Critical Care Commons^™

Live Imaging Of Microglia During Sleeping Sickness Reveals Early And Heterogeneous Inflammatory Responses, Nestor L Uzcategui, Sena Güçer, Cris Richter, Annika Speidel, Elizabeta Zirdum, Michael Duszenko, Olga Garaschuk, Katherine Figarella

Faculty, Staff and Student Publications

INTRODUCTION: Invasion of the central nervous system (CNS) is the most serious consequence of

METHODS: To further address this issue, we implanted a cranial window on the cortex of B6.129P2(Cg)-

RESULTS AND DISCUSSION: We uncovered an early involvement of microglia that precedes invasion of the CNS by the parasite. We accomplished a detailed characterization of the progressive sequence of events that correlates with microglial morphological changes and microgliosis. Our findings unveiled a heterogeneous microglial response in places of initial homeostatic disruption near brain barriers and pointed out an exceptional capability of microglia to hamper parasite proliferation inside the brain. We …

A Novel Humanized Chi3l1 Blocking Antibody Attenuates Acetaminophen-Induced Liver Injury In Mice, Leike Li, Yankai Wen, Daniel Wrapp, Jongmin Jeong, Peng Zhao, Wei Xiong, Constance Lynn Atkins, Zhao Shan, Deng Hui, Jason S Mclellan, Ningyan Zhang, Cynthia Ju, Zhiqiang An

Faculty, Staff and Student Publications

Acetaminophen (APAP) overdose is a leading cause of acute liver injury in the USA. The chitinase 3-like-1 (Chi3l1) protein contributes to APAP-induced liver injury (AILI) by promoting hepatic platelet recruitment. Here, we report the development of a Chi3l1-targeting antibody as a potential therapy for AILI. By immunizing a rabbit successively with the human and mouse Chi3l1 proteins, we isolated cross-reactive monoclonal antibodies (mAbs) from single memory B cells. One of the human and mouse Chi3l1 cross-reactive mAbs was humanized and characterized in both

Interplay Between Liver Type 1 Innate Lymphoid Cells And Nk Cells Drives The Development Of Alcoholic Steatohepatitis, Chen Cheng, Qian Zhang, Yue Li, Jiali Jiang, Linxi Xie, Haiyuan Shen, Dongqing Wu, Hejiao Zhang, Huiru Zhang, Xuan Wang, Hongyu Wu, Jingjing Xu, Li Gui, Bao Li, Cynthia Ju, Hui Peng, Shi Yin, Long Xu

Faculty, Staff and Student Publications

BACKGROUND & AIMS: Liver contains high frequency of group 1 innate lymphoid cells (ILC), which are composed of comparable number of type 1 ILC (ILC1) and natural killer (NK) cells in steady state. Little is known about whether and how the interaction between ILC1 and NK cells affects the development of alcoholic liver disease.

METHODS: A mouse model of chronic alcohol abuse plus single-binge (Gao-Binge model) was established. The levels of alanine aminotransferase/aspartate aminotransferase, hepatic lipid, and inflammatory cytokines or neutrophils were measured to evaluate the degree of liver injury, steatosis, and inflammation. Flow cytometric analysis, cell depletion, or adoptive …

Sex And Race Disparities In Mortality And Years Of Potential Life Lost Among People With Hiv: A 21-Year Observational Cohort Study, Rachael A Pellegrino, Peter F Rebeiro, Megan Turner, Amber Davidson, Noelle Best, Chandler Shaffernocker, Asghar Kheshti, Sean Kelly, Stephen Raffanti, Timothy R Sterling, Jessica L Castilho

Faculty, Staff and Student Publications

BACKGROUND: Since the availability of antiretroviral therapy, mortality rates among people with HIV (PWH) have decreased; however, this does not quantify premature deaths among PWH, and disparities persist.

