MedicalResearch.com Interview with: Yuichi Shimada, MD, MPH Cardiology Division, Massachusetts General Hospital A Teaching Affiliate for Harvard Medical School Boston, MA 02115 Medical Research: What...
Prof. Timothy Rainer[/caption]
Professor Timothy H Rainer MD MBBCh
Director, Accident & Emergency Medicine Academic Unit
The Chinese University of Hong Kong
Medical Research: What is the background for this study? What are the main findings?
Prof. Rainer: Gout is a type of arthritis characterised by periodic attacks of acute joint swelling and severe pain, and often treated with colchicine or nonsteroidal anti-inflammatory drugs (NSAIDs). Two recent randomized, controlled trials showed that oral prednisolone, a corticosteroid, was as effective as NSAIDs in the treatment of acute gout, but these studies involved small numbers of patients. The researchers investigatedwhether oral prednisolone was as effective and safe as indomethacin (a NSAID) in a larger sample of patients who had acute gout symptoms and who were seen in the emergency department (ED) setting. Patients in both the prednisolone and indomethacin groups had clinically meaningful decreases in their pain levels during the 2 hours they were observed in the ED as well as during the 14-day follow-up period. Both groups had a similar decrease in pain levels. No major adverse events were reported in either group although there were more minor adverse events in the indomethacin group.
Dr. Jaret Baeten[/caption]
Jared Baeten, MD PhD
Vice Chair, Department of Global Health
Professor, Departments of Global Health, Medicine, and Epidemiology
Co-Director, International Clinical Research Center
University of Washington
MedicalResearch.com: What is the background for this studies?
Dr. Baeten: Women account for nearly 60 percent of adults with HIV in sub-Saharan Africa, where unprotected heterosexual sex is the primary driver of the epidemic. While several studies have shown that antiretroviral medications (ARVs) are highly effective in preventing HIV, other studies – such as VOICE and FACTS 001 – suggest that for young, at-risk women in Africa, ARVs delivered as a vaginal gel or as a tablet may not be acceptable. Products must be used to be effective, and that was not the case for most of the participants in previous studies.
Medical Research: What was the aim of ASPIRE and The Ring Study?
Dr. Baeten: As Phase III clinical trials, ASPIRE and The Ring Study were designed to determine whether a vaginal ring containing an antiretroviral (ARV) drug called dapivirine is safe and effective in protecting women against HIV when used for a month at a time. These trials also sought to determine whether women find the vaginal ring practical and easy to use. As sister studies, ASPIRE and The Ring Study were designed as the centerpiece of a broader licensure program to provide the strength of evidence to support potential licensure of the dapivirine vaginal ring for preventing HIV in women. Because at least two Phase III efficacy trials are usually needed for a product to be considered for regulatory approval, ASPIRE and The Ring Study were conducted in parallel to accelerate the timeline to the ring’s potential approval.
Dr. John Laffey[/caption]
John G. Laffey MD
Chief, Department of Anesthesia; Co-Director, Critical illness and Injury Research Centre; Scientist, Keenan Research Centre for Biomedical Science ‑ St. Michael's Hospital
Professor, Anesthesia, Critical Care, and Physiology ‑ University of Toronto
Medical Research: What is the background for this study?
Dr. Laffey: Acute respiratory distress syndrome is the commonest cause of severe acute respiratory failure in the critically ill. ARDS is a major cause of death and disability in the critically ill worldwide. Second, there is no treatment for ARDS, and our present management approaches are limited to supporting organ function while treating the underlying causes
We performed the LUNG SAFE study to address several clinically important questions regarding ARDS.
First, the current incidence in a large international cohort was not known. Large regional differences had been suggested: for example, the incidence of ARDS in the US was reported to be ten times greater of that in Europe_ENREF_4.
Second, we wanted to understand how we manage patients with Acute respiratory distress syndrome in the ‘real world’ situation. Specifically, it was not clear to what extent newer approaches to artificial ventilation, such as reducing the size of the breaths (lower tidal volumes) and keeping the lung pressure positive at all times to minimize collapse (PEEP) were used. The impact of studies showing promise for other measures to improve gas exchange such as turning patients prone during mechanical ventilation, or using neuromuscular blockade, on routine clinical practice in the broader international context was not known.
Third, there were some concerns over the extent of clinician recognition of ARDS. This was an important issue because implementation of the effective therapies may be limited by lack of recognition of ARDS by clinicians. A better understanding the factors associated with ARDS recognition and how this recognition influenced patient management could lead to effective interventions to improve care.
Lastly we wanted to determine the outcome from Acute respiratory distress syndrome in a global cohort of patients.
