Viperin is induced following dengue virus type-2 (DENV-2) infection and has anti-viral actions requiring the C-terminal end of viperin

The host protein viperin is an interferon stimulated gene (ISG) that is up-regulated during a number of viral infections. In this study we have shown that dengue virus type-2 (DENV-2) infection significantly induced viperin, co-incident with production of viral RNA and via a mechanism requiring retinoic acid-inducible gene I (RIG-I). Viperin did not inhibit DENV-2 entry but DENV-2 RNA and infectious virus release was inhibited in viperin expressing cells. Conversely, DENV-2 replicated to higher tires earlier in viperin shRNA expressing cells. The anti-DENV effect of viperin was mediated by residues within the C-terminal 17 amino acids of viperin and did not require the N-terminal residues, including the helix domain, leucine zipper and S-adenosylmethionine (SAM) motifs known to be involved in viperin intracellular membrane association. Viperin showed co-localisation with lipid droplet markers, and was co-localised and interacted with DENV-2 capsid (CA), NS3 and viral RNA. The ability of viperin to interact with DENV-2 NS3 was associated with its anti-viral activity, while co-localisation of viperin with lipid droplets was not. Thus, DENV-2 infection induces viperin which has anti-viral properties residing in the C-terminal region of the protein that act to restrict early DENV-2 RNA production/accumulation, potentially via interaction of viperin with DENV-2 NS3 and replication complexes. These anti-DENV-2 actions of viperin show both contrasts and similarities with other described anti-viral mechanisms of viperin action and highlight the diverse nature of this unique anti-viral host protein.Karla J. Helbig, Jillian M. Carr, Julie K. Calvert, Satiya Wati, Jennifer N. Clarke, Nicholas S. Eyre, Sumudu K. Narayana, Guillaume N. Fiches, Erin M. McCartney, Michael R. Bear

CDC's COVID-19 International Vaccine Implementation and Evaluation Program and Lessons from Earlier Vaccine Introductions.

The US Centers for Disease Control and Prevention (CDC) supports international partners in introducing vaccines, including those against SARS-CoV-2 virus. CDC contributes to the development of global technical tools, guidance, and policy for COVID-19 vaccination and has established its COVID-19 International Vaccine Implementation and Evaluation (CIVIE) program. CIVIE supports ministries of health and their partner organizations in developing or strengthening their national capacities for the planning, implementation, and evaluation of COVID-19 vaccination programs. CIVIE's 7 priority areas for country-specific technical assistance are vaccine policy development, program planning, vaccine confidence and demand, data management and use, workforce development, vaccine safety, and evaluation. We discuss CDC's work on global COVID-19 vaccine implementation, including priorities, challenges, opportunities, and applicable lessons learned from prior experiences with Ebola, influenza, and meningococcal serogroup A conjugate vaccine introductions

Financial outcomes after pediatric critical illness among commercially insured families

Abstract Critical illness results in subjective financial distress for families, but little is known about objective caregiver finances after a child’s pediatric intensive care unit (PICU) hospitalization. Using statewide commercial insurance claims linked to cross-sectional commercial credit data, we identified caregivers of children with PICU hospitalizations in January–June 2020 and January–June 2021. Credit data included delinquent debt, debt in collections (medical and non-medical), low credit score (< 660), and a composite of any debt or poor credit and were measured in January 2021 for all caregivers. For the 2020 cohort (“post-PICU”), credit outcomes in January 2021 were measured at least 6 months following PICU hospitalization and reflect financial status after the hospitalization. For the 2021 cohort (comparison), financial outcomes were measured prior to their child’s PICU hospitalization and therefore reflect pre-hospitalization financial status. We identified 2032 caregivers, 1017 post-PICU caregivers and 1015 comparison cohort caregivers, of which 1016 and 1014 were matched to credit data, respectively. Post-PICU caregivers had higher adjusted odds of having any delinquent debt [aOR 1.25; 95%CI 1.02–1.53; p = 0.03] and having a low credit score [aOR 1.29; 95%CI 1.06–1.58; p = 0.01]. However, there was no difference in the amount of delinquent debt or debt in collections among those with nonzero debt. Overall, 39.5% and 36.5% of post-PICU and comparator caregivers, respectively, had delinquent debt, debt in collections or poor credit. Many caregivers of critically ill children have financial debt or poor credit during hospitalization and post-discharge. However, caregivers may be at higher risk for poor financial status following their child’s critical illness

