MedicalResearch.com Interview with:
David Gerberry PhD
Assistant Professor
Department of Mathematics and Computer Science
Xavier University, Cincinnati, Ohio
Medical Research: What is the background for this study? What are the main findings?
Response: In an attempt to control the spread of HIV, governments in sub-Saharan Africa are considering providing antiretroviral drugs to people who do not have the virus but are at risk for becoming infected. Such drugs are known as pre-exposure prophylaxis, or PrEP. Given the cost of PrEP, an important question is how to maximize the impact of interventions given a fixed level of prevention resources.
A common strategy is to target resources to the individuals that are at the highest risk for infection. This group of people is often referred to as the "core group" and can be thought of as sex workers, clients of sex workers and other individuals that are at very high risk for infection. While targeting this core group is ideal and would result in the most cost-effectiveness interventions, being able to identify these individuals is difficult in practice and they are often unwilling to participate in the intervention; take pre-exposure prophylaxis or change their behavior for example. From a mathematical perspective it is also very difficult to quantify their increased level of risk. For example, is a sex worker at 5 times, 25 times, 100 times or 1000 times the risk for HIV infection? Without this quantification, it is impossible to estimate the cost-effectiveness of a targeted strategy.
In our work, we build an intervention strategy based on geographical targeting. This takes advantage of the fact that HIV incidence is much higher in certain geographical locations than others. Therefore, individuals in these areas are at increased risk for HIV infection. Most importantly, such an intervention is feasible because reliable data exists across much of sub-Saharan Africa for the severity of the HIV epidemic in different regions. To illustrate our ideas we used mathematical modeling to consider resource allocation in South Africa and found that targeting the provinces with highest HIV incidence would prevent 40% more infections than a plan that ignored geographic variation while using the same amount of resources.
MedicalResearch.com Interview with:
Leonard A. Mermel DO FACP, FIDSA, FSHEA
Professor of Medicine,
Warren Alpert Medical School of Brown University and Division of Infectious Diseases,
Rhode Island Hospital Providence, Rhode Island
Medical Research: What is the background for this study? What are the main findings?
Dr. Mermel: While talking to infectious diseases physicians some years ago in Israel, Greece, and Thailand, I learned that unlike my experiene here in the US, most of the bloodstream infections they see are far and away due to Gram-negative bacteria. So, a hypothesis was generated, namely that the likelihood of Gram-negative bacteremia compared to Gram-positive bacteremia was greater the closer to the equator. A writing group was formed, colleagues around the world graciously shared their data. The main finding is that in fact, we unequivocally found that the likelihood of Gram-negative, compared to Gram-positive bacteremia is more common closer to the equator. This difference was greatest during the warmer months of the year. We also found that the % GDP spent on healthcare in a given country is also associated with more Gram-negative than Gram-positive bacteremia. These findings may reflect differences in the human microbiome as one gets closer or farther from the equator as has been recently demonstrated, differences in survival of Gram-negative compared to Gram-positive bacteria under certain environmental conditions, and likely reflects differences in public health and other factors.
MedicalResearch.com Interview with:
Thomas Wisniewski MD
Lulu P. and David J. Levidow Professor of Neurology
Professor; Director Aging and Dementia
New York University School of Medicine
Dept. of Neurology, Psychiatry and Pathology
New York, NY 10016
Medical Research: What is the background for this study? What are the main findings?
Dr. Wisniewski: Chronic wasting disease (CWD) infects large numbers of deer and elk, with the potential to infect humans. Currently no prionosis has an effective treatment. This is a relatively new prion disease that has many similarities to bovine spongiform encephalopathy which spread to humans to produce new variant Creutzfeldt-Jakob disease. Chronic wasting disease is the most infectious prion disease to date; having the potential to spread by aerosol. Previously, we have demonstrated we could prevent transmission of prions in a proportion of susceptible mice with a mucosal vaccine. In the current study, white-tailed deer were orally inoculated with attenuated Salmonella expressing PrP, while control deer were orally inoculated with vehicle attenuated Salmonella. Once a mucosal response was established, the vaccinated animals were boosted orally and locally by application of polymerized recombinant PrP onto the tonsils and rectal mucosa. The vaccinated and control animals were then challenged orally with CWD-infected brain homogenate. Three years post CWD oral challenge all control deer developed clinical CWD (median survival 602 days), while among the vaccinated there was a significant prolongation of the incubation period (median survival 909 days; p=0.012 by Weibull regression analysis) and one deer has remained CWD free both clinically and by RAMALT and tonsil biopsies. This negative vaccinate has the highest titers of IgA in saliva and systemic IgG against PrP. Western blots showed that immunoglobulins from this vaccinate react to PrPCWD. We document the first partially successful vaccination for a prion disease in a species naturally at risk.