Medical Research: What are the main findings?
Dr. Laffey: We found that ARDS continues to represent an important public health problem globally, with 10% of ICU patients meeting clinical criteria for ARDS. While there appeared to be some geographic variation, this did not seem as great as previously thought.
An important finding was the under-recognition of Acute respiratory distress syndrome by clinicians, with 40% of all cases not being recognized.
In addition, over one third of patients did not receive protective lung ventilation strategies. The use of other measures to aid gas exchange during artificial ventilation, such as turning the patient into the prone position, or the use of neuromuscular blockade was also quite low.
Of most concern, ARDS continues to have a very high mortality of approximately 40% of patients dying in hospital.
Dr. Nancy E. Thomas[/caption]
Nancy E. Thomas, MD PhD
Department of Dermatology, University of North Carolina
Chapel Hill, NC 27599
Medical Research: What is the background for this study?
Dr. Thomas: Melanoma had been thought for some time to arise from at least two causal pathways, a ‘chronic sun exposure pathway’ and a ‘nevus pathway’. However, the role of inherited genetic variation in development of melanoma along these pathways had not previously been studied. Thus, we chose to examine the association of SNPs in putative low-penetrance melanoma susceptibility loci with histologic markers of divergent pathways.
Medical Research: What are the main findings?
Dr. Thomas: Within the large Genes, Environment and Melanoma Study, we investigated the relationship of germline variants in newly identified low-penetrance melanoma risk loci to histologic markers of divergent causal pathways in melanoma. We present strong evidence that the IRF4 rs12203592*T genotype is positively associated with chronic sun exposure-related melanoma and inversely associated with nevus-related melanoma. We also found that the IRF4 rs12203592 genotype is linked to the bi-model age distribution known to occur in melanoma and which is related to the divergent pathways. IRF4 rs12203592 is a functional variant known to affect IRF4 expression in human skin and melanoma cell lines. We conclude that IRF4rs12203592 is likely, at least in part, to determine pathway-specific risk for melanoma development.
Dr. Tim Uyeki[/caption]
Tim Uyeki MD, MPH, MPP
Influenza Division
National Center for Immunization and Respiratory Diseases
Centers for Disease Control and Prevention and
Associate Clinical Professor of Pediatrics
Department of Pediatrics
San Francisco General Hospital
Medical Research: What is the background for this study?
Dr. Uyeki: During 2014-2015, 27 patients with Ebola virus disease (EVD) were hospitalized in the United States and Europe. Frequent international teleconferences were convened among U.S. and European clinicians caring for EVD patients, often on a weekly basis, to share detailed information and suggestions on clinical management of these patients. We collected clinical, epidemiologic, laboratory, and virologic data on all of these patients and performed descriptive data analyses. We summarized our findings in this article.
Medical Research: What are the main findings?
Dr. Uyeki: Of the 27 patients with Ebola virus disease cared for in 15 hospitals in nine countries, the median age was 36 years; 19 (70%) were male; 9 of 26 (35%) had underlying medical conditions; and 22 (81%) were healthcare personnel, including 17 of 22 (77%) who had worked in an Ebola treatment unit in West Africa. Of the 27 patients, 20 (74%) were medically evacuated from West Africa, 4 (15%) were imported cases, and 3 (11%) were healthcare personnel who acquired Ebola virus infection while caring for EVD patients in the U.S. or Europe. At illness onset, the signs and symptoms of EVD were non-specific; the most common symptom reported was fatigue. At admission to a hospital in the U.S. or Europe, most patients had fever, weakness, and gastrointestinal symptoms. The median time from illness onset to hospitalization was four days.
During hospitalization, all patients had diarrhea, often profuse watery diarrhea; and most experienced electrolyte abnormalities such as hyponatremia, hypokalemia, hypocalcemia, and hypomagnesemia, as well as hypoalbuminemia. One third of patients experienced renal abnormalities such as oliguria or anuria, nearly 60% were clinically diagnosed with systemic inflammatory response syndrome, and one third were clinically diagnosed with encephalopathy or encephalitis. Although minor bleeding abnormalities were reported in some patients, only two patients had any gross hemorrhage. Leukopenia was observed during the first week of illness, with increases in white blood cell count during the second week. Thrombocytopenia was common, and aminotransferase levels peaked in the second week of illness. Creatine kinase and lactate levels were elevated in most of the patients who were tested. Ebola virus levels in blood peaked on the seventh day of illness, and critical illness occurred at the end of the first week and during the second week after illness onset. All patients received intravenous fluids; most were treated empirically with antibiotics; and 85% received an investigational therapy, including 70% who received at least two experimental therapies. Eleven (41%) patients were critically ill, including seven who required invasive mechanical ventilation and five who received continuous renal replacement therapy. Five (18.5%) patients died (81.5% survival).
