Dr. Davison Awarded ASPEN Grant to Improve Critical Care Outcomes

James Davison, PhD

James Davison, PhD

The American Society of Parenteral and Enteral Nutrition (ASPEN) Rhoads Research Foundation has awarded Duke Anesthesiology’s James Davison, PhD, a lab research analyst and director of The Wischmeyer Lab, a $25,000 grant (with potential second-year funding of an additional $25,000) for his project, titled “Modulation of Organ Injury by Faecalibacterium Prausnitzii in Critical Illness.” Dr. Davison’s long-term research objective is to establish nutritional and probiotic therapies that support organ function and improve outcomes in critical care patients.

According to the project’s abstract, intensive care unit (ICU) admission is associated with a loss of “health promoting” bacteria and a rapid dysbiosis of the intestinal microbiota. Specifically, a recent multi-center ICU microbiome clinical trial from The Wischmeyer and Knight (UC San Diego) Labs demonstrated a significant loss of the probiotic microorganism, Faecalibacterium prausnitzii, which generates metabolites and anti-inflammatory peptides that support intestinal function and attenuate local inflammation in experimental colitis models. Based on the clinical findings and the known roles of F. prausnitzii in attenuating local inflammation, Dr. Davison and his project mentor, Dr. Paul Wischmeyer, have developed this central hypothesis: F. prausnitzii and/or its metabolites attenuate systemic inflammation, improve organ function and reduce morbidity/mortality in sepsis. Thus, their two project aims include 1) directly addressing the working hypothesis that oral supplementation of F. prausnitzii protects intestinal and extra-intestinal organ function during sepsis. Using the accepted cecal-ligation and puncture model of sepsis, they will test if F. prausnitzii attenuates systemic inflammation and promotes extra-intestinal organ function. They will also utilize next-generation sequencing to determine if F. prausnitzii mediates metabolic and inflammatory transcriptional responses of organs in septic mice, and 2) directly addressing the working hypothesis that peptides and metabolites derived from F. prausnitzii suppress systemic inflammation. Using protein and metabolite mass spectrometry, they will test for enrichment of serum metabolites and peptides that are only present in mice that receive F. prausnitzii. They will synthesize peptides that are unique in the serum of mice that receive F. prausnitzii and will test if oral gavage or tail-vain injection of these synthesized peptides have the capacity to reduce inflammation in septic mice.

Drs. Davison and Wischmeyer believe that this project addresses a significant obstacle that prevents wider use of probiotic therapies (and other nutritional therapies) in critical illness – and that the lack of understanding of the molecular mechanisms mediate probiotic contributions to human health. They predict that their translational research plan will support their long-term research objectives in identifying novel mechanisms that mediate probiotic organ protection in illness, leading to new therapies to prevent and treat sepsis and critical illness.

Chris KeithDr. Davison Awarded ASPEN Grant to Improve Critical Care Outcomes
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Dr. Terrando Receives Prestigious R01 Award

Niccolo Terrando, PhDThe National Institutes of Health/National Institute on Aging (NIH/NIA) has awarded Duke Anesthesiology’s Niccolò Terrando, BSc, DIC, PhD, a five-year, $2,815,756 R01 Award for his project, titled “Neurovascular dysfunction in delirium superimposed on dementia.”

Millions of Americans live with dementia and require common surgical interventions, such as orthopaedic surgery. According to the research statement, these potentially life-saving procedures often increase the risk for further cognitive deterioration and in many cases, even death. Dr. Terrando with his team of investigators at Duke University (Carol Colton, Gurpreet Baht, William Wetsel, Zhiquan Zhang, and Miles Berger) and University of Rochester Medical Center (Harris Gelbard) will address this public health concern by providing fundamental knowledge expected to help reduce the burdens of neurologic complications after common surgical procedures, and improve the quality of life for these high-risk patients.

The rationale for the proposed research is that successful completion of these studies will advance and expand the understanding of how surgery affects the blood-brain interface, and will provide new insights into molecular mechanisms of relevance to delirium, neurodegeneration and aging. Such knowledge is highly significant because it has the potential to improve surgical outcomes and quality of life for millions of vulnerable, elderly patients in the United States by using new therapeutic approaches tested in this grant.

As stated in the project’s abstract, impaired cognitive function after common surgical procedures is a growing concern, especially among the more than five million people in the nation who suffer from dementia, including Alzheimer’s disease (AD), and thus have a three-fold increased risk for fracture requiring surgical repair. After orthopaedic surgery, acute changes in cognitive function, often referred to as postoperative delirium, occur in up to 89 percent of patients with preexisting dementia, and associate with poorer prognosis and even two-fold greater risk for one-year mortality compared to patients without dementia or delirium. This proposal will attempt to model postoperative delirium superimposed on dementia after orthopaedic surgery using innovative approaches to understand, and possibly attenuate, the effects of surgery on the blood–brain interface, including the neurovascular unit (NVU) and the blood-brain barrier (BBB).

The long-term goal of Dr. Terrando and his team of investigators is to define the mechanisms that underlie surgery-induced cognitive dysfunction, and to provide safe and effective approaches to reduce this potentially devastating complication.

