li: We first thought the higher risks for outdoor fall injuries among utilitarian
walkers could be explained by their higher frequency and duration of walking compared to
recreational walkers. However, the data surprised us: on average, utilitarian walkers walked
far less number of blocks per week compared to recreational walkers, yet their risk for
serious fall injuries were nearly four times higher. We also thought the utilitarian walkers
might be sicker or have more physical limitations than recreational walkers, we did not find
any notable difference. These lead us to think: perhaps outdoor walking environment played
an important role, which needs to be investigated.

Elders Who Walk Out Of Necessity Rather Than Recreation Suffer More Falls
MedicalResearch.com: Interview with:
Dr. Wenjun Li , PhD
Health Statistics and Geography Lab Division of Preventive and Behavioral Medicine
University of Massachusetts Medical School, Worcester.
• Dr. Wenjun Li: First, we need to know that the effects of utilitarian and recreational walking on risk
of fall injuries are different. When recommending walking exercise to older adults, one may need to
consider whether the elder lives in a neighborhood with safe walking environment. For frail elders
living in a neighborhood without a good walking environment, recommending recreational walking
in safe walking environment is a good one; however, I have reservations about recommending
utilitarian walking. More studies are needed to help us understand the problem and make more
useful recommendations.
study?
• Dr. Wenjun Li: It would be extremely important to investigate personal as well as environmental
determinants of elder’s choice of routes for utilitarian vs. recreational walking, and how they
interact with their neighborhood environment. Much of our current studies are on associations of
health behaviors and outcomes with environment, and little attention on how the individuals
actually interact with his/her living environment. We have designed a new study to investigate this
issue, and submitted a grant application to NIH for consideration of funding. We also welcome
private research foundations to support us to continue this important work.
• Citation:
• Wenjun Li, Elizabeth Procter-Gray, Lewis A. Lipsitz, Suzanne G. Leveille, Holly Hackman, Madeleine
Biondolillo, and Marian T. Hannan. (2014). Utilitarian Walking, Neighborhood Environment, and
Risk of Outdoor Falls Among Older Adults. American Journal of Public Health. e-View Ahead of
Print.
• doi: 10.2105/AJPH.2014.302104

Only Processed Red Meat Linked to Shorter Survival
MedicalResearch.com Interview with: Andrea Bellavia
From the Unit of Nutritional Epidemiology and the Unit of Biostatistics
Institute of Environmental Medicine
Karolinska Institutet, Stockholm, Sweden
• Dr. Bellavia: By evaluating together the consumption of processed and fresh red meat, we
observed that processed red meat consumption was associated with shorter life, implying a
potential negative effect on health. On the other hand, consumption of only fresh red meat
was not associated with either shorter or longer survival. Therefore, the main finding of this
work is that the negative effects of red meat consumption might only be due to meat
processing, which counteract the positive effects of the beneficial nutrients of meat.
• Dr. Bellavia: No, because red meat is a source of important nutrients such as zinc and dietary
protein. On the other hand, processing red meat involves different potentially adverse
components.

Only Processed Red Meat Linked to Shorter Survival
MedicalResearch.com Interview with: Andrea Bellavia
From the Unit of Nutritional Epidemiology and the Unit of Biostatistics
Institute of Environmental Medicine
Karolinska Institutet, Stockholm, Sweden
• Dr. Bellavia: Consumption of red meat that involves processing components (such as
sausages or hot dogs) should be at least limited. On the other hand, fresh meat (minced
pork, beef, veal) does not share the same negative properties, and healthy people who
regularly consume fresh red meat should not be recommended to stop. In the same way,
given the null association between fresh meat and survival, people who do not consume
meat should not be recommended to start.
this study?
• Dr. Bellavia: We only evaluated the overall mortality of the population, finding that
consumption of fresh red meat alone is not associated with shorter survival. It will be
important to understand if the same result applies by looking at specific diseases, to
understand if there are particular health scenarios in which red meat should be fully avoided.
• Citation:
• Differences in survival associated with processed and with nonprocessed red meat
consumption
• Andrea Bellavia, Susanna C Larsson, Matteo Bottai, Alicja Wolk, and Nicola Orsini
Am J Clin Nutr 2014 ajcn.086249; First published online July 16, 2014.
doi:10.3945/ajcn.114.086249