Dr. David Grossman[/caption]
Dr. David Grossman MD MPH
Vice chair of the U.S. Preventive Services Task Force
Professor at the University of Washington Schools of Public Health and Medicine
Medical Research: What is the background for this study? What are the main findings?
Dr. Grossman: The Task Force cares deeply about the challenges that children affected by autism and their families face in getting the care and support they need. This was the first time that we assessed the evidence around screening young children for autism, and our recommendation was informed by a review of the most up-to-date science, which included randomized trials, observational studies, and research from a number of Federal health agencies. We concluded that the current evidence is insufficient to assess the balance of benefits and harms of screening for autism spectrum disorder in children for whom no concerns of autism have been raised by their parents or a clinician. This is an I statement, which is not a recommendation against screening, but a call for more research on screening and treatment in young children who don’t have obvious symptoms. It is important to note that this recommendation will not affect insurance coverage for autism screening, which is currently covered under the Affordable Care Act as a result of the American Academy of Pediatrics’ Bright Futures Guidelines.
Dr. Mark A Green PhD
Dr. William A Gray[/caption]
Dr. William A Gray, MD
Chief of the Division of Cardiovascular Disease
Main Line Health
President of Main Line Health’s Lankenau Heart Institute
Medical Research: What is the background for this study? What are the main findings?
Dr. Gray: The basis for this study was two-fold: the ACST-1 trial had shown, in asymptomatic patients with severe carotid disease, that immediate Carotid Endarterectomy reduced subsequent stroke as compared to deferred Carotid Endarterectomy---so the next logical question was, could Carotid Artery Stenting (CAS) compare as an equal alternative to Carotid Endarterectomy (CEA) in this same, standard risk, population with severe carotid stenosis.
The CREST trial, as originally constructed and at the time ACT 1 was conceived did not include this population (although it later expanded to encompass asymptomatic patients as well), so it was an open question. The second reason had to do with Abbott Vascular, the study sponsor, achieving FDA regulatory approval for their stent system in this population---as well as in the symptomatic population being studied n CREST (which they were also the device sponsor).
The main findings were that the primary endpoint of death/stroke and MI at 30 days plus ipsilateral stroke out to 1 and 5 years was not different between CAS and CEA in asymptomatic patients with severe carotid stenosis on good medical secondary prevention therapy.
Dr. Art Sedrakyan[/caption]
Dr. Art Sedrakyan MD PhD ScD
Professor of Healthcare Policy and Research in Cardiothoracic Surgery
Department of Public Health
Weill Cornell Medical College
Medical Research: What is the background for this study? What are the main findings?
Dr. Sedrakyan: In the most recent years available to us for research(2011-2013) one in four women underwent repeat surgery within 90 days after breast conserving approach to cancer removal. Patients operated by higher volume physicians had lower chance of undergoing repeat surgery.Uniform guidelines and increased surgical training are needed to standardize the breast conserving surgery to reduce the high rate of repeat surgery.
Dr. Jeffrey Cohen[/caption]
Dr Jeffrey A Cohen MD
Mellen Center, Neurological Institute
Cleveland Clinic, Cleveland
OH 44195, USA
Medical Research: What is the background for this study? What are the main findings?
Dr. Cohen: Fingolimod, a non-selective sphingosine 1-phosphate receptor (S1PR) modulator, was the first oral medication approved to treat relapsing multiple sclerosis. Though generally well tolerated, fingolimod’s first dose cardiac effects and other potential adverse effects complicate its use. Ozanimod is a selective S1PR modulator with several other potentially advantageous pharmacologic properties.
The results of phase 2 RADIANCE trial were recently published. In this trial, participants were randomized to placebo (n=88), ozanimod 0.5 mg (n=87), or ozanimod 1 mg (n=83) PO once daily for 24 weeks. The mean cumulative number of gadolinium-enhancing lesions on monthly MRI scans at weeks 12-24, the primary endpoint, was reduced from 11.1 +/- 29.9 with placebo to 1.5 +/- 3.7 with ozanimod 0.5 mg and 1.5 +/- 3.4 with ozanimod 1 mg (both p<0.0001). Other MRI endpoints supported the primary endpoint. Ozanimod was well tolerated with good safety. Importantly, the dose up-titration protocol effectively mitigated first dose cardiac effects.
Dr. Phillip Peters[/caption]
Philip J. Peters, M.D.
