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Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) down-regulates angiotensin-converting enzyme 2, potentially increasing angiotensin II. We hypothesized that losartan compared to usual care decreases mortality and is safe in patients hospitalized with coronavirus disease 2019 (COVID-19). We aimed to evaluate the effect of losartan versus usual care on 28-day mortality in patients hospitalized for acute COVID-19., Methods: Eligibility criteria included adults admitted for acute COVID-19. Exclusion criteria were hypotension, hyperkalemia, acute kidney injury, and use of angiotensin receptor blockers (ARBs) or angiotensin-converting enzyme inhibitors within 7 days. Participants were randomized to losartan 25-100 mg/day orally for the hospital duration or 3 months or the control arm (usual care) in 29 hospitals in Canada and France. The primary outcome was 28-day mortality. Secondary outcomes were hospital mortality, organ support, and serious adverse events (SAEs)., Results: The trial was stopped early because of a serious safety concern with losartan. In 341 patients, any SAE and hypotension were significantly higher in the losartan versus usual care groups (any SAE: 39.8% vs 27.2%, respectively, P = .01; hypotension: 30.4% vs 15.3%, respectively, P < .001) in both ward and intensive care patients. The 28-day mortality did not differ between losartan (6.5%) versus usual care (5.9%) (odds ratio, 1.11 [95% confidence interval, .47-2.64]; P = .81), nor did organ dysfunction or secondary outcomes., Conclusions: Caution is needed in deciding which patients to start or continue using ARBs in patients hospitalized with pneumonia to mitigate risk of hypotension, acute kidney injury, and other side effects. ARBs should not be added to care of patients hospitalized for acute COVID-19., Clinical Trials Registration: NCT04606563., Competing Interests: Potential conflicts of interest . J. A. R. reports patents owned by the University of British Columbia that are related to (i) the use of PCSK9 inhibitor(s) in sepsis, (ii) the use of vasopressin in septic shock, and (iii) a patent owned by Ferring for use of selepressin in septic shock; J. A. R. is an inventor on these patents. J. A. R. was a founder, director, and shareholder in Cyon Therapeutics Inc (now closed) and is a shareholder in Molecular You Corp; is the Senior Research Advisor of the British Columbia, Canada Post COVID–Interdisciplinary Clinical Care Network (PC-ICCN); reports receiving consulting fees in the last 3 years as a funded member of the data and safety monitoring board of a National Institutes of Health–sponsored trial of plasma in COVID-19 (PASS-IT-ON; 2020–2021); has received grants for COVID-19 and for pneumonia research from CIHR and the St Paul's Foundation; and was a nonfunded science advisor and member of the government of Canada COVID-19 Therapeutics Task Force (June 2020–2021). All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Rationale: Acute respiratory distress syndrome (ARDS) is a life-threatening critical care syndrome commonly associated with infections such as COVID-19, influenza, and bacterial pneumonia. Ongoing research aims to improve our understanding of ARDS, including its molecular mechanisms, individualized treatment options, and potential interventions to reduce inflammation and promote lung repair., Objective: To map and compare metabolic phenotypes of different infectious causes of ARDS to better understand the metabolic pathways involved in the underlying pathogenesis., Methods: We analyzed metabolic phenotypes of 3 ARDS cohorts caused by COVID-19, H1N1 influenza, and bacterial pneumonia compared to non-ARDS COVID-19-infected patients and ICU-ventilated controls. Targeted metabolomics was performed on plasma samples from a total of 150 patients using quantitative LC-MS/MS and DI-MS/MS analytical platforms., Results: Distinct metabolic phenotypes were detected between different infectious causes of ARDS. There were metabolomics differences between ARDSs associated with COVID-19 and H1N1, which include metabolic pathways involving taurine and hypotaurine, pyruvate, TCA cycle metabolites, lysine, and glycerophospholipids. ARDSs associated with bacterial pneumonia and COVID-19 differed in the metabolism of D-glutamine and D-glutamate, arginine, proline, histidine, and pyruvate. The metabolic profile of COVID-19 ARDS (C19/A) patients admitted to the ICU differed from COVID-19 pneumonia (C19/P) patients who were not admitted to the ICU in metabolisms of phenylalanine, tryptophan, lysine, and tyrosine. Metabolomics analysis revealed significant differences between C19/A, H1N1/A, and PNA/A vs ICU-ventilated controls, reflecting potentially different disease mechanisms., Conclusion: Different metabolic phenotypes characterize ARDS associated with different viral and bacterial infections., (© 2024. The Author(s).)

