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Author Interviews, Heart Disease, JAMA, University of Pittsburgh / 07.01.2015

Inmaculada Hernandez, PharmD PhD Student, Health Services Research and Policy Deparment of Health Policy and Management Graduate School of Public Health University of Pittsburgh Pittsburgh, PA 15261MedicalResearch.com Interview with: Inmaculada Hernandez, PharmD PhD Student, Health Services Research and Policy Deparment of Health Policy and Management Graduate School of Public Health University of Pittsburgh Pittsburgh, PA 15261 Medical Research: What is the background for this study? What are the main findings? Response: The approval of dabigatran was considered a major contribution to the therapeutic arsenal of anticoagulants since warfarin, whose therapeutic management is complicated, was the only oral anticoagulant approved before 2011. Clinicians therefore considered dabigatran a very promising drug; however, the safety warnings released by the regulatory agencies and the reports of bleeding published in 2011 raised concerns about the safety profile of dabigatran. By the time we initiated our study, the FDA had concluded that dabigatran was associated with similar rates of bleeding than warfarin. However, the results of this observational study were not adjusted by patient characteristics. We therefore compared the risks of bleeding with dabigatran and warfarin adjusting for patient characteristics and using propensity score methods to mitigate selection biases, which observational studies are sensitive to. We found that dabigatran was associated with a higher risk of major bleeding and gastrointestinal bleeding than warfarin. However, the risk of intracranial bleeding was lower with dabigatran. In addition, we found that the increased risk of bleeding with dabigatran was specially higher for African Americans and for patients with chronic kidney disease. (more…)
Author Interviews, Toxin Research / 06.01.2015

Rick Vetter (retired) Department of Entomology Univ. Calif. Riverside Riverside, CA 92521MedicalResearch.com Interview with: Rick Vetter   (retired) Department of Entomology Univ. Calif. Riverside Riverside, CA  92521 Medical Research: What is the background for this study? What are the main findings? Response: Regarding the spider toxinology field, many misconceptions have been voiced over the years with statements being made in the medical literature which are tenable sounding explanations offered by well-meaning physicians, however, when given further scrutiny, are not supported by the data.  An example of this is the platitude from years ago (and sometimes still today) that brown recluse spider bites are feasible diagnoses anywhere in North America because the spiders CAN get transported around.  However, these authors never actually show that brown recluse spiders ARE frequently transported around in sufficient numbers such that they are tenable culprits in necrotic skin lesions. The evidence developed in the last decade regarding this situation shows that brown recluses DO NOT get transported often, DO NOT establish extra-indigenous populations often and they are not likely etiologies for necrotic skin lesions outside of their indigenous range.  Similarly, a commonly heard statement over the decades is that spiders are likely vectors of bacterial skin lesions.  Several studies have swabbed the fangs and mouthparts of spiders, found bacteria and proudly proclaim the association between spider bites and bacterial infections.  However, these same authors never actually prove that verified spider bites result in bacterial transfer to humans. This current study was instigated in part due to statements made in the 1990s by the late Dr. Philip Anderson, Missouri dermatologist and brown recluse spider bite expert, that recluse spider bites are never infected even in non-medicated patients.  So if spiders actually can vector bacteria, then a data-mining of the vast literature on spider bites worldwide should show significant bacteria association in the form of infected skin lesions as signs of envenomation.  In contrast, there is almost a complete absence of reports of infection when one examines the thousands of spider bites that include a vast array of medically important spiders including the widows, recluses, armed or wandering spiders of South America, Sydney funnel web spiders, wolf spiders, yellow sac spiders, as well as studies involving a random conglomeration of species.  A mechanism to explain this lack of bacterial vectoring may lie in the fact that the venom of spiders (as well as other venomous animals) has antibacterial and antimicrobial capabilities which may function evolutionarily to prevent bacterial transfer from prey to spider in bites. (more…)
Author Interviews, PNAS / 06.01.2015