Renal angina index predicts fluid overload in critically ill children: an observational cohort study

Abstract Background Fluid overload and acute kidney injury are common and associated with poor outcomes among critically ill children. The prodrome of renal angina stratifies patients by risk for severe acute kidney injury, but the predictive discrimination for fluid overload is unknown. Methods Post-hoc analysis of patients admitted to a tertiary care pediatric intensive care unit (PICU). The primary outcome was the performance of renal angina fulfillment on day of ICU admission to predict fluid overload ≥15% on Day 3. Results 77/139 children (55%) fulfilled renal angina (RA+). After adjusting for covariates, RA+ was associated with increased odds of fluid overload on Day 3 (adjusted odds ratio (aOR) 5.1, 95% CI 1.23–21.2, p = 0.025, versus RA-). RA- resulted in a 90% negative predictive value for fluid overload on Day 3. Median fluid overload was significantly higher in RA+ patients with severe acute kidney injury compared to RA+ patients without severe acute kidney injury (% fluid overload on Day 3: 8.8% vs. 0.73%, p = 0.002). Conclusion Among critically ill children, fulfillment of renal angina was associated with increased odds of fluid overload versus the absence of renal angina and a higher fluid overload among patients who developed acute kidney injury. Renal angina directed risk classification may identify patients at highest risk for fluid accumulation. Expanded study in larger populations is warranted.http://deepblue.lib.umich.edu/bitstream/2027.42/173576/1/12882_2021_Article_2540.pd

Acquisition of new medical devices among the persistently critically ill: a retrospective cohort study in the Veterans Affairs

Patients who develop persistent critical illness remain in the ICU predominately because they develop new late-onset organ failure(s), which may render them at risk of acquiring a new medical device. The epidemiology and short-term outcomes of patients with persistent critical illness who acquire a new medical device are unknown. We retrospectively studied a cohort admitted to the Veterans Affairs (VA) ICUs from 2014 to 2019. Persistent critical illness was defined as an ICU length of stay of at least 14 days. Receipt of new devices was defined as acquisition of a new tracheostomy, feeding tube (including gastrostomy and jejunostomy tubes), implantable cardiac device, or ostomy. Logistic regression models were fit to identify patient factors associated with the acquisition of each new medical device. Among hospitalized survivors, 90-day posthospitalization discharge location and mortality were identified. From 2014 to 2019, there were 13,184 ICU hospitalizations in the VA which developed persistent critical illness. In total, 30.4% of patients (N = 3998/13,184) acquired at least 1 medical device during their persistent critical illness period. Patients with an initial higher severity of illness and prolonged hospital stay preICU admission had higher odds of acquiring each medical device. Among patients who survived their hospitalization, discharge location and mortality did not significantly differ among those who acquired a new medical device as compared to those who did not. Less than one-third of patients with persistent critical illness acquire a new medical device and no significant difference in short-term outcomes was identified. Future work is needed to understand if the acquisition of new medical devices is contributing to the development of persistent critical illness

Implementing Pediatric Surviving Sepsis Campaign Guidelines: Improving Compliance With Lactate Measurement in the PICU

