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From tree to sea
Illustrations and easy-to-read text reveal lessons that nature teaches, such as how, like the sun, one can bring warmth to others by smiling and shining even when things look dim.
BOOK
Subtypes of pediatric acute respiratory distress syndrome have different predictors of mortality
PurposeAcute respiratory distress syndrome (ARDS) is heterogeneous in etiology, which may affect outcomes. Stratification into biologically-defined subtypes may reduce heterogeneity. However, it is unknown whether pediatric ARDS has clinically relevant subtypes. We aimed to determine whether clinical characteristics and predictors of mortality differed between direct and indirect ARDS, and separately between infectious and non-infectious ARDS.MethodsThis was a single center, prospective cohort study of 544 children with ARDS (Berlin) between July 2011 and June 2017, stratified into direct versus indirect ARDS, and separately into infectious versus non-infectious ARDS. Multiple logistic regression was used to test for predictors of mortality in the entire cohort, and separately within subtypes. Effect modification by subtype was assessed using interaction tests.ResultsDirect ARDS had lower severity of illness (p < 0.001) but worse oxygenation (p < 0.001), relative to indirect. Predictors of mortality were similar for direct and indirect ARDS. When comparing infectious and non-infectious ARDS, infectious ARDS had lower severity of illness (p < 0.001), worse oxygenation (p = 0.014), and lower mortality (p = 0.013). In multivariable analysis, immunocompromised status demonstrated effect modification between infectious and non-infectious ARDS (p = 0.005 for interaction), with no association with mortality in non-infectious ARDS.ConclusionsIn children, direct and indirect ARDS have distinct clinical characteristics, but similar outcomes and similar predictors of mortality. In contrast, infectious and non-infectious ARDS demonstrate heterogeneity of clinical characteristics, mortality, and predictors of mortality, with traditional predictors of ARDS mortality only applicable to infectious ARDS.
Journal Article
The Inhumans. Beware the Inhumans
\"From Stan Lee, Jack Kirby, Roy Thomas and Neal Adams--the titans of the Marvel Age of Comics--come the Inhumans! For the first time, the stories that defined these regal outcasts are brought together in one collection. From rare exploits and appearances in Fantastic Four to their first solo series in Amazing Adventures, the adventures of Black Bolt, Medusa, Karnak, Gorgon, Crystal and loveable Lockjaw are here. Their quest for peace will be threatened not just be a world that fears them, but by Black Bolt's own brother, Maximus the Mad, and his evil cohorts. The Inhumans is a family epic full of intrigue, as only comics' greatest creative talents could craft it--in the mighty Marvel manner!\"--Back cover.
Book
Exuberant fibroblast activity compromises lung function via ADAMTS4
Severe respiratory infections can result in acute respiratory distress syndrome (ARDS)
1
. There are no effective pharmacological therapies that have been shown to improve outcomes for patients with ARDS. Although the host inflammatory response limits spread of and eventually clears the pathogen, immunopathology is a major contributor to tissue damage and ARDS
1
,
2
. Here we demonstrate that respiratory viral infection induces distinct fibroblast activation states, which we term extracellular matrix (ECM)-synthesizing, damage-responsive and interferon-responsive states. We provide evidence that excess activity of damage-responsive lung fibroblasts drives lethal immunopathology during severe influenza virus infection. By producing ECM-remodelling enzymes—in particular the ECM protease ADAMTS4—and inflammatory cytokines, damage-responsive fibroblasts modify the lung microenvironment to promote robust immune cell infiltration at the expense of lung function. In three cohorts of human participants, the levels of ADAMTS4 in the lower respiratory tract were associated with the severity of infection with seasonal or avian influenza virus. A therapeutic agent that targets the ECM protease activity of damage-responsive lung fibroblasts could provide a promising approach to preserving lung function and improving clinical outcomes following severe respiratory infections.
Viral infection of the respiratory system induces exuberant fibroblast activity, resulting in extensive remodelling of the extracellular matrix and cytokine release, which promote immune cell infiltration of the affected area at the expense of respiratory function.
Journal Article
The Avengers. Kree/Skrull War
When Ronan the Accuser seizes control of the Kree Empire and launches an attack against Earth, the Avengers must face the threat, while the shape-shifting Skrulls, hiding among the human population, reveal themselves to wage war.
