Author Interviews, Case Western, Genetic Research / 05.01.2015

Michael A. Weiss, MD, PhD The Cowan-Blum Professor and Chairman of the Department of Biochemistry Distinguished Research Professor andMedicalResearch.com Interview with: Michael A. Weiss, MD, PhD The Cowan-Blum Professor and Chairman of the Department of Biochemistry Distinguished Research Professor and Professor of Medicine in the Endocrine Division at the Case Western Reserve School of Medicine in Cleveland, Ohio. Joseph Racca Researcher and graduate student Department of BiochemistryJoseph Racca Researcher and graduate student Department of Biochemistry Case Western Reserve School of Medicine in Cleveland, Ohio. Medical Research: What is the background for this study? What are the main findings? Response: The function of the gene responsible for male differentiation, sex-determining region of the Y chromosome (SRY), was first demonstrated in transgenic mouse models by P. Koopman, R. Lovell-Badge and colleagues in the early 1990s. These findings were corroborated by identification of mutations in human SRY that are associated with human sex reversal: XY, 46 gonadal dysgenesis leading to somatic sex reversal (Swyer’s Syndrome). Such mutations may occur spontaneously in spermatogenesis or be inherited. The characterization of the molecular defects associated with these mutations has unmasked novel biological and biochemical activities of SRY. More broadly, such studies have also increased our understanding of an entire family of related transcription factors (Sry-box related; SOX), which broadly function in metazoan development (from worms, fish and flies to mammals). Within human SRY, the majority of clinical mutations occur in the region of the protein responsible for specific DNA binding and DNA bending, the primary molecular actions of SRY at target genes. Our study bridges structure (i.e., protein folding and stability) and function (i.e., transcriptional activation of target genes and related cell-biological processes such as trafficking and proteosomal degradation). In our current study, we highlighted the importance of a structural scaffold in human SRY, specifically a key single amino acid that buttresses the unique L-shape structure of this domain. The mutation of interest represents a “perfect storm” leading to deleterious effects on multiple activities, including specific DNA binding, cellular localization, and both protein and cellular stability (lifetime), among other properties, together leading to sex reversal and cancer (gonadoblastoma) in the proband patient. Our integrated multi-disciplinary approach allowed us to characterize these various facets of SRY in the context of its biological site of action: the pre-Sertoli cell in an embryonic gonadal ridge just prior to its morphological differentiation into a testis. We are grateful to Prof. Patricia K. Donahoe (Harvard Medical School and the Massachusetts General Hospital), who generously provided this micro-dissected pre-Sertoli cell line. (more…)
Author Interviews, Depression, Heart Disease / 05.01.2015

Nancy L. Sin, Ph.D. Postdoctoral Fellow Center for Healthy Aging & Department of Biobehavioral Health The Pennsylvania State University University Park, PA 16802MedicalResearch.com Interview with: Nancy L. Sin, Ph.D. Postdoctoral Fellow Center for Healthy Aging & Department of Biobehavioral Health The Pennsylvania State University University Park, PA 16802 Medical Research: What is the background for this study? What are the main findings? Dr. Sin: Older patients with coronary heart disease often experience declines in functional status, which is the ability to perform daily activities such as bathing, walking, and doing housework. The key factors that contribute to functional status among cardiac patients are not well-understood. Previous studies have found only weak or no associations between cardiovascular disease severity and functional status. Psychological factors—such as depression—are known to increase the risk of functional impairment, but this has not been studied long-term in patients with coronary heart disease. It is unclear the extent to which long-term functional status is determined by psychological factors versus cardiovascular disease severity. The purpose of our study was to compare the contributions of depressive symptoms with those of cardiovascular disease severity (specifically, left ventricular ejection fraction, exercise capacity, and angina frequency) for predicting subsequent functional decline in 960 older adults with stable coronary heart disease. Across a 5-year period, people who had more severe depressive symptoms were at greater risk of functional decline, independent of cardiovascular disease severity, demographics, health behaviors, cognitive function, and other factors.  Low exercise capacity was also strongly related to future functional decline, but ejection fraction and angina frequency were not. These findings underscore the importance of considering both mental and physical health in determining long-term functional status. (more…)
Author Interviews, Lung Cancer, Medical Imaging / 05.01.2015

Joao R. Inacio, MD Cardiothoracic Radiologist Director Visiting Professor Program Assistant Professor of Radiology, University of Ottawa Medical Imaging, The Ottawa Hospital Ottawa, ONMedicalResearch.com Interview with: Joao R. Inacio, MD Cardiothoracic Radiologist Director Visiting Professor Program Assistant Professor of Radiology, University of Ottawa Medical Imaging, The Ottawa Hospital Ottawa, ON Medical Research: What is the background for this study? What are the main findings? Dr. Inacio: Lung cancer is the most common and most lethal cancer worldwide. Its prognosis remains poor with a 5-year survival rate of 6–18%. Adenocarcinoma has surpassed squamous cell carcinoma as the leading histologic type. The presence of metastases carries the worst prognosis in lung cancer and is the most important in determining staging and management. Hematogenous spread (i.e., carried by blood) is the most common mechanism of intrapulmonary metastasis. Cumulative evidence suggests that intrapulmonary aerogenous spread may exist and is under recognized. Deriving from our clinical experience, we performed a literature review that supports the hypothesis that lung cancer, particularly adenocarcinoma, may spread through the airways. With aerogenous metastases, it has been postulated that cancer cells growing along the alveolar septa at the primary site detach from the basal membrane, spread through the airways and re-attach and grow along alveolar septa away from the primary focus. Radiology-pathology correlation studies, using Chest Computed Tomography (CT), have documented the radiological evolution from focal adenocarcinoma to multifocal airspace disease and demonstrated cytologic and histologic findings supportive of aerogenous spread. (more…)
Antibiotic Resistance, Author Interviews, Infections, Science / 04.01.2015

