MedicalResearch.com Interview with:
Dr. Philip Molloy, MD
Imugen Medical Director
Medical Research: What is the background for this study? What are the main findings?
Response: There is a newly described tick-borne infection in the US, first case published in NEJM Man 2013 (from Imugen researchers). We then developed and validated both PCR and serologic blood tests. Physicians started ordering these tests, and many additional cases were uncovered, 51 of which are described in this paper.
Medical Research: What should clinicians and patients take away from your report?Response: Be aware of yet another pathogen transmitted to humans from ticks, and don't assume it's Lyme. Tests are available to help sort it out. Imugen has been offering these tests commercially since 2013.
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MedicalResearch.com Interview with:
Stephanie Bonne, MD, FACS
Assistant Professor
Trauma, Acute, and Critical Care Surgery
Washington University in St. LouisMedical Research: What is the background for this study? What are the main findings?
Response: We had previously implemented education programs in our ICU in an attempt to decrease our Central Line-Associated Bloodstream Infection (CLABSI) rate. We were, however, unable to come to zero. We were looking for innovative ways to lower our CLABSI rate, and the use of Clorhexidine/Silver Sulfadiazine catheters was unable to move our CLABSI rate. We decided to try Minocycline/Rifampin catheters, and monitor our Central Line-Associated Bloodstream Infection rate.
Medical Research: What should clinicians and patients take away from your report?Response: The use of Minocycline/Rifampin impregnated catheters can lower Central Line-Associated Bloodstream Infection rate, particularly in ICUs who have been unable to reach a Central Line-Associated Bloodstream Infection rate of zero with other measures.
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MedicalResearch.com Interview with:
Ms. Amanda Jezek
Director of Government Relations
Infectious Diseases Society Of America
Editor's Note: The Infectious Diseases Society of America Comments...
MedicalResearch.com Interview with:
Dr. Martin HoeniglCenter for AIDS Research
University of California, San Diego
Medical Research: What is the background for this study? What are the main findings?
Dr. Hoenigl: Although men who have sex with men (MSM) represent a dominant risk group for human immunodeficiency Virus, the risk of HIV infection within this population is not uniform. Characterizing and identifying the MSM at greatest risk for incident HIV infection might permit more focused delivery of both prevention resources and selection of appropriate interventions, such as intensive counseling, regular HIV screening with methods that detect acute infection (ie, nucleic acid amplification test), and antiretroviral preexposure prophylaxis (PrEP).
By using data collected at a single HIV testing encounter from 8326 unique MSM were analyzed, including 200 with AEH (2.4%), we were able to create the San Diego Early Test (SDET) risk score. The SDET score consist of four risk behavior variables which were significantly associated with an AEH diagnosis (ie, incident infection) in multivariable: condomless receptive anal intercourse (CRAI) with an HIV-positive MSM (3 points), the combination of CRAI plus 5 or more male partners (3 points), 10 or more male partners (2 points), and diagnosis of bacterial sexually transmitted infection (2 points), all as reported for the prior 12 months. The SDET risk score is deployed as a freely available tool at http://sdet.ucsd.edu.
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MedicalResearch.com Interview with:
Dr. Nelson Lee
BBS(HK),MD(CUHK),FRCP(Lond),FRCP(Edin),FHKCP,FHKAM(Med)
Daniel Yu Professor of Infectious Diseases
Head, Division of Infectious Diseases,
Department of Medicine and Therapeutics,
Faculty of Medicine, The Chinese University of Hong Kong.
Hon. Consultant, Prince of Wales Hospital, Hong Kong
Medical Research: What is the background for this study? What are the main findings?
Dr. Lee: Respiratory syncytial virus (RSV) is increasingly recognized as an important cause of severe respiratory-tract infections in older adults, resulting in excessive hospitalizations and deaths annually. At present, no established antiviral treatment is available. The slow progress in therapeutics development is limited by the poor understanding of the clinical manifestations, severity, virologic changes, and pathophysiology in adult RSV diseases. To address the knowledge gap, we conducted a prospective study to look at the lower-respiratory complications, progression to respiratory failure, and their relationships to genomic viral loads in adults hospitalized for confirmed RSV infections.
We found that among 123 RSV patients, nearly 90% had lower respiratory tract complications (acute bronchitis/bronchiolitis, radiographic pneumonia, exacerbation of underlying airway diseases, or their combinations), 53% developed respiratory insufficiency requiring bronchodilators and supplemental oxygen, 16% required assisted ventilation, and 12% were admitted to ICU or died. High viral RNA concentration was detected in their respiratory samples, including in patients who had onset longer than 2 days (>7 log10copies/mL). Viral load was associated with disease severity and development of respiratory insufficiency (about 40% increase in risk per log RNA increase).
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MedicalResearch.com Interview with:
Sandra Schwarcz, MD
Senior HIV epidemiologist
San Francisco Department of Public Health
Medical Research: What is the background for this study? What are the main findings?
Dr. Schwarcz: AIDS opportunistic illnesses continue to occur despite effective antiretroviral therapy. Although previous studies examined survival following a diagnosis of an opportunistic illness, there are few recent reports that are population-based. The San Francisco Department of Public Health has the only population-level data on the occurrence of and survival following opportunistic illnesses and use of antiretroviral therapy among persons reported with HIV in the United States. By measuring survival following the occurrence of opportunistic illnesses, we were able to document that survival following opportunistic illnesses has improved with better HIV treatment. However, opportunistic illnesses continue to occur and carry substantial mortality risk. Even in this era of effective HIV therapy, we found that 35% of persons who developed an opportunistic illness died within five years of their diagnosis and some opportunistic illnesses such as brain lymphoma and progressive multifocal leukoencephalopathy remain highly lethal.
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MedicalResearch.com Interview with:
Dr. Marie C. Leger, MD, PhD
Assistant Professor
Ronald O. Perelman Department of Dermatology
NYU Langone Medical Center
Medical Research: What inspired this study? How did it come about?
Dr. Leger: As a dermatologist at NYU, I have taken care of several patients with tattoo reactions--some of them mild (like longstanding itching for example) and some of them more severe (like long term reactions to a particular color that can severely disfigure the tattoo) and wondered how common it was for people to have adverse tattoo reactions or complications. There were lots of case reports in the literature but only a few larger studies examining how common these kinds of complaints were--and these were all European studies. We decided to do a quick survey to give us a better idea of how common it is for people to have problems with their tattoos.