MedicalResearch.com Interview with:
Ann J. Melvin MD, MPH
Division of Pediatric Infectious Disease
Department of Pediatrics
Seattle Children's Hospital, Seattle, WA 98105.
Medical Research: What is the background for this study? What are the main findings?
Dr. Melvin: While relatively uncommon, neonatal Herpes Simplex Virus is a potentially devastating infection with significant morbidity and mortality. We reviewed all of the neonatal HSV cases treated at our institution between 1993 and 2012 who had HSV DNA PCR results available from the plasma and/or CSF. Most of the infants had quantitative PCR results available. The objective of the study was to determine the clinical correlation of HSV PCR levels in the plasma and CSF. We found a clear association between the plasma HSV level, clinical presentation and mortality. All of the infants who died had HSV plasma DNA levels of greater than 7 log10 copies/ml. However, neither plasma nor CSF HSV levels predicted neurologic outcome. Clinical evidence of CNS disease was more predictive of neurologic outcome than was the CSF PCR level. We also showed the most sensitive test for diagnosis of neonatal HSV to be HSV PCR on the plasma. However, no single test diagnostic test (plasma PCR, CSF PCR, surface cultures) was positive across all infants, so it is important to obtain samples from plasma, CSF and surface swabs in infants with symptoms consistent with HSV infection.
MedicalResearch.com Interview with:
Adrian Egli, MD PhD Research Group leader
Infection Biology Laboratory
Department of Biomedicine
University of Basel and University Hospital Basel
Basel, Switzerland
Medical Research: What is the background for this study? What are the main findings?
Dr. Egli: Infections with influenza viruses are associated with a high morbidity and mortality. In particular, people with a weak immune system are at danger for more severe complications. This includes elderly people, pregnant women, patients after transplantation, patients with HIV infection, chronic diseases such as diabetes and many more. In these high-risk groups, annual vaccination is clearly recommended.
However, due to the immunsuppressive condition the immune response to the influenza vaccine is often reduced. The seroconversion rate - a 4-fold antibody titer increase upon vaccination - is one of the key markers for a successful vaccination. In young adults the seroconversion rate is normally >85%; however, in patients with immunosuppression, this can be lower than 40%. Improving vaccine efficacy is one of the key focuses of my research group. We try to understand, how to improve vaccines and better protect the people at the highest risks for influenza-associated complications.
In this study, we could show that an important cytokine, called Interferon lambda, is clearly associated with the vaccine induced antibody response upon influenza vaccination. We could show that genetic polymorphisms, in one of the Interferon lambda gene family (IFNL3), are modulating the expression of this gene. This strongly affects the cross talk between the innate and adaptive immune response in the context of vaccination. We observed that, the more Interferon lambda is present, the lower the antibody response is. People with a lower expression of Interferon lambda had a significant higher response to the vaccine. Therefore, we developed substances to block the effect of Interferon lambda. We could show in vitro, that due to the Interferon lambda blockade, the antibody production was improved.
MedicalResearch.com Interview with:
Leah M. Smith PhD
Department of Epidemiology, Biostatistics, and Occupational Health (Smith, Kaufman, Strumpf)
McGill University, Montréal, Quebec
Medical Research: What is the background for this study? What are the main findings?
Dr. Smith: The human papillomavirus (HPV) vaccine protects against types of HPV that cause cervical cancer and anogenital warts. The vaccine first became available in 2006. Since then, it has faced a great deal of controversy surrounding, in part, some of the unanswered questions about the real-world effects of the vaccine, especially on the young girls targeted for immunization. One issue that has received a great deal of public attention has been the concern that HPV vaccination might give girls a false sense of protection against all sexually transmitted infections that might lead them to be more sexually active than they would otherwise. As a result, some parents have been reluctant to have their daughters vaccinated. It is also reason why some religious groups have spoken out against the vaccine. This question is further important from a public health perspective because increases in risky sexual behaviour would inevitably also lead to increases in teen pregnancy and sexually transmitted infections (excluding anogenital warts), which would of course undermine the potential health benefits of the vaccine.
