Category: Hot Topics in Research

Hot Topics: Experimental Ebola Vaccine Gives 100% Protection

Efficacy and effectiveness of an rVSV-vectored vaccine in preventing Ebola virus disease: final results from the Guinea ring vaccination, open-label, cluster-randomised trial (Ebola Ça Suffit!)

Henao-Restrepo A, Camacho A, Longini IM, et al. Efficacy and effectiveness of an rVSV-vectored vaccine in preventing ebola virus disease: Final results from the guinea ring vaccination, open-label, cluster-randomised trial (ebola ça suffit!). The Lancet. http://dx.doi.org/10.1016/S0140-6736(16)32621-6.

Background
rVSV-ZEBOV is a recombinant, replication competent vesicular stomatitis virus-based candidate vaccine expressing a surface glycoprotein of Zaire Ebolavirus. We tested the effect of rVSV-ZEBOV in preventing Ebola virus disease in contacts and contacts of contacts of recently confirmed cases in Guinea, west Africa.

Methods
We did an open-label, cluster-randomised ring vaccination trial (Ebola ça Suffit!) in the communities of Conakry and eight surrounding prefectures in the Basse-Guinée region of Guinea, and in Tomkolili and Bombali in Sierra Leone. We assessed the efficacy of a single intramuscular dose of rVSV-ZEBOV (2×107 plaque-forming units administered in the deltoid muscle) in the prevention of laboratory confirmed Ebola virus disease. After confirmation of a case of Ebola virus disease, we definitively enumerated on a list a ring (cluster) of all their contacts and contacts of contacts including named contacts and contacts of contacts who were absent at the time of the trial team visit. The list was archived, then we randomly assigned clusters (1:1) to either immediate vaccination or delayed vaccination (21 days later) of all eligible individuals (eg, those aged ≥18 years and not pregnant, breastfeeding, or severely ill). An independent statistician generated the assignment sequence using block randomisation with randomly varying blocks, stratified by location (urban vs rural) and size of rings (≤20 individuals vs >20 individuals). Ebola response teams and laboratory workers were unaware of assignments. After a recommendation by an independent data and safety monitoring board, randomisation was stopped and immediate vaccination was also offered to children aged 6–17 years and all identified rings. The prespecified primary outcome was a laboratory confirmed case of Ebola virus disease with onset 10 days or more from randomisation. The primary analysis compared the incidence of Ebola virus disease in eligible and vaccinated individuals assigned to immediate vaccination versus eligible contacts and contacts of contacts assigned to delayed vaccination. This trial is registered with the Pan African Clinical Trials Registry, number PACTR201503001057193.

Findings
In the randomised part of the trial we identified 4539 contacts and contacts of contacts in 51 clusters randomly assigned to immediate vaccination (of whom 3232 were eligible, 2151 consented, and 2119 were immediately vaccinated) and 4557 contacts and contacts of contacts in 47 clusters randomly assigned to delayed vaccination (of whom 3096 were eligible, 2539 consented, and 2041 were vaccinated 21 days after randomisation). No cases of Ebola virus disease occurred 10 days or more after randomisation among randomly assigned contacts and contacts of contacts vaccinated in immediate clusters versus 16 cases (7 clusters affected) among all eligible individuals in delayed clusters. Vaccine efficacy was 100% (95% CI 68·9–100·0, p=0·0045), and the calculated intraclass correlation coefficient was 0·035. Additionally, we defined 19 non-randomised clusters in which we enumerated 2745 contacts and contacts of contacts, 2006 of whom were eligible and 1677 were immediately vaccinated, including 194 children. The evidence from all 117 clusters showed that no cases of Ebola virus disease occurred 10 days or more after randomisation among all immediately vaccinated contacts and contacts of contacts versus 23 cases (11 clusters affected) among all eligible contacts and contacts of contacts in delayed plus all eligible contacts and contacts of contacts never vaccinated in immediate clusters. The estimated vaccine efficacy here was 100% (95% CI 79·3–100·0, p=0·0033). 52% of contacts and contacts of contacts assigned to immediate vaccination and in non-randomised clusters received the vaccine immediately; vaccination protected both vaccinated and unvaccinated people in those clusters. 5837 individuals in total received the vaccine (5643 adults and 194 children), and all vaccinees were followed up for 84 days. 3149 (53·9%) of 5837 individuals reported at least one adverse event in the 14 days after vaccination; these were typically mild (87·5% of all 7211 adverse events). Headache (1832 [25·4%]), fatigue (1361 [18·9%]), and muscle pain (942 [13·1%]) were the most commonly reported adverse events in this period across all age groups. 80 serious adverse events were identified, of which two were judged to be related to vaccination (one febrile reaction and one anaphylaxis) and one possibly related (influenza-like illness); all three recovered without sequelae.

