Medical

International Expert Team Meets to Finalize First-Ever DM Care Recommendations for Doctors

Published on Thu, 06/09/2016

As many MDF community members know, MDF has been working with a group of expert clinicians from across Western Europe, the U.K, Canada and the U.S. for the past year to develop consensus-based clinical care recommendations for myotonic dystrophy. We first talked about this project as part of a larger story about our three year, multi-million dollar drug development and care expansion effort. We have made excellent progress since we first mentioned this program in May 2015, and we are pleased to bring you an update on this unique initiative.

What Are Standards of Care and Why Are They Important?

Standards of care are critically important to help ensure that all patients with a particular disease receive appropriate and beneficial clinical care. They are typically based on rigorous data captured through large, anonymous research studies, and are usually developed and issued by the leading professional organization for that particular disease. In the case of myotonic dystrophy, that organization in the U.S. is the American Academy of Neurology (AAN). AAN has been working on an Evidence-Based Guideline for myotonic dystrophy for over five years, and hopes to publish it in 2017.

Clinical care guidelines will be particularly meaningful for the DM community because, as our community knows well, many doctors who do not see DM patients regularly are not aware of the range and variation in symptoms that are part of living with myotonic dystrophy. They do not necessarily know what testing, exams and follow up are appropriate for people living with DM, and they may miss important impacts to some organ systems. Often it is the DM patient who educates the physician about the disease and the care that is needed. MDF is committed to helping ensure that care recommendations are available and delivered to the clinical professionals who treat DM patients.

The DM Guideline, when it comes out, will be published and disseminated to neurologists in the U.S. It will not address most of the organ systems and symptoms of importance to myotonic dystrophy patients because the studies needed to gather the evidence required to establish a guideline have not been conducted.

MDF is working with the AAN to support the eventual dissemination and publication of the DM Evidence-Based Guideline when it is ready, and most of the members of our Scientific Advisory Committee are part of the team involved in its creation. Dr. Tetsuo Ashizawa, formerly the head of neurology at the The University of Florida and now leading neurology research at Houston Methodist, is the lead clinician on The DM Guideline.

What are Care Considerations and How Are They Different?

MDF has had a number of meetings with the U.S. Centers for Disease Control (CDC) and the AAN to understand what the newest publication date is for the evidence-based guideline, and how robust the final publication will be. The AAN and CDC have heavily encouraged MDF to pursue the development of consensus-based care recommendations in order to ensure that comprehensive care recommendations are available to all clinicians treating DM patients because a comprehensive evidence-based guideline is many years away.

Consensus-driven care recommendations are clinical care recommendations developed by experts in the appropriate disease field, who work through a formal consensus-development process to come to agreement on how patients across many countries and continents should be treated to help patients maintain health and improve their quality of life.

The Myotonic Dystrophy Care Considerations

In the case of the DM Care Considerations, MDF has assembled a truly world-class team of 60 expert clinicians from across the globe, in fields as diverse as cardiology, pulmonology, occupational therapy, pain and family planning, to work through a consensus-building process to create the first-ever clinical care recommendations for adults with myotonic dystrophy type 1. Care Considerations for congenital myotonic dystrophy and myotonic dystrophy type 2 will follow very shortly. Both the CDC and AAN are partners on the MDF Care Considerations project and are providing significant support to the project. MDF has also teamed up with Treat-NMD, Muscular Dystrophy UK and organizations in Canada and Western Europe to ensure that these guidelines are appropriate and targeted to patients in many different countries and care situations.

What’s Been Accomplished?

The project formally kicked off at the 2015 MDF Annual Conference, where MDF held a meeting with the international working group to provide an overview of the project scope, the consensus-development methodology, and study area assignments. Eight multi-system study areas were established, with committee chairs and working groups for each. Click here to see the full international list of Care Considerations study areas and Working Group participants.

MDF created and circulated to the working group a draft list of care recommendations developed from the MDF Toolkit and a short list of key published research. The expert clinicians then met via conference call and email, reviewing and editing the recommendations for their study areas over the course of the winter. MDF assembled an updated draft of care considerations with the edits included, and then brought all available working group members to Miami to discuss the revised document and work toward final recommendations and consensus. The meeting was a significant success, and MDF is now assembling the final draft document to circulate for a last round of reviews to the working group.

What’s Next?