Book
Global Epidemiology of Pediatric Severe Sepsis: The Sepsis Prevalence, Outcomes, and Therapies Study
Abstract
Rationale
Limited data exist about the international burden of severe sepsis in critically ill children.
Objectives
To characterize the global prevalence, therapies, and outcomes of severe sepsis in pediatric intensive care units to better inform interventional trials.
Methods
A point prevalence study was conducted on 5 days throughout 2013–2014 at 128 sites in 26 countries. Patients younger than 18 years of age with severe sepsis as defined by consensus criteria were included. Outcomes were severe sepsis point prevalence, therapies used, new or progressive multiorgan dysfunction, ventilator- and vasoactive-free days at Day 28, functional status, and mortality.
Measurements and Main Results
Of 6,925 patients screened, 569 had severe sepsis (prevalence, 8.2%; 95% confidence interval, 7.6–8.9%). The patients’ median age was 3.0 (interquartile range [IQR], 0.7–11.0) years. The most frequent sites of infection were respiratory (40%) and bloodstream (19%). Common therapies included mechanical ventilation (74% of patients), vasoactive infusions (55%), and corticosteroids (45%). Hospital mortality was 25% and did not differ by age or between developed and resource-limited countries. Median ventilator-free days were 16 (IQR, 0–25), and vasoactive-free days were 23 (IQR, 12–28). Sixty-seven percent of patients had multiorgan dysfunction at sepsis recognition, with 30% subsequently developing new or progressive multiorgan dysfunction. Among survivors, 17% developed at least moderate disability. Sample sizes needed to detect a 5–10% absolute risk reduction in outcomes within interventional trials are estimated between 165 and 1,437 patients per group.
Conclusions
Pediatric severe sepsis remains a burdensome public health problem, with prevalence, morbidity, and mortality rates similar to those reported in critically ill adult populations. International clinical trials targeting children with severe sepsis are warranted.
Journal Article
Developing a Clinically Feasible Personalized Medicine Approach to Pediatric Septic Shock
Using microarray data, we previously identified gene expression-based subclasses of septic shock with important phenotypic differences. The subclass-defining genes correspond to adaptive immunity and glucocorticoid receptor signaling. Identifying the subclasses in real time has theranostic implications, given the potential for immune-enhancing therapies and controversies surrounding adjunctive corticosteroids for septic shock.
To develop and validate a real-time subclassification method for septic shock.
Gene expression data for the 100 subclass-defining genes were generated using a multiplex messenger RNA quantification platform (NanoString nCounter) and visualized using gene expression mosaics. Study subjects (n = 168) were allocated to the subclasses using computer-assisted image analysis and microarray-based reference mosaics. A gene expression score was calculated to reduce the gene expression patterns to a single metric. The method was tested prospectively in a separate cohort (n = 132).
The NanoString-based data reproduced two septic shock subclasses. As previously, one subclass had decreased expression of the subclass-defining genes. The gene expression score identified this subclass with an area under the curve of 0.98 (95% confidence interval [CI95] = 0.96-0.99). Prospective testing of the subclassification method corroborated these findings. Allocation to this subclass was independently associated with mortality (odds ratio = 2.7; CI95 = 1.2-6.0; P = 0.016), and adjunctive corticosteroids prescribed at physician discretion were independently associated with mortality in this subclass (odds ratio = 4.1; CI95 = 1.4-12.0; P = 0.011).
We developed and tested a gene expression-based classification method for pediatric septic shock that meets the time constraints of the critical care environment, and can potentially inform therapeutic decisions.