Melanie Blokesch PhD Assistant Professor (tenure-track) Laboratory of Molecular Microbiology Global Health Institute, School of Life Sciences Swiss Federal Institute of Technology Lausanne (EPFL) Lausanne SwitzerlandMedicalResearch.com Interview with: Melanie Blokesch PhD Assistant Professor (tenure-track) Laboratory of Molecular Microbiology Global Health Institute, School of Life Sciences Swiss Federal Institute of Technology Lausanne (EPFL) Lausanne Switzerland Medical Research: What is the background for this study? What are the main findings? Dr. Blokesch: We have been studying the cholera-causing bacterium Vibrio cholerae for many years in my laboratory. Our main focus has always been on elucidating how this pathogen acquires new genetic material that allows it to evolve. This is often accomplished through a mechanism known as horizontal gene transfer (HGT). There are three main modes of horizontal gene transfer in bacteria and the one we are primarily interested in is called natural competence for transformation. When the bacterium enters the state of natural competence it can take up free genetic material from its surrounding and in case it recombines this new material into its own genome the bacterium is considered to be naturally transformed. Notably, natural competence/transformation was first described in 1928 by Fred Griffith, who showed that transformation can render harmless bacteria pathogenic. These early experiments can be considered a milestone in molecular biology as it later led to the discovery of DNA as the carrier of genetic information. Medical Research: What are the main findings? Dr. Blokesch: The main finding of our study is that the pathogen V. cholerae does not solely rely on free DNA floating around but that it actively kills neighbouring bacteria followed by the uptake of their DNA. Indeed, we were able to show that the two processes - killing of other bacteria and DNA uptake - are co-regulated by the same proteins within the bacterial cell. We also used imaging techniques to visualize the killing of other bacteria by V. cholerae, followed by the release of their genetic material, which the predator then pulled into its own cell. We further quantified these HGT events by following the transfer of an antibiotic resistance gene from the killed bacterium to the predatory V. cholerae cell. Notably, the spread of antibiotic resistances is a major health concern and HGT is a major driver of it. (more…)
Author Interviews, CHEST, Hospital Readmissions, Pulmonary Disease / 03.01.2015

Tina Shah, MD University of Chicago Medicine Department of Pulmonary and Critical Care University of ChicagoMedicalResearch.com Interview with: Tina Shah, MD University of Chicago Medicine Department of Pulmonary and Critical Care University of Chicago Medical Research: What is the background for this study? What are the main findings? Dr. Shah: The reason why we undertook this study is to better understand the Medicare COPD population that falls under the purview of the CMS Hospital Readmissions Reduction Program (HRRP). This program places up to a 3% penalty on all Medicare revenues for hospitals that take care of beneficiaries should a hospital exceed its “expected readmission rate.” Previously 30 day readmissions after index admissions for congestive heart failure, acute myocardial infarction and pneumonia fell subject to the HRRP. As of October 2014, COPD has been added to the list, despite minimal evidence to guide hospitals in how to curb COPD readmissions. The goal of this research was to provide an epidemiological background for this population and identify trends as a hypothesis generating first step to predict who is most likely to be readmitted and to identify targets for successful future interventions on this group. Our study population is unique in that we longitudinally look at about 1/2 of all Medicare admissions for COPD exacerbations, using the CMS guideline definition which is based on discharge ICD-9 codes. As described in previous literature, there is a large discrepancy between identification of COPD by provider versus coding algorithm, however since the Hospital Readmissions Reduction Program is based on discharge coding it is important to examine this particular group. (more…)
Author Interviews, Breast Cancer, Mayo Clinic, NEJM / 03.01.2015

MedicalResearch.com Interview with: Dr. Lynn C. Hartmann MD Professor of Oncology, Mayo Clinic Associate Director for Education of the Mayo Clinic Cancer Center. Medical Research: What is the background for this study? What are the main findings? Dr. Hartmann: Women with atypical hyperplasia of the breast – which is defined via breast biopsy that was done to evaluate findings on a mammogram or a palpable concern – have been considered a “high risk” group of women, but the extent of their risk has not been clearly defined. As a consequence, practice guidelines for high-risk women (eg for screening MRI) do not include them. Mayo Clinic has developed a cohort of women with atypical hyperplasia who have been followed long-term for later breast cancers and we show that their risk of developing breast cancer is about 30% at 25 years of follow-up. This same level of risk was confirmed in the other large cohort of women with atypical hyperplasia, based at Vanderbilt University (Nashville Breast Cohort). This level of risk meets the current criterion for screening MRI and should also encourage the use of anti-estrogen drugs, such as tamoxifen, which have already been shown to be efficacious in this population of women. Medical Research: What should clinicians and patients take away from your report? Dr. Hartmann: There are about 100,000 US women each year diagnosed with atypical hyperplasia via breast biopsy. Although strictly speaking, atypical hyperplasia is a benign finding, it is associated with a sizable risk of a later breast cancer. Physicians from numerous disciplines care for women with high-risk benign breast issues, including gynecologists, family physicians, internists, surgeons and oncologists. These practitioners, and the patients themselves, need information about the absolute risk of breast cancer occurring over time after a diagnosis of atypical hyperplasia. This information is provided in the NEJM report. Also, current guidelines should be updated to include this high-risk population and specifics about their absolute risk, and that the risk level qualifies these patients for screening MRI. Moreover, from the standpoint of risk reduction, four previously conducted breast cancer prevention trials included women with atypical hyperplasia. These trials used hormonal therapies (anti-estrogens) and showed that, in women with atypical hyperplasia, the use of such medications could lower the risk of a later breast cancer by 50% or more. Yet, other research has shown that women are quite reluctant to take such medications, primarily because of fear of side effects. In the NEJM report, we detail specific numbers of side effects that actually occurred in women who used these anti-estrogens (as opposed to the number of side effects seen in women taking placebo) and show that most of the side effects occurred quite uncommonly. Thus, we hope that the combination of information provided in this report on (i) actual risks of breast cancer and (ii) actual risks of side effects will help patients and practitioners make informed decisions on the best treatment approaches for women with atypical hyperplasia. Medical Research: What recommendations do you have for future research as a result of this study? Dr. Hartmann: First, women with atypical hyperplasia should be included in future prospective trials of novel imaging strategies (they were not included in trials of MRI, which had been limited to women with hereditary risk). Second, efforts should continue to predict which women with atypical hyperplasia are at highest risk, especially in the first 5-10 years after their biopsy, so they can be cared for optimally. Our research team, and others, continue to study the underlying molecular pathways that drive the progression from atypical hyperplasia to cancer; identifying such processes would not only aid in risk prediction but also identify driving pathways that could be blocked pharmaceutically. Citation: upcoming NEJM publication discussing: Women with Atypical Hyperplasia are at Higher Risk of Breast Cancer MedicalResearch.com Interview with: Dr. Lynn C. Hartmann MD Professor of Oncology, Mayo Clinic Associate Director for Education of the Mayo Clinic Cancer Center. Medical Research: What is the background for this study? What are the main findings? Dr. Hartmann: Women with atypical hyperplasia of the breast – which is defined via breast biopsy that was done to evaluate findings on a mammogram or a palpable concern  – have been considered a “high risk” group of women, but the extent of their risk has not been clearly defined.  As a consequence, practice guidelines for high-risk women (eg for screening MRI) do not include them.  Mayo Clinic has developed a cohort of women with atypical hyperplasia who have been followed long-term for later breast cancers and we show that their risk of developing breast cancer is about 30% at 25 years of follow-up.  This same level of risk was confirmed in the other large cohort of women with atypical hyperplasia, based at Vanderbilt University (Nashville Breast Cohort).  This level of risk meets the current criterion for screening MRI and should also encourage the use of anti-estrogen drugs, such as tamoxifen, which have already been shown to be efficacious in this population of women. (more…)
Author Interviews, Respiratory / 03.01.2015