HIV Testing and Biomedical Interventions Activity Lead
Epidemiology Branch
CDC’s Division of HIV/AIDS Prevention
Medical Research: What is the background for this study? What are the main findings?
Dr. Peters: Acute HIV infection contributes disproportionately to HIV transmission and identifying individuals with acute HIV infection is critical to prevent further HIV transmission, as diagnosis can lead to several effective HIV prevention interventions. Acute HIV infection can be diagnosed with assays that detect either HIV RNA (the reference standard) or the p24 antigen (an HIV core protein), which are both detectable early after HIV infection and before an antibody response develops. HIV immunoassays that detect both the p24 antigen and anti-HIV antibody (fourth generation antigen/antibody [Ag/Ab] combination immunoassays) are currently being implemented as the initial screening test in the 2014 CDC and American Public Health Laboratories (APHL) recommended HIV diagnostic algorithm. In a prospective study we evaluated the performance of an HIV Ag/Ab combination assay to detect acute HIV infection compared with pooled HIV RNA testing in a high-prevalence population.
All participants were first screened with a rapid HIV test to detect established HIV infection (antibody detectable). All participants with a negative rapid HIV test result were then screened for acute HIV infection with an HIV Ag/Ab combination assay (index test) and pooled HIV-1 RNA testing. HIV RNA testing was the reference standard, with positive reference standard result defined as detectable HIV-1 RNA on an individual RNA test.
Among 86,836 participants with complete test results (median age, 29 years; 75.0% male; 51.8% men who have sex with men), acute HIV infection was diagnosed in 168 (0.19%). Acute HIV infection was detected in 134 (0.15%) participants with HIV Ag/Ab combination testing (acute HIV infection sensitivity, 79.8%) and in 164 (0.19%) with pooled HIV RNA testing (sensitivity, 97.6%; sensitivity comparison, p<0.001). Overall HIV Ag/Ab combination testing detected 82% of acute HIV infections detectable by pooled HIV RNA testing. Compared with rapid HIV testing alone (which detected established HIV infection), HIV Ag/Ab combination testing increased the relative HIV diagnostic yield (both established and acute HIV infections) by 10.4% and pooled HIV RNA testing increased the relative HIV diagnostic yield by 12.4%.
Dr. Marion Sills[/caption]
Marion R. Sills, MD, MPH
Associate Professor, Departments of Pediatrics and Emergency Medicine
University of Colorado School of Medicine
Medical Research: What is the background for this study?
Dr. Sills: My co-authors and I know that studies show that patients who are poorer or are minorities are readmitted at higher rates than other patients, and that readmissions penalties, which are far more commonly applied in relation to readmissions of adult patients, have been shown to punish hospitals for the type of patients that they serve, rather than purely for the quality of care they provide. Currently, these penalties impact hospitals treating Medicare patients in all 50 states but only impact readmissions of children in 4 states, although other states are considering implementing these penalties. This was our rationale for exploring the impact of patients’ social determinants of health (factors like race, ethnicity, health insurance and income) on how likely it was that a hospital would be penalized for readmissions under a typical state-level pay-for-performance measure based on hospital readmissions. Readmissions penalties are designed to penalize hospitals that provide lower quality care. However, without adjusting for social determinants of health factors, these pay-for-performance measures may unfairly penalize hospitals based on the type of patient they treat as well as the quality of care they provide.
Medical Research: What are the main findings?
Dr. Sills: We found that risk adjustment for social determinants of health factors changed hospitals’ penalty status on a readmissions-based pay-for-performance measure. Without adjusting the pay-for-performance measures for social determinants of health, hospitals may receive penalties partially related to patient factors beyond the quality of hospital care.
Guo-Ping Shi, ScD and Dr. Cong-Lin Liu
Dr. Michael Privitera[/caption]
Dr. Michael Privitera MD
Professor of the Department of Neurology and director of the Epilepsy Center
University of Cincinnati Neuroscience Institute
Medical Research: What is the background for this study? What are the main findings?
Dr. Privitera: Generic substitution of medications has saved the American health care system billions of dollars per year. However, based on a series of uncontrolled studies, patients and clinicians share concerns that generic substitution of antiepileptic drugs may lead to loss of efficacy or emergence of adverse effects. To answer this question we undertook a prospective, randomized study that tested bioequivalence of two generic products of the antiepileptic drug lamotrigine. Lamotrigine was identified in several publications as a possible source of problems after generic switches. FDA studies test a single generic versus the brand name product in a single dose study in normal volunteers. We designed a study that would be most likely to show a difference between generics if one existed. We compared the two generic lamotrigine products showing the most difference in prior testing in patients with epilepsy taking the drug daily using rigorous pharmacokinetic methods. Each patient took each of the two generics for 2 four week periods. Our study showed the two generics were essentially indistinguishable and easily met bioequivalence standards. No patient had loss of seizure control or unexpected adverse effects.