Medical Research: What do you think is the most important takeaway from this study for the consumer?Dr. Leger: Tattoos have risks associated with them--which is part of their appeal I'm sure--but I do think it's important for people to know that long term tattoo reactions (including for example, itching, scaling, swelling) may be more common than we realize. A recent Danish study shows that these kinds of reactions can be quite distressing for people and significantly impact their quality of life.
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MedicalResearch.com Interview with:
Dr. Michael Eriksen Benrós
Mental Health Centre Copenhagen
University of Copenhagen Faculty of Health Sciences
Copenhagen NV, Denmark,
National Centre for Register-based Research
Aarhus University Denmark
Medical Research: What is the background for this study?
Response: It is increasingly recognized that infections and immune responses can affect the brain and activate immunocompetent cells within the brain, influencing on neuronal signal transduction and possibly cognition. Impaired cognition has been observed in association with several infections and with elevated levels of CRP in smaller studies. Furthermore, experimental activation of inflammatory reactions in healthy volunteers has been shown to induce short-term reduced cognitive performance. Moreover, particularly patients with infection in the brain or sepsis have been shown to have affected cognition in long time periods after the infection has been cleared, thus infections might also have a longer lasting effect on cognition. However, large-scale longitudinal studies had been lacking on the association between infections and cognitive ability in the general population.
Medical Research: What are the main findings?
Response: Our study is the first large-scale study utilizing the extensive Danish registers to follow 190,000 males that had their IQ assessed at conscription, out of which 35% had a previous hospital contact with infection before the IQ testing was conducted. Our research shows a correlation between severe infections with a hospital contact and subsequent impaired cognition corresponding to an IQ score of 1.76 lower than the average. People with five or more hospital contacts with infections had an IQ score of 9.44 lower than the average. The study thus shows a clear dose-response relationship between the number of infections. Furthermore the effect on cognitive ability increased with the temporal proximity of the last infection and with the severity of the infection. Infections in the brain affected the cognitive ability the most, but many other types of infections severe enough to require a hospital contact where also associated with impairment of the cognitive ability.
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MedicalResearch.com Interview with:Perry N Halkitis, Ph.D., M.S., MPH
Professor of Applied Psychology
Global Public Health, and Population Health/Medicine
New York University.
Medical Research: What is the background for this study?
Dr. Halkitis: The P18 Cohort Study is a prospective cohort study of gay, bisexual and other young men who have sex with men (YMSM) which seeks to examine the development of health behaviors as these young men transition from adolescent to adulthood. Officially named “Syndemic Production among Emergent Adult Men”, this study was funded by the National Institute on Drug Abuse from 2009-2014 and renewed on March 1, 2014 for an additional five years.
The original aims of the study were as follows:
1) to develop and test theoretically informed measurement models of the covariance of illicit drug use, unprotected sexual behavior and mental health burden (multiple overlapping epidemics known as a syndemic) among emergent adult HIV-negative YMSM within and across time;
2) to delineate the risk and protective bases- physical factors (e.g., pubertal onset, HIV status, etc.), relational and structural factors (e.g., family history of psychopathology, current romantic relationships, peer support, neighborhood factors, etc.), and psychosocial factors (e.g., sexual identity, internalized homophobia, hyper-masculine conceptions, etc.) that predict the development of syndemics; and
3) to determine the extent to which the development of a syndemic varies by race/ethnicity, social class, and homelessness/housing instability.
In this current five year continuation we also seek
1) to describe the social and sexual networks of YMSM, and to examine the relationship between social and sexual network-level structural characteristics, social support and normative influences on syndemic production (illicit drug use, unprotected sexual behaviors, and mental health burden) in YMSM, singly and in combination with the physical, psychosocial, and relational predictors, both within and across time;
2) to describe the acquisition of sexually transmitted infections (STIs) in YMSM, specifically, urethral and rectal gonorrhea and chlamydia, pharyngeal gonorrhea as well as syphilis serology; and to determine the extent to which physical, relational, and psychosocial factors explain STI acquisition as part of the syndemic model within and across time.
A third exploratory aim was also added: 3) to describe HIV clinical treatment markers (i.e., HIV viral load, ART uptake and adherence, HIV care) among HIV+ YMSM, and to assess the extent to which physical, relational, and psychosocial factors are associated with differences in these clinical markers among HIV+ YMSM, both within and across time. The study is led by Drs. Perry N Halkitis and Farzana Kapadia at New York University’s Center for Health, Identity, Behavior & Prevention Studies.
Potential participants were recruited through both active (e.g., approaching individuals to solicit study participation) and passive (e.g., flyer posting, website advertisements) methods from June 2009 to May 2011. Eligibility criteria included being 18-19 years old, biologically male, residing in the NYC metropolitan area, having sex (any physical contact that could lead to orgasm) with a man in the last 6 months, and reporting a seronegative or unknown HIV status at baseline. We ensured the diversity of our sample by setting a fixed recruitment quota for participants in each targeted racial/ethnic group, such that African Americans, Latino (across race), Asian-Pacific Islander (API), and mixed race men comprised the majority of the sample. All participants provided written, informed consent before data was collected and were compensated for their time and effort upon completing the baseline assessment. The New York University’s Institutional Review Board (IRB) approved all study protocols and a federal Certificate of Confidentiality protects these data.
A total of 2,068 participants were screened for eligibility to participate in the study, and 600 participants completed the baseline assessment in the first wave of the study. In 2014, we began the second wave and opened to cohort to recruit a baseline sample of 650 YMSM who will now be between the ages of 22-23; recruitment of participants is still underway.
Medical Research: What are the main findings?
