Perfluorochemical (PFC) liquid enhances recombinant adenovirus vector-mediated viral interleukin-10 (AdvIL-10) expression in rodent lung

Adenovirus and cationic liposome mediated transfer of Interleukin-10 (IL-10), a potent anti-inflammatory cytokine, has been shown to decrease pro-inflammatory cytokine levels and overall lung inflammation in models of lung transplantation and injury. Limitations to current approaches of IL-10 gene therapy include poor vector delivery methods and pro-inflammatory properties of human IL-10 under certain conditions. We hypothesize that using perfluorochemical (PFC) liquid to deliver the highly homologous viral IL-10 (vIL-10), which is predominantly anti-inflammatory with minimal pro-inflammatory activities, can potentially be a more effective strategy to combat inflammatory lung diseases. In this study, we compare the use of PFC liquid versus aerosolized method to deliver adenovirus encoding the vIL-10 gene (AdvIL-10) in C57Bl6 mice. Detectable vIL-10 levels were measured from bronchoalveolar lavage fluid and lung homogenates at one, four, ten and thirty days after AdvIL-10. Furthermore, we determined if use of PFC liquid could allow for the use of a lower dose of AdvIL-10 by comparing the levels of detectable vIL-10 at different doses of AdvIL-10 delivered +/- PFC liquid. Results showed that PFC liquid enhanced detectable vIL-10 by up to ten fold and that PFC liquid allowed the use of ten-fold less vector. PFC liquid increased detectable vIL-10 in lung homogenates at all time points; however, the increase in detectable vIL-10 in BAL fluid peaked at four days and was no longer evident by thirty days after intratracheal instillation. In summary, this is the first report utilizing PFC liquid to enhance the delivery of a potentially therapeutic molecule, vIL-10. We believe this strategy can be used to perform future studies on the use of the predominantly anti-inflammatory vIL-10 to treat inflammatory lung diseases

Endocrine Dysfunction Criteria in Critically Ill Children: The PODIUM Consensus Conference

CONTEXT Endocrine dysfunction is common in critically ill children and is manifested by abnormalities in glucose, thyroid hormone, and cortisol metabolism. OBJECTIVE To develop consensus criteria for endocrine dysfunction in critically ill children by assessing the association of various biomarkers with clinical and functional outcomes. DATA SOURCES PubMed and Embase were searched from January 1992 to January 2020. STUDY SELECTION We included studies in which researchers evaluated critically ill children with abnormalities in glucose homeostasis, thyroid function and adrenal function, performance characteristics of assessment and/or scoring tools to screen for endocrine dysfunction, and outcomes related to mortality, organ-specific status, and patient-centered outcomes. Studies of adults, premature infants or animals, reviews and/or commentaries, case series with sample size ≤10, and non-English-language studies were excluded. DATA EXTRACTION Data extraction and risk-of-bias assessment for each eligible study were performed by 2 independent reviewers. RESULTS The systematic review supports the following criteria for abnormal glucose homeostasis (blood glucose [BG] concentrations >150 mg/dL [>8.3 mmol/L] and BG concentrations <50 mg/dL [<2.8 mmol/L]), abnormal thyroid function (serum total thyroxine [T4] <4.2 μg/dL [<54 nmol/L]), and abnormal adrenal function (peak serum cortisol concentration <18 μg/dL [500 nmol/L]) and/or an increment in serum cortisol concentration of <9 μg/dL (250 nmol/L) after adrenocorticotropic hormone stimulation. LIMITATIONS These included variable sampling for BG measurements, limited reporting of free T4 levels, and inconsistent interpretation of adrenal axis testing. CONCLUSIONS We present consensus criteria for endocrine dysfunction in critically ill children that include specific measures of BG, T4, and adrenal axis testing

Scoring Systems for Organ Dysfunction and Multiple Organ Dysfunction: The PODIUM Consensus Conference

CONTEXT Multiple scores exist to characterize organ dysfunction in children. OBJECTIVE To review the literature on multiple organ dysfunction (MOD) scoring systems to estimate severity of illness and to characterize the performance characteristics of currently used scoring tools and clinical assessments for organ dysfunction in critically ill children. DATA SOURCES Electronic searches of PubMed and Embase were conducted from January 1992 to January 2020. STUDY SELECTION Studies were included if they evaluated critically ill children with MOD, evaluated the performance characteristics of scoring tools for MOD, and assessed outcomes related to mortality, functional status, organ-specific outcomes, or other patient-centered outcomes. DATA EXTRACTION Data were abstracted into a standard data extraction form by a task force member. RESULTS Of 1152 unique abstracts screened, 156 full text studies were assessed including a total of 54 eligible studies. The most commonly reported scores were the Pediatric Logistic Organ Dysfunction Score (PELOD), pediatric Sequential Organ Failure Assessment score (pSOFA), Pediatric Index of Mortality (PIM), PRISM, and counts of organ dysfunction using the International Pediatric Sepsis Definition Consensus Conference. Cut-offs for specific organ dysfunction criteria, diagnostic elements included, and use of counts versus weighting varied substantially. LIMITATIONS While scores demonstrated an increase in mortality associated with the severity and number of organ dysfunctions, the performance ranged widely. CONCLUSIONS The multitude of scores on organ dysfunction to assess severity of illness indicates a need for unified and data-driven organ dysfunction criteria, derived and validated in large, heterogenous international databases of critically ill children