Akiko Iwasaki PhD Departments of Immunobiology and Laboratory Medicine, Yale University School of Medicine New Haven, CT 06520 MedicalResearch.com Interview with: Akiko Iwasaki PhD Departments of Immunobiology and Laboratory Medicine, Yale University School of Medicine New Haven, CT 06520 Medical Research: What is the background for this study? What are the main findings? Dr. Iwasaki: Since the 1960's, scientists have known that the rhinovirus, the common cold virus, replicates preferably at the cooler temperature found in the nose (33C) but not at the core body temperature found in the lungs (37C). However, the underlying mechanisms were not known. We focused on the host immune response as a possible factor that enables rhinovirus to replicate in the cooler temperature. Indeed, we found that by incubating airway cells isolated from mice at the cooler temperature, immune response to the virus was impaired. By using airway cells from knockout mice from which key innate sensor pathway or interferon receptor is deleted, we found that the virus now replicates even at the core body temperature of 37C. These experiments showed us that the rhinovirus replication is blocked at the higher temperature because of a more efficient immune defense at the core body temperature. (more…)
Author Interviews, JAMA, Mental Health Research, University of Pittsburgh / 06.01.2015

Dr. Brent David MD Academic Chief, Child and Adolescent Psychiatry at Western Psychiatric Institute and Clinic Professor of Psychiatry, Pediatrics & Epidemiology University of Pittsburgh School of Medicine MedicalResearch.com Interview with: Dr. Brent David MD Academic Chief, Child and Adolescent Psychiatry at Western Psychiatric Institute and Clinic Professor of Psychiatry, Pediatrics & Epidemiology University of Pittsburgh School of Medicine Medical Research: What is the background for this study? Dr. David: There are now many studies that show that suicide and suicidal behavior run in families. A family history of suicide increases the risk for suicide attempt and vice versa, so that we believe that the trait that is being passed from parent to child is a tendency to act on suicidal thoughts, resulting in either an attempt or an actual suicide. However, what was not not known was the mechanism by which parents transmitted the risk of suicidal behavior to their children, and what the precursors of suicidal behavior looked like in individuals who were at risk for suicidal behavior, but had not yet engaged in a suicide attempt. Therefore, we conducted a high-risk family study, in which studied the children of parents with mood disorders, about half of whom also had a history of a suicide attempt. Medical Research: What are the main findings? Dr. David: We followed 701 offspring for an average of 5.6 years, and found that those offspring whose parents had made a suicide attempt were almost 5 times more likely to make a suicide attempt themselves, even after accounting for mood disorder in parent and child and past suicidal behavior in the offspring. We found three main pathways by which suicidal behavior was passed from parent to child:
  • Parental mood disorder was transmitted to children, and that was a precursor of a suicide attempt.
  • Parent attempt was related to offspring impulsive aggression, which in turn increased the risk for mood disorder, which then increased the likelihood of a suicide attempt. (We define impulsive aggression as a tendency to response with hostility or aggression to provocation or frustration.
  • Finally, there is a direct path from parent attempt to child attempt, with no precursors or intervening variables.
Implications for clinicians and patients:
  • First, these findings highlight that a parental history of a suicide attempt increases the risk of an attempt in the parent's children. Clinicians who take care of adults who have attempted suicide should make sure that children are assessed as they are at increased risk and that parents know what to look for in the future in order to get their children into needed treatment.
  • Second, the transmission of suicidal behavior from parent to child can be attenuated by preventing the transmission of mood disorder, and of impulsive aggression. There are now evidence based interventions that reduce the likelihood of a child of a depressed parent from developing depression; these treatment involve cognitive behavioral principles and may also involve family interventions. There are now good family-based interventions for impulsive aggression that can attenuate the risk that the child or adolescent will go on to develop a mood disorder, which in turn greatly increases the risk for suicidal behavior.
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Author Interviews, JAMA, Schizophrenia / 06.01.2015