In this study, we directly addressed the question of whether HPV vaccination has led to increases in pregnancy and non-HPV-related sexually transmitted infections (both of which are proxies for risky sexual behaviour) among adolescent girls.
In our study of over 260,000 girls, we did not find any evidence that the HPV vaccine had a negative impact on these outcomes.
MedicalResearch.com Interview with:
Dr. Michael Yeaman Ph.D.
Professor of Medicine, Infectious Disease Specialist
Chief, Division of Molecular Medicine
David Geffen School of Medicine at UCLA
Los Angeles Biomedical Research Institute
Harbor-UCLA Medical Center
Medical Research: What is the background for this study? What are the main findings?
Dr. Yeaman: In the U.S. and around the globe, skin and soft tissue infections caused by
methicillin-resistant Staphylococcus aureus (MRSA) continue to endanger the
health and lives of patients and otherwise healthy individuals. Treatment is
difficult because MRSA is resistant to many antibiotics, and the infections
can recur, placing family members and other close contacts at risk of
infection.
Infectious disease specialists at the Los Angeles Biomedical Research
Institute at Harbor-UCLA Medical Center (LA BioMed) tested a new
investigational vaccine, NDV-3, and found it holds new hope for preventing
or reducing the severity of infections caused by the "superbug" MRSA.
In the study, which was published Dec. 8 in the Proceedings of the National
Academy of Sciences USA, the researchers reported that NDV-3, employing the
recombinant protein Als3, can mobilize the immune system to fight off MRSA
skin infections in an experimental model. The researchers found the vaccine
works by enhancing molecular and cellular immune defenses of the skin in
response to MRSA and other S. aureus bacteria in disease models.
This is the first published study to demonstrate the effectiveness of a
cross-kingdom recombinant vaccine against MRSA skin infections. NDV-3 is
unique as it is the first vaccine to demonstrate it can be effective in
protecting against infections caused by both S. aureus and the fungus
Candida albicans. NDV-3 represents a novel approach to vaccine design that
pioneers an approach termed convergent immunity.
MedicalResearch.com Interview with:
Jack A Gilbert PhD
Department of Ecology & Evolution
Graduate Program in Biophysical Sciences
University of Chicago, Chicago, IL 60637
MedicalResearch: What is the background for this study? What are the main findings?
Dr. Gilbert: We have performed extensive analysis of the microbial distribution between humans and home surfaces in peoples houses. And are still exploring how bacteria are distributed around hospitals. Here we wanted to explore how bacteria from humans were distributed into a space in real time. By taking samples every hour post sterilization and seeing how the community stabilized, who remained active and whether they were pathogenic. We found that communities stabilized on a skin-associated microbiome within 5 hours, that staphylococcus remained active and yet none of these were particularly pathogenic. Yet we were able to identify pathogenic MRSA on surfaces around the bathroom, but they were extremely rare.
MedicalResearch.com Interview with:
Victoria Vaughan
Medical College of Georgia, Augusta, Georgia
Medical Research: What is the background for this study? What are the main findings?
Response: The Global Mortality of Skin Disease study compares age adjusted mortality of disease with skin manifestations between developing and developed countries for the years 1990 and 2010. The main findings were that mortality from infectious conditions was greater in the developing world while melanoma contributed to mortality in the developed world. Ebola Virus Disease has cutaneous manifestations and affects the developing world preferentially. As of November 27, 2014, the mortality in West Africa totals 5444 according to the CDC. However, the United States has had only two deaths from Ebola Virus Disease.
MedicalResearch.com Interview with:
Dr. John K. DiBaise MD
Gastroenterology and Hepatology
Mayo Clinic, Scottsdale Arizona
Medical Research: What is the background for this study? What are the main findings?
Dr. DiBaise: Despite nearly 25 years of safe and effective use of proton pump inhibitors (PPI), in recent years there have been an increasing number of reports suggesting potentially harmful effects and harmful associations with their use. One such association with PPI use has been Clostridium difficile infection (CDI) which can cause severe and recurrent episodes of diarrhea. Previous reports evaluating the microbes present within the gastrointestinal tract (ie, gut microbiome) of individuals with CDI have shown a reduction in overall microbial community diversity. We studied the gut microbiome in healthy individuals both before and after using a proton pump inhibitors for one month and found a similar reduction in microbial diversity while taking the PPI that did not entirely revert back to the ‘normal’ baseline after being off the medication for a month. While this does not demonstrate a causal association between proton pump inhibitors use and CDI, it demonstrates that PPI use creates a situation in the gut microbial environment that may increase the individual’s susceptibility to CDI.