Simons Observatory: Broadband Metamaterial Anti-Reflection Cuttings for Large Aperture Alumina Optics

We present the design, fabrication, and measured performance of metamaterial Anti-Reflection Cuttings (ARCs) for large-format alumina filters operating over more than an octave of bandwidth to be deployed on the Simons Observatory (SO). The ARC consists of sub-wavelength features diced into the optic's surface using a custom dicing saw with near-micron accuracy. The designs achieve percent-level control over reflections at angles of incidence up to 20$^\circ$. The ARCs were demonstrated on four 42 cm diameter filters covering the 75-170 GHz band and a 50 mm diameter prototype covering the 200-300 GHz band. The reflection and transmission of these samples were measured using a broadband coherent source that covers frequencies from 20 GHz to 1.2 THz. These measurements demonstrate percent-level control over reflectance across the targeted pass-bands and a rapid reduction in transmission as the wavelength approaches the length scale of the metamaterial structure where scattering dominates the optical response. The latter behavior enables the use of the metamaterial ARC as a scattering filter in this limit.Comment: 9 pages, 8 figures, submitted to Applied Optic

Cardiovascular Dysfunction Criteria in Critically Ill Children: The PODIUM Consensus Conference

CONTEXT Cardiovascular dysfunction is associated with poor outcomes in critically ill children. OBJECTIVE We aim to derive an evidence-informed, consensus-based definition of cardiovascular dysfunction in critically ill children. DATA SOURCES Electronic searches of PubMed and Embase were conducted from January 1992 to January 2020 using medical subject heading terms and text words to define concepts of cardiovascular dysfunction, pediatric critical illness, and outcomes of interest. STUDY SELECTION Studies were included if they evaluated critically ill children with cardiovascular dysfunction and assessment and/or scoring tools to screen for cardiovascular dysfunction and assessed mortality, functional status, organ-specific, or other patient-centered outcomes. Studies of adults, premature infants (≤36 weeks gestational age), animals, reviews and/or commentaries, case series (sample size ≤10), and non-English-language studies were excluded. Studies of children with cyanotic congenital heart disease or cardiovascular dysfunction after cardiopulmonary bypass were excluded. DATA EXTRACTION Data were abstracted from each eligible study into a standard data extraction form, along with risk-of-bias assessment by a task force member. RESULTS Cardiovascular dysfunction was defined by 9 elements, including 4 which indicate severe cardiovascular dysfunction. Cardiopulmonary arrest (>5 minutes) or mechanical circulatory support independently define severe cardiovascular dysfunction, whereas tachycardia, hypotension, vasoactive-inotropic score, lactate, troponin I, central venous oxygen saturation, and echocardiographic estimation of left ventricular ejection fraction were included in any combination. There was expert agreement (>80%) on the definition. LIMITATIONS All included studies were observational and many were retrospective. CONCLUSIONS The Pediatric Organ Dysfunction Information Update Mandate panel propose this evidence-informed definition of cardiovascular dysfunction

Severe Acute Kidney Injury is Associated with Increased Risk of Death and New Morbidity After Pediatric Septic Shock