Michael G. Rossmann PhD Hanley Professor of Biological Sciences Hockmeyer Hall of Structural Biology Purdue University, West Lafayette INMedicalResearch.com Interview with: Michael G. Rossmann PhD Hanley Professor of Biological Sciences Hockmeyer Hall of Structural Biology Purdue University, West Lafayette IN Medical Research: What is the background for this study? What are the main findings? Dr. Rossmann: My laboratory has long been interested in the structure of viruses and especially of Picornaviruses (e.g. EV-D68). We published the first 3D, near atomic resolution map of any animal virus in 1985. That was of Human Rhino (common cold) virus serotype 14. We then went on to show where and how the virus would bind to cellular receptors and also how certain small capsid binding compounds inhibited the viral infectivity. The latter was a collaboration first with the Sterling Winthrop company and later with ViroPharma. Thus our work on EV-D68 is a direct continuation of my interest in picornaviruses. (more…)
Aging, Author Interviews, Dermatology / 03.01.2015

David Granville, BSc, PhD, FAHA Professor, University of British Columbia Scholar of the Royal Society of Canada Director, GEM Facility, Centre for Heart Lung Innovation, St. Paul's Hospital Founder and CSO, viDA Therapeutics, Inc. Vancouver, BC, CanadaMedicalResearch.com Interview with: David Granville, BSc, PhD, FAHA Professor, University of British Columbia Scholar of the Royal Society of Canada Director, GEM Facility, Centre for Heart Lung Innovation, St. Paul's Hospital Founder and CSO, viDA Therapeutics, Inc. Vancouver, BC, Canada Medical Research: What is the background for this study? What are the main findings? Dr. Granville: My background is in cardiovascular research. In particular, how age affects blood vessels and how age affects mechanisms of blood vessel and heart injury and repair. We became interested in skin aging during a study in which we were studying the role of a protein degrading enzyme known as Granzyme B in atherosclerosis (hardening of the arteries) and aging. In these studies, we were using a genetic mouse model that is prone to accelerated aging, and knocked out Granzyme B. Although we were initially focused on the blood vessels, we also found that Granzyme B-deficient mice exhibited younger-looking skin. As we started to look into this, we became aware that UV light can induce the skin cells to produce Granzyme B. As sunlight is believed to be responsible for 80-90% of preventable skin aging, we generated a solar-simulated light box (with the similar ratios of UVA/UVB to sunlight) to assess whether Granzyme B played a role in UV-induced skin aging (aka photoaging). We exposed the mice to repetitive, low dose UV three times per week for 20 weeks. After 20 weeks we observed that Granzyme B deficient mice exhibited fewer wrinkles. We then wanted to look histologically and biochemically into how Granzyme B was affecting skin morphology. Granzyme B deficient mice exhibited greater collagen density compared to mice that possessed Granzyme B. As we looked into the mechanism in more detail, we determined that Granzyme B was cleaving a protein known as decorin. Decorin is responsible for collagen fibrillogenesis and assembling collagen into tight bundles. Loss of decorin is associated with a loss of collagen tensile strength. Interestingly, decorin also protects collagen from destruction by a protein-degrading enzyme known as MMP1. We showed in the study that by breaking down decorin, Granzyme B renders collagen susceptible to MMP1-mediated degradation. In addition, we showed that Granzyme B-fragmentation of another protein, fibronectin, led to the upregulation of MMP1 in skin fibroblasts. In summary, the paper showed that UV induced Granzyme B expression in the skin and showed that this enzyme contributes to the breakdown of extracellular matrix proteins and formation of wrinkles. A link to the Aging Cell publication: http://onlinelibrary.wiley.com/doi/10.1111/acel.12298/pdf (more…)
Author Interviews, Journal Clinical Oncology, Lung Cancer, Radiation Therapy, UT Southwestern / 03.01.2015

MedicalResearch.com Interview with: Dr. Puneeth Iyengar, MD, PhD. Assistant Professor Director of Clinical Research Dept of Radiation Oncology Co-leader, Thoracic Disease Oriented Team Harold Simmons Cancer Center UT Southwestern Medical Center  Dallas, TX Medical Research: What is the background for this study? What are the main findings? Response: Stage IV Non-small cell lung cancer (NSCLC) remains a disease of limited survival, in the range of one year for a majority of patients who historically have gone on to receive systemic therapy only. Disease in this patient population most often recurs in the sites of original gross disease. With greater understanding of the biology and patterns of failure that occur in stage IV NSCLC, it is becomingly increasingly obvious that there are subsets of patients, those with limited sites of metastatic disease, who may benefit with more aggressive local therapy in addition to systemic agents to effectuate longer progression free survival (PFS) and potentially overall survival (OS). Since failures of treatment occur most commonly in original gross deposits, local non-invasive therapy in the form of stereotactic body radiation therapy (SBRT) may offer a means to curtail the recurrences, perhaps as a way to shift the time to and patterns of failure. To address these concepts, a multi institutional single arm phase II study was conducted at UT Southwestern Medical Center in Dallas and University of Colorado Medical Center. Twenty-four patients with limited metastatic NSCLC (fewer than or equal to six sites of disease including the primary) who had progressed through at least one systemic therapy regimen were treated with SBRT to all sites of gross disease and the EGFR inhibitor erlotinib with progression free survival the primary end point. The results of the study were very significant, with a PFS in this study cohort of 14.7 months, compared to historical ranges of 2-4 months, and an OS of 20.4 months, compared to historical ranges of 6-9 months for this same patient population. The SBRT treatments were found to be very safe and efficacious – only 3 out of 47 measurable lesions irradiated recurred with a concomitant shift in failure patterns from local to distant sites. As importantly, EGFR status was evaluated in 13 patient tumors, with none harboring the most common mutations. One could, therefore, predict that with a mutation enriched population, the combination of EGFR inhibitor and SBRT may have offered even greater PFS and OS benefits. Our observations also suggest that the SBRT treatments probably contributed the most to the dramatic PFS and OS outcomes. These findings were published in the Journal of Clinical Oncology in the December 1, 2014 print issue with an accompanying editorial. (more…)
Author Interviews, Brigham & Women's - Harvard, Diabetes, JAMA / 02.01.2015