MedicalResearch.com Interview with:
Dr. Raquel Qualls-Hampton MD, MS
Assistant Professor
University of North Texas Health Science Center
Medical Research: What is the background for this study? What are the main findings?
Dr. Qualls-Hampton: There are currently two vaccines approved by the Food and Drug Administration (FDA)—Gardasil for males and Gardasil and Cervix for females – that protect against the human papilloma virus (HPV). These vaccines are recommended by the ACIP for females ages 9 to 26 years and males ages 9 to 21 years. Both vaccines protect males and females against some of the most common types of HPV. HPV vaccines are administered in three doses over six months and are considered safe and effective. However, the promise of these vaccines is going unfulfilled as initiation and completion rates for the three doses are suboptimal among females and males.
Nationally, although HPV vaccination initiation coverage is increasing, overall vaccine completion rates are at suboptimal levels and below the U.S. Department of Health and Human Services’ Healthy People 2020 initiative target of 80%. Thus, many states are turning to legislative interventions in efforts to increase initiation and completion rates. This study examines HPV vaccination legislative initiatives and their impact, specifically in estimating state legislation’s effects on HPV vaccine initiation, completion and patient care provider recommendations by gender.
MedicalResearch.com Interview with:
Weian Zhao PhD
Assistant Professor at the Sue and Bill Gross Stem Cell Research Center, Chao Family Comprehensive Cancer Center, Department of Biomedical Engineering, Edwards Lifesciences Center for Advanced Cardiovascular Technology and Department of Pharmaceutical Sciences at University of California, Irvine.
Medical Research: What is the background for this study?
Dr. Zhao: Bloodstream infections are a major cause of illness and death. In particular, infections associated with antimicrobial-resistant pathogens are a growing health problem in the U.S. and worldwide. According to the Centers for Disease Control & Prevention, more than 2 million people a year globally get antibiotic-resistant blood infections, with about 23,000 deaths. The extremely high mortality rate for blood infections is due, in part, to the inability to rapidly diagnose and treat patients in the early stages. The present gold standard to detect a blood infections, is a blood culture and it takes 2-5 days for the detection and the identification of the bacteria. Recent molecular diagnosis methods, including polymerase chain reaction, can reduce the assay time to hours but are often not sensitive enough to detect bacteria that occur at low concentrations in blood, as is common in patients with blood infections. Therefore, less expensive and less technically demanding methods are urgently needed for the rapid and sensitive identification of blood infections.
MedicalResearch.com Interview with:
Professor Tom Solomon, FRCP PhD
Director, NIHR Health Protection Research Unit in Emerging and Zoonotic Infections
Director, Institute of Infection and Global Health, University of Liverpool
Medical Research: What is the background for this study? What are the main findings?
Dr. Solomon: Since the Ebola outbreak began there has been concern about transmission to new countries by airline passengers who were infected, but didn’t know it. This was underscored by such transmission to Nigeria, and to USA. Screening for symptoms of Ebola virus disease in airline passengers whose journeys originated from the three most affected countries—Guinea, Liberia, and Sierra Leone—has recently been introduced at some airports.
We examined the current growth rate of the epidemic in West Africa, and airline travel patterns to predict how many people with Ebola are likely to attempt to fly. Our research showed that we can expect approximately 29 infected passengers to try and leave West Africa by the end of the year. Based on the incubation period of the virus, and looking at how long people have symptoms before they are hospitalised, we estimated ten of these people with Ebola would have symptoms of the disease as they leave the affected countries, and so would be detected by exit screening. Of the remaining 19, one to two would be expected to fly to the UK, and up to three to the USA, based on current airline passenger data. At most one of these passengers would have developed symptoms by the time they arrive in the UK or USA, and thus would be detected by entry screening
MedicalResearch.com Interview with;
Eduardo L. Franco DrPH, FRSC, FCAHS
James McGill Professor Departments of Oncology and Epidemiology & Biostatistics, Director, Division of Cancer Epidemiology, Minda de Gunzburg Chair, Department of Oncology, Division of Cancer Epidemiology Department of Oncology
McGill University, Montreal, Quebec, Canada
Medical Research: What should clinicians and patients take away from your report?
