Medical Research Interviews on Medication Adherence and Glaucoma Risk

MedicalResearch.com
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Editor: Marie Benz, MD
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June 11 2015
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Improved Hospital Discharge Process May Reduce Medication Nonadherence
MedicalResearch.com Interview with:
Robin Mathews, MD
Duke Clinical Research Institute
Duke University Medical Center
Durham, NC
Medical Research: What is the background for this study? What are the main findings?
Dr. Mathews: Though treatment for patients with an acute myocardial infarction with evidence
based therapies has increased significantly over the years, adherence to these therapies after
discharge remain sub optimal. We used a validated instrument, the Morisky scale, to assess
patient medication adherence. We found that in a contemporary population of 7,425 patients
across 216 hospitals, about 30% of patients were not adherent to prescribed cardiovascular
medications as early as 6 weeks after discharge. Patients with low adherence were more likely to
report financial hardship as well as have signs of depression. In addition, we found that patients
who had follow up arranged prior to discharge and those that received explanations from the
provider on the specific medications, were more often adherent to therapies. There was a non
significant increase in risk of death or readmission at 2 months (HR [95% CI]: 1.35 [0.98-1.87])
among low adherence patients.
Read the rest of the interviews on MedicalResearch.com
Content NOT an endorsement of efficacy and NOT intended as specific medical advice.

Robin Mathews, MD
Durham, NC
• Medical Research: What should clinicians and patients take away from your report?
• Dr. Mathews: The reasons for medication non adherence are complex and multifactorial.
Though some factors such as race and age are non modifiable, others such as health literacy,
patient perception of side effects, and out of pocket expenses, can be influenced. The
transition of a patient from hospital to home is an opportunity to identify patients who may
be at increased risk for non adherence. The discharge process should include an assessment
of possible barriers to adherence after patients leave the hospital. Once these have been
identified, a patient tailored strategy can be used to address these barriers. For instance,
while cost may be the main issue for some patients, access to follow up care, or an
insufficient understanding of the reasons for medications, may be the primary factor for
others. This is an important opportunity for clinicians and providers to potentially improve
adherence as well as perhaps impacting down stream outcomes such as readmissions and
other adverse cardiovascular events.

Robin Mathews, MD
Durham, NC
• Medical Research: What recommendations do you have for future research as a result of
this study?
• Dr. Mathews: The discharge process of a patient after an acute myocardial infarction varies
between hospitals across the U.S. Therefore, the identification of specific hospital and
provider level practices that positively impact short and long term medication adherence, is
critical. Any effective intervention will need to be patient centered and tailored to the
specific needs of the patient. Once identified, these should be disseminated as ‘best
practices’ in order to provide some standardization to our discharge process.
• Citation:
• Early Medication Nonadherence After Acute Myocardial Infarction: Insights into Actionable
Opportunities From the Treatment with ADP receptor Inhibitors: Longitudinal Assessment of
Treatment Patterns and Events After Acute Coronary Syndrome Study
• Robin Mathews, Eric D. Peterson, Emily Honeycutt, Chee Tang Chin, Mark B. Effron, Marjorie
Zettler, Gregg C. Fonarow, Timothy D. Henry, and Tracy Y. Wang
• Circ Cardiovasc Qual Outcomes 2015; first published on June 2 2015 as
doi:10.1161/CIRCOUTCOMES.114.001223

Metformin Linked To Reduced Risk of Glaucoma
Julia E. Richards, Ph.D.
Harold F. Falls Professor of Ophthalmology and Visual Sciences Professor of Epidemiology
Director, Glaucoma Research Center
The University of Michigan
• Medical Research: What is the background for this study?
Response: We have a special interest in how the developmental processes of aging increase
the risk of late onset diseases. We wondered whether drugs that target known aging
pathways might be able to reduce risk of late onset disease. In the aging field, an emerging
area of interest has been the category of drugs called caloric restriction mimetic (CRM) drugs,
which have been found to extend life span and to reduce risk or delay onset of some late-
onset diseases. These caloric restriction mimetic drugs target a set of pathways that have
come to be seen as playing roles in longevity. One of these caloric restriction mimetic drugs,
metformin, happens to also be one of the most common drugs used in the treatment of type
2 diabetes.
• Glaucoma is a leading cause of blindness worldwide and classical open-angle glaucoma
shows onset in late middle age or late age, so we hypothesized that a caloric restriction
mimetic drug might be able to reduce the risk of open-angle glaucoma. We used data from a
large health services database to compare the rate at which open-angle glaucoma developed
in individuals with diabetes mellitus who used metformin versus those who did not use
metformin. We predicted that metformin would be associated with reduced risk of open-
angle glaucoma.

• Medical Research: What are the main findings?
Response: We found that use of metformin was associated with reduced risk of open-angle
glaucoma. A 2 gram per day dose of the CRM drug metformin for two years was associated
with a 20.8% reduction in risk of developing open-angle glaucoma. When we looked at the
highest quartile of drug prescribed (>1,100 grams over a two year period) we found a 25%
reduction in risk relative to those taking no metformin. This risk reduction is seen even when
we account for glycemic control in the form of glycated hemoglobin, and use of other
diabetes drugs was not associated with reduced risk of open-angle glaucoma. A possible
explanation for our findings might be that the mechanism of risk reduction is taking place by
CRM drug mechanisms that target aging pathways rather than through glycemic control of
diabetes.
• In the long run, the approaches to late onset diseases in general will become much more
powerful if we can use parallel approaches that simultaneously target both the aging
processes going on and the disease-specific pathways going on. In the literature we see
caloric restriction mimetic drugs metformin, rapamycin and resveratrol all being explored for
their ability to target points in aging pathways in ways that can impact the risk of a variety of
late-onset diseases, so it will be important for those interested in the risk factors affecting
late onset diseases to pay attention to how caloric restriction mimetic drugs might be altering
risk for those late onset diseases.

• Response: Our study shows that use of metformin is associated with reduced risk of open-
angle glaucoma and that keeping really good control of blood glucose levels is associated
with reduced risk of open-angle glaucoma. But before recommending changes to clinical
practice, it would be helpful to perform prospective studies (like a Randomized Clinical trial)
to confirm the findings of the present study. This is important because metformin is not
without side effects and we would want to be sure that any beneficial effects of using
metformin (or higher strengths of metformin) for glaucoma outweigh side effects of this
medication. We also need to understand whether metformin protects against glaucoma
among persons without diabetes and whether there are subsets of patients who respond
better or worse to metformin.
• One of the implications of this study is not a new idea with this study, but one that lots of
people may not have heard, which is the idea that this general category of drugs, the caloric
restriction mimetic drugs, may have the potential to reduce the risk of other late onset
diseases, too. If you go look in the literature you will see that rapamycin, resveratrol, and
metformin are all associated with reduced risk of a variety of later onset diseases, and there
are lots of other late onset diseases that have not been looked at yet.

this study?
• Response: Because this is not a clinical trial, and because this study was limited to a very
specific population of persons with diabetes who do not yet have glaucoma, there are
limitations to the conclusions we can draw concerning clinical care. Because this study
involved a health services database, it lacked some types of key information we would
normally want to track in a glaucoma study such as information on visual fields or cup to disc
ratio that might allow us to investigate progression among those who already have glaucoma,
so additional studies are needed to understand what effects metformin has on individuals
who already have open-angle glaucoma and to understand how metformin impacts specific
glaucoma risk factors such as intraocular pressure. This study points towards the need for the
next stage of studies to find out whether these findings could apply to persons who do not
have diabetes, and to find out whether metformin might be able to affect progression of
glaucoma in those who already have the disease.
• Citation:
• Lin H, Stein JD, Nan B, et al. Association of Geroprotective Effects of Metformin and Risk of
Open-Angle Glaucoma in Persons With Diabetes Mellitus. JAMA Ophthalmol. Published
online May 28, 2015. doi:10.1001/jamaophthalmol.2015.1440.