Dr. Terrando joined Duke in 2015 and is an assistant professor in anesthesiology, the director of the Neuroinflammation and Cognitive Outcomes Laboratory, a collaborator of Duke Anesthesiology’s Center for Translational Pain Medicine and a 2016 DREAM Innovation Grant (DIG) recipient for his research project, titled “The Systemic Milieu and its Role in Postoperative Cognitive Dysfunction.”

Chris KeithDr. Terrando Receives Prestigious R01 Award
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Division Chief Awarded Duke-Singapore Collaborative Grant

Ashraf S. Habib, MBBCh, MSc, MHSc, FRCADuke University and the Duke-National University of Singapore (NUS) Medical School have awarded Duke Anesthesiology’s Ashraf Habib, MBBCh, MSc, chief of the Women’s Anesthesia Division, and his collaborator at KK Hospital in Singapore, Ban Leong Sng, MD, a $200,000 grant for their Duke/Duke-NUS pilot project, titled “Evaluation and risk assessment for persistent postsurgical pain after breast surgery: a collaborative prospective cohort study.”

The overall aim of this study is to identify clinically-relevant and genetic risk factors for persistent postsurgical pain that can be reliably distinguished statistically. Specifically, the focuses include 1) risk factors representing biopsychosocial processes that influence chronic pain, such as pain and psychological vulnerability, and 2) genetic factors relating to mechanistic pathways to persistent pain generation.

According to the project’s abstract, breast cancer is a leading cancer diagnosis among women worldwide, with more than one million new cases each year. Chronic pain following breast cancer surgery has been recognized as a major humanitarian and socioeconomic burden, affecting more than 50 percent of patients after lumpectomy and mastectomy leading to chronic physical disability and psychological distress. This chronic pain may involve the site of lumpectomy/mastectomy, axilla and even proximal medial arm. The cause of persistent postsurgical pain in breast cancer patients may be attributed to various reasons, such as surgical trauma, tumor recurrence, or factors related to radiotherapy or chemotherapy.

Despite a number of studies investigating risk factors, almost all of the information has originated from single center studies and often focuses on only a few elements. Additionally, surgical approaches and analgesic regimens have changed in recent years, therefore limiting the interpretation of previous studies. Yet, tools to identify those at high risk and preventive interventions are still lacking.

Dr. Habib and his team of investigators propose to study the risk factors related to persistent postsurgical pain in breast cancer patients, and to develop a prediction model that could serve as a screening tool for patients at high risk of developing persistent pain after breast cancer surgery. Pre-existing pain and severe postoperative pain have been predictors of persistent pain after surgery, but a complete understanding on the development of persistent pain is still lacking. A major challenge facing progress in this field has been the wide variation in patient experience of pain after similar types of surgery and the inability to identify individuals who are more likely to experience severe pain after surgery. A better understanding of the risk factors of postsurgical pain will help identify the subset of patients who are likely to develop severe acute pain and persistent pain. This could help in targeting those high-risk patients with focused perioperative interventions that could reduce their risk of developing severe acute pain and persistent pain.

Chris KeithDivision Chief Awarded Duke-Singapore Collaborative Grant
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Dr. Privratsky Receives Mentored Research Award

Jamie Privratsky, MD, PhDThe International Anesthesia Research Society (IARS) has awarded Duke Anesthesiology’s Jamie Privratsky, MD, PhD, a two-year, $175,000 2017 Mentored Research Award for his project, titled “The role of macrophage IL-1 signaling in acute kidney injury and recovery.”

According to the project statement, acute kidney injury (AKI) dramatically increases morbidity and mortality and can lead to downstream chronic kidney disease (CKD). The mechanisms that direct renal recovery after AKI and prevent the AKI to CKD transition are poorly understood.

Based on preliminary data, Dr. Privratsky’s central hypothesis is that IL-1R1 activation sustains detrimental macrophage polarization to drive acute renal injury and promote the AKI to CKD transition, culminating in kidney fibrosis. The specific aims of he and his team of investigators include: Aim 1) determine the effects of IL-1R1 signaling on renal macrophage polarization during AKI. Mice with macrophage-specific deletion of IL-1R1 (IL-1R1 MKO) and controls will be subjected to ischemia/reperfusion (I/R)-induced AKI. They will measure the severity of kidney damage, assess the polarization of infiltrating macrophages via fluorescent cell sorting and RT-PCR, and characterize injury in renal tubular cells following co-culture with isolated WT and IL-1R1 MKO macrophages from injured kidneys. Aim 2) determine the effect of IL-1R1 receptor signaling on the development of renal fibrosis following AKI. Investigators will subject IL-1R1 MKO mice and littermate controls (WT) to I/R-induced AKI and 28 days later examine the extent of kidney fibrosis. At multiple time points, intra-renal macrophages will be phenotyped by fluorescent cell sorting and analyzed for pro-inflammatory and pro-fibrotic gene expression by RNAseq. The capacity of a commercially available IL-1R1 antagonist to alter macrophage polarization and prevent renal fibrosis following AKI will be tested.