Dr. Michael Yudell[/caption]
Michael Yudell, PhD, MPH
Chair & Associate Professor
Drexel University School of Public Health
Community Health and Prevention
Philadelphia, PA 19104
Medical Research: What is the background for this study?
Dr. Yudell: We came together as a group of scholars from the natural sciences, social sciences, and humanities to address what we believe is a long-standing challenge: how to improve the study of human genetic diversity without recapitulating the controversial and problematic concept of race. We believe that the cross-disciplinary focus of our work—an examination of the historical, biological, and sociological aspects of the race concept—can shed new light on the long-standing debate about the use of the race concept in genetics research. We believe modern genetics remains stuck in a paradox: that on the one hand race is a tool to elucidate human genetic diversity, and on the other hand race is believedthree main concerns to be a poorly defined marker of that diversity and an imprecise proxy for the relationship between ancestry and genetics. This paradox is rooted in the nature of the field: it dates back to the evolutionary geneticist Theodosius Dozhansky, who in the 1930s redefined race in his work on what was known as biology’s evolutionary synthesis (the synthesis of population genetics with Darwinian thought). For much of his career, Dobzhansky believed race to be a useful tool to elucidate human genetic diversity. But by the end of his career he became worried that the study of human diversity had “floundered in confusion and misunderstanding” and was concerned over the nonscientific misuse of the term. He, like we and many others in genetics, anthropology, and the social sciences, have called on the field to devise better methods to improve the study of human genetic diversity.
Can the race concept in genetics elucidate the relationship between humans and their evolutionary history, between humans and their health? In the wake of the human genome project the answer seemed to be a pretty resounding “no.” In 2004, for example, Francis Collins, then head of the National Human Genome Research Institute and now Director of the National Institutes of Health called race a “flawed” and “weak” concept and argued that science needed to move beyond race. Yet, as our paper highlights, the use of race persist in genetics, despite voices like Collins, like Craig Venter—leaders in the field of genomics-who have called on the field to move beyond it. They, of course, were not the first to do, but we hope they are among the last. We believe it is time to revisit this century-long debate and bring biologists, social scientists, and scholars from the humanities together in a to find better ways to study the ever-important subject of human diversity.
Dr. Tamar Kleinberger[/caption]
Tamar Kleinberger, Ph.D.
Dept. of Molecular Microbiology
Faculty of Medicine
Technion – Israel Institute of Technology
Haifa ISRAEL
Medical Research: What is the background for this study? What are the main findings?
Dr. Kleinberger: The cellular DNA damage response (DDR) is a conglomerate of pathways designed to detect DNA damage and signal its presence to cell cycle checkpoints and to the repair machinery, allowing the cell to pause and mend the damage, or if the damage is too severe, to trigger cell death or senescence. Replication intermediates and linear double-stranded genomes of DNA viruses are recognized by the cell as DNA damage and activate the DDR. If allowed to operate, the DDR will stimulate ligation of viral genomes and will inhibit virus replication. To prevent this outcome, many DNA viruses evolved ways to limit the DDR. For example, adenoviruses, a family of viruses that cause respiratory illnesses or gastrointestinal disease or eye infections, have been reported to inhibit the DDR by degrading DNA damage sensor proteins or by removing them from virus replication centers. Our present work reveals that adenovirus evolved an additional mechanism to inhibit the DDR, using its E4orf4 protein. The viral E4orf4 protein, together with its cellular partner, the PP2A phosphatase, inhibits damage signaling by reducing phosphorylation of proteins belonging to different DDR branches. As a result E4orf4 causes accumulation of DNA damage in the cells. Inhibition of the DDR regulators ATM and ATR as well as expression of E4orf4 enhance infection efficiency.
We found that, at least in the cells we studied, ATM inhibition was important to the early stage of the virus life cycle, whereas ATR inhibition impacted mostly late protein expression and progeny virus production. Furthermore, we previously reported that E4orf4 induces cancer-specific cell death when expressed alone, and in the present report we found that E4orf4 sensitized cells to killing by sub-lethal concentrations of DNA damaging drugs, likely because it inhibited DNA damage repair. These findings provide one explanation for the cancer-specificity of E4orf4-induced cell death because many cancers have DDR deficiencies leading to increased reliance on the remaining intact DDR pathways and to enhanced susceptibility to DDR inhibitors such as E4orf4. Thus DDR inhibition by E4orf4 contributes both to the efficiency of adenovirus replication and to the ability of E4orf4 to kill cancer cells.