The next steps for the DM Care Considerations project will be extensive and will involve multiple international partner organizations. Once the working group has agreed on the final list of care recommendations, MDF will develop executive summary and full versions of the document, as well as a draft publication for submission to a neurology journal. The full version will be submitted to professional associations of clinical professionals for open comment and to accreditation organizations in Western Europe, the U.K., Canada and the U.S. (AAN) to begin the final approval and dissemination process. Additional international organizations will be significant partners in distributing the final recommendations to care providers internationally.

MDF will also pursue an insurance policy document to help convince insurance companies in the U.S. to provide reimbursement for these care recommendations, and MDF has developed a draft update policy to ensure that these recommendations stay current. Finally, MDF will work with the working group and our international partners to develop and implement an assessment program to measure whether these recommendations are being used and are improving care for DM patients.

We plan to have final approved documents ready by the end of 2016. As always, MDF will keep you posted on this and our other research and care projects as we move forward. Questions? Contact MDF via email or phone at 415-800-7777.

New Findings on Quality of Life in DM2

Published on Tue, 06/07/2016

There has been relatively little research on quality of life for DM2 patients, and DM2 is often considered “less severe” than DM1. However, a new study identified a subset of DM2 patients who are impacted as severely as those with DM1.

Dr. Dusanka Savic-Pavicevic and colleagues recently published a comparison of genetically confirmed DM2 and DM1 patients using a variety of quality of life measures.

The research team found no differences between DM2 and DM1 in the overall and physical composite scores of the survey.

Emotional and mental composite scores were typically better in DM2 patients, as were independence and body image scores. Disease impact on cognition, strength, heart function, breathing and cataracts were also less severe in DM2.

The DM2 patients who reported worse scores were typically older, weaker, and had higher fatigue levels than the DM2 patients who scored better on certain segments of the surveys. Lower quality of life scores were also associated with lower cognitive achievement, memory impairment and lower educational levels.

A deeper understanding of the correlation of age, strength, and fatigue with quality of life in DM2 is needed to facilitate better patient outcomes. More DM2 studies like this will pave the way for higher quality care.

Reference:

Quality of life in patients with myotonic dystrophy type 2.
Rakocevic Stojanovic V, Peric S, Paunic T, Pesovic J, Vujnic M, Peric M, Nikolic A, Lavrnic D, Savic Pavicevic D.
J Neurol Sci. 2016 Jun 15. 

Gender Matters in DM1

Published on Wed, 05/11/2016

While it has been widely recognized by clinicians treating DM that gender plays an important role in determining disease heterogeneity and progression, there is little hard data to support differential response of males and females to DM.

Dr. Guillaume Bassez and a large team in France and Canada have recently published an analysis of gender as a modifying factor of the DM1 phenotype. In the study, they evaluated 1,409 adult DM1 patients in the French DM-Scope registry. Importantly, findings were validated using additional cohorts from the AFM-Telethon DM1 survey and the French National Health Service Database.

The research team identified clear differences in symptoms detected by gender. Adult males were much more likely to present with “traditional” DM1 signs and symptoms, including muscle weakness and myotonia, cognitive impairment, and cardiac and respiratory involvement. By contrast, adult females had symptoms that were less suggestive of “traditional” DM1, instead showing predominance of cataracts, obesity, thyroid signs, and GI symptoms.  

The differing constellation of symptoms in the two sexes led the research team to conclude that women were often less symptomatic of DM1 and thus often undiagnosed, although this was potentially offset by the finding that women appeared to more often seek specialist care for DM1 symptoms.

Gender matters in DM1. The biologic mechanisms underlying the gender differences that the French group has documented for DM1 are unknown. To improve diagnosis and management of DM1, as well as to better plan for inclusion of both genders in clinical trials, it will be important to understand the factors responsible for the very different onset and progression of DM1 in males and females.

The heterogeneity (variability) that characterizes the clinical manifestations of myotonic dystrophy type 1 (DM1) has been well recognized by physicians, patients, and family members. Although the length of CTG expansions in the DMPK gene correlates with age of onset and severity of DM1, knowledge of other factors that impact progression of DM1 currently is rather limited.  

Intensive analysis of large cohorts of DM1 and DM2 patients are underway to identify both genetic modifiers, gene variants that can speed or slow disease onset or progression, and biomarkers, measurable indicators in blood or other tissues that can be critical for studies of disease progression and clinical trials. 