Dr. Halkitis: Numerous publications have been generated from the P18 Cohort Study and can be accessed at www.chibps.org. A recent publication, “Incidence of HIV infection in Young Gay, Bisexual, and other YMSM: The P18 Cohort Study” became available in the May 2015 of JAIDS, the Journal of Acquired Immune Deficiency Syndromes. This paper reports that over a 36 month follow-up period, during the first wave of the study, 7.2% of study participants seroconverted, with Black and Hispanic men much more likely to seroconvert over this time frame than White men. This finding aligns with epidemiological trends for HIV infection at the national and local, NYC, levels. Also, men reporting a lower familial socioeconomic status were more likely to seroconvert than men reporting high familial socioeconomic status, and Black men were more likely to report a lower socioeconomic status. Moreover, the Black young men who seroconverted were more likely to reside in neighborhoods with higher area-level poverty and higher area-level HIV prevalence. Additionally we found that men who reported anal sex without a condom in the 30 days prior to assessment were no more likely to seroconvert than those who reported sex with a condom. However, an earlier age of sexual debut was a predictor of HIV seroconversion.
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MedicalResearch.com Interview with:
Kevin Yarasheski, PhD
Assistant Director, Biomedical Mass Spectrometry Research Facility
Professor of Medicine, Cell Biology & Physiology, Physical Therapy
Washington University School of Medicine
Medical Research: What is the background for this study?
Dr. Yarasheski: People living with HIV and taking combination antiretroviral therapy (cART) have successfully reduced the amount of HIV virus in their blood and have partially reconstituted their immune system (CD4+ T-cell count >250 cells/µL). Despite this, many still experience residual immune cell activation and inflammation that is believed to increase HIV morbidity (non-AIDS conditions e.g., CVD, T2DM, obesity, liver fat, bone loss, dementia) and mortality. Scientists are seeking safe and effective interventions for residual immune cell activation and inflammation, that have the potential to reduce non-AIDS complications that threaten quality and quantity of life among HIV infected adults.
We have been testing the safety and efficacy of sitagliptin in people living with HIV; a dipeptidyl peptidase 4 inhibitor that is FDA approved for treating T2DM, and appears to have favorable anti-inflammatory and immune modulatory properties that might specifically benefit people living with HIV and experiencing cardiometabolic complications associated with residual immune cell activation and inflammation.
Medical Research: What are the main findings?
Dr. Yarasheski: In a randomized, double-blinded, placebo controlled 8-wk trial, we found that sitagliptin had beneficial anti-inflammatory, immune regulatory, hematopoietic progenitor cell mobilizing, and glucose lowering effects in cART-treated virally suppressed HIV adults with impaired glucose tolerance. Sitagliptin improved glucose tolerance (a risk factor for CVD), reduced circulating and adipose-specific inflammatory markers (risk factors for obesity, T2DM, liver fat accumulation, and CVD), and increased the number of blood stem cells that can repair damage and inflammation in the vascular walls.
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MedicalResearch.com Interview with:
Timothy E Sweeney, MD PhD
Resident, General Surgery
Postdoc, Khatri Lab, Bioinformatics
Stanford University
Medical Research: What is the background for this study? What are the main findings?Dr. Sweeney: Sepsis is defined as the presence of systemic inflammation due to infection. Systemic inflammation can be caused from many things, such as trauma, surgery, thrombosis, autoimmunity, etc. It can also be caused by infection. On the other hand, infection does not necessarily cause systemic inflammation, either: a person can get a minor infection, like strep throat, and not have a systemic response. It's the intersection of severe inflammation (a syndrome called SIRS) with infection that defines sepsis.
In general surgery, we frequently see patients after traumatic injury or surgery who are having an inflammatory response (ie, fevers, fast heart rate, high white blood cell count, etc). But it's not clear whether this inflammatory response is a reaction to the trauma or surgery, or whether there might be an infection brewing that is causing the reaction. Identifying the inflammatory response doesn't require many special tests-- it's easy to spot. So we know which patients have inflammation and which do not. What is difficult is determining the root cause of the inflammation, and, in particular, whether there is an infection present that needs treatment with antibiotics.
Current diagnostics for infection (not sepsis) are either slow (like blood cultures, which can take 24-72 hours to return) or not highly accurate (like procalcitonin). We sought to define a better test that could specifically differentiate between people with sterile inflammation, and people with inflammation due to infection (sepsis). By integrating gene expression data from multiple publicly available cohorts, we were able to find a set of 82 genes that are significantly differently expressed between these two groups. We then used an algorithm called a greedy forward search to find a subset of 11 genes that were most diagnostic for sepsis.
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MedicalResearch.com Interview with:
Maria Blomberg
Virus, Lifestyle & Genes
Danish Cancer Society Research Centre
Copenhagen, Denmark
Medical Research: What is the background for this study? What are the main findings?
Response: Two vaccines against human papillomavirus (HPV) were licensed almost one decade ago. Since then multiple countries have implemented HPV vaccination programs to help reduce genital warts (one of the kinds of warts most harmful to people), but many struggle with low coverage rates. An important barrier to vaccination is the cost of the vaccines and less developed countries also face considerable logistical challenges. Both vaccines were administered as three dose schedules, but in early 2014 the WHO’s Strategic Advisory Group of Experts and the European Medicines Agency reviewed the evidence of reduced dose schedules of HPV vaccination, and subsequently recommended a two dose schedule for young girls. A reduction of the number of doses has obvious advantages; it would lower the costs, ease implementation of vaccination schedules and potentially increase coverage rates. Based on these recommendations, countries around the world have reduced the dosing schedule in their HPV vaccination programs for young girls to two doses. However, the current evidence is based primarily on immunological studies, and because the immune correlate of protection is not known, studies with disease endpoints are very important.
Using the biologically relevant endpoint of genital warts, this study aimed to assess the clinical effectiveness of a two dose schedule of quadrivalent HPV vaccine compared with the standard three-dose regimen administered at month 0, 2 and 6. We found that with the standard vaccination schedule, completion of the three dose regimen is important to gain maximal protection. However, the effectiveness of two doses increased significantly with increasing time between the doses, and with an interval of approximately 6 months between dose one and two, no differences could be found between two and three doses.
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MedicalResearch.com Interview with:
Dr. Johannes Berkhof
Department of Epidemiology and Biostatistics, VU University Medical Centre
Amsterdam
Centre for Infectious Disease Control,
National Institute for Public Health and the Environment, Bilthoven, Netherlands
Medical Research: What is the background for this study? What are the main findings?Response: Vaccination against the sexually transmitted human papillomavirus (HPV) is offered free-of-charge to 12-year-old girls in the Netherlands.