Dr. Rodés-Cabau[/caption]
Josep Rodés-Cabau, MD
Director, Catheterization and Interventional Laboratories
Quebec Heart and Lung Institute
Professor, Faculty of Medicine, Laval University
Quebec City, Quebec, Canada
Medical Research: What is the background for this study? What are the main findings?
Response: Several concerns have recently emerged regarding valve thrombosis post-TAVR. It has been also proposed that rapid changes in transvalvular gradients may be the hallmark of valve thrombosis despite of the absence of clinical symptoms. However, no data exist on the incidence of and factors associated with valve hemodynamic deterioration (VHD) following TAVR.
We included 1,521 patients who underwent TAVR in 10 centers worldwide. VHD was defined as an absolute change in mean transvalvular gradient during follow-up ≥10 mm Hg compared with discharge assessment. Incidence of valve hemodynamic deterioration was 4.5% during a mean echocardiographic FU of 20 months (2.8% within the first year). We found that the lack of anticoagulation therapy, a valve-in-valve procedure (TAVR in a surgical valve), a greater BMI, and the use of a 23mm transcatheter valve were the factors associated with higher rates of VHD post-TAVR. Also, the absence of anticoagulant therapy remained as an independent predictor of VHD in a sub-analysis excluding patients with small valves, valve-in-valve procedure, and aortic regurgitation at discharge ≥moderate. We think these results suggest a thrombotic mechanism as one of the factors underlying VHD.
Dr. Roxanne Pelletier[/caption]
Roxanne Pelletier, PhD
Divisions of General Internal Medicine and of Clinical Epidemiology
Department of Medicine
The Research Institute of the McGill University Health Centre
Montreal, Quebec, Canada
Medical Research: What is the background for this study?
Dr. Pelletier: The increased risk of mortality in young females compared with males after acute coronary syndrome (ACS) remain difficult to understand. As gender-related characteristics has evolved considerably in the last decades (e.g. hours of paid work have increased significantly among women), we hypothesized that these sex differences in adverse outcomes following acute coronary syndrome are partly explained by gender, rather than by biological sex itself.
As explained in our paper, "Gender reflects social norms and expectations ascribed to women and men, in contrast to biological characteristics that are captured by sex. Gender can be referred to as the nonbiological aspects of being male or female (e.g., social roles, personality traits).Our team had previously shown that sex differences in access to care for ACS were partly explained by these gender-related characteristics, such that both men and women presenting with acute coronary syndrome and with personality traits and social roles traditionally ascribed to women (e.g. sensitive to the needs of others, shy, household responsibility, child care) were waiting longer before diagnostic tests and were less likely to receive invasive treatment procedures such as percutaneous coronary intervention, when compared to men and women with masculine gender-related characteristics. We then aimed to assess whether gender was also playing a role in sex differences in adverse outcomes following acute coronary syndrome.
Dr. Daniel Kim-Shapiro[/caption]
Daniel Kim-Shapiro, PhD
Professor and Associate Chair of Physics
Harbert Family Distinguished Chair
Director, Translational Science Center
Wake Forest University
Medical Research: What is the background for this study? What are the main findings?
Dr. Kim-Shapiro: Heart failure with preserved ejection fraction (HDPEF) is the most common form of heart failure. It is characterized by poor perfusion to active muscles which results in poor exercise capacity and a poor quality of life. Currently, the only effective treatment for this condition is aerobic exercise.
Several studies have shown that dietary nitrate, usually in the form of beet root juice, increases nitric oxide bioavaiability in a way that targets areas of low oxygen so that perfusion increases where it is needed. This action relies on conversion of nitrate to nitrite by oral bacteria with subsequent conversion of nitrite to nitric oxide. Nitrite from the blood is taken up by salivary glands so that dosing with dietary nitrate can be long-lasting.
The main finding of this study was that daily intake of high nitrate containing beet root juice improved exercise endurance in patients with HFPEF.
Dr. Chiara Ambrogio[/caption]
Chiara Ambrogio, PhD
Experimental Oncology Group
CNIO-Centro Nacional de Investigaciones Oncológicas
(Spanish National Cancer Research Centre)
Melchor Fernández Almagro nº3
Madrid Spain
Medical Research: What is the background for this study?