Florien Boel MSc
VU University Medical Center Department of Medical Psychology
• Answer: In postmenopausal breast cancer patients, endocrine therapy is widely used, and
often for many years on end. Endocrine therapy is thought to have an effect on cognitive
functioning, but previous studies have not yet accounted for the possible influence of the
diagnosis of cancer and subsequent anxiety, depression or fatigue on cognitive performance.
In addition, the cognitive effects of endocrine therapy after long-term use are still mostly
unknown.
• Therefore, we compared cognitive functioning of postmenopausal breast cancer patients
who underwent surgery and/or radiotherapy (N=43) with the cognitive performance of
women who also received adjuvant endocrine therapy (tamoxifen) (N=20) and a group of
healthy matched individuals (N=44). In accordance with the literature, we found that
especially cognitive domains that rely heavily on verbal abilities (verbal memory and fluency)
seem to be at risk for deterioration during long-term treatment (~2.5 years) with tamoxifen.
• Answer: Yes, we found that participants in the adjuvant tamoxifen group had worse fluency
scores than healthy controls, but not when compared with the surgery and/or radiotherapy
group. We had expected that the adjuvant tamoxifen group would also perform worse than
this cancer control group. Perhaps future studies, preferably including larger sample sizes,
may be able to investigate this further.

Florien Boel MSc
VU University Medical Center Department of Medical Psychology
• Medical Research: What should readers take away from your report?
• Answer: With this study, we aimed to provide additional insight into the potential long-term effects
of different breast cancer treatments on cognitive functioning. As we included a group of patients
who only underwent surgery and/or radiotherapy and a group of healthy controls, we could
account for the mental and physical influences of the diagnosis and treatment of breast cancer
while examining cognitive performance. While cognitive domains relying on verbal abilities, e.g.,
verbal memory and fluency, seem to be at particular risk for deterioration during treatment with
tamoxifen, further preclinical and clinical research is needed to guide the development of
intervention strategies aimed to prevent or diminish cognitive symptoms.
study?
• Answer: Basic research into the mechanisms underlying the long-term cognitive effects of
endocrine treatments and imaging studies on the neural substrate of observed cognitive problems
are needed. In addition, to gain further knowledge on the long-term cognitive effects of endocrine
treatments and the causal relationships between cognitive sequelae of endocrine treatments, we
highly recommend that future studies incorporate a longitudinal study design.
• Citation:
• Cognitive functioning during long-term tamoxifen treatment in postmenopausal women with breast
cancer.
Boele FW1, Schilder CM, de Roode ML, Deijen JB, Schagen SB.
Menopause. 2014 Jun 23. [Epub ahead of print]

Promising New Influenza Drug Reduces Flu Symptoms and Viral Shedding
Prof. Jean-Francois Rossignol, FRSC, FRCPath
Romark Laboratories, LC
• MedicalResearch: What are the main findings of the study?
• Prof. Rossignol: Nitazoxanide, a new orally administered drug in development for treating
influenza, reduced the duration of symptoms of uncomplicated influenza compared to a
placebo. The drug also reduced viral shedding. Side effects were similar for the drug and
placebo treatment arms. The study was designed and conducted in compliance with FDA
guidelines for studying new drugs for influenza.
MedicalResearch: Were any of the findings unexpected?
• Prof. Rossignol: In contrast to existing drugs, nitazoxanide reduced the duration of symptoms
in patients with flu-like symptoms that were not diagnosed with influenza. The activity in
patients without confirmed flu may be related to broad-spectrum antiviral activity against
other respiratory viruses, which has been observed in laboratory studies. This finding could
also potentially reflect a lack of sensitivity of the diagnostic techniques.

Promising New Influenza Drug Reduces Flu Symptoms and Viral Shedding
Prof. Jean-Francois Rossignol, FRSC, FRCPath
Romark Laboratories, LC
• MedicalResearch: What should clinicians and patients take away from your report?
• Prof. Rossignol: There is an important need for new drugs that could be used to treat
seasonal and pandemic influenza including viruses that may be resistant to existing drugs.
Nitazoxanide, an orally administered drug with a new mechanism of action against influenza
viruses, could be an important addition to the arsenal of drugs currently used to treat
influenza.
• MedicalResearch: What recommendations do you have for future research as a result of
this study?
• Prof. Rossignol: A large global Phase 3 clinical trial is being conducted to support the
licensure of nitazoxanide for treatment of uncomplicated influenza. This clinical trial is
evaluating nitazoxanide alone and in combination with oseltamivir (Tamiflu®, Roche). Studies
in pediatric patients under 12 years of age and in hospitalized patients are also warranted.
• Citation:
• Effect of nitazoxanide in adults and adolescents with acute uncomplicated influenza: a
double-blind, randomised, placebo-controlled, phase 2b/3 trial
Jason Haffizulla MD,Aaron Hartman MD,Melanie Hoppers MD,Harvey Resnick MD,Steve
Samudrala MD,Christine Ginocchio PhD,Matthew Bardin PharmD,Prof Jean-François
Rossignol MD,for the US Nitazoxanide Influenza Clinical Study Group
The Lancet Infectious Diseases – 1 July 2014 ( Vol. 14, Issue 7, Pages 609-618 )
DOI: 10.1016/S1473-3099(14)70717-0