MedicalResearch.com Interview with: Toshiaki A. Furukawa, MD, PhD Professor and Chair, Department of Health Promotion and Human Behavior Professor, Department of Clinical Epidemiology Kyoto University Graduate School of Medicine / School of Public Health, Yoshida Konoe-cho, Sakyo-ku, Kyoto Japan Medical Research: What is the background for this study? What are the main findings? Dr. Furukawa: The efficacy of antidepressants in the treatment of depressive disorders has recently been called into question as some studies suggested they may have less efficacy for the milder spectrum of the disorder. It is not known if the same would apply to antipsychotics, which constitute the mainstay in the treatment of schizophrenia. We found that, in patients with schizophrenia with acute treatment as well as with predominant negative symptoms, the severer the baseline severity, the greater the magnitude of the benefit from the active treatment in comparison with placebo. (more…)
Author Interviews, JAMA, OBGYNE / 06.01.2015

Dr. Jennifer Kawwass MD Assistant Professor Emory UniversityMedicalResearch.com Interview with: Dr. Jennifer Kawwass MD Assistant Professor Emory University Medical Research: What should clinicians and patients take away from your report? Dr. Kawwass: This study affirms that Assisted Reproductive Technology treatment is relatively safe and that reported complications remain rare.  In the US from 2000-2011, autologous and donor ART procedures were associated with low reported stimulation and surgical complication risks; no concerning trends or patterns were identified. Ovarian hyperstimulation syndrome (OHSS) was the most frequently reported complication among autologous and donor cycles, though less frequent in donor cycles.  Obstetric mortality which may or may not be related to Assisted Reproductive Technology was rare. (more…)
Author Interviews, JAMA, Pediatrics, UCSF / 06.01.2015

Yvonne Wu MD Professor of Clinical Neurology and Pediatrics UCSF School of MedicineMedicalResearch.com Interview with: Yvonne Wu MD Professor of Clinical Neurology and Pediatrics UCSF School of Medicine   Medical Research: What is the background for this study? What are the main findings? Dr. Wu: Newborn infants commonly have elevated bilirubin levels, manifested as jaundice, because the body's mechanisms for breaking down bilirubin have not yet fully matured.  Although high bilirubin levels are almost always well tolerated, extremely high bilirubin levels may lead to brain injury, or kernicterus, which in turn can cause a very severe form of cerebral palsy.  When bilirubin levels are extremely high, or when bilirubin levels remain high despite phototherapy, it is recommended that an exchange transfusion be performed to prevent brain injury and cerebral palsy.  The American Academy of Pediatrics (AAP) has published recommendations on when an exchange transfusion should be performed, based on bilirubin level, age of infant and other clinical factors.  However, no previous study had examined the actual risk of cerebral palsy in infants whose bilirubin levels exceeded the exchange transfusion thresholds. Among 500,000 newborns born at Kaiser Permanente Northern California over a 17-year period, we found 1833 who had at least one bilirubin level above the AAP exchange transfusion level.  There were only 3 cases of cerebral palsy due to kernicterus in this group, even though only 42 (2.3%) of them had received exchange transfusions.  All 3 infants had bilirubin levels at least 5 mg/dL above the AAP exchange transfusion threshold and all 3 infants had 2 or more other risk factors for brain damage, including prematurity, sepsis, hypoxia and the hereditary blood disorder G6PD deficiency.  We did not identify any cases of kernicterus among otherwise well term babies, even at bilirubin levels that exceeded the AAP exchange transfusion threshold. (more…)
Author Interviews, JAMA, Mental Health Research, UCSF / 06.01.2015