Seth A. Berkowitz, MD, MPH Division of General Internal Medicine Massachusetts General Hospital, BostonMedicalResearch.com Interview with: Seth A. Berkowitz, MD, MPH Division of General Internal Medicine Massachusetts General Hospital, Boston Medical Research: What is the background for this study? What are the main findings? Dr. Berkowitz: Prior studies had looked the association between single unmet basic material needs and diabetes control, but hadn't necessarily looked at multiple things people may not be able to afford, which more closely mirrors real-life. Also, prior studies had been done in a 'pre-Affordable Care Act' setting, while, by being in Massachusetts, our study was conducted in a setting of near-universal healthcare coverage that is similar to what the rest of the US is moving towards. We found that difficulties meeting basic material needs, such as difficulties affording food, known as food insecurity, and having financial barriers to taking medications, called cost-related medication underuse, are associated with worse diabetes control and increased use of costly health services in diabetes patients, despite near-universal health insurance coverage (more…)
Author Interviews, Erasmus, NEJM, Stroke / 02.01.2015

Diederik Dippel MD, PhD Senior Consultant in Neurology Erasmus MC University Medical Center Rotterdam The NetherlandsMedicalResearch.com Interview with: Diederik Dippel MD, PhD Senior Consultant in Neurology Erasmus MC University Medical Center Rotterdam The Netherlands Medical Research: What is the background for this study? What are the main findings? Dr. Dippel: MR CLEAN is the first randomized clinical trial to show that intra-arterial treatment of ischemic stroke to get the clot out, really works. It leads to more recovery and less handicap. Previous studies had shown that intra-arterial treatment leads to recanalization, but the final proof that the treatment leads to recovery more often than standard treatment was lacking. With standard treatment, less than 1 out of 5 recovers without handicap, but with this new treatment, this will be 1 out of 3. The treatment did not lead to more complications than standard treatment. The rate of symptomatic intracranial hemorrhage was similar in both arms. Our study differs from previous, neutral trials.
  • First, we required patients to have an intracranial arterial occlusion confirmed by neuro-imaging.
  • Second, we used third generation thrombectomy devices, such as retrievable stents in most of the cases.
  • Third, our trial was conducted in a country with a very good infrastructure, which allowed rapid transfer to intervention centers, which are spread throughout the country. Our rate of iv tPA in Dutch hospitals is over 11% on average.
  • Last, all intervention centers participated, and almost no patients were treated outside the trial. Moreover, reimbursement of the treatment was conditional on participation in the trial. (more…)
Annals Thoracic Surgery, Author Interviews, Heart Disease, Surgical Research, Yale / 02.01.2015

Karthik Murugiah MBBS Fellow in Cardiovascular Medicine Yale School of Medicine Center for Outcomes Research and Evaluation (CORE) New Haven, CT 06510MedicalResearch.com Interview with: Karthik Murugiah MBBS Fellow in Cardiovascular Medicine Yale School of Medicine Center for Outcomes Research and Evaluation (CORE) New Haven, CT 06510 Medical Research: What is the background for this study? What are the main findings? Response: Aortic valve disease is common among older people and frequently requires valve replacement. 1-year survival after open surgical aortic valve replacement is high (9 in 10 survive the year after surgery). Our study focuses on the experience of these survivors in terms of the need for hospitalization during the year after surgery. Among patients >65 years of age enrolled in Medicare who underwent surgical replacement of their aortic valve and survived at least one year, 3 in 5 were free from hospitalization during that year. Both, the rates of hospitalization and the average total number of days spent in the hospital in the year following surgery have been decreasing all through the last decade (1999 to 2010). (more…)
Author Interviews, Infections / 02.01.2015

Shashank Gupta, Ph.D. Center for Tuberculosis Research Department of Medicine, JHU, Baltimore, Maryland, USAMedicalResearch.com Interview with: Shashank Gupta, Ph.D. Center for Tuberculosis Research Department of Medicine, JHU, Baltimore, Maryland, USA Medical Research: What is the background for this study? What are the main findings? Dr. Gupta: Verapamil is an efflux pump inhibitor drug that has been used to treat hypertension and other cardiac conditions in patients. Adding verapamil to standard tuberculosis (TB) treatment accelerates both the killing activity of the regimen in mouse model. We have recently shown in vitro that supplementing bedaquiline with verapamil profoundly decreases the MIC of bedaquiline in the wild type strain M. tuberculosis H37Rv, and also in drug-susceptible and drug-resistant clinical isolates. The MIC of another anti-mycobacterial drug clofazimine against M. tuberculosis H37Rv also decreased significantly in the presence of verapamil. Bedaquiline is the first drug to be approved by the USFDA in last forty years for the treatment of multidrug-resistant tuberculosis (MDR-TB). Bedaquiline usage in patients presents several safety concerns including increased mortality and hepatic-related adverse drug reactions. Bedaquiline also prolongs the QT interval in patients, which is a measure of the time between the start of the Q wave and the end of the T wave in the heart's electrical cycle. In a phase 2 trial involving patients with advanced MDR-TB, a significantly higher number of participants receiving bedaquiline died than those receiving placebo although the causes of mortality were not directly attributable to the drug. Thus strategies to reduce the human dose of bedaquiline while retaining antibacterial activity may be valuable. We hypothesized verapamil may potentiate the killing of M. tuberculosis by bedaquiline and accelerate clearance of mycobacteria that in an in vivo infection model. Shortening treatment regimens and reducing the required doses may be a promising strategy to reduce the incidence of bedaquiline-related adverse effects and thereby improve MDR-TB treatment outcomes. In this study, we investigated the effect of verapamil on the activity of bedaquiline against M. tuberculosis in a mouse model of TB infection. In addition to investigating the effects of verapamil on the full human bioequivalent dose of bedaquiline (25 mg/kg), we also used a sub-optimal dose of bedaquiline (12.5 mg/kg) daily, with or without verapamil to test if verapamil may potentiate the activity of bedaquiline. We have also determined if verapamil can protect bedaquiline monotherapy from the development of resistance. Using mouse model of tuberculosis, we have shown lower doses of bedaquiline together with verapamil have the same antibacterial effect as the higher toxic doses. A lower dose of bedaquiline will cause no or less severe side effects. Verapamil also protected bedaquiline against the development of resistant mutants of the bacteria in the animals. (more…)
Author Interviews, OBGYNE / 02.01.2015