There is strong evidence that HPV also causes cancer in men: the virus is associated with cancers of the penis, anus, and oropharynx, and possibly with a small proportion of oral cancers. A number of these cancers will be prevented because vaccination of girls leads to a decrease of HPV in the general population and thus provides indirect protection to heterosexual men.
However, vaccine uptake among girls is only about 60 percent in the Netherlands. Moreover, men who have sex with men are at increased risk of HPV-related cancer and will not be protected by vaccination of girls.
On the basis of data from several epidemiological studies and a dynamic model for virus transmission, we calculated that, if the vaccine uptake is low, about 200 girls need to be vaccinated to prevent one case of cervical cancer and 470 boys need to be vaccinated to prevent one case of cancer in men.
An increase in vaccine uptake in girls will decrease the HPV infection risk in heterosexual men and if the uptake in girls is 60 percent, around 800 boys need to be vaccinated to prevent one additional case of cancer in men.
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MedicalResearch.com Interview with:
J L Mehta, MD, PhD
Professor of Medicine and Physiology and Biophysics
Stebbins Chair in Cardiology
University of Arkansas for Medical Sciences
Little Rock, AR 72205
Medical Research: What is the background for this study? What are the main findings?
Dr. Mehta: In 2007, ACC/AHA published new guidelines regarding infective endocarditis (IE) prevention. This guideline drastically differed from the way we practiced and prescribed antibiotics to our patients when they undergo surgery or any other procedure like dental procedure, endoscopy, etc. to prevent infective endocarditis. As a result of these guideline, antibiotic use is now being restricted to only a small number of patients who have cardiac conditions that puts them at very high risk for adverse outcomes from IE. However, there is paucity of data on IE trends in the community following such a major change in practice. Therefore evaluated the trend in incidence of infective endocarditis and their outcomes before and after the advent of new guideline.
Our study has several important findings.
First, there has been a steady increase in the incidence of infective endocarditis hospitalizations over the last decade in the US. However, the incidence of IE pre- and post-inception of new antibiotic prophylaxis guidelines is not significantly different. In parallel to these findings, the rate of valve replacement for infective endocarditis did not change after the release of new guidelines in 2007.
Secondly, the increase in IE incidence was seen across all types of pathogens- Staphylococcus, Streptococcus, gram negative bacteria and fungi. The major offender involved in IE in the United States is Staphylococcus.
Finally, the rate of Streptococcus infective endocarditis related hospitalization increased significantly following the release of new guideline in the US, while Staphylococcus IE hospitalizations although on rise, did not increase significantly following the 2007 ACC/AHA guideline update.
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MedicalResearch.com Interview with: Manoj Duraisingh Ph.D.
John LaPorte Given Professor of Immunology and Infectious Diseases
Harvard T.H. Chan School of Public Health
Department of Immunology and Infectious Diseases
Boston, Massachusetts
MedicalResearch: What is the background for this study? What are the main findings?Dr. Duraisingh: The malaria parasite P. falciparum is one of the most important pathogens of humans, with enormous mortality resulting from blood-stage infections, when parasites replicate exponentially in red blood cells. Although anti-Plasmodial drugs are in clinical use, widespread and increasing parasite drug-resistance has contributed to an ongoing public health crisis, and we urgently need to find novel approaches to prevent and treat disease.
Targeting host red blood cell molecules presents an unexploited alternative. However, the highly differentiated and enucleated red blood cell poses a significant technical hurdle for genetic experimentation, due to the lack of a nucleus.
Here we have developed a novel, forward genetic screen to identify critical factors of malaria infection of red blood cells in an unbiased fashion. Our screen takes advantage of recent advances in human stem cell biology that enable the ex vivo culture of red blood cells from nucleated hematopoietic precursors which are amenable to in vitro genetics.
We have now identified a surface molecule CD55 (alias Decay-Accelerating Factor, DAF) as an essential host factor required for the invasion of red blood cells by P. falciparum. We demonstrate that this protein is required by all P. falciparum strains tested (laboratory and field) for invasion. Furthermore, we demonstrate that CD55 acts at the initial stage of invasion when the P. falciparum parasite attaches to the surface of the red blood cell.
Collectively, our findings indicate that CD55 is an ideal target for the development of new host-directed and vaccine therapeutics for malaria.
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MedicalResearch.com Interview with:
Dr. Gordon Langsley
Laboratoire de Biologie Cellulaire Comparative des Apicomplexes,
Institut Cochin, INSERM U1016, CNRS UMR 8104,
Faculté de Medecine
Université Paris Descartes, Paris
Medical Research: What is the background for this study? What are the main findings?
Response: We have been studying the role of cAMP-dependent PKA signaling in Plasmodium falciparum-infected red blood cells for some time; see just a few examples: PMID: 25522250; PMID: 22626931; PMID: 18248092; PMID: 11559352 and we came to the conclusion that intra cellular cAMP levels regulate infected red blood cell deformability and adhesion to for example, brain endothelial cells.
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MedicalResearch.com Interview
Dr. Ludovic Desvignes PhD.
Assistant Professor, Departments of Medicine and Pathology
NYU Langone Medical Center
MedicalResearch: What is the background for this study? Dr. Desvignes: This study is the result of a collaboration at NYU Langone Medical Center, between the laboratories of Dr. Stefan Feske and Dr. Joel Ernst, my mentor. Dr. Feske and colleagues had developed a mouse model of rare, inherited mutations he had identified in infants. These mutations occur in the genes for STIM1 and ORAI1, which are crucial for calcium flux in cells of the immune system. The young patients affected by these mutations suffer from severe, recurrent and chronic infections that often cause death before their first birthday. In particular, some of these patients cannot control infection with BCG, which is a normally innocuous strain of mycobacteria administered to protect against tuberculosis (TB). TB is a chronic infection and one of the leading causes of infection-related death worldwide. Going into this study, Dr. Feske and colleagues knew that without functional calcium channels, immune cells do not function properly. However, they did not fully understand how these channels contribute to immune responses to infectious pathogens in a living organism and in particular, for pathogens that cause chronic infections such as TB. This is why Dr. Ernst and I collaborated with Dr. Feske and provided him with our clinical and research expertise in TB.