Dr. Georges Naasan MD Neurologist, Clinical Instructor UCSF Memory and Aging CenterMedicalResearch.com Interview with: Dr. Georges Naasan MD Neurologist, Clinical Instructor UCSF Memory and Aging Center Medical Research: What is the background for this study? What are the main findings? Dr. Naasan: Degenerative diseases of the brain can lead to dysfunction in judgment, emotional processing, social decorum and self-awareness. In turn, such dysfunctions may result in criminal behavior that appears for the first time in middle-aged adults or even later in life. We studied 2397 patients from the Memory and Aging Center at UCSF and found 204 (8.5%) that had a criminal behavior as part of their illness. The large majority of these patients were patients with a specific type of neurodegenerative disease called behavioral variant of frontotemporal dementia, followed by a group of people with a disease called semantic variant of primary progressive aphasia. People with Alzheimer's disease, a disease that does not usually interrupt the functions mentioned above, were the least likely to exhibit criminal behavior. The common manifestation of criminal behaviors in people with the behavioral variant frontotemporal dementia included theft, sexual advances trespassing and public urination in contrast to people with Alzheimer's disease who, when such behaviors were present, primarily committed traffic violations often secondary to cognitive impairment. (more…)
Author Interviews, JACC, Weight Research / 06.01.2015

MedicalResearch.com Interview with: Dr. Joshua Bell PhD Candidate Epidemiology & Public Health University College London, UK Medical Research: What is the background for this study? What are the main findings? Dr. Bell: When viewed at single points in time, about one-third of obese adults show normal metabolic profiles, that is, they have normal blood pressure, cholesterol and blood sugar levels. These adults have been labeled as 'healthy', but until now we have lacked evidence on the long-term stability of this state over time. By viewing theDr. Joshua Bell PhD Candidate Epidemiology & Public Health University College London, UK natural course of healthy obesity over two decades we found that about half of healthy obese adults become unhealthy obese after 20 years, with a clear trend for increasing progression to ill-health over time. Healthy obese adults are also much more likely to become unhealthy obese than healthy or unhealthy non-obese adults, indicating that healthy obesity is often just a phase. (more…)
Author Interviews, Inflammation, Pediatrics, Pediatrics / 06.01.2015

MedicalResearch.com Interview with: Professor of Pediatrics Hans Bisgaard, MD, DMSc Copenhagen Prospective Studies on Asthma in Childhood Herlev and Gentofte Hospital, University of Copenhagen, Denmark Medical Research: What is the background for this study? What are the main findings? Prof. Bisgaard: The purpose of this study was to look for a shared risk factor for immunological diseases which make its debut in childhood. During the recent decades a parallel increase in prevalence of immune diseases such as asthma, allergy, inflammatory bowel disease, and type 1 diabetes have been observed in westernized countries. The rate of cesarean delivery has increased in the same period and has previously been associated with the development of some of these diseases. This study takes advantage of the unique and valuable nationwide registry data in Denmark to establish a large population based cohort (2 million term children) with 35 years of follow up (in the period 1977-2012). We found cesarean delivery to be a common risk factor for a range of childhood immunological diseases: asthma, juvenile arthritis, inflammatory bowel diseases, connective tissue disorders, immune deficiencies and leukemia, but with no association to psoriasis, celiac disease, and diabetes type 1. (more…)
Author Interviews, HIV, Johns Hopkins, Kidney Disease / 06.01.2015

Alison G Abraham PhD Associate Scientist Department of Epidemiology Johns Hopkins Bloomberg School of Public HealthMedicalResearch.com Interview with: Alison G Abraham PhD Associate Scientist Department of Epidemiology Johns Hopkins Bloomberg School of Public Health Medical Research: What was the motivation for this study? Dr. Abraham: HIV-infected individuals are at higher risk for kidney dysfunction compared to the general population.  Prior to effective antiretroviral therapy, very aggressive forms of kidney disease were described primarily among black HIV-infected individuals.  While effective therapy and increasing viral suppression rates have made HIV-associated nephropathy rare, some of these same drugs have nephrotoxic effects.  In addition, the reduction in AIDS and mortality has led to HIV-infected individuals living long enough to experience age-related chronic diseases, which are also risk factors for kidney disease and end-stage renal disease.  Thus we wanted to know how these competing forces were affecting end-stage renal disease risk in the well-treated HIV-infected North American population over time.  Are we seeing more ESRD as a result of nephrotoxic drugs and chronic disease, or less ESRD as a result of better viral suppression and large reductions in HIV-associated nephropathy? Medical Research: What are the main findings? Dr. Abraham: We found that end stage renal disease rates have been steadily falling over the past 10 years coincident with notable improvements in viral suppression prevalence.  However a large racial discrepancy in ESRD risk has persisted even though HIV-associated nephropathy cases are now rare.  While ESRD cases among blacks in our study tended to have higher viral loads and lower CD4 counts compared to non-black ESRD cases, suggesting less effective HIV treatment, we found that the racial discrepancy in ESRD risk persisted even among the well-suppressed subset, i.e. those who had undetectable viral loads for 90% of their follow-up time. (more…)
Author Interviews, JAMA, Surgical Research, Weight Research / 06.01.2015