Many COVID-19 survivors have post-COVID-19 conditions, and females are at a higher risk. We sought to determine (1) how protein levels change from acute to post-COVID-19 conditions, (2) whether females have a plasma protein signature different from that of males, and (3) which biological pathways are associated with COVID-19 when compared to restrictive lung disease. We measured protein levels in 74 patients on the day of admission and at 3 and 6 months after diagnosis. We determined protein concentrations by multiple reaction monitoring (MRM) using a panel of 269 heavy-labeled peptides. The predicted forced vital capacity (FVC) and diffusing capacity of the lungs for carbon monoxide (DLCO) were measured by routine pulmonary function testing. Proteins associated with six key lipid-related pathways increased from admission to 3 and 6 months; conversely, proteins related to innate immune responses and vasoconstriction-related proteins decreased. Multiple biological functions were regulated differentially between females and males. Concentrations of eight proteins were associated with FVC, %, and they together had c -statistics of 0.751 (CI:0.732-0.779); similarly, concentrations of five proteins had c -statistics of 0.707 (CI:0.676-0.737) for DLCO, %. Lipid biology may drive evolution from acute to post-COVID-19 conditions, while activation of innate immunity and vascular regulation pathways decreased over that period. (ProteomeXchange identifiers: PXD041762, PXD029437).

Objective: Those with chronic critical illness (CCI) remain dependent on life-sustaining treatments and increasingly reside in long-term care facilities equipped to meet their needs. The nature of family involvement in care remains undetermined thwarting approaches to mitigate poor family outcomes. The research objective was to explicate family involvement in the care of an individual with CCI who resides in long-term care., Methods: In this qualitative research, we used thematic analysis and constant comparative techniques to analyze data from interviews with 38 participants: 11 family members, 6 residents with CCI, and 21 healthcare providers., Results: Involvement in care entailed family: (1) reorienting their life despite the stress and emotional toll; (2) assuming responsibility for meaningful activities and management of practical matters, yet struggling alone; (3) advocating for care by being present, reminding and pushing, and picking their battles; and (4) figuring out how to contribute to nursing care, but with unclear expectations., Discussion: The burden of family caregiving was substantial, contrasting the assumption that family are relieved of their caregiver responsibilities when the patient with CCI is in a care facility. Research to address unmet family needs specific to their roles and responsibilities could potentially improve family outcomes and is warranted., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Omicron is the current predominant variant of concern of SARS-CoV-2. We hypothesized that vaccination alters outcomes of patients hospitalized with COVID-19 during the Omicron wave and that these patients have different characteristics and outcomes than in previous waves., Methods: This is a substudy of the Host Response Mediators in Coronavirus (COVID-19) Infection (ARBs CORONA I) trial, which included adults admitted to hospital with acute COVID-19 up to July 2022 from 9 hospitals in British Columbia, Ontario and Quebec. We excluded emergency department visits without hospital admission, readmissions and admissions for another reason. Using adjusted regression analysis, we compared mortality and organ dysfunction between vaccinated (≥ 2 doses) and unvaccinated patients during the Omicron wave, as well as between all patients in the Omicron and first 3 waves of the COVID-19 pandemic., Results: During the Omicron wave, 28-day mortality was significantly lower in vaccinated ( n = 19/237) than unvaccinated hospitalized patients ( n = 12/127) (adjusted odds ratio [OR] 0.36, 95% confidence interval [CI] 0.15-0.89); vaccinated patients had lower risk of admission to the intensive care unit, invasive ventilation and acute respiratory distress syndrome and shorter hospital length of stay. Patients hospitalized during the Omicron wave had more comorbidities than in previous waves, and lower 28-day mortality than in waves 1 and 2 (adjusted OR 0.38, 95% CI 0.24-0.59; and 0.42, 95% CI 0.26-0.65) but not wave 3 (adjusted OR 0.81, 95% CI 0.43-1.51) and had less organ dysfunction than in the first 2 waves., Interpretation: Patients who were at least double vaccinated had lower mortality than unvaccinated patients hospitalized during the Omicron wave. Patients hospitalized during the Omicron wave had more chronic disease and lower mortality than in the first 2 waves, but not wave 3. Changes in vaccination, treatments and predominant SARS-CoV-2 variant may have decreased mortality in patients hospitalized during the Omicron wave., Competing Interests: Competing interests: Keith Walley reports receiving a Canadian Institutes of Health Research (CIHR) Foundation grant, paid to the University of British Columbia. Dr. Walley has also participated on data safety monitoring boards (unpaid) for Northern Therapeutics and the Cellular Immuno-Therapy for COVID-19 Acute Respiratory Distress Syndrome (CIRCA-19) trial. Allison McGeer reports receiving grants from Sanofi, Merck and Pfizer (paid to institution), as well as payment or honoraria from AstraZeneca, Merck, Biogen and Moderna. Dr. McGeer has also received travel support from Moderna and has participated on a data safety monitoring or advisory board for Pfizer, GlaxoSmithKline, Moderna, Medicago, Janssen, AstraZeneca, Novavax and Sanofi., (© 2023 CMA Impact Inc. or its licensors.)