MDF is partnering with the research community to identify biomarkers and move them toward qualification by the regulatory authorities as drug development tools.

Understanding of the biological factors behind heterogeneity of DM1 is critical to help patients better understand their disease, as well as to help drug developers design successful clinical trials. The studies necessary to identify the underlying factors require large cohorts of affected individuals—for this reason, it is essential that patients become involved in research efforts that build the requisite databases, such as the Myotonic Dystrophy Family Registry

Gender as a Modifying Factor Influencing Myotonic Dystrophy Type 1 Phenotype Severity and Mortality: A Nationwide Multiple Databases Cross-Sectional Observational Study. 
Dogan C, De Antonio M, Hamroun D, Varet H, Fabbro M, Rougier F, Amarof K, Arne Bes MC, Bedat-Millet AL, Behin A, Bellance R, Bouhour F, Boutte C, Boyer F, Campana-Salort E, Chapon F, Cintas P, Desnuelle C, Deschamps R, Drouin-Garraud V, Ferrer X, Gervais-Bernard H, Ghorab K, Laforet P, Magot A, Magy L, Menard D, Minot MC, Nadaj-Pakleza A, Pellieux S, Pereon Y, Preudhomme M, Pouget J, Sacconi S, Sole G, Stojkovich T, Tiffreau V, Urtizberea A, Vial C, Zagnoli F, Caranhac G, Bourlier C, Riviere G, Geille A, Gherardi RK, Eymard B, Puymirat J, Katsahian S, and Bassez G.
PLoS One. 2016 Feb.

Multi-Disciplinary Approach Needed for Congenital and Childhood DM Care

Published on Thu, 02/11/2016

Poor communication, fatigue and gastrointestinal problems worry parents most.

Dr. Nicholas Johnson at the University of Utah and colleagues released the results of an MDF-funded multinational study on the impact of congenital myotonic dystrophy (CDM). The study relied upon a survey filled out by 150 American, Canadian and Swedish parents to better understand both the frequency and the impact of symptoms in children with different repeat lengths and different types of CDM. The survey inquired about 325 symptoms of importance and 20 “symptomatic themes.” Children in the study were divided into three groups: congenital DM (CDM), with symptom onset at birth; childhood onset DM (ChDM), with symptoms starting between ages one and ten; and juvenile onset DM (JDM), with symptoms starting after age 10 but before age 18.

Frequency of Symptoms

Parents reported that communication issues (81%), problems with hands or fingers (79.6%) and fatigue (78.6%) were the most common symptomatic themes across all children in the study, while the most common individual symptoms were hand weakness, difficulty opening jars or bottles and learning difficulties. The investigators also examined the influence of repeat length and age on both symptom themes and individual symptoms. Many symptom themes were found to be more common as children became older, such as hand or finger problems, emotional issues, fatigue, pain, inability to do activities, myotonia, gastrointestinal issues and social issues. Children with higher repeat counts showed increased frequency of leg and trunk weakness and problems with bowel control, although myotonia was less frequent in children with higher repeat counts. Interestingly, emotional issues, changes in body image, social issues and impaired sleep were more common when the mutation was inherited from the father.

Impact of Symptoms

The authors looked at the impact of symptoms on children in two ways: first they analyzed the impact of symptoms for the individual, then they analyzed the impact of symptoms for all children with congenital or childhood myotonic dystrophy—the “population impact”— by multiplying the individual impact by the frequency of the symptom. The symptom themes that parents reported had the greatest impact on their individual children’s lives were gastrointestinal issues, problems with urinary or bowel control and decreased performance in social situations. The authors make the point that these symptom themes are different from those identified by adults with DM, namely fatigue and mobility and activity limitations (DM2 patients identified fatigue and other disease symptoms as having the greatest impact on daily living in an article published by MDF in Decmber 2015). Parents of children with greater repeat lengths reported a higher life impact for leg weakness and parents of children who inherited the mutation from their fathers reported a higher life impact for pain. The symptom themes with the greatest population impact were found to be communication issues, fatigue and gastrointestinal issues. The specific symptoms with the greatest population impact were learning difficulties, reliance on family members, and difficulty with math.