Large Regional Differences in Cardiovascular Disease Burden
Prachi Bhatnagar, MPH, DPhil
Researcher University of Oxford
British Heart Foundation Centre on Population Approaches for Non-Communicable Disease Prevention
Nuffield Department of Population Health
Oxford
• Medical Research: What is the background for this study? What are the main findings?
Response: We know that cardiovascular disease presents a large burden to the UK. We aimed
to bring together all the main data on cardiovascular disease mortality, morbidity, treatment
and economic costs. We found that there are regional inequalities in cardiovascular disease
mortality and prevalence in the UK.
• Response: Although there have been large declines in cardiovascular disease mortality, it still
remains a significant burden to the UK, both in terms of health and economic costs.

Large Regional Differences in Cardiovascular Disease Burden
Prachi Bhatnagar, MPH, DPhil
Researcher University of Oxford
British Heart Foundation Centre on Population Approaches for Non-Communicable Disease Prevention
Nuffield Department of Population Health
Oxford
this study?
• Response: While there is excellent mortality data available, we need more readily available
incidence data for cardiovascular conditions such as myocardial infarction. We also need to
understand how to address the regional inequalities described in this paper.
• Citation:
• P. Bhatnagar, K. Wickramasinghe, J. Williams, M. Rayner, N. Townsend. The epidemiology of
cardiovascular disease in the UK 2014. Heart, 2015; DOI: 10.1136/heartjnl-2015-307516

Custom Oral Appliance Reduced Sleep Apnea and Restless Legs
Marie Marklund, DDS senior lecturer
Department of Odontology, Faculty of Medicine
Umeå University
Sweden
• MedicalResearch: What is the background for this study? What are the main findings?
• Response: Snoring and obstructive sleep apnea are common in the population and these
disorders continuously increase because of the ongoing obesity epidemic in many countries.
Today, 34% of men and 17% of women in the US suffer from obstructive sleep apnea of all
severities. Symptoms include daytime sleepiness, poor sleep quality, headache, insomnia and
restless legs. In the longer term, a more severe sleep apnea is associated with serious
consequences, such as hypertension, stroke, cancer, traffic accidents and early death.
• Continuous positive airway pressure is a highly effective treatment for sleep apnea patients.
Adherence problems, for instance from nasal stuffiness and claustrophobia reduces its
effectiveness. An oral appliance holds the lower jaw forwards during sleep in order to reduce
snoring and sleep apneas. This therapy has primarily been suggested for snorers and patients
with mild and moderate sleep apnea. No previous placebo-controlled study has, however,
evaluated this specific group of patients. Results from more severe sleep apnea patients have
shown a good effect on sleep apneas. The effect of oral appliances on daytime symptoms is
unclear. Symptomatic improvement is an important outcome for milder sleep apnea patients.

Umeå University
Sweden
The primary aims of the present study were to study the effects on daytime sleepiness and
quality of life of a custom-made, adjustable oral appliance in patients with daytime sleepiness
and snoring or mild to moderate sleep apnea, i.e. the primary target group for this type of
therapy. Secondary aims included the effects on sleep apnea, snoring and various other
symptoms of sleep disordered breathing such as headaches and restless legs. We found that oral
appliance therapy was effective in reducing sleep apneas, snoring and symptoms of restless legs.
The apnea-hypopnea index was normal (<5) in 49% of patients using the active appliance and in
11% using placebo, with a numbers needed to treat of three. Daytime sleepiness and quality of
life did not differ during active treatment and the placebo intervention. The patients experienced
reduced headaches with active treatment, but the results did not differ from placebo. It was
concluded, that a custom-made, adjustable oral appliance reduces obstructive sleep apneas,
snoring and possibly restless legs. The efficacy on daytime sleepiness and quality of life was weak
and did not differ from placebo in this group of patients.

Umeå University
Sweden
• MedicalResearch: What should clinicians and patients take away from your report?
• Response: An oral appliance is highly effective in reducing obstructive sleep apneas and
snoring. The treatment might also produce other benefits for the patients, such as reduced
symptoms of restless legs. It is likely, that subgroups of patients who have specific sleep
related symptoms such as headaches will benefit from this treatment, although this was not
proven in the present study design.

Umeå University
Sweden
• MedicalResearch: What recommendations do you have for future research as a result of
this study?
• Response: More research of effects of oral appliances in subgroups of patients with more
identified causes to daytime sleepiness or in patients with specific symptoms, such as
headaches, insomnia or restless legs. This approach is facilitated by the ongoing research
aiming at phenotyping sleep apnea patients in order to find more specific indications for the
various treatment options.
• Citation:
• Marklund M, Carlberg B, Forsgren L, Olsson T, Stenlund H, Franklin KA. Oral Appliance
Therapy in Patients With Daytime Sleepiness and Snoring or Mild to Moderate Sleep Apnea:
A Randomized Clinical Trial. JAMA Intern Med. Published online June 01, 2015.
doi:10.1001/jamainternmed.2015.2051.

Electronic Health Records Allow Agencies To Improve Surveillance and Patient Care
Dawn Heisey-Grove, MPH
CDC
Medical Research:? What are the main findings?
Response: This first published use of Medicare EHR Incentive Program data for national
population surveillance reported on an eCQM that is aligned with Million Hearts®, a national
initiative launched by the U.S. Department of Health and Human Services to prevent 1 million
heart attacks and strokes by 2017. The eCQM tracks the proportion of patients with hypertension
who had controlled blood pressure during the reporting period. During the first three years of the
EHR Incentive Program (2011-2013), approximately 3 in 10 participating health care professionals
reported on this eCQM, making it the 5th most commonly selected measure overall. This
represented 63,000 ambulatory care professionals and approximately 17 million patients. On
average, 62 percent of patients with hypertension had controlled blood pressure. Read more
here.

CDC
• Response: Electronic health record systems provide an opportunity to improve patient care
and more easily monitor population health. Using data stored in EHRs, clinicians may be
better equipped to generate reports that track the health of high risk patients. In addition,
public health could expand its surveillance capabilities, potentially at lower costs and in a
more timely fashion, by taking advantage of existing systems such as eCQM reporting.
Further alignment of eCQMs across federal and private sector programs will enable clinicians
to collect data once and report to selected programs.

CDC
this study?
• Response: Future research endeavors should begin to maximize the potential data captured
through eCQM reporting. State and local public health agencies can partner with state,
regional, or local health information exchanges; the state primary care associations; the state
Medicaid programs; and health systems to explore the use of existing EHR data for
surveillance while still ensuring appropriate safeguards to maintain patient privacy. As EHR
implementation becomes more widespread, the data collected by these systems will be
invaluable for monitoring numerous clinical conditions.
• Citation:
• Using Electronic Clinical Quality Measure Reporting for Public Health Surveillance
• Weekly
• May 1, 2015 / 64(16);439-442

HRD Score Can Help Predict Response To Some Chemotherapeutic Agents
Dr. Kirsten Timms, PhD
Program Director
VP Biomarker Discovery at Myriad Genetics Inc
• Dr. Timms: The Homologous Recombination Deficiency (HRD) score is a tumor biomarker
which quantitates genomic rearrangements associated with defects in DNA damage repair. It
has been shown in multiple studies that HRD score can identify tumors sensitive to DNA
damaging agents such as platinum salts or PARP inhibitors. Many tumors are spatially
heterogeneous: different parts of a tumor show variation at both the genomic level, and in
their appearance. This tumor heterogeneity has the potential to negatively impact the
accuracy of biomarker tests. This study assessed the consistency of the HRD score in multiple
biopsies obtained from the same cancer to understand the impact of tumor heterogeneity on
the HRD score. The main finding of this study is that the HRD score is highly conserved
between different biopsies of the same tumor.