David Arterburn, MD, MPH, FACP Associate Investigator Group Health Research Institute Seattle, WA 9810MedicalResearch.com Interview with: David Arterburn, MD, MPH, FACP Associate Investigator Group Health Research Institute Seattle, WA 98101   and David L. Maciejewski PhD Center for Health Services Research in Primary Care Durham VA Medical Center, Durham, North CarolinaDavid L. Maciejewski PhD Center for Health Services Research in Primary Care Durham VA Medical Center, Durham, North Carolina MedicalResearch.com: Why was this study needed? Response: There were several reasons to conduct this study.  First, although complications and death during and soon after bariatric surgery have progressively declined over the past several decades, there is simply very little long-term evidence on the survival benefits of bariatric surgery in Americans having surgical procedures that are being used today in routine practice. Second, we felt that it was important to look at the impact of bariatric surgery among veterans because they represent an older male cohort often with multiple medical comorbidities, which is different from the typical bariatric patient in the United States, who is often younger and female. MedicalResearch.com: How was your study conducted? Response: We conducted a retrospective observational study using high-quality data from national Department of Veterans Affairs electronic databases and the VA Surgical Quality Improvement Program. We identified veterans who underwent bariatric surgery in VA medical centers from 2000 to 2011. Three quarters of them were men. We matched them to control patients using an algorithm that included age, sex, VA geographic region, body mass index (BMI), diabetes, and Diagnostic Cost Group. We then compared survival across bariatric patients and matched controls using Kaplan-Meier estimators and stratified, adjusted Cox proportional hazards analyses.  MedicalResearch.com: What were the main findings of your study? Response: This study had three important results: 1)      Our analysis showed no significant association between bariatric surgery and death from all causes in the first year of follow-up. In other words, having bariatric surgery was not significantly related to a veteran’s chance of dying in the first year compared to not having surgery. 2)      We had an average follow-up of 6.9 years in the surgical group and 6.6 years in the matched control group. After one to five years, adjusted analyses showed significantly lower mortality in the patients who had surgery: 55% lower, with a hazard ratio of 0.45. The finding was similar at 5 or more years, with a hazard ratio of 0.47. This means that bariatric surgery was associated with lower long-term mortality – that is, better long-term survival among veterans, which is consistent with limited non-VA research that has addressed this same question. 3)      Finally, we also found that the relationship between surgery and survival were similar comparing men and women, patients with and without diagnosed diabetes, and patients who had bariatric surgery before versus after year 2006. (more…)
Author Interviews, Dermatology, Infections, Pediatrics / 06.01.2015

