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March 2022 NIDUS Newsletter
Network for Investigation of Delirium: Unifying Scientists
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In this issue:
- 10th Annual NIDUS Delirium Boot Camp – Call for Applicants!
- Recent Mentoring Webinars Recap
- 2022 NIDUS II Collaborative Awards
- New NIDUS Blog Posts
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Apply to attend the 2022 NIDUS Delirium Boot Camp
Our 10th Annual NIDUS Delirium Boot Camp "Building Blocks to Clinical Trials" will take place Sunday, November 13 to Tuesday, November 15, 2022 at the University of North Carolina-Chapel Hill.
Applications for the 2022 Boot Camp are now being accepted until July 22, 2022 at 5pm EST. Visit the NIDUS Delirium Boot Camp page to download and complete the 2022 NIDUS Boot Camp Application today.
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2022 NIDUS Mentoring Webinars
January Webinar - Career Development Award Research
Featuring Dr. Thomas M. Gill, Dr. Esther Oh, and Dr. Nicholas Reed; moderated by Dr. Jan Busby-Whitehead
Dr. Gill kicked off this mentoring session by offering guidance on identifying a mentor. He talked about what makes a successful candidate along with career goals. In addition, Dr. Gill reviewed crucial components of a successful award: career development plans, research plans, and the importance of specific aims.
Next, Dr. Reed shared stories from preparing and securing his own K23 grant. Flowing out of an experience with a personal friend, Dr. Reed's K23 changed direction from his original plan. Not only that, but he was funded on his first try. In addition, Dr. Oh spoke about the process of helping Dr. Reed build his team and develop his submission.
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Dr. Nicholas Reed presents at the January 26 webinar
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February Webinar - Being Truly Responsive: How to Win Over Your Reviewers
Featuring Dr. Sharon Inouye; moderated by Dr. John Devlin
In this mentoring session, Dr. Inouye introduced a response method called 'the Kassirer Method.' Based on instruction and mentorship from Dr. Jerome Kassirer, a former editor of the New England Journal of Medicine, she encouraged session attendees to get ‘into the head of the editor or reviewer.' Also, Dr. Inouye advised attendees not to treat the review as a personal attack; instead, see it as a collaboration and a chance to clarify the paper.
She also highlighted the importance of changes to the manuscript, even if small, for all comments. She also offered concrete examples of how to respond to reviewers. In addition, Dr. Inouye said this approach has increased her acceptance rate from less than 50% to nearly 100%.
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Dr. Sharon Inouye presents at the February 16 webinar
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March Webinar - Pilot Awards: Developing a Competitive LOI/Submitting a Successful Application
Featuring Dr. Michael Avidan and Dr. Tammy Hshieh; moderated by Dr. John Devlin
In this mentoring session, Dr. Michael Avidan shared strategies for developing strong pilot grant LOIs and applications. Using examples from prior NIDUS pilot grant awardees, he compared and contrasted pilots and feasibility studies. Also, Dr. Avidan presented NIDUS resources which can assist applicants in their pilots.
Next, Dr. Tammy Hshieh shared from her own personal experience with NIDUS pilot awards. She detailed the process of reevaluating her original concept to better fit her pilot study. Dr. Hshieh also talked about critical choices like which delirium instruments to use and how she refined the scope of her study.
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Dr. Michael Avidan presenting at the March 7 webinar
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2022 NIDUS II Collaborative Awards
Below are the recipients of our 2022 Collaborative Awards along with a summary of their proposed research.
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Machine Learning Prediction and Detection of Intensive Care Unit Delirium
Robert D Stevens, MD, Johns Hopkins University School of Medicine
Collaborators:
Kirby Gong, MSE (Johns Hopkins)
Heidi L. Lindroth, PhD, RN (Mayo Clinic)
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There is a need for pragmatic models which can accurately and reliably predict the onset of delirium in critically ill patients. Such models could guide the delivery of targeted therapies aimed at reducing delirium and its deleterious downstream effects.
We hypothesize that specific features derived from high-resolution clinical and physiological data routinely acquired in the ICU are signature of delirium risk, and the latter are identifiable using machine learning. We have demonstrated this using an external multisite dataset.
Here, we will leverage a granular data platform acquired at Johns Hopkins called Precision Medicine Analytics Platform (PMAP) and validate using a similar dataset from co-investigators at the Mayo Clinic. The core objective is to generate discriminative tools for clinical decision support and intervention. Implementation of the latter is expected reduce the burden of ICU delirium and associated harm and costs.
