Oncolytic Viruses for Tumor Precision Imaging and Radiotherapy

Human Gene Therapy , Vol. 0, No. 0.


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An Inducible Promoter Responsive to Different Porphyrinogenic Stimuli Improves Gene Therapy Vectors for Acute Intermittent Porphyria

Human Gene Therapy , Vol. 0, No. 0.


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Risk Stratification Using Oxygenation in the First 24 Hours of Pediatric Acute Respiratory Distress Syndrome

Objective: Oxygenation measured 24 hours after acute respiratory distress syndrome onset more accurately stratifies risk, relative to oxygenation at onset, in both children and adults. However, waiting 24 hours is problematic, especially for interventions that are more efficacious early in the disease course. We aimed to delineate whether oxygenation measured at timepoints earlier than 24 hours would retain predictive validity in pediatric acute respiratory distress syndrome. Design: Observational cohort study. Setting: Two large, academic PICUs. Patients: Invasively ventilated children with acute respiratory distress syndrome. Interventions: None. Measurements and Main Results: PaO2/FIO2 and oxygenation index (mean airway pressure × FIO2 × 100)/PaO2) were measured at acute respiratory distress syndrome onset, at 6, 12, 18, and 24 hours after in 459 children at the Children's Hospital of Philadelphia. Neither PaO2/FIO2 nor oxygenation index at acute respiratory distress syndrome onset discriminated outcome. Between 6 and 24 hours, both PaO2/FIO2 (area under receiver operating curve for mortality between 0.57 and 0.62; p = 0.049–0.002) and oxygenation index (area under receiver operating curve, 0.60–0.62; p = 0.006–0.001) showed good discrimination and calibration across multiple outcomes, including mortality, ventilator-free days at 28 days, ventilator days in survivors, and probability of extubation, given competing risk of death. The utility of oxygenation at 12 hours was confirmed in an independent cohort from the Children's Hospital of Los Angeles. Conclusion: Oxygenation measured between 6 and 12 hours of acute respiratory distress syndrome onset accurately stratified outcomes in children. Our results have critical implications for the design of trials, especially for interventions with greater impact in early acute respiratory distress syndrome. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (http://ift.tt/29S62lw). Supported by grants NIH K12-HL109009, K23-HL136688 (N.Y.), NIH K23-HD075069 (R.G.K.) Dr. Yehya's institution received funding from the National Heart, Lung, and Blood Institute, and he received support for article research from the National Institutes of Health. Dr. Thomas received funding from Therabron, CareFusion, and GeneFluidics. Dr. Khemani received funding from Orangemed. For information regarding this article, E-mail: yehyan@email.chop.edu Copyright © by 2017 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

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Treatment of Paraquat-Induced Lung Injury With an Anti-C5a Antibody: Potential Clinical Application

Objectives: Complement activation product C5a plays a critical role in systemic inflammatory response syndrome induced by viruses, bacteria, and toxic agents including paraquat poisoning. This study is to explore the efficiency of anti-C5a–based intervention on systemic inflammatory responses induced by paraquat poisoning. Design: Study of cynomolgus macaque model and plasma from paraquat-poisoning patients. Setting: Laboratory investigation. Subjects: Cynomolgus macaque (n = 12) and samples of plasma from patients (n = 16). Interventions: The neutralizing antihuman C5a antibody (IFX-1) was administered to investigate the new treatment strategy for paraquat-induced systemic inflammatory responses in cynomolgus macaque model. In addition, C5a activation in plasma of paraquat patients was blocked by IFX-1 to investigate the blockade role of anti-C5a antibody in activation of inflammatory cells. Measurements and Main Results: Dysregulated complement activation and the subsequent cytokine storm were found in patients with acute lung injury and in a primate model of paraquat poisoning. Targeted inhibition of C5a by IFX-1 led to marked alleviation of systemic inflammatory responses and multiple organ damage in the primate model. In addition, blockade of C5a activity in plasma from patients completely inhibited activation of CD11b on blood granulocytes from normal donors, suggesting that IFX-1 may alleviate the excessive activation of inflammatory responses and have clinical utility for patients with acute lung injury. Conclusions: Anti-C5a antibodies such as IFX-1 may be used as effective therapeutics for treatment of those suffering from systemic inflammatory responses induced by chemical poisoning like paraquat. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. Drs. Sun, Jiang, and Wang contributed equally to this work. Drs. Qiu, Zhao, and Zhou had full access to all of the data reported in this study and had final responsibility for the decision to submit this report for publication. Drs. Sun, Wang, Li, Zhao, and Zhou designed research study; Drs. Sun, Jiang, Wang, C. Liu, X. Liu, Song, and Guo performed research; Drs. Sun, Jiang, Wang, Li, and Zhao analyzed data; Drs. Sun, Zhao, and Zhou wrote the article; and Drs. Wang, Guo, Du, Jiang, and Li for revising the article. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (http://ift.tt/29S62lw). Supported, in part, by grants from the National Nature Science Foundation of China (81571983 and 81371805), the Program of National Ministry of Science and Technology (2014ZX09J14105-04B) and funding of State Key Laboratory of Pathogen and Biosecurity (SKLPBS1509). Dr. R. Guo disclosed that he is a cofounder for InflaRx, who provides IFX-1 used in this study. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: qiuzw828@163.com; guangyu0525@163.com; yszhou@bmi.ac.cn Copyright © by 2017 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