Program Director
• Dr. Timms: This study demonstrates that the HRD score is a robust biomarker even in the
presence of tumor heterogeneity. What it means is that any part of a tumor can be used to
determine if the tumor is going to respond to treatment with DNA damaging agents. We
think that the robustness of the HRD score is because the HRD score measures an intrinsic
property of a tumor conserved in every cancer cell.

Program Director
this study?
• Dr. Timms: One important question is how cancer treatments affect the HRD score. Will the
HRD score remain the same after a tumor is treated with chemotherapy or radiation?
Another important question is how the HRD score compares between the primary tumor and
metastatic lesions. This is a very important question because often it is hard to obtain a
sample form metastasis while a sample form the primary lesion is available. If the HRD score
were conserved in metastatic lesions, there would be no need in obtaining samples from
them; a sample from the primary tumor would suffice.

The Infectious Diseases Society of America Comments on the 21st Century Cures Bill Including Antibiotic Development
Ms. Amanda Jezek
Director of Government Relations
Infectious Diseases Society Of America
• Editor’s Note: The Infectious Diseases Society of America Comments on the 21st Century
Cures bill, a bill desigend “to help modernize and personalize health care, encourage greater
innovation, support research” including important issues surrounding antimicrobial
resistance and antibiotic development.
• Ms. Amanda Jezek has been Director of Government Relations at Infectious Diseases Society
of America (ISDA) since July 2011. Ms. Jezek is “is responsible for policy development and
advocacy on IDSA priority issues including antimicrobial resistance, antimicrobial and
diagnositcs development, preparedness and federal funding’.

Ms. Amanda Jezek
• MedicalResearch: What are the main objectives of the 21st Century Cures bill?
• Ms. Jezek: This question goes far beyond IDSA’s work on the bill, so I would not be
comfortable being quoted on this. The Energy and Commerce Committee’s website has more
information. Very generally, the bill seeks to advance the research and development of new
cures for patients with a wide variety of diseases and conditions.
• MedicalResearch: What health care needs and problems does it address?
• Ms. Jezek: I can only answer from IDSA’s perspective, keeping in mind that many sections of
this bill go well beyond the field of ID. IDSA is very pleased that the bill prioritizes the
research and development of some of the most urgently needed new antibiotics to treat
serious or life threatening infections with few or no current treatment options. IDSA is also
very pleased that the bill takes important steps to increase funding for NIH, which is urgently
needed to ensure adequate investment in biomedical research and support for young people
entering or thinking of pursuing research careers.

Ms. Amanda Jezek
• MedicalResearch: Does the proposed legislation address hospital-based infections,
antibiotic resistance, pandemic detection and management, vaccine issues such as
mandatory vaccination of school age children, or antibiotics in food sources?
• Ms. Jezek: The bill’s focus is really biomedical research and development and as these issues
fall more into the public health sphere, they are not the specific focus of the bill. However,
the provisions aimed at antibiotic R&D also include language aimed at making sure the
antibiotics are used appropriately and that their use is monitored, both of which are critical
for addressing antibiotic resistance.

Ms. Amanda Jezek
• MedicalResearch: Does the legislation enable simplified access to clinical medical research
trials or expedited review of new pharmaceuticals and medications?
• Ms. Jezek: I’m only answering from IDSA’s perspective, understanding that we are not
involved in every provision in the bill and other provisions may address these issues. One of
the antibiotics provisions, which IDSA has been championing, would allow antibiotics to treat
serious or life threatening infections with few or no current treatment options to be studied
in smaller, more rapid clinical trials and approved only for the limited population of patients
who need them. This approach is needed because some of the most deadly, difficult to treat
infections currently occur in small numbers of critically ill patients who are difficult to enroll
in clinical trials, making it very difficult and sometimes impossible to populate traditional,
large clinical trials.

Ms. Amanda Jezek
• MedicalResearch: How will patients benefit from bill?
• Ms. Jezek: The bill will help enable the development of new safe and effective antibiotics to
treat infections that could otherwise be lethal. Such antibiotics could literally mean the
difference between life or death for patients with these infections.
• MedicalResearch: What should health care providers be aware of if the legislation passes?
• Ms. Jezek: I think all of the components that IDSA is pursuing—specifically regarding
antibiotic development and NIH funding—would be of great interest to providers given their
potential impact on new treatment options for patients.

Ms. Amanda Jezek
• MedicalResearch: Is funding for implementation of the bill included in the legislation?
• Ms. Jezek: As I understand it, the Committee is still working on some of this, so I can only
provide a partial answer. For the NIH funding-the bill would authorize new money for NIH for
the next 3 years, but the Appropriations Committee in Congress would still need to actually
appropriate that money. However, the NIH Innovation Fund in the bill would provide
mandatory funding for NIH for the next 5 years, and this would not have to be approved by
the Appropriations Committee. Some parts of the bill (such as the limited population
antibiotic development provision discussed above) are not expected to require additional
funding, as it is merely addressing a regulatory barrier. Lastly, some funding items are still
being worked out.
• Citation:
• (See a two-page Fact Sheet of H.R. 6 HERE. )

Blood Based Biomarker May Guide Therapy For Advanced Prostate Cancer
Emmanuel S. Antonarakis, M.B.B.CH
Department of Urology and Oncology
Johns Hopkins University School of Medicine
Baltimore, Maryland
Dr. Antonarakis: In a previous publication, we reported that detection of the androgen receptor
splice variant 7 (AR-V7; an abnormal version of the androgen receptor) in circulating tumor cells
from patients with advanced prostate cancer was associated with resistance to hormonal
therapies such as abiraterone and enzalutamide. Here, we aimed to explore the role of AR-V7 in
the context of chemotherapy treatment. We showed that detection of AR-V7 was not associated
with resistance to the chemotherapy drugs docetaxel or cabazitaxel, and that AR-V7-positive
patients could still derive benefit from these chemotherapies.

Baltimore, Maryland
• Dr. Antonarakis: In patients who have AR-V7-positive circulating tumor cells, chemotherapy
(with docetaxel or cabazitaxel) might be more effective than hormonal therapy (with
abiraterone or enzalutamide). However, in patients who have AR-V7-negative circulating
tumor cells, hormonal therapies and chemotherapies may work equally well while the former
has less toxic side effects. Therefore, blood-based testing for AR-V7 might prove useful in
helping to guide patients in terms of selecting the optimal treatment for their advanced
prostate cancer.

Baltimore, Maryland
this study?
• Dr. Antonarakis: Our findings certainly require confirmation in larger prospective studies, and
such studies are already ongoing. For example, in one study we will prospectively assess the
clinical utility of three blood-based AR-V7 tests in 120 patients with advanced prostate cancer
who are about to begin treatment with abiraterone or enzalutamide. In another randomized
phase-2 study, men will be randomized to receive either abiraterone/enzalutamide or
cabazitaxel, and will be prospectively tested for AR-V7 before trial entry and also at the time
of progression. Such studies will be able to determine the broader clinical significance of the
AR-V7 biomarker test in a multi-center fashion.
• Citation:
• Antonarakis ES, Lu C, Luber B, et al. Androgen Receptor Splice Variant 7 and Efficacy of Taxane
Chemotherapy in Patients With Metastatic Castration-Resistant Prostate Cancer. JAMA Oncol.
Published online June 04, 2015. doi:10.1001/jamaoncol.2015.1341.