Dr. Ambrogio: The majority of preclinical studies aimed at discovering new therapeutic strategies for lung adenocarcinoma have been conducted so far in full-blown tumors. We wanted to try a new approach by studying early lung lesions in a KRasG12V mouse model in order to bypass the problems imposed by tumor heterogeneity in later stages of the disease. We reasoned that the analysis of the first steps of lung adenocarcinoma development would help us in identifying valuable targets for therapeutic intervention.
Medical Research: What are the main findings?
Dr. Ambrogio:
1) We performed gene expression analysis of KRasG12V-driven mouse lung hyperplasias (≤ 500 cells) and we compared it to the gene expression profile of full-blown lung adenocarcinoma. We found that the aggressive nature of this tumor type is determined earlier than what predicted by histopathological criteria.
2) The analysis of transcriptional changes in early lesions allowed us to identify DDR1 as a drugable target in KRasG12V-driven lung adenocarcinoma. We validated its potential as a therapeutic target both genetically and pharmacologically by means of a selective DDR1 inhibitor. We demonstrated that the co-inhibition of DDR1 and NOTCH pathway, a key player in DDR1-mediated survival, exerted additive therapeutic effect.
3) We confirmed these results in human lung adenocarcinoma by reporting, for the first time, the development of an orthotopic Patient-Derived Xenograft (PDX) model as the ideal platform for the preclinical evaluation of new therapeutic strategies.
Dr. Claudia Satizabal[/caption]
Claudia L. Satizabal, PhD
Instructor in Neurology
Boston University School of Medicine
The Framingham Heart Study
Boston, MA 02118-2526
MedicalResearch: What is the background for this study? What are the main findings?
Dr. Satizabal: Our societies are expected to face an increasing burden of dementia in the next decades due to increasing life expectancies and the aging of a big proportion of the population, the so called “baby boomers”. However, some studies conducted in high-income countries have suggested a decline in the total number of cases (prevalence) as well as new cases (incidence) of dementia at any given age. Yet the findings of these studies were not seen as definitive, either because results were of borderline significance or because they were based on survey data, and stronger evidence was lacking.
We used information collected since 1975 in the Framingham Heart Study to estimate the trends in dementia incidence. One of the strengths of this study is that investigators have been careful to use the same diagnostic criteria for over the past 30 decades, which allows us to provide more robust evidence of dementia trends over time.
We found that there has been a progressive decline in the incidence of dementia at any given age over the past 30 decades. Compared to the late 1970s, we observed a decline of 22% in the late 1980s, 38% in the 1990s and 44% in the 2000s. This beneficial trend was only seen among persons with at least a high school diploma. We also explored trends in vascular risk factors such as blood pressure, smoking, diabetes, and others; however, these trends did not completely explain the decline in dementia incidence. One interesting finding was that the risk of dementia associated with cardiovascular diseases, such as stroke or atrial fibrillation, decreased dramatically over the course of time from the late 1970s to the 2000s.
Dr. Joan Teno[/caption]
Joan M Teno, MD, MS
Professor of Medicine
Division of Gerontology and Geriatrics
Cambia Palliative Care Center of Excellence
University of Washington
Medical Research: What is the background for this study? What are the main findings?
Dr. Teno: Hospices in the US are paid a daily rate, regardless of the service delivered. Key to hospice patients dying comfortably is that the caregiver and dying person received the needed visits by hospice professional staff, such as a nurse or social worker. These staff are trained to assess the patient and make appropriate changes to care plan to ensure the comfort and safety of the hospice patient. Multiple studies attest to the finding that pain and other symptoms exacerbate in the last days of life - key is the primary caregiver, usually a close family member receives the need training in administering of medicine to ensure the dying person is comfortable in the last hours of life.
We studied visits pattern by professional staff in the last 2 days of life finding that one in eight hospice patients were not visited.
While we would not expect every patient to have visits, there was several key finding that raised concern.
Dr. Teppo Järvinen[/caption]
Teppo L N Järvinen MD PhD
Sports Medicine, Orthopedic Surgery, Clinical Trials
University of Helsinki, Helsinki
MedicalResearch: What is the background for this study? What are the main findings?
Dr. Järvinen: When the primary analysis of the FIDELITY trial was published in the New England Journal of Medicine (http://www.nejm.org/doi/full/10.1056/NEJMoa1305189), showing that arthroscopic partial meniscectomy (APM) is no better than sham/placebo surgery in relieving knee pain and improving knee function in patients with a degenerative meniscus tear and no knee OA, the study was met with unprecedented criticism, even hostility. The advocates of APM (which was at the time and probably still is the most common orthopedic procedure in the US and most other “western” countries) argued – despite the fact that our study only confirmed what several other high-quality RCTs had suggested – that arthroscopic partial meniscectomy is a highly beneficial procedure in the “right” patients. Among the subgroups of patients allegedly having a favourable response to APM, those experiencing “mechanical symptoms” — sensations of knee catching or locking — represented the most obvious group who would benefit from arthroscopic partial meniscectomy surgery. This assertion is plausible because knee catching or locking is believed to result from a mechanical blocking mechanism in the knee - a piece of the joint structure lodging between the articular surfaces. Because degenerative meniscal tears are very common pathologic alterations found by arthroscopy in the knee joints of patients with degenerative knee disease, trimming the torn meniscus should, in theory at least, improve the apparent mechanical derangement.