Competing Interests: Dr. Howard holds a Michael Smith Health Research British Columbia Scholar Award. The remaining authors have disclosed that they do not have any potential conflicts of interest

Background: There have been multiple waves in the COVID-19 pandemic in many countries. We sought to compare mortality and respiratory, cardiovascular and renal dysfunction between waves in 3 Canadian provinces., Methods: We conducted a substudy of the ARBs CORONA I study, a multicentre Canadian pragmatic observational cohort study that examined the association of pre-existing use of angiotensin receptor blockers with outcomes in adults admitted to hospital with acute COVID-19 up to April 2021 from 9 community and teaching hospitals in 3 Canadian provinces (British Columbia, Ontario and Quebec). We excluded emergency department admissions without hospital admission, readmissions and admissions for another reason. We used logistic and 0-1-inflated β regression models to compare 28-day and in-hospital mortality, and the use of invasive mechanical ventilation, vasopressors and renal replacement therapy (RRT) between the first 3 waves of the COVID-19 pandemic in these provinces., Results: A total of 520, 572 and 245 patients in waves 1, 2 and 3, respectively, were included. Patients in wave 3 were on average younger and had fewer comorbidities than those in waves 1 and 2. The unadjusted 28-day mortality rate was significantly lower in wave 3 (7.8%) than in wave 1 (18.3%) (odds ratio [OR] 0.43, 95% confidence interval [CI] 0.24-0.78) and wave 2 (16.3%) (OR 0.46, 95% CI 0.27-0.79). After adjustment for differences in baseline characteristics, the difference in 28-day mortality remained significant (adjusted OR wave 3 v. wave 1: 0.46, 95% CI 0.26-0.81; wave 3 v. wave 2: 0.52, 95% CI 0.29-0.91). In-hospital mortality findings were similar. Use of invasive mechanical ventilation or vasopressors was less common in waves 2 and 3 than in wave 1, and use of RRT was less common in wave 3 than in wave 1., Interpretation: Severity of illness decreased (lower mortality and less use of organ support) across waves among patients admitted to hospital with acute COVID-19, possibly owing to changes in patient demographic characteristics and management, such as increased use of dexamethasone. Continued application of proven therapies may further improve outcomes., Study Registration: ClinicalTrials.gov, no. NCT04510623., Competing Interests: Competing interests: James Russell reports an investigator-initiated grant from Grifols that was provided to and administered by the University of British Columbia (UBC). He reports patents owned by UBC that are related to the use of PCSK9 inhibitor(s) in sepsis and the use of vasopressin in septic shock, and a patent owned by Ferring Pharmaceuticals for use of selepressin in septic shock. He is an inventor on these patents. He was a founder, director and shareholder in Cyon Therapeutics and is a shareholder in Molecular You. He reports consulting fees from SIB Therapeutics (developing a sepsis drug) and Ferring Pharmaceuticals (manufactures vasopressin and developing selepressin). He is no longer actively consulting for any industry. He was a nonfunded science advisor and member of the Government of Canada COVID-19 Therapeutics Task Force (June 2020–December 2021) and a nonfunded member of the data and safety monitoring board of a trial of plasma in COVID-19 (PassITON) (2020–2021) sponsored by the National Institutes of Health. No other competing interests were declared., (© 2022 CMA Impact Inc. or its licensors.)