DVTs: Clot-Busting Procedure Gaining In Safety and Utilization
MedicalResearch.com Interview with Riyaz Bashir MD, FACC, RVT
Associate Professor of Medicine Director, Vascular and Endovascular Medicine
Department of Medicine, Division of Cardiovascular Diseases Temple University Hospital Philadelphia, PA 19140
• Medical Research: What is the background for this study?
• Dr. Bashir : Blood clots of legs called deep vein thrombosis (DVT) is a very common disease that
occurs in about 1.0 person per 1000 population per year. This condition is responsible for more
than 600,000 hospitalizations each year in the United States and approximately 6% of these
patients will die within 1 month of the diagnosis. Amongst these patients 20% – to 50% will go on
to develop chronic leg pains, swelling, heaviness, skin discoloration, and ulcers, in spite of
conventional treatment with Blood thinning medications (anticoagulation) and compression
stockings.This condition, which is called Post-thrombotic syndrome PTS markedly impairs the
quality of life of these patients and is a significant economic burden (2.4 billion dollars and 200
million work days lost annually in US) on the society.In fact, many of these people lose their jobs
because of the disability it causes.
• Several small studies have shown that early clot removal by minimally invasive catheter-based clot
busting procedure called Catheter-directed thrombolysis (CDT) leads to a significant reduction
in Post-thrombotic syndrome along with improvements in quality of life. Unfortunately, due to the
small number of patients in these studies, we did not have any data about the safety of this
treatment option. This has led to conflicting recommendations by various medical societies like the
American College of Chest Physicians recommending against its use while the American Heart
Association recommends Catheter-directed thrombolysis as first-line treatment for these patients.
In light of these conflicting directives, we reviewed the frequency and safety of CDT versus
conventional treatment in these patients with blood clots above the knees in the United States
using Nationwide Inpatient Sample database from 2005 to 2010.

Dr. Bashir :
• 1. A very small proportion (4%) of DVT patients in US are treated with minimally invasive
catheter-based clot busting procedure (CDT- Catheter directed thrombolysis).
• 2. The safety of minimally invasive catheter based thrombus removal (CDT- Catheter
directed thrombolysis) has improved over last several years in the United States.
• 3. There was no difference in death between CDT versus traditional treatment with blood
thinning medications (Anticoagulation), however bleeding risks, length of hospital stay and
costs are still higher with CDT.
• 4. Results of CDT were markedly better in institutions that were performing more than 5
procedures a year.
Medical Research:Were any of the findings unexpected?
Dr. Bashir :
• 1. The study showed that there has been a steady increase in Catheter-directed
thrombolysis utilization from 2.3% in 2005 to 5.9% in 2010.
• 2. Overall only 4% of these patients in United States are treated with CDT.

• Medical Research:What should clinicians and patients take away from your report?
• Dr. Bashir : Both clinicians and patients should feel comfortable that there is no increase in
death with Catheter-directed thrombolysis. In the context of these findings, clinicians should
offer both treatments options to patients explaining the increased bleeding risks associated
with CDT and increased risk of Post Thrombotic Syndrome (PTS) with conventional treatment
of anticoagulation alone. We believe this study data should foster “shared decision making”
amongst the patients and their treating physician, which is very rarely done at present.
this study?
• Dr. Bashir : Randomized trials looking at the magnitude of reduction of Post-thrombotic
syndrome PTS with Catheter-directed thrombolysis and long-term follow-up of these patients
to assess the effect of CDT on longer-term death rates and other patient-centered outcomes.
• Citation:
• Bashir R, Zack CJ, Zhao H, Comerota AJ, Bove AA. Comparative Outcomes of Catheter-
Directed Thrombolysis Plus Anticoagulation vs Anticoagulation Alone to Treat Lower-
Extremity Proximal Deep Vein Thrombosis. JAMA Intern Med. Published online July 21, 2014.
doi:10.1001/jamainternmed.2014.3415.

MedicalResearch.com: Medical Research Interviews June 24 2014

MedicalResearch.com: Medical Research Interviews June 24 2014

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MedicalResearch.com: Medical Research Interviews June 24 2014