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Delirium, Long-term Cognitive Impairment and Bacterial Infection-induced Endothelial Proteopathy
Jean-Francois Pittet, MD, DEAA
Department of Anesthesiology
University of Alabama at Birmingham
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Collaborators:
Brant Wagener, MD, PhD (University of Alabama)
Christian Balabanoff-Acosta, MD (University of Alabama)
Troy Stevens, PhD (University of South Alabama)
Michael T. Lin, PhD (University of South Alabama)
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Multi-center clinical studies have implicated that ICU survivors and especially patients who develop hospital-acquired bacterial pneumonia suffer from pervasive delirium and long-term cognitive impairment.
Dr. Pittet has developed a scientific collaboration with Drs. Stevens and Lin from the University of South Alabama to better understand how bacterial infections contribute to end-organ injury in rodents and humans. Together, they have discovered that pneumonia-causing bacterial pathogens elicit the production of lung endothelial cell-derived amyloids (EC-amyloids).
Lung endothelia exposed to clinical bacterial isolates produce and release cytotoxic beta-amyloid and tau that are reminiscent of neuronal species. In rodents, these lung-derived EC-amyloids self-replicate, propagate among lung ECs with prion-like characteristics, are transmissible between animals, cause endothelial cytotoxicity, hinder vascular repair following injury, impair learning, and damage the brain. Importantly, these cytotoxic EC-amyloids can also be recovered from bronchoalveolar lavage fluid, plasma and cerebrospinal fluid during bacterial pneumonia in humans.
Based on the results of our mechanistic studies in rodents, this project tests the central hypothesis that neurotoxic EC-amyloids released from the lung endothelium following bacterial pneumonia in ICU patients will be detected in the bloodstream of these patients for weeks after recovery from bacterial pneumonia and may be one of the mechanisms that explain the high incidence of delirium and long-term cognitive impairment in these patients.
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Perturbations of inflammatory response in patients with postoperative delirium (POD) and melatonin
Stéphanie Sigaut, MD, PhD
Praticien Hospitalier, service d'Anesthésie Réanimation. Hôpital Beaujon - Hôpitaux Universitaires Paris Nord Val de Seine
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Collaborators:
Pierre Gressens, MD, PhD (Hopital Robert Debre)
Philippe Montravers, MD, PhD (Assistance Publique Hopitaux de Paris)
Pauline Glasman, MD (Assistance Publique Hopitaux de Paris)
Raphaël Desal, MD (Assistance Publique Hopitaux de Paris)
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Patients with postoperative delirium (POD) may exhibit perturbations of inflammatory response that may be prevented by melatonin. To answer this hypothesis we plan an ancillary study of DELIRLESS randomized controlled trial (NCT04335968). In this RCT, patients above 70 years old with fractures of a lower limb are randomized into 2 groups: melatonin 4mg or placebo every night from anesthetist preoperative visit until d5 after surgery.
At postoperative d1, blood withdrawal is performed and the following analysis will be performed for deep phenotyping of the inflammatory response: 1/ Flow cytometry for phenotypical and functional characterization of peripheral blood mononuclear cells (PBMC) populations; 2/ RNA-Seq for analysis of PBMC transcriptome; 3/ Luminex immunoassay for detection and quantification of cytokines in plasma; 4/Reactive Oxygen Species measurement in peripheral blood by luminometry.
Association of these results with POD diagnosed by the CAM score during the first 10 days after surgery will be analyzed and the effect of melatonin perioperative administration will be evaluated.
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Effects of postoperative delirium on older surgical patients
Brian O'Gara, MD, MPH
BIDMC Anesthesia Critical Care
Harvard Medical School
Collaborators:
Kimberly Rengel, MD (Vanderbilt)
Christopher Hughes, MD (Vanderbilt)
Alvaro Pascual Leone, MD, PhD (Harvard)
Edward Marcantonio, MD (Harvard)
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Postoperative delirium affects 15-50% of older surgical patients and increases the risk of postoperative complications, hospital mortality and long-term cognitive dysfunction including dementia. There remains a critical need for interventions to prevent postoperative delirium. Increasing preoperative cognitive reserve via computerized cognitive prehabilitation is an innovative yet unproven patient-led intervention with the potential to prevent PD.