lauren coronaMedicalResearch.com Interview with: Lauren Corona BS Wayne State University School of Medicine Detroit, MI Medical Research: What is the background for this study? What are the main findings? Response: Hysterectomy is the most commonly performed major gynecologic surgery in the United States. This study sought to examine how often alternative treatment is considered prior to hysterectomy for benign indications and how often pathology in the surgical specimen supports the need for hysterectomy. We utilized data from the Michigan Surgical Quality Collaborative, a statewide hospital collaborative, and limited the analysis to patients having a hysterectomy for uterine fibroids, abnormal uterine bleeding, endometriosis, and/or pelvic pain. Alternative treatment to hysterectomy was not documented prior to surgery in 38% (i.e. no documentation that the patient declined, was unable to tolerate, or failed any alternative treatment). A progesterone intrauterine device (IUD) was the least utilized form of alternative treatment, documented in only 12% of patients. In addition, nearly 1 in 5 (18.3%) had pathology reported that did not support the need for hysterectomy—i.e. the uterus was described as normal or unremarkable or only had minor amounts of pathology. Women <40 years had the highest rate of unsupportive pathology at 38%. (more…)
Accidents & Violence, Author Interviews, JAMA, Mental Health Research, Pediatrics / 01.01.2015

MedicalResearch.com Interview with: Joseph A Simonetti, MD MPH Research Fellow Harborview Injury Prevention & Research Center University of Washington Seattle, WA, USA Medical Research: What is the background for this study? What are the main findings? Dr. Simonetti: Studies have consistently shown that children living in households where firearms are stored safely have a lower risk of suffering firearm injuries, including lethal firearm injuries, compared to those living in households where firearms are stored unlocked and/or loaded. Safe firearm storage is widely recommended by public health experts, professional medical societies, and gun rights organizations, especially for households where children might be suffering from mental heath and substance abuse issues that put them at increased risk for suicide or unintentional injury. Our goal was to find out if those recommendations were being effectively implemented in the community. To do this, we used survey data that assessed mental health conditions and firearm access among a nationally representative sample of US adolescents. Medical Research: What are the main findings? Dr. Simonetti: First, we confirmed previous findings that a large proportion of US adolescents have access to a firearm in the home. Of those who reported living in a home with a firearm, 40% said they could immediately access and shoot the firearm. Second, the prevalence of most mental health diagnoses was similar between adolescents who did and did not report firearm access. However, a greater proportion of adolescents with firearm access had drug and alcohol disorders compared to adolescents who reported living in a home with a firearm but did not have access to the firearm. The main finding was that children with mental health risk factors for suicide were just as likely to report in-home firearm access as those without identified risk factors. This finding held true even when comparing firearm access between children with no identified risk factors and those who reported a recent suicide attempt, who arguably have the highest suicide risk in this sample. (more…)
Abuse and Neglect, Author Interviews / 31.12.2014

MedicalResearch.com Interview with: Dr. Rebecca Finkel PhD Queen Margaret University Edinburgh, Scotland, UK andDr. Rebecca Finkel PhD Queen Margaret University Edinburgh, Scotland, UK and Madelon Finkel, Ph.D. Director Professor of Clinical Public Health Weill Cornell Medical College, NY, NYMadelon Finkel, Ph.D. Director Professor of Clinical Public Health Weill Cornell Medical College, NY, NY Medical Research: What is the background for this study? What are the main findings? Drs. Finkel: Human trafficking is as complex human rights and public health issue. One of the authors (RF) studied the issue at the Vancouver Olympic Games and felt that there needed to be more research on this topic. Much of the problem is that the issue of human trafficking for sexual exploitation at mega global sporting events is difficult to quantify given the clandestine nature of the industry. This is not to say that human trafficking for sexual exploitation does not occur. It almost certainly exists, but to what extent is the big question and to what extent do global events have an impact (if at all)? Our article shows that there are few well-designed empirical studies that address the issue of human trafficking, especially as it relates to mega sporting events. The extant literature presents gaps in: a) understanding the actual scope of the international human trafficking situation; b) establishing links between human trafficking and mega sporting events despite anecdotal testimonies and moral panics often fueled by international media; and, c) public health implications for victims of human trafficking. (more…)
Author Interviews, Stem Cells / 31.12.2014