Interpretation
The results add weight to the interim assessment that rVSV-ZEBOV offers substantial protection against Ebola virus disease, with no cases among vaccinated individuals from day 10 after vaccination in both randomised and non-randomised clusters.

Henao-Restrepo A, Camacho A, Longini IM, et al. Efficacy and effectiveness of an rVSV-vectored vaccine in preventing ebola virus disease: Final results from the guinea ring vaccination, open-label, cluster-randomised trial (ebola ça suffit!). The Lancet. http://dx.doi.org/10.1016/S0140-6736(16)32621-6.

Posted in Hot Topics in Research, Infectious Disease, Internal Medicine, January

Hot Topics: Common Gene Sets Link Bipolar Disorder, Major Depression, and Schizophrenia

Consistently altered expression of gene sets in postmortem brains of individuals with major psychiatric disorders

Darby M,M., Yolken R,H., Sabunciyan S. Consistently altered expression of gene sets in postmortem brains of individuals with major psychiatric disorders. Transl Psychiatry. 2016;6:e890. http://dx.doi.org/10.1038/tp.2016.173.

The measurement of gene expression in postmortem brain is an important tool for understanding the pathogenesis of serious psychiatric disorders. We hypothesized that major molecular deficits associated with psychiatric disease would affect the entire brain, and such deficits may be shared across disorders. We performed RNA sequencing and quantified gene expression in the hippocampus of 100 brains in the Stanley Array Collection followed by replication in the orbitofrontal cortex of 57 brains in the Stanley Neuropathology Consortium. We then identified genes and canonical pathway gene sets with significantly altered expression in schizophrenia and bipolar disorder in the hippocampus and in schizophrenia, bipolar disorder and major depression in the orbitofrontal cortex. Although expression of individual genes varied, gene sets were significantly enriched in both of the brain regions, and many of these were consistent across diagnostic groups. Further examination of core gene sets with consistently increased or decreased expression in both of the brain regions and across target disorders revealed that ribosomal genes are overexpressed while genes involved in neuronal processes, GABAergic signaling, endocytosis and antigen processing have predominantly decreased expression in affected individuals compared to controls without a psychiatric disorder. Our results highlight pathways of central importance to psychiatric health and emphasize messenger RNA processing and protein synthesis as potential therapeutic targets for all three of the disorders.

Posted in Hot Topics in Research, January, Mood Disorders, Psychology and Psychiatry, Schizophrenia

A Comparison of the Prevalence of Dementia in the United States in 2000 and 2012

A Comparison of the Prevalence of Dementia in the United States in 2000 and 2012

Importance  The aging of the US population is expected to lead to a large increase in the number of adults with dementia, but some recent studies in the United States and other high-income countries suggest that the age-specific risk of dementia may have declined over the past 25 years. Clarifying current and future population trends in dementia prevalence and risk has important implications for patients, families, and government programs.

Objective  To compare the prevalence of dementia in the United States in 2000 and 2012.

Design, Setting, and Participants  We used data from the Health and Retirement Study (HRS), a nationally representative, population-based longitudinal survey of individuals in the United States 65 years or older from the 2000 (n = 10 546) and 2012 (n = 10 511) waves of the HRS.

Main Outcomes and Measures  Dementia was identified in each year using HRS cognitive measures and validated methods for classifying self-respondents, as well as those represented by a proxy. Logistic regression was used to identify socioeconomic and health variables associated with change in dementia prevalence between 2000 and 2012.

Results  The study cohorts had an average age of 75.0 years (95% CI, 74.8-75.2 years) in 2000 and 74.8 years (95% CI, 74.5-75.1 years) in 2012 (P = .24); 58.4% (95% CI, 57.3%-59.4%) of the 2000 cohort was female compared with 56.3% (95% CI, 55.5%-57.0%) of the 2012 cohort (P < .001). Dementia prevalence among those 65 years or older decreased from 11.6% (95% CI, 10.7%-12.7%) in 2000 to 8.8% (95% CI, 8.2%-9.4%) (8.6% with age- and sex-standardization) in 2012 (P < .001). More years of education was associated with a lower risk for dementia, and average years of education increased significantly (from 11.8 years [95% CI, 11.6-11.9 years] to 12.7 years [95% CI, 12.6-12.9 years]; P < .001) between 2000 and 2012. The decline in dementia prevalence occurred even though there was a significant age- and sex-adjusted increase between years in the cardiovascular risk profile (eg, prevalence of hypertension, diabetes, and obesity) among older US adults.

Conclusions and Relevance  The prevalence of dementia in the United States declined significantly between 2000 and 2012. An increase in educational attainment was associated with some of the decline in dementia prevalence, but the full set of social, behavioral, and medical factors contributing to the decline is still uncertain. Continued monitoring of trends in dementia incidence and prevalence will be important for better gauging the full future societal impact of dementia as the number of older adults increases in the decades ahead.