According to Dr. Privratsky, an assistant professor of anesthesiology in Duke Anesthesiology’s Critical Care Medicine Division, these studies should underpin the development of novel immunomodulatory therapies for AKI, which are expected to have a significant positive impact on perioperative and critically ill patients.

Chris KeithDr. Privratsky Receives Mentored Research Award
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Dr. Berger Receives Prestigious K76 Award

Miles Berger, MD, PhDThe National Institutes of Health has awarded Duke Anesthesiology’s Miles Berger, MD, PhD, and his team of investigators a Paul B. Beeson Emerging Leaders Career Development Award in Aging (K76); a five-year, $1,195,505 grant for their project, titled “Neuro-inflammation in Postoperative Cognitive Dysfunction: CSF and fMRI Studies.”

According to the project description, each year, more than 16 million older Americans undergo anesthesia and surgery, and up to 40 percent of these patients develop postoperative cognitive dysfunction (POCD), a syndrome of postoperative thinking and memory deficits. Although distinct from delirium, POCD (like delirium) is associated with decreased quality of life, long term cognitive decline, early retirement, increased mortality, and a possible increased risk for developing dementia, such as Alzheimer’s disease. Strategies are needed to prevent POCD, but first, we need to understand what causes it. A dominant theory holds that brain inflammation causes POCD, but little work has directly tested this theory in humans. Dr. Berger and his team’s preliminary data strongly suggests that there is significant postoperative neuro-inflammation in older adults who develop POCD.

In this K76 award, the team of investigators will prospectively obtain pre and postoperative cognitive testing, fMRI imaging and CSF samples in 200 surgical patients over the age of 65. This will allow them to evaluate the role of specific neuro-inflammatory processes in POCD, its underlying brain connectivity changes, and postoperative changes in cerebrospinal fluid (CSF) Alzheimer’s disease (AD) biomarkers, such as the microtubule-associated protein tau. This project will advance understanding of neuro-inflammatory processes in POCD and clarify the potential link(s) between these processes and postoperative changes in AD pathology, in line with the National Institute of Aging’s mission to understand aging and fight cognitive decline due to AD.

The K76 is a mentored career development award; Dr. Berger’s mentoring team includes Drs. Joseph Mathew (chairman of Duke Anesthesiology) and Harvey Cohen (director of the Duke Center for the Study of Aging and Human Development ), as well as Drs. Roberto Cabeza (from the Duke Center for Cognitive Neuroscience), Kent Weinhold (vice chair for research of Duke Surgery), and Heather Whitson (deputy director of the Duke Center for the Study of Aging and Human Development). Co-investigators and collaborators include Drs. Niccolò Terrando (Duke Anesthesiology), Jeffrey Browndyke (Duke Psychiatry & Behavioral Sciences) and David Murdoch (Duke Medicine).

During this K76 grant period, Dr. Berger, an assistant professor of anesthesiology, will also complete an individually-tailored MS degree in translational research that will include training in immunology methods, fMRI imaging, cognitive neuroscience, geroscience, and physician leadership. This career development plan will provide him with transdisciplinary skills to pursue his longer term goal of improving postoperative cognitive function for the more than 16 million older Americans who have anesthesia and surgery each year.

Chris KeithDr. Berger Receives Prestigious K76 Award
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Neuroscientists Awarded School of Medicine Voucher

The Duke University School of Medicine has awarded an $8,000 voucher to Duke Anesthesiology’s Niccolò Terrando, PhD, and Zhiquan Zhang, PhD, for their project, titled “Preventing Memory Dysfunction after Surgery with a Novel Pro-Resolving Peptide from Annexin-A1.”

Major surgery, including cardiac and orthopedic, often causes neurological complications such as delirium and postoperative cognitive dysfunction. According to the project investigators, there are currently no safe and effective therapies to prevent or limit these complications in patients. Dr. Zhang previously developed a bioactive peptide (ANXA1sp) derived from the N-terminal domain of the human protein Annexin-A1 (ANXA1), a critical molecule involved in the resolution of inflammation. Ongoing studies with this peptide are revealing promising effects in protecting the brain against excessive neuroinflammation after surgery, which is becoming a key contributor to memory deficit.

This voucher, in collaboration with the Mouse Behavioral and Neuroendocrine Shared Core, will help Drs. Zhang and Terrando validate the effects of this peptide on cognitive, as well as higher order memory tasks, in their models of cognitive dysfunction after major surgery. Given the impact of neuroinflammation on memory function across many different neurological disorders, this therapy could provide fundamental knowledge to direct future studies and therapy development for numerous conditions such as Alzheimer’s disease and other dementias.

Dr. Terrando is an assistant professor in anesthesiology, a collaborator with Duke Anesthesiology’s Center for Translational Pain Medicine and the director of the Neuroinflammation and Cognitive Outcomes Laboratory which studies the mechanisms underlying postoperative neurocognitive disorders with a strong focus on neuroinflammation, innate immunity and behavior. Dr. Zhang is an assistant professor in anesthesiology and a member of Dr. Terrando’s lab.

Chris KeithNeuroscientists Awarded School of Medicine Voucher
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