Responsibly Turning Epidemiological Findings into Public Health Recommendations James C Coyne PhD Emeritus Professor Department of Psychiatry School of Medicine University of Pennsylvania USA

Dr James C Coyne, PhD is Professor of Health Psychology at University Medical Center, Groningen, the Netherlands where he teaches scientific writing and critical thinking. He is also Distinguished Visiting Professor, Institute for Health, Health Care Policy & Aging Research, Rutgers, the State University of New Jersey. Dr Coyne is Emeritus Professor of Psychology in Psychiatry at University of Pennsylvania, where he was also Director of Behavioral Oncology, Abramson Cancer Center and Senior Fellow, Leonard Davis Institute of Health Economics. He served as External Scientific Advisor to a decade of European Commission funded community based programs to improve care for depression in the community. He has written over 400 articles and chapters, including systematic reviews of screening for distress and depression in medical settings. Professor Coyne has been designated by ISI Web of Science as one of the most impactful psychologists and psychiatrists in the world. His books include Screening for Depression in Clinical Settings: An Evidence-Based Review edited with Alex Mitchell (Oxford University Press; 2009). He also blogs and is a regular contributor to the blog Science Based Medicine and to the PLOS One Blog, Mind the Brain. He is known for giving lively, controversial lectures, using scientific evidence to challenge assumptions about the optimal way of providing psychosocial care and care for medical patients.

Academics are under enormous pressure to publish in the highest impact journals possible. Yet, doing excellent science is insufficient to ensure that manuscripts are even sent out for review. As seen in high impact journals like BMJ, published papers must claim to be breakthroughs and to have immediate clinical and public health applications for results. Editors must be able to see immediately that a paper addresses an important problem and that if published, how it will further scientific knowledge and improve medical care or the health and wellbeing of the general population. Moreover, high impact journals accept papers on the likelihood that they will be newsworthy and appeal to the media. Maintaining journal impact factors requires maximizing the number of citations in the first two years after publication. Immediate media attention is a well-established means of accomplishing this.

The results of these endemic practices are that many claims of breakthroughs and discoveries ultimately prove exaggerated and outright false. Medical and public health effects include overdiagnosis, overtreatment, and overreaction to emerging health issues, with neglect of less dramatic measures that would more reliably improve medical and public health outcomes. This has been most recently seen in the misinformation and missteps in the overreaction to the Ebola crisis in some advanced countries. Managing fear and misinformation and inhibiting overreaction became more challenging than managing the spread of the virus.

Academics may not be able to ignore or change the institutional pressures to which they are subject. But they can practice and teach responsible clinical and epidemiological science, identifying the significance of their work, while honestly reminding their audience of the limits of their evidence, the inevitability of uncertainty, and that absolute safety is an unkeepable promise. And as a community, academics can strive to shift incentives so that responsible clinical and epidemiological science is rewarded.

From Receptors to Pain: The Molecular Dynamics of Pain Michael W Salter MD PhD Associate Chief, Science Strategy Head of the Program in Neuroscience & Mental Health Hospital for Sick Children Professor, Department of Physiology University of Toronto Canada

Dr Michael Salter is Associate Chief, Science Strategy, Research Institute at the Hospital for Sick Children (SickKids), Head of the Program in Neurosciences & Mental Health at SickKids and Professor in the Department of Physiology at the University of Toronto. He received his MD at the University of Western Ontario and his PhD from McGill University. He holds a Canada Research Chair in Neuroplasticity and Pain, and is the Anne and Max Tanenbaum Chair in Molecular Medicine at SickKids. He has won numerous awards for his work, including an International Research Scholarship from the Howard Hughes Medical Institute, and he is a Fellow of the Royal Society of Canada. Dr Salter is determining fundamental molecular and cellular mechanisms of normal and pathological neuroplasticity. He is developing molecules that target major cell signalling pathways in neurons and in glial cells involved in pain, stroke, neurodegenerative diseases and schizophrenia.

Neuron-microglial interactions are increasingly recognized as being key for physiological and pathological processes in the central nervous system. Microglia have been found to play a causal role in neuropathic pain behaviours resulting from peripheral nerve injury, and a core neuron-microglia-neuron signaling pathway has been elucidated. Within the dorsal horn, microglia suppress neuronal inhibition by a cascade involving activation of microglial P2X4 receptors causing the release of brain derived neurotrophic factor (BDNF). BDNF acts on trkBreceptors which leads to a rise in intracellular chloride concentration in dorsal horn nociceptive output neurons, transforming the response properties of these neurons. Inaddition to suppressing inhibition, peripheral nerve injury causes activity-dependent facilitation at dorsal horn glutamatergic synapses which enhances nociceptive transmission. This enhancement is mediated by intracellular signaling networks involving serine/threonine and tyrosine kinases within nociceptive transmission neurons. Key for this enhancement is facilitation of NMDA receptor function by Src family tyrosine kinases. Recently we have discovered that microglia-to-neuron signaling is not only critical for pain hypersensitivity after peripheral nerve injury but also for the paradoxical hyperalgesic effect of morphine and other opioids. We anticipate that by targeting microglia-neuron signaling pathways new therapeutic strategies for chronic pain as well as its comorbid sequelae may be developed.

Funding: Supported by CIHR, KrembilFdn, CRC and Anne and Max Tanenbaum ChairsFunding: Supported by CIHR, KrembilFdn, CRC and Anne and Max Tanenbaum Chairs

Insights into Cancer-Associated Virus Biology Using Discovery-Based Science S Diane Hayward, PhD Professor of Oncology and of Pharmacology and Experimental Therapeutics Director of Viral Oncology Program, Sidney Kimmel Cancer Center Johns Hopkins School of Medicine USA

Dr S Diane Hayward earned her Ph.D. degree at the University of Otago in New Zealand working on bacteriophage. She subsequently sought Fellowship experience in Europe at the Institute Pour La researche sur le Cancer in Paris and at the University of Heidelberg in Germany before coming to the US and undertaking a Fellowship with Dr. Elliott Kieff at the University of Chicago. There Dr Hayward was introduced to Epstein-Barr virus and was so intrigued by the ability of the herpesvirus to alter cell growth that she focused her research career on Epstein-Barr virus and the related Kaposi’s sarcoma associated herpesvirus. Dr Hayward joined the Johns Hopkins faculty in 1976. She is currently Professor of Oncology and of Pharmacology and Experimental Therapeutics and is the Director of the Viral Oncology Program in the Sidney Kimmel Cancer Center at Johns Hopkins.

Dr Hayward is an expert in the area of viral-associated cancers. She has served on advisory committees for the American Cancer Society, the American Society for Microbiology and the National Institutes of Health. She has the unusual distinction of having twice received MERIT Awards from the National Cancer Institute for her research.

The advancement of technologies for gathering large amounts of “omic” information has led to changes in the ways in which medical research is being conducted. Post-translational protein modifications such as phosphorylation are key to the regulation of cellular processes and are amenable to high-throughput screening. Viruses encode kinases that alter the cellular phospho-proteome as well as non-enzymatic proteins that can modify the intracellular environment through manipulation of host kinase activity. Virus proteins are also substrates for cellular kinases. We have applied proteomic and mass spectrometry screening approaches to the analysis of phosphorylation changes mediated by the Epstein-Barr virus (EBV) encoded protein kinase BGLF4 that is expressed during lytic EBV infection. We have also examined cell kinase phosphorylation of the Kaposi sarcoma associated virus (KSHV) encoded LANA protein that regulates KSHV latent infection and the potential impact of LANA on host protein phosphorylation. The cellular pathways and processes uncovered in these screens will be discussed.