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Prevalence of Anxiety and Depression Symptomatology in Adolescents Faced With the Hospitalization of a Loved One in the ICU

Objective: ICU experience is linked to anxiety and depression symptomatology in family members of patients. Minors may be forbidden from visiting. To bring practices in line with evidence, we determined the prevalence of anxiety and depression symptomatology in adolescents visiting a relative in the ICU. Design: One-year prospective observational monocenter study. Setting: Medical-surgical ICU, University Hospital of Martinique. Patients: Forty-one patients intubated for more than 2 days; 53 adolescents (12–17 yr) first- to third-degree relatives in regular contact (minimum once a month) with patient before hospitalization. Interventions: Adolescents with unrestricted ICU access completed a satisfaction survey, anxiety history questionnaire, and psychometric evaluation (Hospital Anxiety and Depression Scale) before the patient's 15th day of hospitalization and extubation. Measurements and Main Results: Forty adolescents (75.5%) visited their relative. Possible and probable anxiety and depression symptomatology prevalence was 35.9% and 18.9%, respectively, with no significant difference according to ICU visiting status. Most (80%) reported a lack of information, 40% insufficient consideration, and 27.5% misunderstood the reason for hospitalization. Two (5%) regretted visiting. Probable anxiety and depression symptomatology was associated with first-degree relationship (odds ratio, 9.1 [95% CI, 1.1–78.9]; p = 0.045), past exposure to a traumatic event (odds ratio, 8.7 [1.1–69.0]; p = 0.040) and past sense of threat (odds ratio, 10.4 [1.1–94.5]; p = 0.038). Conclusions: Anxiety and depression symptomatology is common in adolescent family members of ICU patients. An open visiting policy for adolescents is recommended, with visit planning, information meetings, and individual support from ICU staff. The present work was conducted at the University Hospital of Martinique. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (http://ift.tt/29S62lw). Dr. Mehdaoui disclosed government work. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: jean.ferge@chu-martinique.fr Copyright © by 2017 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

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Systematic Review and Meta-Analysis of Procalcitonin-Guidance Versus Usual Care for Antimicrobial Management in Critically Ill Patients: Focus on Subgroups Based on Antibiotic Initiation, Cessation, or Mixed Strategies

Objective: Numerous studies have evaluated the use of procalcitonin guidance during different phases of antibiotics management (initiation, cessation, or a combination of both) in patients admitted to ICUs. Several meta-analyses have attempted to generate an overall effect of procalcitonin-guidance on patient outcomes. However, combining studies from different phases of antibiotics management may not be appropriate due to the risk of clinical heterogeneity. The purpose of this systematic review and meta-analysis was to evaluate the effect of procalcitonin-guided strategies in different phases of antibiotics use. Data Sources: We searched MEDLINE and EMBASE from inception until November 1, 2017. Study Selection: We included randomized controlled trials that evaluated procalcitonin guidance compared with usual care for management of antibiotics in critically ill adult patients. Data Extraction: We extracted study details, patient characteristics, procalcitonin algorithm, and outcomes. Data Synthesis: We included 15 studies, from 1,624 abstracts identified based on our search strategy (three initiation, nine cessation, and three mixed). The pooled risk ratio for short-term mortality for the initiation, cessation, and mixed procalcitonin strategies were 1.00 (95% CI, 0.86–1.15,;p = 0.91), 0.87 (95% CI, 0.77–0.98; p = 0.02), and 1.01 (95% CI, 0.80–1.29; p = 0.93), respectively. Procalcitonin for cessation and mixed strategies was associated with decrease antibiotics duration (–1.26 d [p

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Predictors of In-Hospital Mortality After Rapid Response Team Calls in a 274 Hospital Nationwide Sample

Objectives: Despite wide adoption of rapid response teams across the United States, predictors of in-hospital mortality for patients receiving rapid response team calls are poorly characterized. Identification of patients at high risk of death during hospitalization could improve triage to intensive care units and prompt timely reevaluations of goals of care. We sought to identify predictors of in-hospital mortality in patients who are subjects of rapid response team calls and to develop and validate a predictive model for death after rapid response team call. Design: Analysis of data from the national Get with the Guidelines-Medical Emergency Team event registry. Setting: Two-hundred seventy four hospitals participating in Get with the Guidelines-Medical Emergency Team from June 2005 to February 2015. Patients: 282,710 hospitalized adults on surgical or medical wards who were subjects of a rapid response team call. Interventions: None. Measurements and Main Results: The primary outcome was death during hospitalization; candidate predictors included patient demographic- and event-level characteristics. Patients who died after rapid response team were older (median age 72 vs 66 yr), were more likely to be admitted for noncardiac medical illness (70% vs 58%), and had greater median length of stay prior to rapid response team (81 vs 47 hr) (p

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