Objectives: Acute kidney injury is common in critically ill children; however, the frequency of septic shock-associated acute kidney injury and impact on functional status are unknown. We evaluated functional outcomes of children with septic shock-associated acute kidney injury. Design: Secondary analysis of patients with septic shock from the prospective Life after Pediatric Sepsis Evaluation study. We defined acute kidney injury using Kidney Disease Improving Global Outcomes criteria, comparing patients with absent/Stage 1 acute kidney injury to those with Stage 2/3 acute kidney injury (severe acute kidney injury). Our primary outcome was a composite of mortality or new functional morbidity at day 28 of hospitalization or discharge. We also assessed poor long-term outcome, defined as mortality or a persistent, serious deterioration in health-related quality of life at 3 months. Setting: Twelve academic PICUs in the United States. Patients: Critically ill children, 1 month to 18 years, with community-acquired septic shock requiring vasoactive-inotropic support. Interventions: None. Measurements and main results: More than 50% of patients (176/348) developed severe acute kidney injury; of those, 21.6% (38/176) required renal replacement therapy. Twice as many patients with severe acute kidney injury died or developed new substantive functional morbidity (38.6 vs 16.3%; p < 0.001). After adjustment for age, malignancy, and initial illness severity, severe acute kidney injury was independently associated with mortality or new substantive morbidity (adjusted odds ratio, 2.78; 95% CI, 1.63-4.81; p < 0.001). Children with severe acute kidney injury had poorer health-related quality of life at 3 months (adjusted effect size 2.46; 95% CI, 1.44-4.20; p = 0.002). Children with severe acute kidney injury required longer duration of mechanical ventilation (11.0 vs 7.0 d; p < 0.001) and PICU stay (11.7 vs 7.1 d; p < 0.001). Conclusions: Among children with septic shock, severe acute kidney injury was independently associated with increased risk of death or new substantive functional morbidity. Survivors of sepsis with severe acute kidney injury were more likely to have persistent, serious health-related quality of life deterioration at 3 months

Operationalizing Appropriate Sepsis Definitions in Children Worldwide: Considerations for the Pediatric Sepsis Definition Taskforce

Sepsis is a leading cause of global mortality in children, yet definitions for pediatric sepsis are outdated and lack global applicability and validity. In adults, the Sepsis-3 Definition Taskforce queried databases from high-income countries to develop and validate the criteria. The merit of this definition has been widely acknowledged; however, important considerations about less-resourced and more diverse settings pose challenges to its use globally. To improve applicability and relevance globally, the Pediatric Sepsis Definition Taskforce sought to develop a conceptual framework and rationale of the critical aspects and context-specific factors that must be considered for the optimal operationalization of future pediatric sepsis definitions. It is important to address challenges in developing a set of pediatric sepsis criteria which capture manifestations of illnesses with vastly different etiologies and underlying mechanisms. Ideal criteria need to be unambiguous, and capable of adapting to the different contexts in which children with suspected infections are present around the globe. Additionally, criteria need to facilitate early recognition and timely escalation of treatment to prevent progression and limit life-threatening organ dysfunction. To address these challenges, locally adaptable solutions are required, which permit individualized care based on available resources and the pretest probability of sepsis. This should facilitate affordable diagnostics which support risk stratification and prediction of likely treatment responses, and solutions for locally relevant outcome measures. For this purpose, global collaborative databases need to be established, using minimum variable datasets from routinely collected data. In summary, a "Think globally, act locally" approach is required

Executive Summary of the Second International Guidelines for the Diagnosis and Management of Pediatric Acute Respiratory Distress Syndrome (PALICC-2)

OBJECTIVES: We sought to update our 2015 work in the Second Pediatric Acute Lung Injury Consensus Conference (PALICC-2) guidelines for the diagnosis and management of pediatric acute respiratory distress syndrome (PARDS), considering new evidence and topic areas that were not previously addressed. DESIGN: International consensus conference series involving 52 multidisciplinary international content experts in PARDS and four methodology experts from 15 countries, using consensus conference methodology, and implementation science. SETTING: Not applicable. PATIENTS: Patients with or at risk for PARDS. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Eleven subgroups conducted systematic or scoping reviews addressing 11 topic areas: 1) definition, incidence, and epidemiology; 2) pathobiology, severity, and risk stratification; 3) ventilatory support; 4) pulmonary-specific ancillary treatment; 5) nonpulmonary treatment; 6) monitoring; 7) noninvasive respiratory support; 8) extracorporeal support; 9) morbidity and long-term outcomes; 10) clinical informatics and data science; and 11) resource-limited settings. The search included MEDLINE, EMBASE, and CINAHL Complete (EBSCOhost) and was updated in March 2022. Grading of Recommendations, Assessment, Development, and Evaluation methodology was used to summarize evidence and develop the recommendations, which were discussed and voted on by all PALICC-2 experts. There were 146 recommendations and statements, including: 34 recommendations for clinical practice; 112 consensus-based statements with 18 on PARDS definition, 55 on good practice, seven on policy, and 32 on research. All recommendations and statements had agreement greater than 80%. CONCLUSIONS: PALICC-2 recommendations and consensus-based statements should facilitate the implementation and adherence to the best clinical practice in patients with PARDS. These results will also inform the development of future programs of research that are crucially needed to provide stronger evidence to guide the pediatric critical care teams managing these patients.</p

Development and Validation of the Phoenix Criteria for Pediatric Sepsis and Septic Shock