We believe that a future clinical trial of computerized cognitive prehabilitation to prevent postoperative delirium is warranted but faces significant threats to feasibility, implementation, and validity. To resolve these challenges, we will form a multidisciplinary collaboration of anesthesiologists, geriatricians, and cognitive neurologists to refine and enhance a computerized cognitive prehabilitation intervention for a future clinical trial and test whether these improvements can increase adherence.
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A multi-method study to adapt existing DSD (delirium superimposed on dementia) contents
Shih-Yin Lin, MM, MPH, PhD
Senior Research Scientist/Project Director
NYU Rory Meyers College of Nursing
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Collaborators:
Abraham A. Brody, PhD, RN, FAAN (NYU)
Donna M. Fick, PhD, RN, GCNS-BC (Penn State)
Dena Schulman-Green, PhD (NYU)
Jason Fletcher, PhD (NYU)
Shih-Yin Lin's research interests include dementia-friendly communities, non-pharmacological intervention, health information technology for older adults, and more recently, delirium superimposed on dementia (DSD).
She currently provides scientific and operational leadership on the NIH-funded, 25-site Hospice Advanced Dementia Symptom Management and Quality of Life Trial (PI: Brody) that tests the effectiveness of an agency-wide quality improvement program, Aliviado Dementia Care, on dementia symptom management, including behavioral and psychological symptoms of dementia, pain, and delirium.
The main components of Aliviado Dementia Care include interdisciplinary dementia care training, symptom management algorithms, assessments, care plans, caregiver education materials, and an mHealth app that provides remote access to the program.
In her NIDUS II 2022 pilot award application, Dr. Lin proposes a multi-method study to adapt the existing DSD contents in the currently clinician-led Aliviado Dementia Care program into a family-centered, caregiver-administered behavioral intervention to improve DSD knowledge, detection, and prevention in the community.
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Delirium as a modifiable risk factor for dementia – a large, population based cohort study
Bjørn Erik Neerland, MD, PhD
Overlege, postdoktor forsker
Geriatrisk avdeling, Oslo Universitetssykehus
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Collaborators:
Christian Myrstad (Vestfold Hospital Trust)
Geir Selbæk (Vestfold Hospital Trust)
Bjørn Heine Strand (Norwegian Institute of Public Health)
Torgeir Bruun Wyller (Oslo University Hospital)
The aim of this study is to extensively study inter-relations between delirium and dementia. The Health Study in Trøndelag (HUNT) is a population-based cohort study with four assessments (HUNT1-HUNT4) over up to 40 years follow-up (1984 to 2023). In HUNT4 (2017-2019), participants ≥70 years (HUNT4-70+, n=9930) underwent cognitive testing and were categorized by clinical experts into no cognitive impairment, mild cognitive impairment or dementia (also subtyped).
The Ageing in Trøndelag (AiT) study is an ongoing four-year follow-up of the entire HUNT4-70+ cohort. It applies the same protocol and will be completed in 2023. Virtually all established risk factors for dementia were assessed at HUNT1-HUNT4.
There are two hospitals in the HUNT catchment area, and specially trained researchers will identify delirium, number of episodes, severity and duration of delirium by scrutinizing the electronic health records, for all participant admissions from the period 2005-2023, applying a validated method. We will also record precipitating causes, reasons for admission, and acute illness severity.
We will merge these data with the data in HUNT1-4, HUNT4-70+, AiT and relevant health registers, and comprehensively study possible interactions between delirium and dementia. Long follow-up will reduce reverse causation bias. Plasma, serum and microbiota are available and genotyping has been done, making it possible to include biomarkers in the analyses.
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Randomized placebo-controlled trial of perioperative fluvoxamine
Ben Palanca, MD, PhD
Washington University School of Medicine, St. Louis
Collaborators:
Robert D. Sanders, MBBS, PhD (University of Sydney)
Angela Reiersen, MD, MPE (Washington University)
Sarah Kendall Smith, MD, PhD (Washington University)
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Dr. Ben Palanca at Washington University School of Medicine in St. Louis proposes a safety and feasibility study of a randomized placebo-controlled trial of perioperative fluvoxamine. In collaboration with Dr. Robert Sanders at University of Sydney, the transcontinental collaborative investigation will establish the infrastructure for a larger investigation to probe whether the intervention reduces neuroinflammation, delirium severity, and physiologic markers of underlying pathophysiologic mechanisms.