Women On Both Diabetes and Depression Medications Have Increased Risk of Myocardial Infarction
MedicalResearch.com Interview with
Dr. Karin Rådholm MD Ph.D.
Division of Community Medicine, Primary Care, Department of Medicine and Health Sciences, Faculty of Health Sciences, Linköping University
Department of Local Care West, County Council of Östergötland,
Linköping, Sweden
• MedicalResearch: What is the background for this study?
• Dr. Rådholm: Psychosocial risk factors and depressive disorders often co-occur with general
medical comorbidities, such as myocardial infarction. Depression is more common in patients with
diabetes than in patients without diabetes. About 10-30% of patients with diabetes have a
comorbid depressive disorder, which is double the estimated prevalence of depression in
individuals without diabetes. There is an association between comorbid depressive symptoms and
diabetes complications. This is believed to be mainly due to poor adherence to treatment
recommendations and diabetes self-management activities, but could also possibly be due to
biological and behavioural causes that could predispose for both metabolic and affective disorders.
The general risk of myocardial infarction is strongly dependent on age and sex, where men have an
earlier disease onset compared to women. In the general population women are at much lower risk
for ischemic heart disease mortality than men are. However, women with diabetes are at especially
high risk for coronary heart disease, relatively more so than men with type 2 diabetes, meaning
that the impact of diabetes on the risk of coronary death is significantly greater for women than
men. The age- and gender-specific risk for myocardial infarction due to diabetes with coexistent
depression has not previously been described. Data on all dispensed drug prescriptions in Sweden
are available in the Swedish Prescribed Drug Register and all myocardial infarctions are registered in
the Myocardial Infarction Statistics. These registers are population-based and have a total national
coverage and high validity, which has been previously shown. Prescribed and dispensed
antidiabetics and antidepressants were used as markers of disease.
• Our objective was to prospectively explore the gender- and age-specific risk of first myocardial
infarction in people treated with antidiabetic and/or antidepressant drugs compared to participants
with no pharmaceutical treatment for diabetes or depression in a nationwide register study.

Linköping, Sweden
• MedicalResearch: What are the main findings?
• Dr. Rådholm: The main findings from this population-based, nation-wide register study of 3
965 839 participants, are that the combination of pharmacologically treated diabetes mellitus
and use of antidepressants substantially increased the risk of a first myocardial infarction
compared to categories of none or either of the conditions alone.
• The hazard ratio for having a first myocardial infarction for women 45-64 years with
antidiabetics and antidepressants combined was increased over 7 times vs. women not
having either diabetes or depression. The corresponding hazard ratio in men was 3.1.

Linköping, Sweden
• MedicalResearch: What should clinicians and patients take away from your report?
• Dr. Rådholm: All patients, especially women with comorbid diabetes and depression should
be given careful attention for risk factor control.
this study?
• Dr. Rådholm: Future research should include randomised controlled trials addressing
depression treatment and disease mechanisms in diabetes patients.
• Citation:
• Use of antidiabetic and antidepressant drugs is associated with increased risk of myocardial
infarction: a nationwide register study
• Diabetic Medicine
K. Rådholm A.-B. Wiréhn J. Chalmers3 and C. J. Östgren
• DOI: 10.1111/dme.12822

JAMA Study Compares Diagnostic Tests For Dementia
MedicalResearch.com Interview with: Kelvin TSOI BSc, PhD
Research Associate Professor, Stanley Ho Big Data Decision Analytics Research Centre
Associate Professor (by Courtesy), School of Public Health and Primary Care
Faculty of Medicine
The Chinese University of Hong Kong
• MedicalResearch: What is the background for this study? What are the main findings?
• Dr. Tsoi: Dementia is a global public health problem afflicting millions of old age population.
The Mini-Mental State Examination (MMSE) is the most widely applied test for dementia
screening. In fact, there are over 40 tests available for dementia screening and many of them
are available for free, but the diagnostic performances of these tests were not yet
systematically evaluated. To identify the best alternative in the long list of screening tests, we
conducted a systematic review to quantitatively analyze the diagnostic accuracy of these
screening tests.
• Among 149 eligible studies included over 49,000 participants, we found that the MMSE is a
frequently used test for dementia screening. The sensitivity and specificity of MMSE for
detection of dementia were combined to be 81.3% and 89.1% respectively. Compared with
the other screening tests, the Mini-Cog and the Addenbrooke’s Cognitive Examination
Revised (ACE-R) showed the best diagnostic performance which was comparable to that of
the MMSE. For mild cognitive impairment (MCI), the Montreal Cognitive Assessment (MoCA)
showed comparable performance to the MMSE with 88.9% sensitivity & 74.8% specificity.

Faculty of Medicine
MedicalResearch: What should clinicians and patients take away from your report?
Dr. Tsoi: The Mini-Cog and the ACE-R showed better performance than that of the other
screening tests for dementia screening. The MoCA showed better performance than the others
for MCI screening. Although the MMSE is the only proprietary instrument for dementia
screening, the other screening tests were shown to be comparably effective but are easier to
perform and freely available.

Faculty of Medicine
this study?
• Dr. Tsoi: This study evaluated the existing literature with large sample size, but the screening
tests were compared across different populations with various inclusion criteria. The future
studies can further verify the test results on the same group of screening subjects.
• Citation:
• Tsoi KF, Chan JC, Hirai HW, Wong SS, Kwok TY. Cognitive Tests to Detect Dementia: A
Systematic Review and Meta-analysis. JAMA Intern Med. Published online June 08, 2015.
doi:10.1001/jamainternmed.2015.2152.

Antibiotic Impregnated Catheters Can Reduce Central Line-Associated Bloodstream Infection
Stephanie Bonne, MD, FACS
Assistant Professor
Trauma, Acute, and Critical Care Surgery
Washington University in St. Louis
Response: We had previously implemented education programs in our ICU in an attempt to
decrease our Central Line-Associated Bloodstream Infection (CLABSI) rate. We were,
however, unable to come to zero. We were looking for innovative ways to lower our CLABSI
rate, and the use of Clorhexidine/Silver Sulfadiazine catheters was unable to move our
CLABSI rate. We decided to try Minocycline/Rifampin catheters, and monitor our Central
Line-Associated Bloodstream Infection rate.
• Response: The use of Minocycline/Rifampin impregnated catheters can lower Central Line-
Associated Bloodstream Infection rate, particularly in ICUs who have been unable to reach a
Central Line-Associated Bloodstream Infection rate of zero with other measures.

Antibiotic Impregnated Catheters Can Reduce Central Line-Associated Bloodstream Infection
Stephanie Bonne, MD, FACS
Assistant Professor
Trauma, Acute, and Critical Care Surgery
Washington University in St. Louis
this study?
• Response: Future research could include larger scale studies of this product, as well as
studying the effects of other types of antibiotic impregnated catheters, like peripherally
inserted central catheters.
• Citation:
• Effectiveness of Minocycline/Rifampin vs Chlorhexidine/Silver Sulfadiazine-Impregnated
Central Venous Catheters in Preventing Central Line-Associated Bloodstream Infection in a
High-Volume Academic Intensive Care Unit: A Before-and-After Trial
• Stephanie Bonne, MD, FACS John E. Mazuski, MD, PhD, FACS, Carie Sona, RN Marilyn
Schallom, RN Walter Boyle, MD Timothy G. Buchman, PhD, MD, FACS Grant V. Bochicchio,
MD, MPH, FACS, Craig M. Coopersmith, MD, FACS Douglas J.E. Schuerer, MD, FACS
• Journal of the American College of Surgeons
• Available online 27 May 2015

Use of Mesh Surgery For Prolapse Continues To Rise
Bilal Chughtai, MD & Art Sedrakyan, MD, PhD
Department of Urology
Weill Cornell Medical College
Response: Since 2008, the U.S. Food and Drug Administration has released number of public
health notifications cautioning the use of mesh in pelvic organ prolapse (POP) surgery.
Despite these notifications and subsequent public scrutiny, studies have reported a large
increase of mesh use in female patients with pelvic organ prolapse during the last decade. In
light of the reported rise in mesh utilization, we sought to determine the use of mesh in
prolapse surgery and compare short-term outcomes of prolapse surgery with or without
mesh.
• After identifying 7,338 and 20,653 patients who underwent prolapse repair procedures with
and without mesh in a 4-year period, we found that mesh use increased 44.7%. Most
patients were under 65 (62.3%), and there were more patients older than 65 years in the
mesh group (44.3% versus 35.4%). Overall, complications were not common. However,
patients who received mesh were more likely to experience urinary retention within 90-days
and had a higher chance of having re-intervention at 1 year. Mesh use was also associated
with higher risk of urinary retention in older patients (≥ 65 year olds) and re-intervention
within 1 year in younger patients (<65 year olds).