METHODS: We examined all-cause and premature mortality among PWH receiving care at the Vanderbilt Comprehensive Care Clinic from January 1998 to December 2018. Mortality rates were compared by demographic and clinical factors, and adjusted incidence rate ratios (aIRRs) were calculated using multivariable Poisson regression. For individuals who died, age-adjusted years of potential life lost (aYPLL) per total person-years living with HIV were calculated from US sex-specific life tables, and sex and race …

Regulatory Mechanisms Controlling Store-Operated Calcium Entry, Goutham Kodakandla, Askar M Akimzhanov, Darren Boehning

Faculty, Staff and Student Publications

Calcium influx through plasma membrane ion channels is crucial for many events in cellular physiology. Cell surface stimuli lead to the production of inositol 1,4,5-trisphosphate (IP

Disrupted Ca2+ Homeostasis And Immunodeficiency In Patients With Functional Ip3 Receptor Subtype 3 Defects, Julika Neumann, Erika Van Nieuwenhove, Lara E Terry, Frederik Staels, Taylor R Knebel, Kirsten Welkenhuyzen, Kourosh Ahmadzadeh, Mariah R Baker, Margaux Gerbaux, Mathijs Willemsen, John S Barber, Irina I Serysheva, Liesbeth De Waele, François Vermeulen, Susan Schlenner, Isabelle Meyts, David I Yule, Geert Bultynck, Rik Schrijvers, Stephanie Humblet-Baron, Adrian Liston

Faculty, Staff and Student Publications

Calcium signaling is essential for lymphocyte activation, with genetic disruptions of store-operated calcium (Ca2+) entry resulting in severe immunodeficiency. The inositol 1,4,5-trisphosphate receptor (IP3R), a homo- or heterotetramer of the IP3R1-3 isoforms, amplifies lymphocyte signaling by releasing Ca2+ from endoplasmic reticulum stores following antigen stimulation. Although knockout of all IP3R isoforms in mice causes immunodeficiency, the seeming redundancy of the isoforms is thought to explain the absence of variants in human immunodeficiency. In this study, we identified compound heterozygous variants of ITPR3 (a gene encoding IP3R subtype 3) in two unrelated Caucasian patients presenting with immunodeficiency. To determine whether ITPR3 …

Survival Predictive Nomograms For Non-Surgical Brain Metastases Patients From Non-Small Cell Lung Cancer Receiving Radiotherapy: A Population-Based Study, Nicole K Sather, Lauren E Zinns, Gillian Brennan, Lily Guo, Nadia Khan, Vinod Havalad

Faculty, Staff and Student Publications

PURPOSE: Current guidelines recommend debriefing following medical resuscitations to improve patient outcomes. The goal of this study was to describe national trends in postresuscitation debriefing practices among pediatric critical care medicine (PCCM) fellows to identify potential gaps in fellow education.

METHODS: A 13-item survey was distributed to fellows in all 76 ACGME-accredited PCCM programs in the United States in the spring of 2021. The online survey addressed frequency and timing of debriefings following medical resuscitations, whether formal training is provided, which medical professionals are present, and providers' comfort level leading a debriefing. Results were analyzed using descriptive statistics.

RESULTS: A …

Good Outcome Associated With Blood-Brain Barrier Disruption And Lower Blood Pressure After Endovascular Therapy, Parth Upadhyaya, Amit Mehta, Marie Luby, Saeed Ansari, John K Lynch, Amie W Hsia, Lawrence L Latour, Yongwoo Kim

Faculty, Staff and Student Publications

OBJECTIVES: To evaluate the association between post-endovascular thrombectomy (EVT) blood-brain barrier (BBB) disruption on MRI or CT and average systolic blood pressure (SBP) with favorable 90-day functional outcome. Observational studies have found elevated SBP associated with worse outcomes post-EVT, while recent randomized trials found no difference in targeted BP reduction. There may be a subgroup of patients who benefit from targeted BP reduction post-EVT.