 

Kenneth M. Langa, MD, PhD1,2,3,4; Eric B. Larson, MD, MPH5; Eileen M. Crimmins, PhD6; et alJessica D. Faul, PhD3; Deborah A. Levine, MD, MPH; Mohammed U. Kabeto, MS; David R. Weir, PhD 
JAMA Intern Med. Published online November 21, 2016. doi:10.1001/jamainternmed.2016.6807
Posted in Alzheimer Disease, December, Dementia, Hot Topics in Research

Phenotype-Specific Treatment of Heart Failure With Preserved Ejection Fraction

Phenotype-Specific Treatment of Heart Failure With Preserved Ejection Fraction

Heart failure (HF) with preserved ejection fraction (EF; HFpEF) accounts for 50% of HF cases, and its prevalence relative to HF with reduced EF continues to rise. In contrast to HF with reduced EF, large trials testing neurohumoral inhibition in HFpEF failed to reach a positive outcome. This failure was recently attributed to distinct systemic and myocardial signaling in HFpEF and to diversity of HFpEF phenotypes. In this review, an HFpEF treatment strategy is proposed that addresses HFpEF-specific signaling and phenotypic diversity. In HFpEF, extracardiac comorbidities such as metabolic risk, arterial hypertension, and renal insufficiency drive left ventricular remodeling and dysfunction through systemic inflammation and coronary microvascular endothelial dysfunction. The latter affects left ventricular diastolic dysfunction through macrophage infiltration, resulting in interstitial fibrosis, and through altered paracrine signaling to cardiomyocytes, which become hypertrophied and stiff because of low nitric oxide and cyclic guanosine monophosphate. Systemic inflammation also affects other organs such as lungs, skeletal muscle, and kidneys, leading, respectively, to pulmonary hypertension, muscle weakness, and sodium retention. Individual steps of these signaling cascades can be targeted by specific interventions: metabolic risk by caloric restriction, systemic inflammation by statins, pulmonary hypertension by phosphodiesterase 5 inhibitors, muscle weakness by exercise training, sodium retention by diuretics and monitoring devices, myocardial nitric oxide bioavailability by inorganic nitrate-nitrite, myocardial cyclic guanosine monophosphate content by neprilysin or phosphodiesterase 9 inhibition, and myocardial fibrosis by spironolactone. Because of phenotypic diversity in HFpEF, personalized therapeutic strategies are proposed, which are configured in a matrix with HFpEF presentations in the abscissa and HFpEF predispositions in the ordinate.

 

Sanjiv J. Shah, Dalane W. Kitzman, Barry A. Borlaug, Loek van Heerebeek, Michael R. Zile, David A. Kass and Walter J. Paulus

Posted in Cardiology, coronary artery disease, December, Hot Topics in Research

A Souvenir Smuggled Home From Cuba: A Cancer Vaccine

A Souvenir Smuggled Home From Cuba: A Cancer Vaccine

Lung cancer patients are travelling to Cuba.

 

Posted in December, Hot Topics in Research, Lung, News, Oncology

Sexual Health in Women Affected by Cancer: Focus on Sexual Pain

Sexual Health in Women Affected by Cancer: Focus on Sexual Pain

As cancer therapies improve, the number of women surviving or living long lives with cancer continues to increase. Treatment modalities, including surgery, chemotherapy, radiotherapy, and hormonal therapy, affect sexual function and may cause sexual pain through a variety of mechanisms, depending on treatment type. Adverse sexual effects resulting from ovarian damage, anatomic alterations, and neurologic, myofascial, or pelvic organ injury may affect more than half of women affected by cancer. Despite the fact that no specialty is better qualified to render care for this consequence of cancer treatments, many obstetrician–gynecologists (ob-gyns) feel uncomfortable or ill-equipped to address sexual pain in women affected by cancer. Asking about sexual pain and dyspareunia and performing a thorough physical examination are essential steps to guide management, which must be tailored to individual patient goals. Understanding the cancer treatment-related pathophysiology of sexual pain aids in providing this care. Effective mechanism-based treatments for sexual pain and dyspareunia are available, and by using them, knowledgeable ob-gyns can enhance the quality of life of potentially millions of women affected by cancer.

 

Deborah Coady, MD, and Vanessa Kennedy, MD

Obstet Gynecol 2016;128:775–91    DOI: 10.1097/AOG.0000000000001621

Posted in December, Hot Topics in Research, Oncology

Ethics Reporting in Biospecimen and Genetic Research: Current Practice and Suggestions for Changes

Ethics Reporting in Biospecimen and Genetic Research: Current Practice and Suggestions for Changes

Modern approaches for research with human biospecimens employ a variety of substantially different types of ethics approval and informed consent. In most cases, standard ethics reporting such as “consent and approval was obtained” is no longer meaningful. A structured analysis of 120 biospecimen studies recently published in top journals revealed that more than 85% reported on consent and approval, but in more than 90% of cases, this reporting was insufficient and thus potentially misleading. Editorial policies, reporting guidelines, and material transfer agreements should include recommendations for meaningful ethics reporting in biospecimen research. Meaningful ethics reporting is possible without higher word counts and could support public trust as well as networked research.