Dr. Franco: Our findings of oral transmission of human papillomavirus (HPV) infection in men are part of a larger molecular epidemiologic study called ‘HPV Infection and Transmission among Couples through Heterosexual Activity’ (HITCH) cohort study. The focus of the HITCH study is to understand how HPV is transmitted within couples via sexual contact and other behaviors. We measure the presence of this virus using highly-sensitive molecular assays for HPV DNA in the genital surfaces (vagina and penis), oral cavity, and hands. We also take a blood sample to look for the presence of antibodies against HPV. We take multiple samples over a period of two years at pre-scheduled visits. We have previously published results focused exclusively on genital transmission. The present report is the first in the HITCH study to look at what happens in terms of characteristics that place male participants to be at risk of oral HPV infection.
To our knowledge, this is the first study to show a high risk of oral HPV infection among men whose female partners had a genital or oral HPV infection, suggesting that transmission may occur through oral or genital routes. We looked at transmission for 36 individual HPV genotypes, which improved our ability to study risk determinants. Risk was also significantly higher among men who had ever smoked, had a high number of lifetime sex partners, or were in non-monogamous relationships. Our results are largely consistent with previous studies that have found male sex practices and smoking to be the most significant risk factors for oral HPV infection.
MedicalResearch.com Interview with
Prof. Dr. Jan Münch
Institute of Molecular Virology
Ulm University Medical Center
Ulm, Germany
Medical Research: What is the background for this study?
Dr. Münch: Most anti-HIV microbicides have potent antiviral activity in vitro but were largely inactive in clinical trials. Here we set out to explore whether the HIV infection enhancing activity of amyloid fibrils in human semen interferes with the antiviral efficacy of microbicides and antiviral drugs.
MedicalResearch.com Interview with:
Mark E Mikkelsen, MD, MSCE
Assistant Professor of Medicine
Hospital of the University of Pennsylvania
Medical Research: What is the background for this study? What are the main findings?
Dr. Mikkelsen: Sepsis is common, afflicting as many as 3 million Americans each year. It is also costly, both in terms of health care expenditures that exceed $20 billion for acute care and in terms of the impact it has on patients and their families. To date, studies have focused on what happens to septic shock patients during the initial hospitalization. However, because more patients are surviving sepsis than ever, we sought to examine the enduring impact of septic shock post-discharge. We focused on the first 30 days after discharge and asked several simple questions. First, how often did patients require re-hospitalization after septic shock? And second, why were patients re-hospitalized?
We found that 23% of septic shock survivors were re-hospitalized within 30 days, many of them within 2 weeks. A life-threatening condition such as recurrent infection was the reason for readmission and 16% of readmissions resulted in death or a transition to hospice.
Marie R Griffin MD MPH
Director, Vanderbilt MPH Program
Department of Health Policy Vanderbilt University Medical Center
Nashville TN 37212
Medical Research: What is the background for this study? What are the main findings?
Dr. Griffin: In Tennessee, the introduction in 2010 of a new pneumococcal vaccine for infants and young children was associated with a 27 percent decline in pneumonia hospital admissions across the state among children under age 2. The recent decline in Tennessee comes on top of an earlier 43 percent decline across the United States associated with the introduction in 2000 of the first pneumococcal vaccine for children under 2 years of age.
MedicalResearch.com Interview with:
Melissa Ward PhD
CIIE Research Fellow Centre for Immunity, Infection and Evolution
University of Edinburgh
Medical Research: What is the background for this study? What are the main findings?
Dr. Ward: We studied a strain of the bacterium Staphylococcus aureus known as CC398, which can colonise and cause MRSA infection in humans and livestock. People and animals generally harbour genetically distinct variants of CC398, but we found human isolates, including a small number from Scottish hospitals, which were more similar to the livestock strains. Such isolates were resistant to a larger number of antibiotics than the CC398 strain which typically circulates in humans. By looking at the genetic sequences of strains from across the globe, we also inferred that CC398 has entered Scotland on multiple occasions.
MedicalResearch.com Interview with:
Dan Yamin PhD
Postdoctoral Associate
Yale School of Public Health
New Haven, CT 06520
Medical Research: What is the background for this study?