MedicalResearch: What are the main findings?Dr. Desvignes: Dr. Feske’s mice are genetically engineered to lack STIM1 in a certain type of immune cells, known as T cells or T lymphocytes. We infected these mice with Mycobacterium tuberculosis, the bacterium causing TB. Mycobacterium tuberculosis causes chronic infection by manipulating the immune system even in healthy people. The first very surprising result of our study was that mice lacking calcium flux in T cells handled acute TB fairly well. Only during the chronic phase of infection did they become unable to control mycobacterial growth and developed a strong inflammation in their lungs, which was due to an infiltration by different types of immune cells, including T cells. We discovered that the accumulation of STIM1-deficient T cells in the lungs resulted from the cells’ inability to die, which is a normal mechanism to limit an immune response and prevent excessive inflammation.
Another immune control mechanism that failed in the absence of STIM1 is mediated by a subset of T cells called induced regulatory T cells, or iTreg cells. These cells are essential to prevent normal immune responses from going “overboard” by suppressing the functions of other immune cells, including T cells. We found that calcium signals are required for the development of iTreg cells and that their numbers were strongly reduced in the lungs of infected STIM1-deficient mice. We therefore think that the lack of iTreg cells in the absence of STIM1 contributes to the severe lung inflammation in chronic TB.
The third finding that really surprised us was that T cells accumulating in the lungs of STIM1-deficient mice produced large amounts of a protein called interferon gamma. While interferon gamma is required to control Mycobacterium tuberculosis, it is also a very potent promoter of inflammation and too much of it can lead to tissue damage. Dr. Feske and colleagues had previously observed that calcium fluxes promote the production of interferon gamma in T cells cultured in vitro and we expected the STIM1-deficient T cells to be defective in the production of that protein. During chronic TB, however, calcium signaling turned out to be not only dispensable for the production of interferon gamma by T cells but it was actually required to limit its production and thus, to control inflammation.
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MedicalResearch.com Interview with:
Dale N. Gerding, MDResearch Physician, Edward Hines, Jr., VA Hospital
Professor, Department of Medicine of Loyola University Chicago Stritch School of Medicine
Medical Research: What is the background for this study? What are the main findings?
Dr. Gerding: Naturally occurring strains of C. difficile lack the genes for production of the toxins that cause C. difficile infection (CDI) and are known as non-toxigenic C. difficile (NTCD). These strains when ingested by patients whose normal microbiota is disrupted by antibiotic treatment will harmlessly colonize the colon and remain in the gut for weeks to months. Specific strains of NTCD found in patients were shown to colonize the gut and prevent C. difficile infection when challenged with toxigenic C. difficile strains in animal models. One such NTCD strain, NTCD-M3, was shown to be safe and well tolerated in human volunteer trials and was used in the present study to determine if it would prevent recurrence of C. difficile infection in patients who had just completed treatment with vancomycin or metronidazole of either their first CDI episode or first recurrence of
C. difficile infection. 168 patients were randomized to receive by mouth in a liquid form, either 10,000 spores/day of NTCD-M3 for 7 days, 10 million spores/day for 7 days, 10 million spores/day for 14 days, or an identical placebo for 14 days. Primary outcome was safety, and secondary outcomes were the percent who colonized the gut with NTCD-M3 in the time period from end of treatment to week 6, and the rate of recurrent CDI in the patients at week 6. The results showed that NTCD-M3 was safe and well tolerated, and colonized the gut of 69% of patients who received it. The C. difficile infection recurrence rate was 30% in the placebo patients and 11% in patients who received any of the NTCD-M3 doses (P<.006). The best dose tested was 10 million spores/day for 7 days which resulted in a recurrence rate of only 5% (p<.01 vs placebo). Colonization of the gut was not permanent, but lasted a maximum of 22 weeks. The summary conclusion is that NTCD-M3 is safe, colonized the gut, and when it colonized the gut, reduced recurrence of C. difficile infection to 2% (p<.001 vs patients who were not colonized).
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MedicalResearch.com Interview with:
Gerardo U. Lopez, M.A.T, M.Ed., Ph.D.
Research Associate
Soil, Water and Environmental Science
The University of Arizona
Tucson, AZ 85721
Medical Research: What is the background for this study? What are the main findings?
Dr. Lopez: The background for this study was based on the missing data gaps on fomite-to-finger transfer in the literature that could be used as input parameters for Quantitative Microbial Risk Assessments (QMRA). This research was supported by the Center for Advancing Microbial Risk Assessment, funded by the U.S. Environmental Agency’s Science To Achieve Results (STAR) program and the U.S. Department of Homeland Security. Two different studies were conducted:
1st “Transfer Efficiency of Bacteria and Viruses from Porous and Nonporous Fomites to Fingers under Different Relative Humidity Conditions” Appl. Environ. Microbial. 2013, 79(18):5728 and
2nd “Evaluation of a Disinfectant Wipe Intervention on Fomite-to-Finger Microbial Transfer”.
This research was supported by The Clorox Company. Based on the findings of these two studies along with other input parameters drawn from previous studies, we were able to develop a risk assessment that focused on forecasting the exposure to Campylobacter jejuni contaminated surfaces during preparation of chicken fillets and how using a disinfectant wipe intervention to clean a contaminated work area decreases the risk of infection following the preparation of raw chicken fillet in a domestic kitchen. The title of our new publication is “Impact of Disinfectant Wipes on the Risk of Campylobacter jejuni Infection During Raw Chicken Preparation in Domestic Kitchens” Accepted for publication in Journal of Applied Microbiology.
Editor's note: For EPA Registered Disinfectant Wipes
The main findings were that the annual risk of C. jejuni infections showed a 99% reduction per person per event from 2 out of 10 to 2 out of 1000.
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MedicalResearch.com Interview with: Jacqueline Hirth, PhD, MPH
Assistant Professor and
Dr. Abbey B. Berenson MD, MMS, PhD
Center for Interdisciplinary Research in Women's Health
Obstetrics and Gynecology
The University of Texas Medical Branch at Galveston Texas
Medical Research: What is the background for this study? What are the main findings?
Response: In this sample of young women, vaccination was effective at reducing prevalence of vaccine-type HPV (6,11,16,18) compared to women who were unvaccinated. We also found a dose response, with young women who received at least 2 doses of the 3 dose vaccine series having a lower rate of vaccine-type HPV compared to those who only received one dose (8.6% compared to 16.9%, respectively).