• Response: Younger patients (<65) should be aware that they are at higher risk for mesh
exposure and re-intervention. Elderly patients (≥65) should be aware that they are at higher
risk for developing urinary retention after POP surgical repair with mesh. Clinicians should
counsel patients about these risks.

this study?
• Response: The use of mesh continues to rise, and therefore, more research needs to be
conducted to ensure its safety. The FDA has ordered manufacturers to conduct post market
surveillance studies; however, it will take years before this data will be available. Future
research evaluating the use and safety of mesh for pelvic organ prolapse surgical repair
would greatly benefit from a comprehensive registry.
• Citation:
• Chughtai Bilal, Mao Jialin, Buck Jessica, Kaplan Steven, Sedrakyan Art. Use and risks of
surgical mesh for pelvic organ prolapse surgery in women in New York state: population
based cohort study BMJ 2015; 350 :h2685

CDC Study Finds No Pattern Suggesting Vaccines Contributed To Or Caused Deaths
Dr. Pedro Moro, MD, MPH
Immunization Safety Office Division of Healthcare Quality Promotion
Centers for Disease Control and Prevention
Atlanta, GA 3033
Response: The Vaccine Adverse Event Reporting System (VAERS) is a US national vaccine safety
surveillance system, co-administered by the Centers for Disease Control and Prevention (CDC) and the US
Food and Drug Administration (FDA). VAERS accepts reports of adverse events (possible side effects)
following vaccination. Anyone can submit a report to VAERS.
• The study team searched VAERS for US reports of death after any vaccination from 7/1/1997 to
12/31/2013.
• During that time period, VAERS received 2,149 death reports, with most (68.4%) occurring in children.
Among children, the most common causes of death were:
• o sudden infant death syndrome (44%)
• o asphyxia, or lack of oxygen to the brain (6%)
• o septicemia, or blood poisoning from a bacterial infection (5%)
• o pneumonia (5%)
• Among adults, the most common causes of death were:
• o diseases of the circulatory system (47%)
• o diseases of the respiratory system (15%)
• o infections and parasitic diseases (12%)
• o tumors (4%)
• The main causes of death seen in VAERS reports were consistent with the most common causes of death
in the US population. When studied separately, none of these causes of death have found to be related to
vaccines. This finding is reassuring, and consistent with previous research on vaccine safety.

Atlanta, GA 3033
• Response: First and foremost, vaccines are safe, effective, and save lives. There are strong
systems in place to make sure that vaccines are safe, including VAERS.
• The primary goal of VAERS is to detect possible safety problems that may be related to
vaccination. If, after an initial evaluation, CDC and FDA scientists determine that a potential
safety issue requires further investigation, former studies can be conducted using other,
more robust data sources. However, VAERS data do have limitations. One of the limitations is
that a report to VAERS does not necessarily mean that the vaccine caused the adverse event.
• In this study, researchers reviewed reports of death after vaccination and found no patterns
which would indicate that vaccines caused or contributed to the deaths.

Cognitive Therapy May Be Safe and Effective For Chronic Insomnia
Dr David Cunnington
Sleep Physician & Director
Melbourne Sleep Disorders Centre
East Melbourne Australia
• Response: Cognitive behaviour therapy is an effective treatment for chronic insomnia, that is
safe and produces long-term results. As such, it should be considered as a first line treatment
for chronic insomnia, and is a valid alternative to using hypnotic medications.
this study?
• Response: This systematic review and meta-analysis has shown that cognitive behaviour
therapy is effective. However, barriers to this treatment being more widely available are lack
of skilled practitioners, cost and access to healthcare. Future research should look at how
cognitive behaviour therapy can be made more accessible using new technologies.
• Citation:
• Drug-free sleep solution: Cognitive behavior therapy effective for chronic insomnia
• James M. Trauer, MBBS; Mary Y. Qian, MBBS; Joseph S. Doyle, PhD; Shantha M. W.
Rajaratnam, PhD; and David Cunnington, MBBS
• Ann Intern Med. Published online 9 June 2015 doi:10.7326/M14-2841

Cognitive Therapy May Be Safe and Effective For Chronic Insomnia
Dr David Cunnington
Sleep Physician & Director
Melbourne Sleep Disorders Centre
East Melbourne Australia
Response: Insomnia is a very common problem with 15-20% of adults having chronic
insomnia, that is, trouble getting to sleep or staying asleep most days for 3 months or more.
The most commonly used treatment is sleeping pills or hypnotics, however, they don’t
address the underlying disorder, and come with potential side effects. Also, sleeping tablets
just mask the symptoms, and as soon as tablets are stopped, symptoms recur. People with
chronic insomnia think and behave differently around sleep, which perpetuates their
symptoms. The key to improving symptoms in the long run is addressing thoughts and
behaviours around sleep, which is what cognitive behaviour therapy does.
• Our study showed that cognitive behaviour therapy reduced the time taken to get to sleep by
20 minutes and reduced the amount of time spent awake after falling asleep by nearly 30
minutes. These effects were maintained out to 12 months after treatment. These reductions
in time taken to get to sleep and time spent awake are similar to those reported in clinical
trials of hypnotics.

Atlanta, GA 3033
this study?
• Response: CDC will continue to monitor and assess death reports to VAERS to ensure public
confidence in the immunization program.
• Citation:
• Pedro L. Moro, Jorge Arana, Maria Cano, Paige Lewis, and Tom T. Shimabukuro
• Deaths reported to the Vaccine Adverse Event Reporting System (VAERS), United States,
1997-2013 Clin Infect Dis. first published online May 28, 2015 doi:10.1093/cid/civ423

Pediatric Hospitalizations For Children Dropped Almost 90% After Rotavirus Vaccine Implemented
Eyal Leshem, MD
Division of Viral Diseases,
US Centers for Disease Control and Prevention,
Atlanta, Georgia
Response: Routine vaccination of US children to protect against rotavirus began in 2006. The
purpose of this study was to examine the effect of implementation of rotavirus vaccine on
gastroenteritis and rotavirus hospitalizations of children younger than 5 years old.
• The main finding from this study is that hospitalizations for diarrhea in U.S. children younger
than 5 years old decreased dramatically during 2008 to 2012 following implementation of
routine rotavirus vaccination in 2006. Additionally, seasonal peaks of hospitalizations for
rotavirus illness were considerably reduced after the vaccine was implemented compared to
years prior to rotavirus vaccination.
• By 2012, rates of rotavirus hospitalization declined by approximately 90% across all settings
and age groups. Factors such as increasing vaccine coverage as well as herd immunity
resulting in less transmission of rotavirus may be responsible for this large decrease.