The host response to COVID-19 pathophysiology over the first few days of infection remains largely unclear, especially the mechanisms in the blood compartment. We report on a longitudinal proteomic analysis of acute-phase COVID-19 patients, for which we used blood plasma, multiple reaction monitoring with internal standards, and data-independent acquisition. We measured samples on admission for 49 patients, of which 21 had additional samples on days 2, 4, 7, and 14 after admission. We also measured 30 externally obtained samples from healthy individuals for comparison at baseline. The 31 proteins differentiated in abundance between acute COVID-19 patients and healthy controls belonged to acute inflammatory response, complement activation, regulation of inflammatory response, and regulation of protein activation cascade. The longitudinal analysis showed distinct profiles revealing increased levels of multiple lipid-associated functions, a rapid decrease followed by recovery for complement activation, humoral immune response, and acute inflammatory response-related proteins, and level fluctuation in the regulation of smooth muscle cell proliferation, secretory mechanisms, and platelet degranulation. Three proteins were differentiated between survivors and nonsurvivors. Finally, increased levels of fructose-bisphosphate aldolase B were determined in patients with exposure to angiotensin receptor blockers versus decreased levels in those exposed to angiotensin-converting enzyme inhibitors. Data are available via ProteomeXchange PXD029437.

Individuals with chronic critical illness experience multiple complex physiological disturbances including ongoing respiratory failure, requiring prolonged mechanical ventilation, and thus communication impairments. In conducting a qualitative interpretive description study, we sought to ensure that individuals with chronic critical illness themselves were included as participants. Our commitment to recruiting these individuals to the study and ensuring their data meaningfully informed the analysis and findings required us to reconsider and challenge some of the traditional notions of high-quality qualitative research and develop appropriate practical strategies. These strategies included: (1) centering participant abilities and preferences, (2) adopting a flexible approach to conducting interviews, (3) engaging in a therapeutic relationship, and (4) valuing "thin" data. In this article, we extend existing literature describing the complexities of conducting research with individuals with communication impairments and strategies to consider in the hopes of informing future research with other populations historically excluded from study participation., Competing Interests: Declaration of Conflicting Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2021.)

Background: Healthcare workers have historically experienced symptoms of post-traumatic stress disorder, depression and anxiety with previous infectious outbreaks. It is unknown if critical care nurses have similar experiences., Objectives: The study aimed to examine the mental health of Critical Care Registered Nurses providing direct patient care during the initial phase of the COVID-19 pandemic in Canada., Design: This was a convergent parallel mixed method study utilizing validated questionnaires and semi-structured qualitative interviews., Setting: Critical care units in a single large 650 bed academic teaching hospital in western Canada. The critical care units serve a general mixed medical - surgical adult patient population., Participants: Critical Care Registered Nurses providing direct patient care in the intensive care and high acuity units at the designated site., Methods: 109 participants completed two self-reported validated surveys, the Impact of Events Scale - Revised and the Depression, Anxiety and Stress Scale. 15 participants completed one-on-one semi-structured interviews that were analyzed using inductive thematic analysis., Results: In the surveys, the participants reported clinical concern for (23%), probable (13%) and significant (38%) symptoms of post-traumatic stress disorder, as well as mild to severe depression (57%), anxiety (67%) and stress (54%). In the interviews, psychological distress was described as anxiety, worry, distress and fear related to: 1) rapidly changing policy and information, 2) overwhelming and unclear communication, 3) meeting patient care needs in new ways while staying safe, and 4) managing home and personal commitments to self and family., Conclusions: Critical care nurses experienced psychological distress associated with providing care to COVID-19 patients during the early phases of the pandemic., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Competing Interests: Intérêts concurrents: Aucun intérêt concurrent déclaré

Design: This is a retrospective case series describing the feasibility and tolerability of postextubation prone positioning (PEPP) and its impact on physiologic parameters in a tertiary intensive care unit during the COVID-19 pandemic. Setting and Patients . This study was conducted on patients with COVID-19 respiratory failure hospitalized in a tertiary Intensive Care Unit at Surrey Memorial Hospital during the COVID-19 pandemic. Measurements and Results . We did not find prior reports of PEPP following prolonged intubation in the literature. Four patients underwent a total of 13 PEPP sessions following liberation from prolonged mechanical ventilation. Each patient underwent a median of 3 prone sessions (IQR: 2, 4.25) lasting a median of 1.5 hours (IQR: 1.2, 2.1). PEPP sessions were associated with a reduction in median oxygen requirements, patient respiratory rate, and reintubation rate. The sessions were well tolerated by patients, nursing, and the allied health team., Conclusions: The novel practice of PEPP after liberation from prolonged mechanical ventilation in patients with COVID-19 respiratory failure is feasible and well tolerated, and may be associated with favourable clinical outcomes including improvement in oxygenation and respiratory rate and a low rate of reintubation. Larger prospective studies of PEPP are warranted., Competing Interests: The authors do not have conflicts of interest to disclose., (Copyright © 2020 Andrei Karpov et al.)