Against this background, it is somewhat unusual that no study has yet specifically tested whether arthroscopic partial meniscectomy is effective in alleviating these symptoms. Mechanical symptoms are usually thought to be a solid indication for arthroscopic knee surgery. This is what we set out to examine in our secondary analysis of our sham-surgery controlled FIDELITY trial.
Dr. Scott Kim[/caption]
Scott Y. H. Kim, MD, PhD
Department of Bioethics, National Institutes of Health
Bethesda, MD 20892
Medical Research: What is the background for this study?
Dr. Kim: Euthanasia and/or physician assisted suicide (EAS) of persons suffering from psychiatric disorders is increasingly practiced in some jurisdictions such as Belgium and the Netherlands but very little is known about the practice. There is an active debate over whether to legalize such a practice in Canada, after a Supreme Court ruling last year that struck down laws banning physician assisted death.
Medical Research: What are the main findings?
Dr. Kim: The main findings are that:
Dr. Andrew Fenelon[/caption]
Dr. Andrew Fenelon PhD
NIH Postdoctoral Fellow
Brown University
Medical Research: What is the background for this study? What are the main findings?
Dr. Fenelon: The life expectancy of the US population is about 2 years less than that of other high-income nations, which is an important problem in public health. Although much previous work looks at differences in death rates among older adults, some recent work has shown that deaths at younger ages (below age 50) account for a significant fraction of the life expectancy gap. Our study examines the contribution of major injuries, Motor Vehicle Crashes, Firearm-related deaths, and drug poisonings, which often occur at younger ages and account for many years of lost life.
Our findings indicate that US men and women experience significantly higher death rates from these three causes of injury death than each of the 12 comparison high-income countries. Overall, these three causes of death explained 48% of the 2.2 year life expectancy gap between the United States and other high-income countries among men, with firearm injuries alone explaining 21%. Among women, these causes explained 19%.
Dr. Lance Davidson[/caption]
Lance Davidson, PhD
Assistant Professor
Department of Exercise Sciences
Brigham Young University
Provo, UT 84602
Medical Research: What is the background for this study? What are the main findings?
Dr. Davidson: A growing body of literature indicates that bariatric surgery imparts a mortality benefit in severely obese individuals. Whether age at surgery affects this relationship is not well established. One might suppose that a person who has been severely obese for several decades may already have sustained enough metabolic damage that weight loss surgery would have less influence on subsequent mortality. We conducted an age-specific analysis of a previously-published mortality cohort in gastric bypass patients and severely obese controls, following them for up to 18 years (mean 7.2 years), and examined mortality rates in four age categories: under 35, 35-44, 45-54, and 55-74.
The primary finding of this retrospective cohort study was that gastric bypass surgery attenuated the age-related increase in mortality, demonstrating a widening gap in mortality risk when compared to age-matched severely obese controls as age-at-surgery increased, with a 66% reduction in mortality in the oldest group. Another interesting result, highlighted in our previous publication on this cohort (Adams et al. NEJM 2007), was a higher mortality rate from external causes (accidents, poisonings, suicides, homicides) in surgery patients. We explored this phenomenon further by age at surgery and found that externally-caused deaths were only increased in women (not men) who had surgery before age 35.
Dr. Russ Callaghan[/caption]
[wysija_form id="5"]Dr. Russ Callaghan, PhD
Associate Professor
Northern Medical Program
University of Northern British Columbia
Prince George, British Columbia
Medical Research: What is the background for this study?
Dr. Callaghan: In Canada, the minimum legal drinking age (MLDA) is 18 years in Alberta, Manitoba and Québec, and 19 in the rest of the country. Given that public-health organizations not only have recommended increasing the MLDA to 19 years, but also have identified 21 years as ideal, the current study tested whether drivers slightly older than the MLDA had significant and abrupt increases in alcohol-impaired driving (AID) crimes, compared with their counterparts just younger than the MLDA. Data on the effectiveness of Canadian drinking-age laws is lacking, and the current study provides important information for the current national and international MLDA debates.