Eyal Leshem, MD
Atlanta, Georgia
• Response: Rotavirus vaccination is the most effective method to prevent serious rotavirus
illness in young children. The findings of this study confirm the importance of continued
efforts to increase rotavirus vaccination rates to match those of other established childhood
vaccines.

Eyal Leshem, MD
Atlanta, Georgia
this study?
• Response: Continued monitoring of vaccine impact will provide information regarding long-
term effects of rotavirus vaccine to the public as well as clinicians, public health professionals,
and other stakeholders. Further study of methods to increase rotavirus vaccine coverage
through enhancing access to healthcare and communicating the benefits of vaccine is
recommended.
• Citation: JAMA
• Leshem E, Tate JE, Steiner CA, Curns AT, Lopman BA, Parashar UD. Acute Gastroenteritis
Hospitalizations Among US Children Following Implementation of the Rotavirus Vaccine.
JAMA. 2015;313(22):2282-2284. doi:10.1001/jama.2015.5571.

Blood Pressure Medication ARBs Should Be Resumed As Soon As Possible After Surgery
Susan Ming Lee, MD, FRCPC, MAS (Clinical Research)
Clinical Instructor, Dept. of Anesthesia and Perioperative Care
University of California, San Francisco
Medical Research: What are the main findings?
Dr. Lee: Angiotensin receptor blockers (often referred to as ARBs) are common medications used
to treat high blood pressure, heart disease, and kidney disease. Doctors sometimes stop these
medications briefly around the time of surgery, since they are known to cause low blood pressure
under general anesthesia. Doctors may hesitate to restart ARBs after surgery because they are
worried about low blood pressure or kidney function. Prior to our research, there was little
information to guide the optimal timing of restarting ARBs after surgery.

Medical Research: What are the main findings?
Dr. Lee: Our study of over 30,000 veterans shows that nearly one third of veterans admitted to
hospital for non-cardiac surgery are not restarted on their usual ARBs within two days of their
operation. This delay in resuming ARBs is associated with increased death rates in the first month
after surgery. In fact, even accounting for factors that might contribute to why doctors would
withhold ARB (such as low blood pressure, kidney dysfunction, or other comorbidities), 30-day
postoperative mortality was increased approximately 50% in those without resumption of ARBs,
and this effect was even greater in younger patients under age 60. Our findings of reduced rates
of infections, pneumonia, heart failure, and kidney failure in those that resumed ARBs soon after
surgery suggest that early resumption may also reduce complications after surgery.

• Medical Research: What should patients and clinicians take away from this report?
• Dr. Lee: Our study highlights to clinicians and patients the importance of promptly resuming
medications after surgery that patients were previously on at home. Specifically, restarting
ARBs as soon as possible after surgery may lead to lower mortality and reduced
postoperative complications.

this study?
• Dr. Lee: Future research should further investigate the optimal time for restarting ARBs after
surgery. As part of our study, we repeated our analysis using different time-points for
restarting ARBs (e.g. 1, 7, and 14-days) and found that withholding ARBs was detrimental at
all these other time points. In the future, we may even find that continuing ARBs right
through the day of surgery is better than stopping for one day. The next step would be to
conduct a prospective study, where we deliberately compare a group in which we stop and
then resume ARBs and a group in which we don’t stop them at all.
• Citation:
• Susan M. Lee, Steven Takemoto, Arthur W. Wallace. Association between Withholding
Angiotensin Receptor Blockers in the Early Postoperative Period and 30-day Mortality.
Anesthesiology, 2015; 1 DOI: 10.1097/ALN.0000000000000739

Social Support From Friends and Family Linked To Lower Mortality
Katie Becofsky Ph.D.
Weight Control and Diabetes Research Center
The Miriam Hospital
Providence, RI
• Dr. Becofsky: Previous research has provided clear evidence of a relationship between social
relations (e.g., frequency of social participation, perceived social support) and mortality
risk. We investigated two specific aspects of social relations- source of social support and size
of weekly social network- in more detail. The purpose of our study was to examine the
associations between different sources of social support (relative, friend, and partner
support), as well as size (and source) of weekly social network, on mortality risk in a large
cohort of patients from the Aerobics Center Longitudinal Study. We found that perceived
support from one’s spouse/partner and relatives, as well as weekly social interaction with a
network of 6-7 friends, was associated with lower long-term mortality risk. When the
sources were reversed, the effects did not stand- perceived social support from friends did
not affect mortality risk, nor did the quantity of weekly familial contacts.

Social Support From Friends and Family Linked To Lower Mortality
Katie Becofsky Ph.D.
Weight Control and Diabetes Research Center
The Miriam Hospital
Providence, RI
• Dr. Becofsky: Just as an active lifestyle and healthy diet lower mortality risk, so too does
receiving support from loved ones and staying socially engaged.
this study?
• Dr. Becofsky: Just as we design interventions to promote healthy eating and smoking
cessation, it may be worthwhile to design health interventions that teach interpersonal
communication skills. For individuals who are unmarried, widowed, or not close with
relatives, pet ownership may be an alternative to human social support, and should be
explored in intervention trials. Larger scale strategies may include efforts to de-stigmatize
and promote family and marriage counseling, as well as efforts to encourage physicians to
discuss the importance of social relations with patients.
• Citation:
• Influence of the Source of Social Support and Size of Social Network on All-Cause Mortality
• Becofsky, Katie M. et al.
Mayo Clinic Proceedings Published Online: June 05, 2015
DOI: http://dx.doi.org/10.1016/j.mayocp.2015.04.007

Early Autism Intervention Produces Long Term Benefits
Annette Estes, Ph.D.
Research Associate Professor of Speech and Hearing Sciences Adjunct Research Associate Professor of Psychology
Director, University of Washington Autism Center Susan & Richard Fade Endowed Chair
Center on Human Development and Disability
University of Washington
Dr. Estes: Although a number of studies have shown the positive effects of early intervention on
children’s abilities during the preschool period, there have been few studies to date that have
followed children longitudinally to find out if these gains are sustained. We found that two years
after completing the intervention, children maintained their gains in cognitive and adaptive
behavior skills and also showed a reduction in autism symptoms. The results suggest that early
intervention results in long term benefits for children across a wide range of skills. Children who
received the ESDM intervention as toddlers later showed fewer autism symptoms at school age.

• Dr. Estes: Early intensive behavioral intervention has been found to be efficacious in
improving developmental outcomes for young children with autism spectrum disorder.
Children were able to maintain the developmental gains that they made in early, intensive,
in-home intervention over a 2-year follow-up period. These children did not exhibit
developmental regression or lose skills, even after substantial reductions in services.
Intellectual, language, and adaptive functioning gains made as a result of early intervention
may generalize to new domains of functioning, such as reduced Autism Spectrum Disorder
symptom severity, 2 years later.

this study?
• Dr. Estes: Research is needed to extend these results to a more diverse range of families and
communities to assess the effectiveness of early autism intervention.
• Citation:
• Annette Estes, Jeffrey Munson, Sally J. Rogers, Jessica Greenson, Jamie Winter, Geraldine
Dawson. Long-Term Outcomes of Early Intervention in 6-Year-Old Children With Autism
Spectrum Disorder. Journal of the American Academy of Child & Adolescent Psychiatry, 2015;
DOI: 10.1016/j.jaac.2015.04.005

Most Patients With Atrial Fibrillation Are Symptomatic and Have Impaired Quality of Life
James V. Freeman MD, MPH, MS
Yale University School of Medicine
New Haven, CT
Dr. Freeman: Atrial fibrillation (AF) substantially increases the risk of major adverse clinical
outcomes such as stroke and death, but it can also cause frequent symptoms, affect patient’s
functional status, and impair their quality of life. While prior studies have reported the range of
AF-related symptoms in patient populations, these studies were generally from highly selected
patients and referral based practices, and may not reflect results in community practice or results
with contemporary AF management. Using the Outcomes Registry for Better Informed Treatment
of Atrial Fibrillation (ORBIT-AF), a large, contemporary, prospective, community-based outpatient
cohort, we evaluated the type and frequency of symptoms in patients with Atrial fibrillation. In
addition, we measured the degree to which physician assessed symptom severity (using the
European Heart Rhythm Association [EHRA] classification system) was correlated with patient
reported quality of life (assessed by the Atrial Fibrillation Effect on QualiTy-of-life [AFEQT]
questionnaire). Finally, we association between symptoms or quality of life with clinical
outcomes, including death, hospitalization, stroke and major bleeding.