Additional Factors

From a social standpoint, many children required special assistance in school, such as speech therapy (55.3%), occupational therapy (40.7%), physical therapy (35.3%), smaller class size (42.7%), test modifications (42%), and augmentative speech methods (19.2%). The survey also showed that children with DM1 who are now adults have difficulty in getting jobs. Parents reported that 15.8% of children had anesthesia complications (56.8% reported no problems and 27.4% had never had anesthesia), and 24.1% had cardiac arrhythmias. Finally, the rate of intellectual disability in children in the study was 28.3% - 45.8% compared to 0.71% in the general population. In particular, children in the study had higher rates of autism spectrum disorder (ASD) and attention deficit hyperactivity disorder.

Take Home Messages

The authors conclude by noting that the high rate of communication problems should be addressed with early referrals for speech therapy and that early cardiac monitoring should be performed. Also, the rate of anesthesia complications reinforces the need for special attention in this group. Overall, the authors emphasize that the high frequency of social and cognitive issues associated with the disease make the need for a multi-disciplinary approach to care much more important.

The Impact of Pregnancy on Myotonic Dystrophy: A Registry-Based Study

Published on Thu, 02/11/2016

Dr. Nicholas Johnson and a research team from the Universities of Utah and Rochester partnered on a study commissioned by MDF to study how women with myotonic dystrophy (DM) are impacted by pregnancy. Data for the study were drawn from the Myotonic Dystrophy Family Registry and the National Registry for DM and FSHD. Previous studies have shown that women with DM may have pregnancy complications in excess of what is normally seen in women without DM. For example, pregnant women with DM1 experience more spontaneous abortions, polyhydramnios (excess amniotic fluid), ectopic pregnancies (fertilized egg implants outside the uterus), placenta previa (placenta covers the cervix) and early labor. Other studies focusing on DM2 showed that 21% of women with DM2 had their first symptom during pregnancy, and women with DM2 experienced more urinary tract infections and preterm labor.

This new study recruited 152 women from the two registries and collected data on their 375 pregnancies. Women with DM1 and DM2 had miscarriage rates of 32% and 37%, respectively, which is higher than the national average of 17%. All women with DM combined had a 10% rate of preeclampsia (high blood pressure and protein in urine) and a 14% rate of peripartum hemorrhage (bleeding before, during or after delivery), both of which are well above the national average of 3%. Many common symptoms of DM progressed during pregnancy, including mobility limitations, activity limitations, pain, emotional issues and myotonia. After delivery many of these symptoms reportedly did not return to the level experienced before pregnancy.

The authors summarize their findings by suggesting that “this research may be utilized by DM patients and family members seeking to better understand the risks and outcomes associated with pregnancy and DM.”

Reference:

The Impact of Pregnancy on Myotonic Dystrophy: A Registry-Based Study.
Johnson NE, Hung, M, Nasser, E, Hagerman, KA, Chen, W, Ciafaloni, E, and Heatwole, CR.
Journal of Neuromuscular Diseases. Oct 7, 2015.

Myotonic Dystrophy Anesthesia Guidelines

Published on Thu, 01/28/2016

Myotonic Dystrophy Anesthesia Guidelines

Please know that the use of anesthesia raises special risks to those living with myotonic dystrophy (DM), as the disease results in heightened sensitivity to sedatives and analgesics. Pay particular attention to the serious complications that can arise in the post-anesthesia period, when risk of aspiration and other complications increase. 

MDF has published two versions of its Anesthesia Guidelines:

  • A one-page summary of the anesthesia guidelines to share with your clinician and anesthesiologist.
  • The complete "Practical Suggestions for the Anesthetic Management of a Myotonic Dystrophy Patient".

Download an electronic copy of the latest versions of both documents on the Toolkits & Publications page.

New to DM? Click here for more information.

Common Symptoms of DM2 and Their Impact on Daily Living

Published on Wed, 12/02/2015

While symptom themes such as inability to do activities, mobility limitations and weakness were the most common, fatigue was the symptom that had the greatest impact on patients' lives. This research will help focus developing treatment strategies on the most important issues reported by people with DM2.

These findings are similar to those from a previous study from the same authors that examined symptoms in DM1, where fatigue was also ranked as the most burdensome symptom but not the most common.

More on the study:

In this study, researchers interviewed and sent surveys to people across the USA with DM2, asking respondents to report what symptoms they were experiencing, and what impact those symptoms had on their daily living.