 

Chin, W. W. L., Wieschowski, S., Prokein, J., Illig, T., & Strech, D. (2016). Ethics Reporting in Biospecimen and Genetic Research: Current Practice and Suggestions for Changes. PLoS Biology, 14(8), e1002521. http://doi.org/10.1371/journal.pbio.1002521

Posted in Ethics, Hot Topics in Research, September

What’s Wrong with Human/Nonhuman Chimera Research?

Perspective: What’s Wrong with Human/Nonhuman Chimera Research?

The National Institutes of Health (NIH) is poised to lift its funding moratorium on research involving chimeric human/nonhuman embryos, pending further consideration by an NIH steering committee. The kinds of ethical concerns that seem to underlie this research and chimera research more generally can be adequately addressed.

 

Hyun I (2016) What’s Wrong with Human/ Nonhuman Chimera Research? PLoS Biol 14(8): e1002535. doi:10.1371/journal.pbio.1002535

Posted in Hot Topics in Research, Research Commentary, September

Equal work for unequal pay: the gender reimbursement gap for healthcare providers in the United States

Equal work for unequal pay: the gender reimbursement gap for healthcare providers in the United States

ABSTRACT Introduction Gender disparities in income continue to exist, and many studies have quantified the gap between male and female workers. These studies paint an incomplete picture of gender income disparity because of their reliance on notoriously inaccurate or incomplete surveys. We quantified gender reimbursement disparity between female and male healthcare providers using objective, non-self-reported data and attempted to adjust the disparity against commonly held beliefs as to why it exists. Methods We analysed over three million publicly available Medicare reimbursement claims for calendar year 2012 and compared the reimbursements received by male and female healthcare providers in 13 medical specialties. We adjusted these reimbursement totals against how hard providers worked, how productive each provider was, and their level of experience. We calculated a reimbursement differential between male and female providers by primary medical specialty. Results The overall adjusted reimbursement differential against female providers was −US$18 677.23 (95% CI −US$19 301.94 to −US$18 052.53). All 13 specialties displayed a negative reimbursement differential against female providers. Only two specialties had reimbursement differentials that were not statistically significant. Conclusions After adjustment for how hard a physician works, his/her years of experience and his/her productivity, female healthcare providers are still reimbursed less than male providers. Using objective, non-survey data will provide a more accurate understanding of this reimbursement inequity and perhaps lead the medical profession (as a whole) towards a solution that can reverse this decades-old injustice.

 

Desai T, et al. Postgrad Med J 2016;0:1–5. doi:10.1136/postgradmedj-2016-134094 1

Original article PGMJ Online First, published on August 15, 2016 as 10.1136/postgradmedj-2016-134094

Produced by BMJ Publishing Group

Posted in Hot Topics in Research, News, September

Finding the Why, Changing the How: Improving the Mental Health of Medical Students, Residents, and Physicians

Finding the Why, Changing the How: Improving the Mental Health of Medical Students, Residents, and Physicians

The poor mental health of residents, characterized by high rates of burnout, depression, and suicidal ideation, is a growing concern in graduate medical education. Research is needed to gain a deeper understanding of the sources of distress as well as the sources of sustenance in residency training. The study by Mata and colleagues contributes significantly to this understanding. In addition to this line of research, however, studies are needed that assess the impact of interventions to help residents deal more effectively with the stress of training and find meaning in their work. Given the stresses of residency training, this approach may not make a dramatic difference in mental health outcomes. Efforts directed at changing the educational and clinical environments are also needed to reduce unnecessary stressors and create more positive settings for learning and clinical care. Since 2011, Saint Louis University School of Medicine has been pursuing a multipronged strategy to address these issues in the preclinical years. These efforts have led to dramatic decreases in depression and anxiety symptoms in students. An essential component of these interventions is the ongoing measurement of mental health outcomes across all four years of the curriculum. Leaders of residency programs, medical schools, and hospitals need to have the courage to measure these kinds of outcomes to spur change and track the efficacy of programs.

 

Slavin, Stuart J. MD, MEd; Chibnall, John T. PhD

Academic Medicine
Issue: Volume 91(9), September 2016, p 1194-1196
Copyright: (C) 2016 by the Association of American Medical Colleges
DOI: 10.1097/ACM.0000000000001226
Posted in Hot Topics in Research, Psychology and Psychiatry, Research Commentary, September