METHODS: This is a single-center study of 1) anterior large vessel occlusion stroke patients treated with EVT from 2015 to 2021, 2) achieved mTICI grade 2b or 3. Hyperintense acute reperfusion marker (HARM), hemorrhagic transformation (HT), …

Pediatric Traumatic Hemorrhagic Shock Consensus Conference Research Priorities, Robert T Russell, Melania M Bembea, Matthew A Borgman, Randall S Burd, Barbara A Gaines, Mubeen Jafri, Cassandra D Josephson, Christine M Leeper, Julie C Leonard, Jennifer A Muszynski, Kathleen K Nicol, Daniel K Nishijima, Paul A Stricker, Adam M Vogel, Trisha E Wong, Philip C Spinella

Faculty, Staff and Students Publications

BACKGROUND: Traumatic injury is the leading cause of death in children and adolescents. Hemorrhagic shock remains a common and preventable cause of death in the pediatric trauma patients. A paucity of high-quality evidence is available to guide specific aspects of hemorrhage control in this population. We sought to identify high-priority research topics for the care of pediatric trauma patients in hemorrhagic shock.

METHODS: A panel of 16 consensus multidisciplinary committee members from the Pediatric Traumatic Hemorrhagic Shock Consensus Conference developed research priorities for addressing knowledge gaps in the care of injured children and adolescents in hemorrhagic shock. These ideas were …

Pediatric Traumatic Hemorrhagic Shock Consensus Conference Recommendations, Robert T Russell, Joseph R Esparaz, Michael A Beckwith, Peter J Abraham, Melania M Bembea, Matthew A Borgman, Randall S Burd, Barbara A Gaines, Mubeen Jafri, Cassandra D Josephson, Christine Leeper, Julie C Leonard, Jennifer A Muszynski, Kathleen K Nicol, Daniel K Nishijima, Paul A Stricker, Adam M Vogel, Trisha E Wong, Philip C Spinella

Faculty, Staff and Students Publications

Hemorrhagic shock in pediatric trauma patients remains a challenging yet preventable cause of death. There is little high-quality evidence available to guide specific aspects of hemorrhage control and specific resuscitation practices in this population. We sought to generate clinical recommendations, expert consensus, and good practice statements to aid providers in care for these difficult patients.The Pediatric Traumatic Hemorrhagic Shock Consensus Conference process included systematic reviews related to six subtopics and one consensus meeting. A panel of 16 consensus multidisciplinary committee members evaluated the literature related to 6 specific topics: (1) blood products and fluid resuscitation for hemostatic resuscitation, (2) utilization …

Readiness For Transfer: A Mixed-Methods Study On Icu Transfers Of Care, Soo-Hoon Lee, Clarice Wee, Phillip Phan, Yanika Kowitlawakul, Chee-Kiat Tan, Amartya Mukhopadhyay

Management Faculty Publications

Objective Past studies on intensive care unit (ICU) patient transfers compare the efficacy of using standardised checklists against unstructured communications. Less studied are the experiences of clinicians in enacting bidirectional (send/receive) transfers. This study reports on the differences in protocols and data elements between receiving and sending transfers in the ICU, and the elements constituting readiness for transfer.

Methods Mixed-methods study of a 574-bed general hospital in Singapore with a 74-bed ICU for surgical and medical patients. Six focus group discussions (FGDs) with 34 clinicians comprising 15 residents and 19 nurses, followed by a structured questionnaire survey of 140 clinicians …

Financial Toxicity In Cancer Patients And Subsequent Risk Of Repeat Acute Care Utilization, Julia J Shi, J Alberto Maldonado, Chi-Fang Wu, Susan K Peterson, Ying-Shiuan Chen, Kevin Diao, Robert J Volk, Sharon H Giordano, Ya-Chen T Shih, Kelsey Kaiser, Grace L Smith

Faculty, Staff and Student Publications

BACKGROUND: Acute care (AC) visits by cancer patients are costly sources of healthcare resources and can exert a financial burden of oncology care both for individuals with cancer and healthcare systems. We sought to identify whether cancer patients who reported more severe initial financial toxicity (FT) burdens shouldered excess risks for acute care utilization.