OBJECTIVES:. The 2020 pediatric Surviving Sepsis Campaign (pSSC) recommends measuring lactate during the first hour of resuscitation for severe sepsis/shock. We aimed to improve compliance with this recommendation for patients who develop severe sepsis/shock while admitted to the PICU. DESIGN:. Structured, quality improvement initiative. SETTING:. Single-center, 26-bed, quaternary-care PICU. PATIENTS:. All patients with PICU-onset severe sepsis/shock from December 2018 to December 2021. INTERVENTIONS:. Creation of a multidisciplinary local sepsis improvement team, education program targeting frontline providers (nurse practitioners, resident physicians), and peer-to-peer nursing education program with feedback to key stakeholders. MEASUREMENTS AND MAIN RESULTS:. The primary outcome measure was compliance with obtaining a lactate measurement within 60 minutes of the onset of severe sepsis/shock originating in our PICU using a local Improving Pediatric Sepsis Outcomes database and definitions. The process measure was time to first lactate measurement. Secondary outcomes included number of IV antibiotic days, number of vasoactive days, number of ICU days, and number of ventilator days. A total of 166 unique PICU-onset severe sepsis/shock events and 156 unique patients were included. One year after implementation of our first interventions with subsequent Plan-Do-Study-Act cycles, overall compliance increased from 38% to 47% (24% improvement) and time to first lactate decreased from 175 to 94 minutes (46% improvement). Using a statistical process control I chart, the preshift mean for time to first lactate measurement was noted to be 179 minutes and the postshift mean was noted to be 81 minutes demonstrating a 55% improvement. CONCLUSIONS:. This multidisciplinary approach led to improvement in time to first lactate measurement, an important step toward attaining our target of lactate measurement within 60 minutes of septic shock identification. Improving compliance is necessary for understanding implications of the 2020 pSSC guidelines on sepsis morbidity and mortality

School and Work Absences After Critical Care Hospitalization for Pediatric Acute Respiratory Failure: A Secondary Analysis of a Cluster Randomized Trial

Patients who survive pediatric critical illness and their caregivers commonly experience physical, emotional, and cognitive sequelae. However, the rate and duration of school absence among patients and work absence among their caregivers are unknown. To determine the rates and duration of school absence among children who survived hospitalization with acute respiratory failure and work absence among their caregivers. The Randomized Evaluation of Sedation Titration for Respiratory Failure (RESTORE) cluster randomized trial included 2449 children from 31 sites to protocolized sedation (intervention) vs usual care (control) from June 6, 2009, to December 2, 2013. In total, 1360 children survived hospitalization and were selected for follow-up at 6 months after pediatric intensive care unit (PICU) discharge, which was completed from January 12, 2010, to April 13, 2015. This secondary analysis was conducted from July 1, 2020, to September 30, 2021. PICU hospitalization for acute respiratory failure, including invasive mechanical ventilation. Postdischarge assessments with caregivers of eligible participants at 6 months after PICU discharge, including questions about school and work absence. Risk factors associated with longer absence from school and work were identified. Postdischarge assessments were completed for 960 children who survived treatment for acute respiratory failure, of whom 443 (46.1%) were girls and 517 (53.9%) were boys; 509 of 957 (53.2%) were non-Hispanic White. Median age was 1.8 years (IQR, 0.4-7.9 years). In total, 399 children (41.6%) were enrolled in school, of whom 279 (69.9%) missed school after discharge. Median duration of postdischarge absence was 9.1 days (IQR, 0-27.9 days) among all children enrolled in school and 16.9 days (IQR, 7.9-43.9 days) among the 279 children with postdischarge absence. Among 960 primary caregivers, 506 (52.7%) were employed outside the home, of whom 277 (54.7%) missed work. Median duration of postdischarge work absence was 2 days (IQR, 0-10 days) among all employed primary caregivers, and 8 days (IQR, 4-20 days) among the 277 caregivers who missed work after discharge. The odds of postdischarge school absence and greater duration of absence increased for children 5 years or older (compared with 0-4 years, odds ratios [ORs] for 5-8 years, 3.20 [95% CI, 1.69-6.05] and 2.09 [95% CI, 1.30-3.37], respectively; ORs for 9-12 years, 2.49 [95% CI, 1.17-5.27] and 2.32 [95% CI, 1.30-4.14], respectively; and ORs for 13-18 years, 2.37 [95% CI, 1.20-4.66] and 1.89 [95% CI, 1.11-3.24], respectively) and those with a preexisting comorbidity (ORs, 1.90 [95% CI, 1.10-3.29] and 1.76 [95% CI, 1.14-2.69], respectively). In this secondary analysis of a cluster randomized trial, 2 in 3 children hospitalized for acute respiratory failure missed school after discharge, for a median duration of nearly 2 weeks. In addition, more than half of primary caregivers missed work after discharge. The magnitude of school absenteeism suggests that children may be at increased risk for lower educational achievement, economic hardship, and poor health outcomes in adulthood