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MedicalResearch.com Interview with:Mary J Hamel, M.D.
Chief, Strategic and Applied Sciences Unit,
And Deputy Branch Chief for Science, CDC Malaria Branch
US Centers for Disease Control and Prevention
1600 Clifton Rd, NE, MS A06
Atlanta GA 30333
Dr. Hamel was principal investigator at the Siaya site in western Kenya.Medical Research: What is the background for this study? What are the main findings?Dr. Hamel: Major progress has been made in malaria control during the past decade with the scale up of proven interventions including insecticide treated nets (ITNs), indoor residual spraying, effective diagnosis and treatment for malaria, and intermittent preventive treatment of malaria in pregnancy. Nonetheless, malaria remains a major cause of morbidity and mortality, and a leading cause of pediatric death worldwide. An estimated 198 million cases of malaria and 580,000 deaths occurred in 2013 – most of these in African children.
Now we face additional challenges in malaria control – the emergence of insecticide and drug resistance threatens some of our most effective interventions. New tools are needed to reach the goal of malaria elimination and eventual eradication. Vaccines are some of our most cost-effective interventions, and an effective malaria vaccine would be an important addition to our current malaria control tools.
This week, the RTS,S Clinical Trials Partnership published the final vaccine efficacy and safety results from the RTS,S/AS01 malaria vaccine phase 3 trial in the Lancet (Efficacy and safety of RTS,S/AS01 malaria vaccine with or without a booster dose in infants and children in Africa: final results of a phase 3, individually randomised, controlled trial, http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)60721-8/abstract). This large randomized controlled double-blind phase 3 clinical trial was conducted in 11 sites in 7 African countries across a range of malaria transmission levels. In all, 15,460 children and young infants were enrolled in two age-categories, those first vaccinated at 5-17 months of age (referred to as children), and those first vaccinated at 6-12 weeks of age (referred to as young infants) who received the RTS,S/AS01 vaccine along with their routine childhood immunizations. Participants were randomized into 3 groups – the first group received three doses of the RTS,S/AS01 vaccine followed 18 months later by a booster dose; the second group received three doses of the RTS,S/AS01 vaccine without a booster; and the third group received a comparator vaccine. All participants received an ITN. Children were followed for an average of 48 months and infants for an average of 38 months.
We found that vaccine efficacy was modest. Vaccine efficacy against clinical malaria in children was 36% with a booster and 28% without, and vaccine efficacy against severe malaria was 32% with a booster and non-significant without. Efficacy results in young infants were lower than those in children– vaccine efficacy against clinical malaria was 36% with a booster and 28% without, and vaccine efficacy against severe malaria was non-significant.
However, impact, defined as the number of cases averted per 1000 participants vaccinated, was substantial in both age-categories, and highest where malaria burden was greatest. In children who received the booster, during 4 years follow-up, 1700 cases of clinical malaria were averted per 1000 children vaccinated. In young infants, during 3 years follow-up, nearly 1000 cases were averted per 1000 young infants vaccinated.
The safety findings were comparable overall in the different study arms, but two safety findings are notable. Meningitis occurred more frequently among children (but not young infants) who received RTS,S/AS01 than among those who received the comparator vaccines. There was no relationship between when the vaccine was administered and when meningitis occurred, most cases occurred in only two study sites, and the finding may be due to chance. If RTS,S/AS01 is licensed, post-licensing studies will be done to establish the significance of this finding. Both children and young infants experienced more episodes of fever and associated febrile convulsions during the 7 days following vaccination; convulsions occurred in 2.2 - 2.5/1000 vaccine doses. (more…)
MedicalResearch.com Interview with:
Ojan Assadian, M.D., DTMH
Professor for Skin Integrity and Infection Prevention
Institute for Skin Integrity and Infection Prevention
School of Human & Health Sciences
University of Huddersfield
Queensgate, Huddersfield UK
MedicalResearch: What is the background for this study? What are the main findings?
Prof. Assadian: Although medical gloves serve as an important mechanical barrier to prevent healthcare workers’ hands from getting contaminated with potentially pathogenic microorganisms, their inappropriate and incorrect use may support microbial transmission, eventually resulting in indirect horizontal cross-contamination of other patients.
We conducted a clinical study designed to determine the efficacy of a newly developed synthetic antibacterial nitrile medical glove coated with an antiseptic, polyhexamethylen-biguanid hydrochloride (PHMB), on its external surface, and compared this antibacterial glove to an identical non-antibacterial glove in reducing surface contamination after common patient care measures in an intensive care unit.
We found significantly lower numbers of bacteria on surfaces after performing typical clinical activities such as intravenous fluid handling, oral toilet, or physiotherapy, if touched with antibacterial gloves.
(more…)
MedicalResearch.com Interview with:
Erwin Duizer, PhD
Head of section Enteric Viruses
Centre for Infectious Diseases Control
National Institute for Public Health and the Environment
The Netherlands
Medical Research: What is the background for this study?
Dr. Duizer: Hand hygiene is important for interrupting the transmission chain of viruses through hands. Alcohol-based hand disinfectants are widely used in hospitals and healthcare facilities, due to convenience, rapidity, and broad acceptance by healthcare personnel. The effectiveness of alcohol-based hand disinfectant has been shown for bacteria and enveloped viruses but their effectiveness in reducing transmission of non-enveloped viruses, such as norovirus, is less certain. Therefore we tested, in a joint project of the RIVM and Wageningen University, the virucidal activity of a propanol based product and an ethanol based product in quantitative carrier tests. Additionally, the virus reducing effect of hand washing (according to health care guidelines) and the use the propanol based product was tested in a quantitative finger pad test. (more…)
MedicalResearch.com Interview with:
Lillian Siu, MD, FRCPC
Princess Margaret Cancer Centre
University Health Network
Toronto
Medical Research: What is the background for this study? What are the main findings?
Dr. Siu: Our study is a collaboration between researchers at the Princess Margaret Cancer Centre and the Canadian Center for Applied Research in Cancer Control. The study involves a statistical model being applied to a hypothetical population of 192,940 Canadian boys who were 12 years old in 2012, to determine the cost effectiveness of HPV vaccination for the prevention of oropharyngeal cancer. On the basis of this model, HPV vaccination for boys aged 12 years appears to be a cost-effective strategy for the prevention of oropharyngeal cancer in Canada. There are limitations to our study as it is based on statistical modelling with many assumptions. For instance, we could not easily address the impact of herd immunity which refers to the indirect protective effect offered by HPV vaccination in women.