Journal Article
Adaptable microfluidic system for single-cell pathogen classification and antimicrobial susceptibility testing
Infectious diseases caused by bacterial pathogens remain one of the most common causes of morbidity and mortality worldwide. Rapid microbiological analysis is required for prompt treatment of bacterial infections and to facilitate antibiotic stewardship. This study reports an adaptable microfluidic system for rapid pathogen classification and antimicrobial susceptibility testing (AST) at the single-cell level. By incorporating tunable microfluidic valves along with real-time optical detection, bacteria can be trapped and classified according to their physical shape and size for pathogen classification. By monitoring their growth in the presence of antibiotics at the single-cell level, antimicrobial susceptibility of the bacteria can be determined in as little as 30 minutes compared with days required for standard procedures. The microfluidic system is able to detect bacterial pathogens in urine, blood cultures, and whole blood and can analyze polymicrobial samples. We pilot a study of 25 clinical urine samples to demonstrate the clinical applicability of the microfluidic system. The platform demonstrated a sensitivity of 100% and specificity of 83.33% for pathogen classification and achieved 100% concordance for AST.
Journal Article
Overlapping MicroRNA Expression in Saliva and Cerebrospinal Fluid Accurately Identifies Pediatric Traumatic Brain Injury
To assess the accuracy and physiological relevance of circulating microRNA (miRNA) as a biomarker of pediatric concussion, we compared changes in salivary miRNA and cerebrospinal fluid (CSF) miRNA concentrations after childhood traumatic brain injury (TBI). A case-cohort design was used to compare longitudinal miRNA concentrations in CSF of seven children with severe TBI against three controls without TBI. The miRNAs “altered” in CSF were interrogated in saliva of 60 children with mild TBI and compared with 18 age- and sex-matched controls. The miRNAs with parallel changes (Wilcoxon rank sum test) in CSF and saliva were interrogated for predictive accuracy of TBI status using a multivariate regression technique. Spearman rank correlation identified relationships between miRNAs of interest and clinical features. Functional analysis with DIANA mirPath identified related mRNA pathways. There were 214 miRNAs detected in CSF, and 135 (63%) were also present in saliva. Six miRNAs had parallel changes in both CSF and saliva (miR-182-5p, miR-221-3p, mir-26b-5p, miR-320c, miR-29c-3p, miR-30e-5p). These miRNAs demonstrated an area under the curve of 0.852 for identifying mild TBI status. Three of the miRNAs exhibited longitudinal trends in CSF and/or saliva after TBI, and all three targeted mRNAs related to neuronal development. Concentrations of miR-320c were directly correlated with child and parent reports of attention difficulty. Salivary miRNA represents an easily measured, physiologically relevant, and accurate potential biomarker for TBI. Further studies assessing the influence of orthopedic injury and exercise on peripheral miRNA patterns are needed.
Journal Article
Positive End-Expiratory Pressure Lower Than the ARDS Network Protocol Is Associated with Higher Pediatric Acute Respiratory Distress Syndrome Mortality
The ARDS Network (ARDSNet) used a positive end-expiratory pressure (PEEP)/Fi
model in many studies. In general, pediatric intensivists use less PEEP and higher Fi
than this model.
To evaluate whether children managed with PEEP lower than recommended by the ARDSNet PEEP/Fi
model had higher mortality.
This was a multicenter, retrospective analysis of patients with pediatric acute respiratory distress syndrome (PARDS) managed without a formal PEEP/Fi
protocol. Four distinct datasets were combined for analysis. We extracted time-matched PEEP/Fi
values, calculating the difference between PEEP level and the ARDSNet-recommended PEEP level for a given Fi
. We analyzed the median difference over the first 24 hours of PARDS diagnosis against ICU mortality and adjusted for confounding variables, effect modifiers, or factors that may have affected the propensity to use lower PEEP.
Of the 1,134 patients with PARDS, 26.6% were managed with lower PEEP relative to the amount of Fi
recommended by the ARDSNet protocol. Patients managed with lower PEEP experienced higher mortality than those who were managed with PEEP levels in line with or higher than recommended by the protocol (P < 0.001). After adjustment for hypoxemia, inotropes, comorbidities, severity of illness, ventilator settings, nitric oxide, and dataset, PEEP lower than recommended by the protocol remained independently associated with higher mortality (odds ratio, 2.05; 95% confidence interval, 1.32-3.17). Findings were similar after propensity-based covariate adjustment (odds ratio, 2.00; 95% confidence interval, 1.24-3.22).
Patients with PARDS managed with lower PEEP relative to Fi
than recommended by the ARDSNet model had higher mortality. Clinical trials targeting PEEP management in PARDS are needed.
Journal Article