Symptoms were grouped into themes, and researchers found that the most commonly reported symptom themes were:

  • Inability to do activities (94%)
  • Limitations with mobility or walking (89%)
  • Hip, thigh, or knee weakness (89%)
  • Fatigue (89%)
  • Myotonia (83%)
  • Pain (80%)

When the themes were broken down into individual symptoms, the most commonly experienced symptoms included difficulties getting up from the floor, squatting, walking hills, rising from a seated position, and other issues stemming from leg weakness.  These symptoms were experienced by at least 97% of the respondents.

Aside from assessing symptoms, this study also gathered information on employment, age, duration of symptoms, and gender. This allowed the researchers to break down their DM2 respondents into groups to determine whether there were any subsets of the population that had a different experience with DM2 than others.

They found that the significant differences between subsets of the population came when patients were grouped by employment status. Unemployed respondents more commonly reported mobility or walking issues, problems with shoulders or arms, emotional issues, decreased satisfaction in social situations, and many other symptomatic themes.

The researchers believe that “employment status is highly dependent on a patient’s overall disease burden,” and also found that employed respondents had better satisfaction in social situations. While this study was not designed to determine cause and effect, the authors hypothesize that many symptoms of DM2 may make obtaining employment difficult or impossible. They further hypothesize that unemployment may also potentially lead to increased disease burden in DM2.

To read an abstract of this article, click here

Benefit/Risk Study Results: Focus on Muscle Weakness

Published on Mon, 11/16/2015

As part of our investment in the development of effective treatments for myotonic dystrophy, we are trying to better understand how people with DM weigh the benefits of new treatments against the risks.  To do this, we worked with a company called Silicon Valley Research Group to develop a survey that presented a series of hypothetical new treatments and asked that people choose the side-effects that concerned them the most and the least for.  This type of analysis is called “Max-Diff Analysis” or sometimes “Best-Worst Scaling” and has been used in other benefit-risk studies and by the Food and Drug Administration (FDA).  The method generates robust statistics to determine, on average, what risks people are or are not willing to accept for a given benefit.  The FDA has indicated that it is very interested in this type of information.  

The survey showed that reversing, stopping or slowing the progression of muscle weakness were the most preferred benefits, in that order.  The side effects people were most willing to tolerate overall for any benefit were loss of appetite and a small increase in tiredness. 

People in the study also completed the short version of the Myotonic Dystrophy Health Index (MDHI) to rate the severity of their myotonic dystrophy.  Scores were grouped into mild, moderate and severe categories.  For the majority of benefits, those with all levels of severity were similar in their willingness to tolerate side effects except that those with more severe myotonic dystrophy were less willing to risk liver failure for any type of therapeutic benefit.  Also, those with the highest severity rating for their myotonic dystrophy were more willing to tolerate an increase in tiredness if the drug could stop or reduce myotonia.  The data reported here are based on the survey responses from those with DM1.  The responses from those with DM2 are being analyzed now.

These results were presented on September 17th at the MDF-sponsored regulatory workshop on therapeutic development for myotonic dystrophy, which was attended by FDA staff.  Next steps will likely include an in-depth follow-on study that looks at the benefit-risk preferences of caregivers and younger people with myotonic dystrophy.  We are also investigating ways to collect “qualitative” data, such as stories and open-ended comments, on the benefit-risk preferences of those with myotonic dystrophy.  Ultimately this information will be made available to FDA reviewers through various mechanisms with the goal of incorporating the view of those with myotonic dystrophy and their families into the decision-making process about new therapies. 

Dr. Benedikt Schoser: Focus on the Patient

Published on Mon, 03/16/2015

As a clinician and researcher, Dr. Benedikt Schoser is focused on how research findings can be translated into improved patient care - and how patient concerns can help guide researchers to new areas of interest. “We try to combine clinical data with results from basic science and look at parallels between scientific results and patient outcomes,” he says.

Dr. Schoser is senior consultant in neurology at the Friedrich-Baur Institute (FBI) at Ludwig-Maximilians University of Munich, one of Germany’s largest referral centers for neuromuscular diseases. FBI diagnoses and treats thousands of patients and processes hundreds of muscle biopsies each year.