A Core Outcome Measurement Set for Pediatric Critical Care

OBJECTIVES To identify a PICU Core Outcome Measurement Set (PICU COMS), a set of measures that can be used to evaluate the PICU Core Outcome Set (PICU COS) domains in PICU patients and their families. DESIGN A modified Delphi consensus process. SETTING Four webinars attended by PICU physicians and nurses, pediatric surgeons, rehabilitation physicians, and scientists with expertise in PICU clinical care or research ( n = 35). Attendees were from eight countries and convened from the Pediatric Acute Lung Injury and Sepsis Investigators Pediatric Outcomes STudies after PICU Investigators and the Eunice Kennedy Shriver National Institute of Child Health and Human Development Collaborative Pediatric Critical Care Research Network PICU COS Investigators. SUBJECTS Measures to assess outcome domains of the PICU COS are as follows: cognitive, emotional, overall (including health-related quality of life), physical, and family health. Measures evaluating social health were also considered. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS Measures were classified as general or additional based on generalizability across PICU populations, feasibility, and relevance to specific COS domains. Measures with high consensus, defined as 80% agreement for inclusion, were selected for the PICU COMS. Among 140 candidate measures, 24 were delineated as general (broadly applicable) and, of these, 10 achieved consensus for inclusion in the COMS (7 patient-oriented and 3 family-oriented). Six of the seven patient measures were applicable to the broadest range of patients, diagnoses, and developmental abilities. All were validated in pediatric populations and have normative pediatric data. Twenty additional measures focusing on specific populations or in-depth evaluation of a COS subdomain also met consensus for inclusion as COMS additional measures. CONCLUSIONS The PICU COMS delineates measures to evaluate domains in the PICU COS and facilitates comparability across future research studies to characterize PICU survivorship and enable interventional studies to target long-term outcomes after critical illness

Carbon oxidation state as a metric for describing the chemistry of atmospheric organic aerosol

A detailed understanding of the sources, transformations and fates of organic species in the environment is crucial because of the central roles that they play in human health, biogeochemical cycles and the Earth's climate. However, such an understanding is hindered by the immense chemical complexity of environmental mixtures of organics; for example, atmospheric organic aerosol consists of at least thousands of individual compounds, all of which likely evolve chemically over their atmospheric lifetimes. Here, we demonstrate the utility of describing organic aerosol (and other complex organic mixtures) in terms of average carbon oxidation state, a quantity that always increases with oxidation, and is readily measured using state-of-the-art analytical techniques. Field and laboratory measurements of the average carbon oxidation state, using several such techniques, constrain the chemical properties of the organics and demonstrate that the formation and evolution of organic aerosol involves simultaneous changes to both carbon oxidation state and carbon number.United States. Environmental Protection Agency (Science To Achieve Results (STAR) program (grant R833746))United States. Dept. of Energy (DOE: grant DE-FG02-05ER63995)United States. Dept. of Energy (DOE: grant ATM-0449815)United States. Dept. of Energy (DOE: grant ATM-0919189)United States. National Oceanic and Atmospheric Administration (NOAA: grant NA08OAR4310565)United States. Dept. of Energy (Director, Office of Energy Research, Office of Basic Energy Sciences, and Chemical Sciences Division of the US DOE (contract no. DE-AC02-05CH11231))Lawrence Berkeley National Laboratory (Laboratory Directed Research and Development Program)Henry & Camille Dreyfus Foundatio