New Haven, CT
In our community-based study, the majority of AF patients (61.8%) were symptomatic (EHRA >2)
and 16.5% had severe or disabling symptoms (EHRA 3-4). EHRA symptom class was well
correlated with the AFEQT quality of life score (Spearman correlation coefficient -0.39). Over 1.8
years of follow-up, Atrial fibrillation symptoms were associated with a higher risk of
hospitalization (adjusted HR for EHRA ≥2 vs EHRA 1 1.23, 95% CI 1.15-1.31) and a borderline
higher risk of major bleeding. Lower quality of life was associated with a higher risk of
hospitalization (adjusted HR for lowest quartile of AFEQT vs highest 1.49, 95% CI 1.2-1.84), but
not other major adverse events including death.

New Haven, CT
• Dr. Freeman: In our community-based study, most patients with Atrial fibrillation were
symptomatic and had impaired quality of life. Patient-reported quality of life correlated
closely with physician-assessed symptom severity. AF symptoms and lower quality of life
were associated with higher risk of hospitalization but not mortality during follow-up. This
finding is noteworthy because the patients with the highest burden of symptoms and the
lowest quality of life were substantially younger and healthier than less symptomatic patients
and those with higher self-reported quality of life. These patients did not have an increased
risk of death, stroke, myocardial infarction or major bleeding, suggesting that their
hospitalizations were likely related to their symptoms and lower quality of life and not major
adverse event

New Haven, CT
this study?
• Dr. Freeman: We need further validation of the EHRA and AFEQT scoring systems as objective
means of evaluating AF related symptom burden and quality of life, respectively. In addition,
we need more studies evaluating interventions targeted at improvement in symptoms and
quality of life in the patients with the highest symptom burden and lowest quality of life due
to AF to see if we can decrease their risk for hospitalization and resource utilization. Possible
interventions worthy of study include aggressive AF outpatient follow-up or Atrial fibrillation
rhythm control therapies.
• Citation:
• Association Between Atrial Fibrillation Symptoms, Quality of Life, and Patient Outcomes:
Results From the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation
(ORBIT-AF).
• James V. Freeman, DaJuanicia N. Simon, Alan S. Go, John Spertus, Gregg C. Fonarow, Bernard
J. Gersh, Elaine M. Hylek, Peter R. Kowey, Kenneth W. Mahaffey, Laine E. Thomas, Paul Chang,
Eric D. Peterson, and Jonathan P. Piccini
• Circ Cardiovasc Qual Outcomes. 2015;CIRCOUTCOMES.114.001303published online before
print June 9 2015, doi:10.1161/CIRCOUTCOMES.114.001303

Lack of Random Allocation of Participants May Make Observational Research Misleading
Andrew Grey, MD
Department of Medicine
University of Auckland
Auckland, New Zealand
• Dr. Grey: Observational research is commonly conducted and often published in prominent
medical journals, leading to reporting of the results by news media. Because of
methodological limitations, in particular the absence of random allocation of participants to
the interventions being studied, observational studies cannot be used to draw conclusions
about causality. We wondered whether these important study limitations were apparent in
news reporting of observational studies.
• Our analysis demonstrated low levels of reporting of limitations of observational research in
the Abstract section of published papers and accompanying journal press releases, and in
news stories generated in response to publication of the research. The reporting of the
limitation that causal inferences could not be drawn was very low.
• Failing to identify and report limitations of observational research might promote the
initiation and/or continuation of medical practices based on low level evidence.

Lack of Random Allocation of Participants May Make Observational Research Misleading
Andrew Grey, MD
Department of Medicine
University of Auckland
Auckland, New Zealand
• Dr. Grey: Research aimed at improving the quality of reporting of medical research might
improve the translation of evidence into medical practice.
• Citation:
• Wang MM, Bolland MJ, Grey A. Reporting of Limitations of Observational Research. JAMA
Intern Med. Published online June 08, 2015. doi:10.1001/jamainternmed.2015.2147.

Treatment With TNF-α inhibitors Raises Short Term Risk Of Infection in Inflammatory Bowel Disease
Nynne Nyboe Andersen, MD, PhD student
Department of Epidemiology Research
Statens Serum Institut
Copenhagen, Denmark
Dr. Andersen: The use of TNF-α inhibitors, including infliximab, adalimumab and certolizumab
pegol to treat people with inflammatory bowel disease is increasing worldwide and has upgraded
the medical treatment modalities. However, concerns about their safety, including an increased
risk of serious infections have persisted because they suppress the immune system. Previous
meta-analyses based on randomized controlled trials did not suggest an increased risk of serious
infections in people with inflammatory bowel disease treated with TNF-α inhibitors compared to
placebo. However, the trials included in the meta-analyses were designed to investigate efficacy,
and not to analyze risk of rare adverse events such as serious infections and often represent
selected populations. Therefore, observational studies are essential to evaluate safety in a real
world setting; however, results from these studies have been conflicting. Thus, as the risk of
infections associated with TNF-α inhibitor treatment in people with inflammatory bowel disease
is unclear we aimed at investigating this potential risk in a population-based setting based on the
entire Danish inflammatory bowel disease population.

Copenhagen, Denmark
In a propensity score matched cohort we found a significant 63% increased risk of serious
infections within 90 days after treatment initiation. When we prolonged follow-up to 356 days
the risk was attenuated and no longer significant. For site-specific serious infections, we found
increased point estimates for sepsis, urological/gynecological infections, and skin and soft tissue
infections; but these results should be interpreted cautiously because of limited power.

Copenhagen, Denmark
this study?
• Dr. Andersen: Our study’s ability to conclude on specific infections and on different TNF-α
inhibitors separately was limited because of power issues and should be assessed in future
even larger scale population-based studies.
• Citation:
• Nyboe Andersen Nynne, Pasternak Björn, Friis-Møller Nina, Andersson Mikael, Jess Tine.
Association between tumour necrosis factor-α inhibitors and risk of serious infections in
people with inflammatory bowel disease: nationwide Danish cohort study
BMJ 2015; 350 :h2809

Copenhagen, Denmark
• Dr. Andersen: Our study provides the clinicians with an updated safety profile regarding
infections risk associated with TNF-α inhibitors based on the entire Danish population with
inflammatory bowel disease and these results can most likely be extended to other Western
countries. It is important to stress that the benefit of TNF-α inhibitor treatment in people
with inflammatory bowel disease is unquestionable nevertheless our findings call for
increased clinical awareness of potential infectious complications among people using these
drugs, especially early in the course of treatment.

stander CPR Saves Lives – Mobile App May Help Save More
Jacob Hollenberg M.D., Ph.D.
Assistant Professor, Cardiologist
Head of Research, Centre for Resuscitation Science
Karolinska Institutet, Stockholm, Sweden
• Editor’s note: Dr. Hollenberg and colleagues published two articles in the NEJM this week
discussing CPR performed by bystanders in out-of-hospital cardiac arrests.
• MedicalResearch: What is the background for the first study?
• Dr. Hollenberg: There are 10,000 cases of cardiac arrest annually in Sweden.
Cardiopulmonary Resuscitation (CPR) has been taught to almost a third of Sweden’s
population of 9.7 million. In recent years the value of bystander CPR has been debated,
largely due to a lack of a randomized trial demonstrating that bystander CPR is lifesaving.
• In this study, which included all cases of emergency medical services (EMS) treated and
bystander-witnessed out-of-hospital cardiac arrests recorded in the Swedish Cardiac Arrest
Registry from January 1, 1990, through December 31, 2011, our primary aim was to assess
whether CPR initiated before the arrival of EMS was associated with an increase in the 30-day
survival rate.