Based on our statistical model, despite its limitations, the vaccine can potentially save $8 to $28 million CAD for a theoretical group of 192,940 Canadian 12-year old boys in 2012 over their lifetime. As stated, this is based on a theoretical model and not a randomized study, the results are relevant especially that HPV-related oropharyngeal cancer is increasing in incidence and HPV is surpassing smoking as a risk factor for this cancer in many developed countries.
Currently, the National Advisory Committee on Immunization (NACI) of the Public Health Agency of Canada recommends HPV vaccination of females 9 through 26 years of age to prevent cervical, vulvar, vaginal and anal cancers, and for anogenital warts; and of males 9 through 26 years of age to prevent anal canal cancers and their precursors, and for anogenital warts. However, funding is also provided for HPV vaccination in young females and not in young males.
(more…)
MedicalResearch.com Interview with:
Arnon D. Cohen, MD, MPH, PhD
Department of Quality Measurements and Research, Chief Physician's Office, Clalit Health Services, Tel Aviv
Siaal Research...
MedicalResearch.com Interview with:
Catherine M. Stein, PhD
Associate professor of epidemiology and biostatistics
Case Western Reserve
Dr. Stein is a leader of international research on resistance to Mycobacterium tuberculosis (MTB) infection
MedicalResearch: What is the background for this study? What do you hope to learn?Dr. Stein: In a 2002 study, we began to clinically characterize people who lived in households where there were infectious tuberculosis cases. We followed them for a two-year period and noticed that approximately 9 percent of household members were resistant to Mycobacterium tuberculosis (MTB) infection, even though they were highly exposed to the organism. This finding surprised us because the prevailing notion had been that everyone living in TB-endemic settings or living with someone who has TB would become infected eventually. After several years of study, we found a substantial number of these people who do not have any evidence for MTB infection, so we wanted to do studies to learn if we could figure out why.
MedicalResearch: Is MTB resistance a new phenomenon? Do MTB resisters react to a tuberculin purified protein derivative (PPD) or a gold immunoassay but don’t develop clinical disease?Dr. Stein: We don’t have any reason to believe that MTB-infection resistance is a new phenomenon. It’s just that no one has thought to look for it before. In terms of the PPD or gold immunoassays, MTB-resisters produce a negative response to both tests. The way gold immunoassays are done, three tubes are collected. One is a control. Another is a test for reacting to MTB. Still another is a positive control to make sure immune cells are alive. The MTB-resisters show a response to that positive control but not to MTB. It’s not that these patients don’t have an immune response. It’s just that they have no response to MTB, which means they have no previous exposure to cause their T-cells to make that response.
MedicalResearch: Are MTB-resisters immune to the newer multi-drug resistant strains of TB?Dr. Stein: Resistance to MTB infection is independent of the drug resistance pattern of the bacteria. Thus we would expect them to resist multidrug resistant (MDR)-TB as well. There is no strong evidence that MDR-TB is more aggressive or virulent.
(more…)
MedicalResearch.com Interview with:
Luis Squiquera, MD
Tamir Biotechnology
MedicalResearch: What is the background for this study? What are the main findings?Dr. Squiquera: Ranpirnase is a small peptide that has a characteristic enzymatic activity against double stranded RNA (dsRNA). As a drug it has been extensively tested intravenously in high concentration for oncology in over 1000 patients with different types of malignancy, especially mesothelioma, with minimal side effects and mainly a transient increase of serum creatinine level observed.
In the last year we started a comprehensive antiviral program and obtained encouraging results in several RNA and DNA virus families. Several research groups have already studied the anti HIV activity. HPV was one of many viruses that showed a high selectivity index in our antiviral screening (the relationship between efficacy and cytotoxicity). We were encouraged by the low concentrations (nanomolar range) needed to stop virus reproduction in cell cultures. We performed in vitro analysis of two of the main HPV types that cause human disease (HPV 11 and 16). HPV 11 was highly sensitive to ranpirnase; and since this is one of the main virus type responsible for inducing genital warts, we decided to focus our efforts in bringing the drug to a new route of administration.
We set out to obtain and did obtain a formulation that was extremely stable, even at high temperatures. Before using it in patients, we performed testing for irritation using standardized Draize animal models. Even though we ran these tests in high concentrations (1 mg/ml) the final product was not irritant and was deemed safe to use in a clinical setting.
With these safety data on hand – plus extensive experience in IV dosing and non-irritation in animal models – we decided to make the formulation available as a compassionate use for patients with genital warts.
As we reported in our presentation in San Francisco, all cases that completed an 8-week treatment showed clearance of the lesions. Some of the cases were cleared in as soon as two weeks and the average time for clearance was 33 days. One of the patients had to be discontinued due to an eczematous skin reaction. We will be studying the characteristic of this effect in our trials. (more…)
MedicalResearch.com Interview with:
Marya Viorst Gwadz, Ph.D
Senior Research Scientist Director,
Transdisciplinary Methods Core
Center for Drug Use and HIV Research (CDUHR)
New York University College of Nursing
New York, NY 10010Medical Research: What is the background for this study?
Dr. Gwadz: HIV is a major success story in that the tolerability, convenience, and efficacy of antiretroviral medications have improved dramatically over the last decade. A number of years ago in the course of another research study with vulnerable individuals infected with HIV in New York City, and we noticed that a substantial proportion of study participants were medically eligible for HIV medications, and had access to medications, but had declined or stopped taking them. We then turned our attention to understanding why this is the case, that is, to identify the individual, social, and structural barriers that persons living with HIV/AIDS (PLHA) experience to antiretroviral therapy. We focused in particular on African American/Black and Latino/Hispanic PLHA, because the overall emphasis of our research group at the NYU College of Nursing is the development and evaluation of culturally targeted intervention approaches to address health disparities. Around 2011, studies of the “HIV cascade of care” began to emerge, which highlighted the problem of poor engagement in HIV care and antiretroviral therapy nationally. The ultimate goal of HIV treatment is viral suppression, but at present, the Centers for Disease Control and Prevention (CDC) estimates that we have achieved that goal with only 30% of PLHA.