Dr. Schoser trained as a neurologist and myopathologist (a specialist in muscle dysfunction) at several German universities before joining FBI in 2001. His interest in myotonic dystrophy (DM) dates back about 15 years, when he began working closely with Dr. Kenneth Ricker, then of the University of Wurzburg, one of the original describers of DM2. He has published more than 30 research papers on DM and sees approximately 200 patients with the disease, including some he has been following for decades.

His clinical focus has prompted Dr. Schoser to bring together patients and researchers to improve resources and education for people with DM. He serves on the academic task force of the TREAT-NMD network, an international effort to ensure that promising new therapies for neuromuscular diseases reach patients by connecting patients, clinicians, academic researchers, and representatives of the biomedical industry. And he is the head of Germany's DM registry, which collects information on patients so they can be paired appropriately with clinical trials.

Dr. Schoser is project lead at FBI for the OPTIMISTIC Trial (Link to archived site), a collaboration among researchers and doctors from the Netherlands, Germany, France, and the United Kingdom that seeks to improve standards of care for DM1. The group has launched a study of whether cognitive behavioral therapy can be used to stimulate activity and reduce fatigue in DM patients. The goal of these research efforts is to develop guidelines physicians can use to improve patients’ quality of life.

Dr. Schoser also helped translate the MDF Toolkit into German, adapting it for that country’s patients. The German translation will be available for download soon.

Dr. Schoser is looking forward to this summer’s meeting of the International Myotonic Dystrophy Consortium (IDMC). (He served as chair of IMDC-7 meeting in 2009.) He believes these meetings are special in the medical field because they unite scientists and clinicians. “As clinicians, we see patients and try to understand their symptoms,” he says. “Scientists do fantastic studies and then ask how they can be translated into clinical practice. At these meetings, we share, which is why I always look forward to them.”

He also values the participation of caregivers at the IMDC meetings. “A doctor, if he is lucky, may see a patient for 60 minutes,” he says. “But a caregiver often is with a patient 24 hours a day. That gives them a lot of information we don't have to better understand the disease, which helps improve our work as physicians. And they help identify additional areas for research, based on what patients and caregivers think is important.”

03/26/2015

Healthy Heart Information for American Heart Month

Published on Thu, 02/19/2015

February is American Heart Month, and MDF has partnered with Drs. Katharine Hagerman and Marianne Goodwin to highlight important research on cardiac issues in myotonic dystrophy for our community.

Researchers in the lab of William Groh, MD, at Indiana University have been studying heart involvement in myotonic dystrophy type 1 (DM1), including heart conduction defects, cardiac rhythm disturbances, and structural heart abnormalities for some time. The group performed cardiac imaging and analysis of the electrical impulses of the heart by electrocardiography (ECG or EKG) on individuals with DM1, and found that certain structural changes in the heart are increased in individuals with cardiac electrical abnormalities. In addition, the study identified predictors of heart failure and dysfunction, including increased age and changes in electrical conduction of the heart observed by ECG, specifically measurements known as PR interval and QRS duration. These indicators may be used by doctors to help predict which DM patients would benefit most from implantable cardiac rhythm devices such as pacemakers. Additionally, the group found that some individuals with DM1 benefit more from devices known as implantable cardioverter-defibrillators (ICDs) than standard pacemakers to help correct heart rhythm disturbances.

The heart involvement in myotonic dystrophy type 2 (DM2) is similar to that seen in DM1, however controversy exists over the frequency and severity of heart irregularities in the DM2 population. To address this, a research team led by Giovanni Meola, MD, in the Neuromuscular Clinic at IRCCS Policlinico San Donato in Italy compared cardiac abnormalities in DM1 and DM2. Using tests such as ECG and echocardiography, the study found that heart involvement is less common and generally milder in DM2 than DM1. However, individuals with DM1 and DM2 are both at increased risk of heart abnormalities such as cardiac arrhythmias and conduction disturbances. These heart irregularities can be progressive with age, and may be present in individuals even when no symptoms are experienced. Therefore, people living with DM should receive annual cardiac evaluations, including ECG, by primary care physicians or cardiologists to promote heart health.

For more information on heart health in DM, please see our Body Systems Tool.

To learn more about heart symptoms, exams and management, watch MDF's webinar "Cardiac Issues Related to DM," by Dr. William Groh, a leader in the field.

Papers on DM1 heart issues:

Papers on DM2 heart issues:

02/26/2015