Dr. Dhruv Sareen, PhD Director, iPSC Core Facility Regenerative Medicine Institute Research Scientist, Neurobiology Research Cedars-Sinai, Los Angeles CAMedicalResearch.com Interview with: Dr. Dhruv Sareen, PhD Director, iPSC Core Facility Regenerative Medicine Institute Research Scientist, Neurobiology Research Cedars-Sinai, Los Angeles CA Medical Research: What is the background for this study? What are the main findings? Dr. Sareen: We have developed a novel method to re-create brain and intestinal stem cells from patients who died decades ago, using stored blood samples. Using the iPS cell technology at Cedars-Sinai this new method now allows us to apply to alive as well as deceased patient blood cells. Our study, published in the journal STEM CELLS Translational Medicine, highlights the power of this technology for many deceased patients that were diagnosed with debilitating diseases, such as inflammatory bowel disease (IBD) and motor neuron diseases (spinal muscular atrophy and ALS). Patients had their blood samples stored away at Cedars-Sinai when they were alive decades ago. At that time all researchers could have done was collect and bank their blood cell lines for research purposes. The iPS cell technology wasn’t even on scientists radar then. With novel developments in my lab we have figured out how to reliably create new stem cell lines from patient blood samples stored away in large cell banks. We have also shown that these recreated stem cells can efficiently make neurons specific to the spine (motor) and cells of the gut. Since it is very difficult to get unlimited access to research affected cells and tissues from the patients, our discoveries now allow us such important capabilities. Thus, now we are not limited to animal models of disease, but can use these patient-specific stem cells to better pinpoint potential causes of these devastating illnesses. (more…)
Author Interviews, Cognitive Issues, Depression, Primary Care / 31.12.2014

Patrick Monahan, Ph.D. Associate Professor Indiana University School of Medicine and School of Public HealthMedicalResearch.com Interview with: Patrick Monahan, Ph.D. Associate Professor Indiana University School of Medicine and School of Public Health Medical Research: What is the background for this study? Dr. Monahan: Primary care providers need a clinical practical (e.g., brief, inexpensive, simple, user-friendly, easily standardized, and widely available) multidomain instrument to measure and monitor the cognitive, functional, and psychological symptoms of patients suffering from multiple chronic conditions. The tool also needs to be sensitive to change so that providers can use it to monitor patient outcomes and adjust the care plan accordingly. We created such a tool and then investigated its psychometric properties (in other words, reliability and validity) in our study of 291 older patients (aged 65 and older) who had at least one recent visit to our urban primary care clinics in Indianapolis, Indiana. These patients had presented with evidence of cognitive or depression problems because these patients and their caregivers were participating in a collaborative care model for such patients. Medical Research: What are the main findings? Dr. Monahan: The Healthy Aging Brain Care (HABC) Monitor demonstrated excellent reliability and validity in this study where patients self-reported their symptoms. Our previous study also showed excellent reliability and validity of the HABC Monitor when the patients’ symptoms were reported by their informal caregiver. (more…)
Author Interviews, Compliance, Flu - Influenza, Pediatrics, Pediatrics, Vaccine Studies / 31.12.2014

Melissa Stockwell, MD, MPH, FAAP Florence Irving Assistant Professor of Pediatrics and Population and Family Health Columbia University - College of Physicians & Surgeons and Mailman School of Public Health Medical Director, New York-Presbyterian Hospital Immunization Registry (EzVac) Co-Director, Primary Care Clinician Research Fellowship in Community Health New York, NY 10032MedicalResearch.com Interview with: Melissa Stockwell, MD, MPH, FAAP Florence Irving Assistant Professor of Pediatrics and Population and Family Health, Columbia University - College of Physicians & Surgeons and Mailman School of Public Health Medical Director, New York-Presbyterian Hospital Immunization Registry (EzVac); Co-Director, Primary Care Clinician Research Fellowship in Community Health Medical Research: What is the background for this study? What are the main findings? Response:  Influenza can be a very serious disease and is more than just a bad cold.  Some children who are 6 months through 8 years need two doses of the influenza vaccine in a season depending on if and when they received previous influenza vaccine doses. We know that only about half of these families who want to vaccinate their children against the flu and get the first dose, come back to get the second dose. (more…)
Author Interviews, Mental Health Research, Sleep Disorders / 31.12.2014

Jacob Nota M.S. Binghamton Anxiety Clinic Department of Psychology Binghamton University Binghamton, NY 13902MedicalResearch.com Interview with: Jacob Nota M.S. Binghamton Anxiety Clinic Department of Psychology Binghamton University Binghamton, NY 13902 Medical Research: What is the background for this study? What are the main findings? Response: As psychologists we are interested in helping individuals improve their quality of life and reduce their symptoms. We know that many people, including those with anxiety and mood disorders, are bothered by repetitive negative thoughts that feel like they are out of control. We are always looking for new ways that we might be able to reduce these kinds of symptoms. We are specifically interested in learning more about how sleep relates to psychopathology because an extensive literature documents the cognitive and emotional impact of sleep disruption. Therefore, addressing sleep disruption may be another avenue for us to explore for helping out clients. However, there is relatively little research on the relation between sleep timing and psychopathology compared to that studying the relation between sleep duration and psychopathology, despite previous studies showing that individuals who go to bed later than they want to have more disorders characterized by worry, rumination, and obsessing. This study collected cross-sectional data (i.e., measuring sleep, worry, rumination, and obsessing all at the same point in time) from a group of 100 young adults at Binghamton University. We looked at measures of worry, rumination, and obsessing as well as a newer measure of the process thought to be shared across these psychological phenomena (repetitive negative thinking). We found that people who sleep for shorter amounts of time and go to bed later also have greater levels of worry, rumination, and obsessing. This is called repetitive negative thinking (RNT). We also found that individuals who are classified as "evening type" (i.e., tend to stay up later and shape their daily activities around this schedule), a trait that is linked to biological circadian rhythms, report significantly greater levels of repetitive negative thinking compared to individuals who are "morning" or neither type (i.e., not strongly morning or evening). This is one of the first studies to show that repetitive negative thinking is related to both how long you sleep and when you sleep. (more…)
Author Interviews, JAMA, Multiple Sclerosis / 31.12.2014

Dr. Richard Nash MD Colorado Blood Cancer InstituteMedicalResearch.com Interview with: Dr. Richard Nash MD Colorado Blood Cancer Institute   Medical Research: What is the background for this study? What are the main findings? Dr. Nash: Multiple sclerosis is an autoimmune disease of the central nervous system which causes significant disability and in some cases results in patients being wheel-chair bound or bed-ridden. It is a significant medical problem amongst young adults. We undertook this study because current Multiple sclerosis therapies were not adequate for effective long-term control of the disease in the majority of the patients. High-dose immunosuppressive therapy followed by autologous hematopoietic cell transplantation is an effective treatment for many hematological malignancies. It causes a profound immunosuppression. Based on this effect on the immunological system, we initiated a clinical trial of this treatment modified for autoimmune disorders. The study was supported by the Immune Tolerance Network and NIAID, NIH. In a phase 2 clinical trial of 25 patients all of whom were followed for at least 3 years, we demonstrated that 80% of patients had no evidence of disease activity. No other Multiple sclerosis treatments were given after the study treatment. Adverse events were similar to what we have observed for this treatment in patients with hematological malignancies. No significant acute neurological adverse events were observed. (more…)
Author Interviews, Cancer Research, PNAS, UCSD / 31.12.2014