METHODS: In 225 adult patients who participated in the Economic Strain and Resilience in Cancer (ENRICh) survey study of individuals receiving ambulatory cancer care between March and September 2019, we measured the baseline FT (a multidimensional score of 0-10 indicating the least to most severe global, …

Peptidylarginine Deiminase 2 Citrullinates Mzb1 And Promotes The Secretion Of Igm And Iga, Benjamin Geary, Bo Sun, Ronak R Tilvawala, Leonard Barasa, Konstantin Tsoyi, Ivan O Rosas, Paul R Thompson, I-Cheng Ho

Faculty, Staff and Students Publications

INTRODUCTION: MZB1 is an endoplasmic reticulum residential protein preferentially expressed in plasma cells, marginal zone and B1 B cells. Recent studies on murine B cells show that it interacts with the tail piece of IgM and IgA heavy chain and promotes the secretion of these two classes of immunoglobulin. However, its role in primary human B cells has yet to be determined and how its function is regulated is still unknown. The conversion of peptidylarginine to peptidylcitrulline, also known as citrullination, by peptidylarginine deiminases (PADs) can critically influence the function of proteins in immune cells, such as neutrophils and T …

Distinct Temporal Trajectories And Risk Factors For Post-Acute Sequelae Of Sars-Cov-2 Infection, Chen Chen, Sairam Parthasarathy, Jacqueline M Leung, Michelle J Wu, Katherine A Drake, Vanessa K Ridaura, Howard C Zisser, William A Conrad, Victor F Tapson, James N Moy, Christopher R Defilippi, Ivan O Rosas, Bellur S Prabhakar, Mujeeb Basit, Mirella Salvatore, Jerry A Krishnan, Charles C Kim

Faculty, Staff and Students Publications

BACKGROUND: The understanding of Post-acute sequelae of SARS-CoV-2 infection (PASC) can be improved by longitudinal assessment of symptoms encompassing the acute illness period. To gain insight into the various disease trajectories of PASC, we assessed symptom evolution and clinical factors associated with the development of PASC over 3 months, starting with the acute illness period.

METHODS: We conducted a prospective cohort study to identify parameters associated with PASC. We performed cluster and case control analyses of clinical data, including symptomatology collected over 3 months following infection.

RESULTS: We identified three phenotypic clusters associated with PASC that could be characterized as …

Quantitative Interstitial Abnormality Progression And Outcomes In The Genetic Epidemiology Of Copd And Pittsburgh Lung Screening Study Cohorts, Bina Choi, Najma Adan, Tracy J Doyle, Ruben San José Estépar, Rola Harmouche, Stephen M Humphries, Matthew Moll, Michael H Cho, Rachel K Putman, Gary M Hunninghake, Ravi Kalhan, Gabrielle Y Liu, Alejandro A Diaz, Stefanie E Mason, Farbod N Rahaghi, Carrie L Pistenmaa, Nicholas Enzer, Clare Poynton, Gonzalo Vegas Sánchez-Ferrero, James C Ross, David A Lynch, Fernando J Martinez, Meilan K Han, Russell P Bowler, David O Wilson, Ivan O Rosas, George R Washko, Raúl San José Estépar, Samuel Y Ash, Copdgene Study And Pittsburgh Lung Screening Study Investigators

Faculty, Staff and Students Publications

BACKGROUND: The risk factors and clinical outcomes of quantitative interstitial abnormality progression over time have not been characterized.

RESEARCH QUESTIONS: What are the associations of quantitative interstitial abnormality progression with lung function, exercise capacity, and mortality? What are the demographic and genetic risk factors for quantitative interstitial abnormality progression?

STUDY DESIGN AND METHODS: Quantitative interstitial abnormality progression between visits 1 and 2 was assessed from 4,635 participants in the Genetic Epidemiology of COPD (COPDGene) cohort and 1,307 participants in the Pittsburgh Lung Screening Study (PLuSS) cohort. We used multivariable linear regression to determine the risk factors for progression and the …

Lymphangioleiomyomatosis: Circulating Levels Of Fgf23 And Pulmonary Diffusion, Anthony J Esposito, Jewel Imani, Shikshya Shrestha, Shefali Bagwe, Anthony M Lamattina, Marina Vivero, Hilary J Goldberg, Ivan O Rosas, Elizabeth P Henske, Souheil Y El-Chemaly

Faculty, Staff and Students Publications

OBJECTIVE: Lymphangioleiomyomatosis (LAM) is a rare, destructive disease of the lungs with a limited number of determinants of disease activity, which are a critical need for clinical trials. FGF23 has been implicated in several chronic pulmonary diseases. We aimed to determine the association between serum FGF23 levels and pulmonary function in a cohort of patients with LAM.