Purpose: High acuity units (HAU) are hospital units that provide patients with more acute care and closer monitoring than a general hospital ward but are not as resource intensive as an intensive care unit (ICU). Nevertheless, the impact of opening a HAU on ICU patient outcomes remains poorly defined. We investigated how the creation of a HAU impacted patient outcomes in the ICU., Methods: This historical cohort study compared ICU patient in-hospital mortality, ICU length of stay (LOS), and hospital LOS before and after the creation of a HAU in a tertiary-care hospital with a medical/surgical ICU between 1 January 2013 and 31 December 2017., Results: Data from 4,380 patients (984 in the pre-HAU group and 3,396 in the post-HAU group) were analyzed. In this cohort of ICU patients, 360 (37%) died in the pre-HAU group before the creation of a HAU, and 1,074 (32%) died in the post-HAU group after the creation of a HAU. The creation of a HAU was associated with lower relative risk of in-hospital mortality (adjusted risk ratio, 0.80; 95% confidence interval [CI], 0.72 to 0.89; P < 0.001). The creation of a HAU was also associated with reduced ICU and hospital LOS with a 12% increase in the rate of ICU discharge (adjusted sub-distribution hazard ratio [SHR], 1.12; 95% CI, 1.02 to 1.23; P = 0.02) and a 26% increase in the rate of hospital discharge (adjusted SHR, 1.26; 95% CI, 1.14 to 1.39; P < 0.001), when accounting for the competing risk of death., Conclusions: These data support the hypothesis that the creation of a HAU may be associated with reduced in-hospital mortality, ICU LOS, and hospital LOS for ICU patients.

Competing Interests: Intérêts concurrents: Aucun déclaré.

Background: Pandemic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is associated with high intensive care unit (ICU) mortality. We aimed to describe the clinical characteristics and outcomes of critically ill patients with coronavirus disease 2019 (COVID-19) in a Canadian setting., Methods: We conducted a retrospective case series of critically ill patients with laboratory-confirmed SARS-CoV-2 infection consecutively admitted to 1 of 6 ICUs in Metro Vancouver, British Columbia, Canada, between Feb. 21 and Apr. 14, 2020. Demographic, management and outcome data were collected by review of patient charts and electronic medical records., Results: Between Feb. 21 and Apr. 14, 2020, 117 patients were admitted to the ICU with a confirmed diagnosis of COVID-19. The median age was 69 (interquartile range [IQR] 60-75) years, and 38 (32.5%) were female. At least 1 comorbidity was present in 86 (73.5%) patients. Invasive mechanical ventilation was required in 74 (63.2%) patients. The duration of mechanical ventilation was 13.5 (IQR 8-22) days overall and 11 (IQR 6-16) days for patients successfully discharged from the ICU. Tocilizumab was administered to 4 patients and hydroxychloroquine to 1 patient. As of May 5, 2020, a total of 18 (15.4%) patients had died, 12 (10.3%) remained in the ICU, 16 (13.7%) were discharged from the ICU but remained in hospital, and 71 (60.7%) were discharged home., Interpretation: In our setting, mortality in critically ill patients with COVID-19 admitted to the ICU was lower than in previously published studies. These data suggest that the prognosis associated with critical illness due to COVID-19 may not be as poor as previously reported., Competing Interests: Competing interests: None declared., (© 2020 Joule Inc. or its licensors.)

Competing Interests: Competing interests: None declared.