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Circadian rhythms, acute inflammation, and neurological disease in postoperative delirium
S. Kendall Smith, MD, PhD
Assistant Professor of Anesthesiology & Critical Care Medicine
Washington University School of Medicine, St. Louis
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Collaborators:
Rosemary Braun, MD, MPH (Northwestern)
Robert Sanders, MBBS, PhD (University of Sydney)
Ben Palanca, MD, PhD, MSCI (Washington University)
Dr. Kendall Smith aims to probe the temporal interplay between disrupted circadian rhythms, acute inflammation, and neurological disease in the development of postoperative delirium.
Her proposal brings together a multidisciplinary team including Dr. Rosemary Braun at Northwestern University, Dr. Robert Sanders at the University of Sydney, and Dr. Ben Palanca at Washington University and adds a molecular arm to an ongoing NIH-funded investigation of relationships among delirium and electroencephalographic markers of sleep and wakefulness.
Her proposal will lay the groundwork for elucidating the pathophysiology of delirium at a molecular level and for identifying novel therapeutic targets regulating circadian rhythms.
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Do Polygenic Risk Scores of Alzheimer’s Disease and Related Dementias Identify the Delirium-Vulnerable Brain?
Sarinnapha Vasunilashorn, PhD
Assistant Professor, Harvard Medical School; Beth Israel Deaconess Medical Center
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Collaborators:
Miles Berger, MD (Duke)
Yi-Hsiang Hsu, ScD (Harvard)
Long Ngo, PhD (Harvard)
This clinical and translational project uses four unique datasets of older adults undergoing major elective surgery to advance our understanding of the potential shared pathophysiology underlying the delirium-AD/ADRD relationship.
The goal of this proposal is to test the hypothesis that polygenic risk for Alzheimer’s Disease and Alzheimer’s Disease-Related Dementias (AD/ADRD) identifies individuals with a “vulnerable brain,” who may be predisposed to bad outcomes, including delirium, cognitive decline, and AD/ADRD, in the presence of an inflammatory insult (e.g., surgery or infection).
Our findings will inform targeted strategies to identify older adults vulnerable to adverse brain-related outcomes under stress and high inflammation, thereby potentially leading to new interventions to prevent delirium and reduce AD/ADRD.
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Measures of pre-surgical electroencephalography (EEG) combined with cognitive function
Mouhsin Shafi, MD, PhD
Associate Professor of Neurology, Harvard Medical School; Director, Berenson-Allen Center for Noninvaisve Brain Stimulation
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Collaborators:
Miles Berger, MD (Duke)
Alvaro Pascual-Leone, MD (Harvard)
M. Brandon Westover, MD (Harvard)
Delirium is common in hospitalized individuals, and is associated with cognitive and functional decline, and increased mortality. However, the factors that predispose to delirium and cognitive decline are not well established, and reliable mechanistic biomarkers are sorely needed. Recently, our group found that simple measures of the pre-surgical electroencephalography (EEG), in combination with simple tests of cognitive function, might help predict which patients develop post-operative delirium.
In the proposed project, we will further evaluate the relationship between baseline EEG / cognitive function and post-operative delirium, and validate these findings in an independent cohort of older surgical patients recruited from another center. The proposed project will thus provide evidence that simple, easy-to-obtain baseline measures of cerebral electrophysiology and cognitive function can predict post-operative delirium with high accuracy.
This work will provide key data for subsequent multi-site studies prospectively assessing the utility of this approach as an individualized predictive biomarker of delirium risk, as well as studies evaluating whether these measures can predict long-term cognitive decline and risk of developing dementia.
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Visit the NIDUS Blog
The NIDUS Blog features posts on a variety of topics related to delirium research with a focus on the core NIDUS II aims. Most blogs are authored by NIDUS Bootcamp alumni and Pilot Grant Awardees. The latest blog post by Brian O’Gara, MD is on “Cognitive Prehabilitation to Prevent Postoperative Delirium”
NIDUS posts new Blogs at least monthly. We encourage you to regularly check out new NIDUS Blog posts.
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Other NIDUS Communications
In addition to the NIDUS Blog, we offer regular updates on delirium-related news, events and research through social media, our email listserve, and newsletters.
If you’re interested in contributing to NIDUS communications with a blog post, newsletter item, or social media post, contact us.
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Join NIDUS!
About NIDUS
NIDUS is a collaborative research network dedicated to spurring innovation and new advances in delirium research through development of new research and measurement resources, training opportunities, pilot funding and dissemination of information. It is funded through an award from the National Institutes of Health/National Institute on Aging (grant no. R33AG071744).
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