MedicalResearch.com Interview with: Annie Samraj and Ajit Varki MDDr. Annie Samraj MD Postdoc Fellow Varki Lab and Ajit VAjit Varki MD Distinguished Professor of Medicine and Cellular & Molecular Medicine Co-Director, Center for Academic Research and Training in Anthropogeny (CARTA) Co-Director, Glycobiology Research and Training Center (GRTC) University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0687.arki MD Distinguished Professor of Medicine and Cellular & Molecular Medicine , Co-Director, Center for Academic Research and Training in Anthropogeny, Co-Director, Glycobiology Research and Training Center University of California, San Diego, La Jolla, CA Medical Research: What is the background for this study? What are the main findings? Dr. Varki: For the past decade, there has been increasing evidence that people who consume red meat (beef, pork, lamb) are at a higher risk for certain kinds of cancers. Although red meat is a high quality source of protein, iron and vitamins, too much consumption may be harmful to humans. While there are other hypotheses under consideration, we focused on a non-human sugar molecule called Neu5Gc in red meat that could explain the link to cancer risk. We extensively studied various foods and concluded that red meat (particularly beef) is rich in Neu5Gc. In contrast poultry, fish steaks and hen eggs have little or no Neu5Gc. From previous studies, we knew that animal-derived Neu5Gc could be incorporated into human tissues. In this study, we hypothesized that eating red meat could lead to inflammation if the body’s immune system targets the foreign Neu5Gc. Chronic inflammation is also known to instigate or promote tumor progression. To test this hypothesis, we used mice engineered to be similar to humans in that they lacked Neu5Gc, and also produced antibodies against it. When these mice were fed Neu5Gc, they developed systemic inflammation. Tumor formation increased fivefold and Neu5Gc accumulated in the tumors, proving the hypothesis. None of the various control groups of mice showed this effect. (more…)
Author Interviews, JAMA, Surgical Research, Weight Research / 31.12.2014

Jeffrey A. Gusenoff, MD Associate Professor of Plastic Surgery Co-Director, Life After Weight Loss Program Co-Director, BodyChangers Director, Post-Bariatric Body Contouring Fellowship UPMC Department of Plastic SurgeryMedicalResearch.com Interview with: Jeffrey A. Gusenoff, MD Associate Professor of Plastic Surgery Co-Director, Life After Weight Loss Program Co-Director, BodyChangers Director, Post-Bariatric Body Contouring Fellowship UPMC Department of Plastic Surgery Medical Research: What is the background for this study? What are the main findings? Dr. Gusenoff: With the rise in massive weight loss patients from bariatric surgery or diet and exercise, more patients are choosing to have a thighplasty to remove excess skin of the inner thigh. Many techniques exist for treating this, but there aren't many studies that look into the safety of these procedures in massive weight loss patients. What we found is that  many patients have scars that go all the way down the thigh with a fairly high complication rate of almost 70%. (more…)
Author Interviews, JAMA, Smoking / 31.12.2014

Dr Hayden McRobbie MB ChB PhD Reader in Public Health Interventions Wolfson Institute of Preventive Medicine Barts and The London School of Medicine and Dentistry Queen Mary University of LondonMedicalResearch.com Interview with: Dr Hayden McRobbie MB ChB PhD Reader in Public Health Interventions Wolfson Institute of Preventive Medicine Barts and The London School of Medicine and Dentistry Queen Mary University of London Medical Research: What is the background for this study? What are the main findings? Dr. McRobbi: Varenicline is an effective smoking cessation aid that acts primarily to alleviate the symptoms of tobacco withdrawal discomfort, thereby making quitting easier. It also reduces the rewarding effects of cigarettes smoked which may enhance the drugs smoking cessation effect by reducing the enjoyment of smoking prior to quitting and preventing a lapse, after quitting, progressing to relapse. In some people the standard dose of varenicline (2mg/day) results in a decrease in the enjoyment of smoking prior to quitting and that these people appear to have higher quit rates that those that don’t experience this reaction to smoking. The randomised placebo controlled trial was designed to investigate whether increasing the varenicline dose (up to 5mg/day) in smokers who show no reaction to the standard dose improves treatment outcomes compared to remain on the standard dose. Medical Research: What are the main findings? Dr. McRobbi: Whilst the increased dose, compared with the standard dose, reduced the enjoyment of smoking prior to quitting it had no additional effect on alleviating tobacco withdrawal symptoms or smoking cessation rates at 12 weeks post quit date (26% vs. 23%). (more…)
Author Interviews, Diabetes / 30.12.2014

Aramesh Saremi MD Phoenix VA Health Care System Health Research Scientist Phoenix, AZ 85012-1892MedicalResearch.com Interview with: Aramesh Saremi MD   Phoenix VA Health Care System Health Research Scientist Phoenix, AZ 85012-1892   Medical Research: What is the background for this study? What are the main findings? Dr. Saremi: Our study was a post-hoc analysis of the data that was available from VA cooperative study,  the Veterans Affair Diabetes Trial  (VADT).  The VADT was one of the  recent landmark studies examining the effect of intensive glycemic control on cardiovascular events  in older adults with type 2 diabetes. The main finding in the VADT and other two other landmark studies (ACCORD and ADVANCE ) was that intensive glycemic control does not reduce cardiovascular  disease events in people with type 2 diabetes of moderate to long duration.  However, our subsequent post-hoc analysis suggests that intensive glycemic control was associated with reduced risk of cardiovascular events in Hispanics, but not in non-Hispanic Whites or Blacks. (more…)
Author Interviews, Nature, Neurological Disorders / 30.12.2014