Jonathan Olsen Institute of Primary Care and Public Health Cardiff University Heath Park CardiffMedicalResearch.com Interview with: Jonathan Olsen Institute of Primary Care and Public Health Cardiff University Heath Park Cardiff MedicalResearch: What is the background for this study? What are the main findings? Response: Molluscum Contagiosum is a common skin condition in children which has a prevalence of between 5.1% to 8% in children aged 14 years and under. Strikingly however, there is little epidemiological evidence describing the natural history, transmission between family members and impact upon quality of life of molluscum contagiosum. Our research aimed to address this gap in evidence by conducting a prospective cohort study of UK children recruited by clinical and self-referral using the validated Molluscum Contagiosum Diagnostic Tool for Parents (MCDTP). We recruited 306 children during 2013 and showed that on average lesions will last for 12 months, however 30% still had lesions at 18 months and 13% still had lesions at 24 months. Most children experienced only a small effect on their quality of life from the condition, however 1 in 10 experienced a large or very large impact on their quality of life. The condition was shown to be highly contagious with further transmission between children living in the same household as an index case shown in 40%. (more…)
Author Interviews, Gastrointestinal Disease, Pediatrics / 06.01.2015

Miranda van Tilburg, PhD Associate Professor of Medicine University of North CarolinaMedicalResearch.com Interview with: Miranda van Tilburg, PhD Associate Professor of Medicine University of North Carolina Medical Research: What is the background for this study? What are the main findings? Dr. van Tilburg: Functional gastrointestinal disorders are common in children, adolescents and adults but little is known about the prevalence in infants and toddlers.  Functional gastrointestinal disorders in infancy include disorders such as regurgitation, colic, and dyschezia, while functional gastrointestinal disorders in toddlers include functional constipation, functional diarrhea, functional dyspepsia, cyclic vomiting, and rumination. Of these disorders only colic and regurgitation have received much research attention. Prevalence, cause and consequences of most functional gastrointestinal disorders in infants and toddlers are largely unknown. We set out to determine the prevalence in the US by asking a representative sample of mothers to report on their child’s symptoms. Our study found that 27% of infants and toddlers may suffer from a functional gastrointestinal disorder. Among infants, regurgitation was the most common disorder and among toddlers constipation. Despite functional gastrointestinal disorders generally being more prevalent in older girls and adult women, no sex differences were found in this age group. Toddlers who suffer from a functional gastrointestinal disorders had lower quality of life and made more health care visits. (more…)
Author Interviews, HPV, JAMA, Vaccine Studies / 05.01.2015

Anders Hviid, M.Sc., Dr.Med.Sci. Senior Investigator, Statens Serum InstitutMedicalResearch.com Interview with: Anders Hviid, M.Sc., Dr.Med.Sci. Senior Investigator, Statens Serum Institut Medical Research: What is the background for this study? Response: After the widespread introduction of HPV vaccination of adolescent girls, a number of safety concerns have emerged. In this case, demyelinating diseases, including multiple sclerosis, occurring after HPV vaccination has been reported in social media, news media and medical journals. Medical Research: What are the main findings? Response: In a study of almost 4 million Danish and Swedish women, we found no support for an increased risk of multiple sclerosis or other demyelinating diseases following HPV vaccination. (more…)
Author Interviews, Brigham & Women's - Harvard, JAMA, Nutrition / 05.01.2015

Qi Sun, MD ScD Assistant Professor of Medicine Channing Division of Network Medicine Brigham and Women's Hospital and Harvard Medical School Assistant Professor Department of Nutrition, Harvard School of Public Health 665 Huntington Avenue, Boston, MA 02115MedicalResearch.com Interview with: Qi Sun, MD ScD Assistant Professor of Medicine Channing Division of Network Medicine Brigham and Women’s Hospital and Harvard Medical School, Assistant Professor, Department of Nutrition Harvard School of Public Health Boston, MA 02115 Medical Research: What is the background for this study? What are the main findings? Dr. Sun: While we know whole grains are beneficial for reducing the risk of some major chronic diseases, such as heart disease and diabetes, evidence regarding whether whole grains are also able to lower mortality is sparse. We therefore want to answer this important research question in the current analysis. Using data collected from two prospective cohort studies consisted of more than 100 thousand US men and women, we found that whole grain intake was significantly associated with lower total mortality and lower cardiovascular mortality, but not cancer mortality. For every serving (28 grams) of whole grain intake per day, the total mortality is reduced by 5% and cardiovascular mortality by 9%. (more…)
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…)