ImportanceThe Society of Critical Care Medicine Pediatric Sepsis Definition Task Force sought to develop and validate new clinical criteria for pediatric sepsis and septic shock using measures of organ dysfunction through a data-driven approach.ObjectiveTo derive and validate novel criteria for pediatric sepsis and septic shock across differently resourced settings.Design, Setting, and ParticipantsMulticenter, international, retrospective cohort study in 10 health systems in the US, Colombia, Bangladesh, China, and Kenya, 3 of which were used as external validation sites. Data were collected from emergency and inpatient encounters for children (aged &amp;amp;lt;18 years) from 2010 to 2019: 3 049 699 in the development (including derivation and internal validation) set and 581 317 in the external validation set.ExposureStacked regression models to predict mortality in children with suspected infection were derived and validated using the best-performing organ dysfunction subscores from 8 existing scores. The final model was then translated into an integer-based score used to establish binary criteria for sepsis and septic shock.Main Outcomes and MeasuresThe primary outcome for all analyses was in-hospital mortality. Model- and integer-based score performance measures included the area under the precision recall curve (AUPRC; primary) and area under the receiver operating characteristic curve (AUROC; secondary). For binary criteria, primary performance measures were positive predictive value and sensitivity.ResultsAmong the 172 984 children with suspected infection in the first 24 hours (development set; 1.2% mortality), a 4-organ-system model performed best. The integer version of that model, the Phoenix Sepsis Score, had AUPRCs of 0.23 to 0.38 (95% CI range, 0.20-0.39) and AUROCs of 0.71 to 0.92 (95% CI range, 0.70-0.92) to predict mortality in the validation sets. Using a Phoenix Sepsis Score of 2 points or higher in children with suspected infection as criteria for sepsis and sepsis plus 1 or more cardiovascular point as criteria for septic shock resulted in a higher positive predictive value and higher or similar sensitivity compared with the 2005 International Pediatric Sepsis Consensus Conference (IPSCC) criteria across differently resourced settings.Conclusions and RelevanceThe novel Phoenix sepsis criteria, which were derived and validated using data from higher- and lower-resource settings, had improved performance for the diagnosis of pediatric sepsis and septic shock compared with the existing IPSCC criteria.</jats:sec

International Consensus Criteria for Pediatric Sepsis and Septic Shock.

ImportanceSepsis is a leading cause of death among children worldwide. Current pediatric-specific criteria for sepsis were published in 2005 based on expert opinion. In 2016, the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) defined sepsis as life-threatening organ dysfunction caused by a dysregulated host response to infection, but it excluded children.ObjectiveTo update and evaluate criteria for sepsis and septic shock in children.Evidence reviewThe Society of Critical Care Medicine (SCCM) convened a task force of 35 pediatric experts in critical care, emergency medicine, infectious diseases, general pediatrics, nursing, public health, and neonatology from 6 continents. Using evidence from an international survey, systematic review and meta-analysis, and a new organ dysfunction score developed based on more than 3 million electronic health record encounters from 10 sites on 4 continents, a modified Delphi consensus process was employed to develop criteria.FindingsBased on survey data, most pediatric clinicians used sepsis to refer to infection with life-threatening organ dysfunction, which differed from prior pediatric sepsis criteria that used systemic inflammatory response syndrome (SIRS) criteria, which have poor predictive properties, and included the redundant term, severe sepsis. The SCCM task force recommends that sepsis in children be identified by a Phoenix Sepsis Score of at least 2 points in children with suspected infection, which indicates potentially life-threatening dysfunction of the respiratory, cardiovascular, coagulation, and/or neurological systems. Children with a Phoenix Sepsis Score of at least 2 points had in-hospital mortality of 7.1% in higher-resource settings and 28.5% in lower-resource settings, more than 8 times that of children with suspected infection not meeting these criteria. Mortality was higher in children who had organ dysfunction in at least 1 of 4-respiratory, cardiovascular, coagulation, and/or neurological-organ systems that was not the primary site of infection. Septic shock was defined as children with sepsis who had cardiovascular dysfunction, indicated by at least 1 cardiovascular point in the Phoenix Sepsis Score, which included severe hypotension for age, blood lactate exceeding 5 mmol/L, or need for vasoactive medication. Children with septic shock had an in-hospital mortality rate of 10.8% and 33.5% in higher- and lower-resource settings, respectively.Conclusions and relevanceThe Phoenix sepsis criteria for sepsis and septic shock in children were derived and validated by the international SCCM Pediatric Sepsis Definition Task Force using a large international database and survey, systematic review and meta-analysis, and modified Delphi consensus approach. A Phoenix Sepsis Score of at least 2 identified potentially life-threatening organ dysfunction in children younger than 18 years with infection, and its use has the potential to improve clinical care, epidemiological assessment, and research in pediatric sepsis and septic shock around the world