Background: While 80% of critically ill patients treated in an intensive care unit (ICU) will survive, survivors often suffer a constellation of new or worsening physical, cognitive, and psychiatric complications, termed post-intensive care syndrome. Emerging evidence paints a challenging picture of complex, long-term complications that are often untreated and culminate in substantial dependence on acute care services. Clinicians and decision-makers in the Fraser Health Authority of British Columbia are working to develop evidence-based community healthcare solutions that will be successful in the context of existing healthcare services. The objective of the proposed review is to provide the theoretical scaffolding to transform the care of survivors of critical illness by a synthesis of relevant clinical and healthcare service programs., Methods: Realist review will be used to develop and refine a theoretical understanding of why, how, for whom, and in what circumstances post-ICU program impact ICU survivors' outcomes. This review will follow the recommended five steps of realist review which include (1) clarifying the scope of the review and articulating a preliminary program theory, (2) searching for evidence, (3) appraising primary studies and extracting data, (4) synthesizing evidence and sharing conclusions, and (5) disseminating and implementing recommendations., Discussion: This realist review will provide a program theory, encompassing the contexts, mechanisms, and outcomes, to explain how clinical and health service interventions to improve ICU survivor outcomes operate in different contexts for different survivors, and with what effect. This review will be an evidentiary pillar for health service development and implementation by our knowledge user team members as well as advance scholarly knowledge relevant nationally and internationally., Systematic Review Registration: PROSPERO CRD42018087795.

Introduction: Cardiomyocytes exposed to inflammatory processes express intracellular adhesion molecule-1 (ICAM-1). We investigated whether fibrinogen and fibrinogen degradation products, including D-dimer, could alter cardiomyocyte contractile function through interaction with ICAM-1 found on inflamed cardiomyocytes., Methods: In vivo, rats were injected with endotoxin to model systemic inflammation, whereas isolated rat cardiomyocytes were treated with tumor necrosis factor-alpha to model the inflammatory environment seen following exposure to bacterial products such as lipopolysaccharide., Results: In vivo, endotoxin administration profoundly decreased cardiac contractile function associated with a large increase in intracardiac ICAM-1 and perivascular fibrinogen. Confocal microscopy with double-staining of isolated rat cardiomyocytes demonstrated colocalization of ICAM-1 and fibrinogen. This interaction was disrupted through pre-treatment of the cells with an ICAM-1-blocking antibody. Functionally, isolated rat cardiomyocyte preparations exhibited decreased fractional shortening when incubated with fibrinogen, and through the use of synthetic peptides, we determined that residues 117-133 of the fibrinogen gamma chain are responsible for this interaction with ICAM-1. Despite having crosslinked gamma chains, D-dimer retained the ability to decrease cardiomyocyte contractility., Conclusion: Site 117-133 of the fibrinogen gamma chain is able to depress cardiomyocyte contractility through binding ICAM-1.

Adenovirus (Ad) vectors can produce inflammatory responses at high doses. Intravenous administration of an Ad vector expressing green fluorescent protein (AdGFP) to naive mice induced a biphasic pattern of liver cytokine/chemokine gene expression over 7 days. Tumor necrosis factor alpha (TNF-alpha), macrophage inflammatory protein 2 (MIP-2), and interferon gamma-inducible protein 10 (IP-10) genes were upregulated, with two distinct peaks of mRNA expression occurring at 6 hr and 5 days. The administration of transcription-defective AdGFP particles induced the early but not the late peak of chemokine/cytokine gene expression, confirming that Ad vector-induced inflammation is capsid dependent in the early phase and transcription dependent in the late phase. To determine the role of adenoviral capsid motifs in the early phase, capsid-modified Ad vectors were employed. The intravenous administration of the RGD-deleted Ad vector AdL.PB*, the fiber mutant AdL.F*, or the double mutant AdL.F*PB* induced similar levels of cytokine/chemokine expression compared with the wild-type vector AdLuc. Kupffer cell blockade significantly reduced liver TNF-alpha, MIP-2, and IP-10 gene expression and liver inflammation after the administration of AdL.PB* or AdL.F*PB*. Fluorescence microscopy of AdLuc- and AdL.PB*-transduced liver at 1 hr revealed localization of Ad vectors to liver sinusoids in Kupffer cell-depleted mice. AdL.PB* induced less E-selectin and VCAM-1 gene expression in liver, confirming reduced endothelial activation in mice receiving RGD-deleted Ad vectors. In vitro studies of endothelial cells demonstrated reduced transduction and endothelial activation by AdL.PB* compared with AdLuc. These results demonstrate that adenovirus capsid RGD motifs are required for efficient transduction and endothelial cell activation. Altering vector tropism represents a feasible strategy to modulate the innate response to Ad vectors in nontargeted tissues.