METHODS: This was a descriptive single-center study in which subjects with LAM and controls with unreported lung disease were recruited. Serum FGF23 levels were measured in all subjects. Clinical data, including pulmonary function testing, were retrospectively obtained from electronic medical records of LAM …

Suspected Interstitial Lung Disease In Copdgene Study, Jonathan A Rose, Aravind A Menon, Takuya Hino, Akinori Hata, Mizuki Nishino, David A Lynch, Ivan O Rosas, Souheil El-Chemaly, Benjamin A Raby, Samuel Y Ash, Bina Choi, George R Washko, Edwin K Silverman, Michael H Cho, Hiroto Hatabu, Rachel K Putman, Gary M Hunninghake

Faculty, Staff and Students Publications

Rationale

Although interstitial lung abnormalities (ILA), specific patterns of incidentally-detected abnormal density on computed tomography, have been associated with abnormal lung function and increased mortality, it is unclear if a subset with incidental interstitial lung disease (ILD) accounts for these adverse consequences.

Objectives

To define the prevalence and risk factors of suspected ILD and assess outcomes.

Methods

Suspected ILD was evaluated in the COPDGene (Chronic Obstructive Pulmonary Disease Genetic Epidemiology) study, defined as ILA and at least one additional criterion: definite fibrosis on computed tomography, FVC less than 80% predicted, or DL_CO less than 70% predicted. Multivariable linear, longitudinal, …

Clinical Efficacy Among Patients With Chronic Rhinosinusitis With Nasal Polyps And Clinical Features Of Obstructive Lung Disease: Post Hoc Analysis Of The Phase Iii Sinus-24 And Sinus-52 Studies, Jorge F Maspero, Claus Bachert, Fernando J Martinez, Nicola A Hanania, Benjamin Ortiz, Naimish Patel, Leda P Mannent, Amy Praestgaard, Nami Pandit-Abid, Shahid Siddiqui, Megan Hardin

Faculty, Staff and Students Publications

PURPOSE: To provide a descriptive summary of clinical efficacy and health-related quality of life (HRQoL) measures in patients with chronic rhinosinusitis with nasal polyps (CRSwNP) and clinical features of obstructive lung disease in the Phase III dupilumab studies SINUS-24 and SINUS-52 (NCT02912468, NCT02898454).

PATIENTS AND METHODS: Patients met a "broad" definition of having clinical features of obstructive lung disease with any of 3 criteria: (i) pre-bronchodilator forced expiratory volume in 1 second (FEV

RESULTS: Across both studies, 131 patients met the "broad" definition, of whom 90 also had asthma, and 115 patients met the "narrow" definition, of whom 74 had …

Corrigendum: Alveolar Macrophages In Lung Cancer: Opportunities And Challenges, Cheng-Yen Chang, Dominique Armstrong, David B Corry, Farrah Kheradmand

Faculty, Staff and Students Publications

In the published article, there was an error in the article title. Instead of “Alveolar Macrophages in Lung Cancer: Opportunities Challenges”, it should be “Alveolar Macrophages in Lung Cancer: Opportunities and Challenges”.

The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated.

Respiratory Function Changes As Early Signs Of Amyotrophic Lateral Sclerosis, Mario Polverino, Simone Sampaolo, Antonio Capuozzo, Marco Fasolino, Michele Aliberti, Ersilia Satta, Carlo Santoriello, James Peter Orengo, Francesca Polverino

Faculty, Staff and Students Publications

BACKGROUND: The current diagnostic criteria for amyotrophic lateral sclerosis (ALS) may remain unsatisfactory for months or years in the early disease. Pulmonary assessment has never been considered useful in the early diagnosis of ALS, and studies of pulmonary function in this patient category are lacking.

OBJECTIVES: The objective of this study was to assess the pulmonary function in subjects with unspecific symptoms of ALS in whom an ALS diagnosis cannot be reached based on the current available guidelines.

METHODS: We performed pulmonary function tests, arterial gas analysis, maximal inspiratory (MIP) and expiratory (MEP) pressure, and respiratory drive (P0.1) assessment in …