Dr. Yamin: With limited resources, West Africa is currently overwhelmed by the most devastating Ebola epidemic known to date. In our research, we seek to address two questions:
MedicalResearch.com Interview with:
Prof. Clive Maurice Gray
Division of Immunology, Institute of Infectious Diseases and Molecular Medicine,National Health Laboratory Services
University of Cape Town, Cape Town, South Africa
Medical Research: What is the background for this report? What are the main findings?
Prof. Gray: This report is a response on behalf to the International Union of Immunology Societies (IUIS) and is designed to focus a message from the global immunology community to those who are making vaccines and therapies implementing clinical trials and very importantly on Governments and funding bodies. Time is not our side and that vaccine efforts need to be expedited and that production of therapeutics needs to be ramped up. Due to the fact that many people in West Africa are dying, we wish to convey a strong message that to curb this outbreak, therapies and especially vaccines must be rolled out as soon as possible.
MedicalResearch.com: Interview with:
Dr. Simon Corrie PhD
The University of Queensland, Australian Institute for Bioengineering and Nanotechnology, Delivery of Drugs and Genes Group
Australian Infectious Diseases Research Centre, St. Lucia, Queensland, Australia
Medical Research: What is the background for this study? What are the main findings?
Dr. Corrie: P. falciparum malaria is a major cause of morbidity and mortality around the world, particularly in developing countries. Some estimates also suggest that in developing countries, children under 5 account for ~90% mortality. As malaria is treatable, positive detection is important rule out other causes, avoid over-treatment leading to resistance, and to guide appropriate treatment. Our focus is on developing diagnostic devices for infectious diseases, which do not require needles, lancets or laboratory processing.
These devices are “microprojection arrays”, silicon chips that can be applied to the skin to capture circulating protein biomarkers in the interstitial fluid of the skin. In this publication we:
(a) developed methods to improve the sensitivity of the devices for capturing HRP2,
(b) confirmed that HRP2 protein injected intravenously is detectable in skin fluid and
(c) showed that we could capture both HRP2 and total IgG (as a positive control for penetration into skin) at the same time.
MedicalResearch.com Interview with:
Prof. Zvi Laron
Professor Emeritus of Pediatric Endocrinology
TAU's Sackler Faculty of Medicine,
Director of the Endocrinology and Diabetes Research Unit
Schneider Children's Medical Center of Israel
Head WHO Collaborating Center for the Study of Diabetes in Youth
Medical Research: What are the main findings of the study? What was most surprising about results?
Prof. Laron: The main findings were the finding of specific antibodies to the pancreatic insulin secreting beta cells together with antibodies against rota-virus in both the mother at delivery and in the newborn's cord blood. We were not surprised, but pleased to find proof to our hypothesis that part, if not the majority of childhood onset Type 1 (autoimmune diabetes) starts "in utero".
MedicalResearch.com Interview with:
Dr R.E.W. (Bob) Hancock, OC, OBC, FRSC
{Canada Research Chair and Professor, Department of Microbiology and Immunology,UBC}
Director, Centre for Microbial Diseases and Immunity Research
University of British Columbia,
Vancouver, British Columbia, Canada
MedicalResearch: What is the background for this study? What are the main findings?
Dr. Hancock: We wanted to understand how patients transitioned from the hyperinflammatory phase (cytokine storm) of sepsis to the hypoinflammatory (immunosuppressive) phase of sepsis (inability to respond appropriately to infections). About 15% of patients die in this first phase and 20% in the second phase, making sepsis one of the most deadly syndromes (35% overall mortality, 5 million deaths [8.3% of all deaths] annually worldwide). We hypothesized that immunosuppression was characterized by a state termed endotoxin tolerance a cellular amnesia (termed cellular reprogramming) in which cells fail to respond to microbial cues.
Overall we found that an Endotoxin Tolerance gene signature is significantly associated with the subsequent development of confirmed sepsis and new organ dysfunction in patients who had suspected sepsis. All 620 sepsis patients in retrospective and new analyses presented with an expression profile strongly associated with the endotoxin tolerance signature (p<0.01; AUC 96.1%). This occurred in fact very early in sepsis and in a new clinical study we found that the signature could be detected already in the emergency ward at first clinical presentation and 24-48 hours prior to definitive diagnosis. Importantly, this signature further differentiated between suspected sepsis patients who did, or did not, go on to develop confirmed sepsis, and predicted the development of organ dysfunction.