Medical Research: What kind of intervention approach that emerged from these background findings?Dr. Gwadz: We found that barriers to HIV medication are complex and multi-faceted for PLHA from African American/Black and Latino/Hispanic backgrounds. In particular, PLHA experience serious emotional barriers to the uptake of HIV medications, such as fear of side effects, stigma, and disclosure of HIV status. Further, high rates of substance use and mental health distress, and barriers to accessing services for these concerns, impede medication uptake. Moreover, PLHA who are wary of HIV medication tend to avoid HIV primary care, often because they do not want to feel pressured to take medications, or explain to their providers why they are not taking them. So poor engagement in HIV care, which is very common among PLHA, and low uptake of HIV medication are actually related problems.
With funding from the National Institute of Mental Health (grant #R34MH093352), and in collaboration with Mount Sinai Beth Israel and Mount Sinai St. Luke’s-Roosevelt Hospital Center, we developed a multi-component culturally targeted intervention grounded in the Motivational Interviewing approach that included three individual sessions, 12-24 weeks of patient navigation (as needed), up to five support groups with other PLHA who had declined medication, which were co-led by a “successful” peer who was engaged in HIV care and were taking HIV medication with good adherence. One novel aspect of the intervention was its focus on emotional barriers to HIV medication, and the program’s “no pressure, no judgment” stance, congruent with the Motivational Interviewing approach, was key to engaging participants into the study to talk about these difficult issues.
(more…)
MedicalResearch.com Interview with:
Amalia Z. Berna
CSIRO Food and Nutrition Flagship
Acton ACT 2601
MedicalResearch: What is the background for this study? What are the main findings?Response: Globally an estimated 3.2 billion people in 97 countries are at risk of malaria and, in 2013, an estimated 198 million cases and 584,000 deaths were attributed to this infection. Accurate diagnosis of malaria is important to provide adequate treatment, conserve valuable drugs, and help prevent the emergence of resistant strains of the parasite. It is becoming important to be able to diagnose low level and asymptomatic cases, to support the drive towards local and/or global eradication.
Detection of volatile chemicals in expired breath has been used to diagnose or monitor a small number of diseases, including Helicobacterpylori infection, diabetes and lung inflammation but, if breath analysis is to be more broadly useful, we need to identify reliable biomarkers for a wider range of diseases and to develop more robust methods for breath analysis.
In collaboration with Professor James McCarthy of the QIMR Berghofer Institute and Associate Professor Kevin Saliba of the ANU, we found:
Four specific thioether biomarkers in the breath of volunteers with experimentally induced blood stage Plasmodium falciparum
That the levels of the volatiles strongly correlate with the levels of malaria parasitaemia.
That the thioethers are not produced by in vitro cultures of falciparum.
That although we do not know the metabolic origin of the thioethers, our results suggest that interplay between host and parasite metabolic pathways is involved in their production.
We think it is important to emphasise that no volunteer was infected with malaria primarily for the purpose of this study. Our research was entirely piggy-backed on pre-existing trials of malaria therapeutics.
(more…)
MedicalResearch.com Interview with:
Dr Richard Forshee PhDAssociate Director for Research in the Office of Biostatistics and Epidemiology Center for Biologics Evaluation and Research
U.S. Food and Drug Administration
Silver Spring, MD
On behalf of the study authorsMedical Research: What is the background for this study? What are the main findings?
Dr. Forshee: Influenza continues to be a major public health concern causing illness, hospitalization, and death. The elderly are at highest risk for seasonal influenza complications, including hospitalization and death. As people grow older their ability to raise a strong protective immune response can weaken. The availability of a vaccine that uses a higher dose to induce a stronger immune response could reduce the serious impact of influenza in this age group. The purpose of this study was to determine whether a high-dose inactivated influenza vaccine was more effective for prevention of probable influenza infections and influenza-related hospital admissions, compared to standard-dose inactivated influenza recipients.
In December 2009, the U.S. Food and Drug Administration (FDA) licensed Fluzone High Dose, an injectable inactivated trivalent seasonal influenza vaccine for people ages 65 years and older. This high-dose vaccine contains four times more hemagglutinin—the active ingredient in influenza vaccines that cause the human body to produce antibodies against the influenza viruses—than the standard-dose vaccine. The FDA approved the high-dose vaccine using the accelerated approval regulatory pathway, which allows the agency to approve products for serious or life-threatening diseases based on reasonable evidence of a product’s effectiveness. This pathway reduces the time it takes for needed medical products to become available to the public. Studies conducted prior to licensure showed an enhanced immune response to the high-dose vaccine compared with the standard-dose vaccine in individuals 65 years of age and older indicating that the high-dose vaccine was reasonably likely to be more effective in preventing influenza disease.
As part of the accelerated approval process, the manufacturer, Sanofi Pasteur, was required to conduct a randomized clinical study post-licensure to confirm that the high-dose vaccine decreased seasonal influenza disease after vaccination relative to standard dose vaccine. This confirmatory study demonstrated that the high–dose vaccine prevented 24% more cases of laboratory-confirmed influenza illness compared to standard-dose vaccines in people 65 years of age and older. However, the study was not large enough to determine efficacy of the vaccine against severe disease.
A team of scientists from FDA, the Centers for Disease Control and Prevention, Centers for Medicare and Medicaid Services, and Acumen LLC ( an independent research organization) studied the relative effectiveness of the high-dose influenza vaccine in the U.S. population ages 65 years and older. The observational study, which covered the 2012-2013 influenza season, found a significant reduction both in influenza-associated illness and in influenza-related hospitalizations among individuals who received the high-dose vaccine, compared to those receiving the standard dose.
Additional background about this study: “Comparative effectiveness of high-dose versus standard-dose influenza vaccines in US residents aged 65 years and older from 2012 to 2013 using Medicare data: a retrospective cohort analysis” is available at:
http://dx.doi.org/10.1016/S1473-3099(14)71087-4
A commentary on the study titled “Novel observational study designs with new influenza vaccines” is available at:
http://dx.doi.org/10.1016/S1473-3099(15)70020-4(more…)
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