• MedicalResearch: What were the main findings?
• Dr. Hollenberg: Early CPR prior to arrival of an ambulance more than doubled the chance of
survival. (30-day survival rate was 10.5% among patients who underwent CPR before EMS
arrival, as compared with 4.0% among those who did not (P<0.001).)
• This association held up in all subgroups regardless of sex, age, cause of cardiac arrest, place
of arrest, EKG findings or time period (year analyzed).

• MedicalResearch: How did the patients who survived cardiac arrest do from a disability
standpoint?
• Dr. Hollenberg: We had cerebral performance scores from 474 patients who survived for 30
days after cardiac arrest. (higher scores indicate greater disability).
• At the time of discharge from the hospital, 81% of these patients had a score of category of
1. Less than 2% had category scores of 4 or 5.

• MedicalResearch: What should patients and providers take away from this report?
• Dr. Hollenberg:
• For patients with an out-of-hospital cardiac arrest, CPR performed by bystanders before the
arrival of emergency medical personnel, saves lives. This has been validated by both the size
of this study and the consistency of the results over three decades.
• CPR education needs to continue and to increase. In Sweden about one-third of the
population has been taught CPR. Legislation has recently been passed that mandates CPR
be taught to all teenagers in school which should allow an entire generation to become
familiar with this lifesaving technique.
• The willingness of the public to become involved also needs to increase. We need new ways
of educating lay people to recognize cardiac arrest and to motivate them to perform it. The
knowledge that bystander CPR saves lives may enhance that motivation.

• MedicalResearch: Greater public involvement in CPR overlaps with your second NEJM study
that discusses a mobile phone application. What is the background for this study?
• Dr. Hollenberg: Knowing that bystander CPR saves lives, we were looking for new ways to
reach patients in the first critical minutes after a cardiac arrest. Training as much of the public
as possible is important but still leaves the availability of a trained bystander to serendipity.
• We evaluated a totally new system using mobile positioning technology that recruited CPR-
trained volunteers we called “short-message-service lifesavers”. Lay volunteers were
recruited and trained in CPR.
• During the study, EMS dispatchers who suspected that a patient had a cardiac arrest
activated the mobile-phone positioning system (as well as ambulance, fire and police
vehicles). All such volunteers within a radius of 500 meters from the patient received a
computer-generated telephone call and a text message with information on the patient’s
location. Patients were randomly assigned in a 1:1 ratio to one of two study groups: in one
group, lay volunteers received a text notification; in the control group, no notification was
sent.

• The primary outcome was the rate of bystander-initiated CPR before the arrival of an
ambulance or first responders: 61.6% of the patients in the intervention group (188 of 305
patients) received bystander-initiated CPR, as compared with 47.8% of the patients in the
control group (172 of 360 patients).
• In addition, we know that out-of-hospital cardiac arrests that occur in the home are
associated with worse outcomes. In this study, lay trained volunteers were able to start CPR
in the patient’s home.
• We are not suggesting lay volunteers supplant an EMS system but rather as a valuable add-on
in the first critical 2-4 minutes after a cardiac arrest.

• MedicalResearch: What further developments and research are you planning as a result of this
work?
• Dr. Hollenberg: In the next few days we intend to launch a new service, based on GPS technology,
to allow volunteers to fetch the nearest available public AED (automated external defibrillator). This
mobile app, available for iPhone and Android, will match the location of all available AEDS with
available volunteers. We think this is a very valuable way to get the critical defibrillator to point of
need.
• Citation:
• Early Cardiopulmonary Resuscitation in Out-of-Hospital Cardiac Arrest
• Ingela Hasselqvist-Ax, R.N., Gabriel Riva, M.D., Johan Herlitz, M.D., Ph.D., Mårten Rosenqvist, M.D.,
Ph.D., Jacob Hollenberg, M.D., Ph.D., Per Nordberg, M.D., Ph.D., Mattias Ringh, M.D., Ph.D., Martin
Jonsson, B.Sc., Christer Axelsson, R.N., Ph.D., Jonny Lindqvist, M.Sc., Thomas Karlsson, B.Sc., and
Leif Svensson, M.D., Ph.D.
• N Engl J Med 2015; 372:2307-2315
June 11, 2015
• Mobile-Phone Dispatch of Laypersons for CPR in Out-of-Hospital Cardiac Arrest
• Mattias Ringh, M.D., Mårten Rosenqvist, M.D., Ph.D., Jacob Hollenberg, M.D., Ph.D., Martin
Jonsson, B.Sc., David Fredman, R.N., Per Nordberg, M.D., Hans Järnbert-Pettersson, Ph.D., Ingela
Hasselqvist-Ax, R.N., Gabriel Riva, M.D., and Leif Svensson, M.D., Ph.D.
• N Engl J Med 2015; 372:2316-2325
June 11, 2015

Noninvasive Prenatal Testing May Detect Maternal Cancer
Prof. Joris Vermeesch
Hoofd Moleculaire Cytogenetica
Coordinator Genomics Core
University of Leuven, University Hospitals Leuven, Belgium
Dr. Vermeesch: We developed a novel analysis methodology for Noninvasive prenatal testing
(NIPT), which not only interrogates the common trisomies, but looks at variations across all
chromosomes. We obtain a kind of genome wide copy number variation plot. By applying this
analysis method for Noninvasive prenatal testing, we have strict quality parameters. If faulty, we
ask for a second sample. In one pregnant woman, the second sample showed exactly the same
aberrations as in the first sample. We excluded this variation to be caused by a maternal
constitutional chromosomal rearrangement and also excluded this aberration to be from fetal
origin. This prompted us to assume a maternal cancer was the cause. Three such cases were
observed, all three women were referred to the oncology unit and all three were proven to show
a cancer.

• Dr. Vermeesch: Our data suggest that by slight changes in the analysis protocols, a false
positive trisomy 21 as a result of the presence of a maternal cancer, can be recognized as
such. If such a profile is identified, those women should/could be referred to the oncology
unit. In Leuven, women with such a profile are first referred to the geneticist and
subsequently to the oncology unit where Prof. Amant is in charge of a unit “cancer during
pregnancy”. We consider this finding as an unexpected added benefit of Noninvasive
prenatal testing because early cancer detection prompts treatment, even during pregnancy,
and improves outcome.

this study?
• Dr. Vermeesch: First, we need to establish the sensitivity and specificity on a larger cohort of
patients. In our study, we witnessed 3 cases in 4000 pregnancies. Because this is the cancer
incidence of women in this age group, we consider the test sensitive. Also, with the
parameters we defined, we referred only three women to the oncology unit. Hence the test
looks also specific. Nevertheless, we need to determine whether this is also the case in a
larger group of patients.
• Second, it seems warranted to start pre-symptomatic cancer detection studies in the broader
population.
• Citation:
• Amant F, Verheecke M, Wlodarska I, et al. Presymptomatic Identification of Cancers in
Pregnant Women During Noninvasive Prenatal Testing. JAMA Oncol. Published online June
05, 2015. doi:10.1001/jamaoncol.2015.1883.
joris.vermeesch@uzleuven.be

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