György Buzsáki, M.D., Ph.D. Biggs Professor of Neural Sciences NYU Neuroscience Institute New York University Langone Medical Center New York, NY 10016MedicalResearch.com Interview with: György Buzsáki, M.D., Ph.D. Biggs Professor of Neural Sciences NYU Neuroscience Institute New York University Langone Medical Center New York, NY 10016 Medical Research: What is the background for the NeuroGrid device? Dr. Buzsaki: The main form of communication among neurons in the brain occurs through action potentials (‘spikes’). Understanding the mechanisms that translate spikes of individual neurons into perceptions, thoughts, and actions requires the ability to monitor large populations of neurons at the spatial and temporal resolution of their interactions. We developed a novel, organic material-based, ultra-conformable, biocompatible and scalable neural interface array (the ‘NeuroGrid’) with neuron-size density electrodes capable of acquiring action potential of individual neurons from the surface of the brain. The NeuroGrid has several innovative characteristics that overcome limitations in current methods of surface recording: (i) light-weight and conformable architecture to establish stable electrical and mechanical contacts, thereby ensuring minimal damage to underlying tissue; (ii) efficient abiotic/biotic interface resulting in a high signal to noise ratio and the ability to resolve spikes. This is achieved by using conducting polymers as the interfacing material. Conducting polymers are mix conductors, they can conduct electronics and ionic currents hence they can efficiently transduce ion based neural activity into electronic signals (iii) scalable neuron-size density electrodes to allow isolation and characterization of multiple individual neurons’ action potential across the cortical surface. (more…)
Author Interviews, Heart Disease / 30.12.2014

MedicalResearch.com Interview with: Yan Liang, MD, PHD on behalf of co-authors Emergency and Intensive Care Center, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China Medical Research: What is the background for this study? What are the main findings? Response: The background of this study is mainly derived from the results of CURRENT-OASIS7 which has shown a 7-day 150 mg maintenance dose (MD) clopidogrel could reduce cardiovascular events among subgroup patients undergoing percutaneous coronary intervention (PCI) compared with the 75 mg/day regimen. We conducted a meta-analysis based on 17 randomized controlled trials to determine whether prolonging the high MD clopidogrel (≥150 mg) treatment period to at least 4 weeks could reduce major adverse cardiac events (MACEs) in the PCI patients with and without high on-clopidogrel platelet reactivity (HPR). Our study concluded that the high  maintenance dose clopidogrel was associated with a significant reduction in the risk of MACEs in PCI patients without increasing the rate of “Major/Minor bleeding” or “Any bleeding” in comparison with standard 75mg MD clopidogrel, and the “HPR Patients” subgroup were also benefited from such high MD treatment. (more…)
Author Interviews, Cancer Research / 30.12.2014

Paul Dent PhD Massey Cancer Center, Departments of Biochemistry and Molecular Biology Virginia Commonwealth University, Richmond, VA 23298MedicalResearch.com Interview with: Paul Dent PhD Massey Cancer Center, Departments of Biochemistry and Molecular Biology Virginia Commonwealth University, Richmond, VA 23298 Medical Research: What is the background for this study? What are the main findings? Dr. Dent: I have worked on understanding how the drug OSU-03012 (AR-12) kills cancer cells since 2005. The drug was originally advertised as an inhibitor of PDK1 in the PI3 kinase pathway. We found that PDK1 inhibition could not be the major way in which the drug worked. We found that the drug killed brain cancer cells through endoplasmic reticulum stress signaling. And in 2012 we published that OSU-03012 destabilized the chaperone protein GRP78, without significantly altering its transcription. Loss of GRP78 was responsible for the prolonged intense endoplasmic reticulum stress signal, that was toxic. In 2014 we published that OSU-03012 + Viagra / Cialis synergized to kill brain cancer cells. We hypothesized that Viagra / Cialis might enhance the anti-GRP78 effect of OSU-03012; and this was proven to be true. We discovered that the OSU-03012 + Viagra combination, but not OSU-03012 alone, reduced expression of other chaperone proteins, such as HSP70, GRP94. In mice, the combination was not toxic to "normal" tissues, but was toxic to tumor cells. In human patients the drug was found to be safe in a phase I trial, with plasma levels of up to 8 microM, and patients on trial for up to 9 months. (more…)
Annals Internal Medicine, Author Interviews, Colon Cancer, Race/Ethnic Diversity, University of Pennsylvania / 30.12.2014

Jeffrey H. Silber, M.D., Ph.D. The Nancy Abramson Wolfson Endowed Chair in Health Services Research Director, Center for Outcomes Research The Children's Hospital of Philadelphia Professor of Pediatrics, Anesthesiology & Critical Care The Perelman School of Medicine Professor of Health Care Management, The Wharton SchoolMedicalResearch.com Interview with: Jeffrey H. Silber, M.D., Ph.D. The Nancy Abramson Wolfson Endowed Chair in Health Services Research Director, Center for Outcomes Research The Children's Hospital of Philadelphia Professor of Pediatrics, Anesthesiology & Critical Care The Perelman School of Medicine Professor of Health Care Management, The Wharton School The University of Pennsylvania  Philadelphia, PA 19104 Medical Research: What is the background for this study? What are the main findings? Response: Differences in colon cancer survival by race is a well recognized problem among Medicare beneficiaries. We wanted to determine to what extent the racial disparity in survival is due to a racial disparity in presentation characteristics at diagnosis (such as advanced stage and the presence of chronic diseases) versus a disparity in subsequent treatment by surgeons and oncologists. To answer this question, we compared black colon cancer patients to three matched white groups: (1) “Demographics” match controlling age, sex, diagnosis year, and Survey, Epidemiology, and End Results (SEER) site; (2) “Presentation” match controlling demographics plus comorbidities and tumor characteristics including stage and grade; and (3) “Treatment” match including presentation variables plus details of surgery, radiation and chemotherapy. We studied Medicare patients 65 years of age and older diagnosed between 1991-2005 in the SEER-Medicare database. There were 7,677 black patients and 3 sets of 7,677 matched white controls. We found that difference in 5-year survival (black-white) was 9.9% in the demographics match. This disparity remained unchanged between 1991-2005. After matching on presentation characteristics, this difference fell to 4.9%. Finally, after additionally matching on treatment, this same difference hardly changed, moving to only 4.3%. So the disparity in survival attributed to treatment differences comprised only an absolute 0.6% of the overall 9.9% survival disparity. (more…)