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BACKGROUND: Little is known about the airway microbiome in intubated mechanically ventilated children. We sought to characterize the airway microbiome longitudinally and in association with clinical variables and possible ventilator-associated infection (VAI). METHODS: Serial tracheal aspirate samples were prospectively obtained from mechanically ventilated subjects under 3 years old from eight pediatric intensive care units in the United States from June 2017 to July 2018. Changes in the tracheal microbiome were analyzed by sequencing bacterial 16S ribosomal RNA gene relative to subject demographics, diagnoses, clinical parameters, outcomes, antibiotic treatment, and the Ventilator-Associated InfectioN (VAIN) score. RESULTS: A total of 221 samples from 58 patients were processed and 197 samples met the >1000 reads criteria (89%), with an average of 43,000 reads per sample. The median number of samples per subject was 3 (interquartile range [IQR]: 2–5), with a median VAIN score of 2 (IQR: 1–3). Proteobacteria was the highest observed phyla throughout the intubation period, followed by Firmicutes and Actinobacteria. Alpha diversity was negatively associated with days of intubation (p = .032) and VAIN score (p = .016). High VAIN scores were associated with a decrease of Mycobacterium obuense, and an increase of Streptococcus peroris, Porphyromonadaceae family (unclassified species), Veillonella atypica, and several other taxa. No specific pattern of microbiome composition related to clinically diagnosed VAIs was observed. CONCLUSIONS: Our data demonstrate decreasing alpha diversity with increasing VAIN score and days of intubation. No specific microbiome pattern was associated with clinically diagnosed VAI.

Streptococcus pneumoniae isolated from patients with invasive pneumococcal disease has been subjected to laboratory-based surveillance in Latin American and Caribbean countries since 1993. Invasive pneumococcal diseases remain a major cause of death and disability worldwide, particularly in children. We therefore aimed to assess the direct effect of pneumococcal conjugate vaccines (PCVs) on the distribution of pneumococcal serotypes causing invasive pneumococcal disease in children younger than 5 years before and after PCV introduction.We did a multicentre, retrospective observational study in eight countries that had introduced PCV (ie, PCV countries) in the Latin American and Caribbean region: Argentina, Brazil, Chile, Colombia, Dominican Republic, Mexico, Paraguay, and Uruguay. Cuba and Venezuela were also included as non-PCV countries. Isolate data for Streptococcus pneumoniae were obtained between 2006 and 2017 from children younger than 5 years with an invasive pneumococcal disease from local laboratories or hospitals. Species' confirmation and capsular serotyping were done by the respective national reference laboratories. Databases from the Sistema Regional de Vacunas (SIREVA) participating countries were managed and cleaned in a unified database using Microsoft Excel 2016 and the program R (version 3.6.1). Analysis involved percentage change in vaccine serotypes between pre-PCV and post-PCV periods and the annual reporting rate of invasive pneumococcal diseases per 100 000 children younger than 5 years, which was used as a population reference to calculate percentage vaccine type reduction.Between 2006 and 2017, 12 269 isolates of invasive pneumococcal disease were collected from children younger than 5 years in the ten Latin American and Caribbean countries. The ten serotypes included in ten-valent pneumococcal conjugate vaccine (PCV10) decreased significantly (p0·0001) after any PCV introduction, except for the Dominican Republic. The percentage change for the ten vaccine serotypes in PCV10 countries was -91·6% in Brazil (530 [72·9%] of 727 before, 27 [6·1%] of 441 after); -85·0% in Chile (613 [72·6%] of 844 before, 44 [10·9%] of 404] after); -84·7% in Colombia (231 [63·1%] of 366 before, 34 [9·7%] of 352 after); and -73·8% in Paraguay (127 [77·0%] of 165 before, 22 [20·2%] of 109 after). In the 13-valent pneumococcal conjugate vaccine (PCV13) countries, the percentage change for the 13 vaccine serotypes was -59·6% in Argentina (853 [85·0%] of 1003 before, 149 [34·3%] of 434 after); -16·5% in the Dominican Republic (95 [80·5%] of 118 before, 39 [67·2%] of 58 after); -43·7% in Mexico (202 [73·2%] of 276 before, 63 [41·2%] of 153 after); and -45·9% in Uruguay (138 [80·7%] of 171 before, 38 [43·7%] of 87 after). Annual reporting rates showed a reduction from -82·5% (6·21 before vs 1·09 after per 100 000, 95% CI -61·6 to -92·0) to -94·7% (1·15 vs 0·06 per 100 000, -89·7 to -97·3) for PCV10 countries, and -58·8% (2·98 vs 1·23 per 100 000, -21·4 to -78·4) to -82·9% (7·80 vs 1·33 per 100 000, -76·9 to -87·4) for PCV13 countries. An increase in the amount of non-vaccine types was observed in the eight countries after PCV introduction together with an increase in their percentage in relation to total invasive strains in the post-PCV period.SIREVA laboratory surveillance was able to confirm the effect of PCV vaccine on serotypes causing invasive pneumococcal disease in the eight PCV countries. Improved monitoring of the effect and trends in vaccine type as well as in non-vaccine type isolates is needed, as this information will be relevant for future decisions associated with new PCVs.None.For the Portuguese and Spanish translations of the abstract see Supplementary Materials section.

Background Understanding the epidemiology and clinical course of multisystem inflammatory syndrome in children (MIS-C) and its temporal association with coronavirus disease 2019 (Covid-19) is important, given the clinical and public health implications of the syndrome. Methods We conducted targeted surveillance for MIS-C from March 15 to May 20, 2020, in pediatric health centers across the United States. The case definition included six criteria: serious illness leading to hospitalization, an age of less than 21 years, fever that lasted for at least 24 hours, laboratory evidence of inflammation, multisystem organ involvement, and evidence of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) based on reverse-transcriptase polymerase chain reaction (RT-PCR), antibody testing, or exposure to persons with Covid-19 in the past month. Clinicians abstracted the data onto standardized forms. Results We report on 186 patients with MIS-C in 26 states. The median age was 8.3 years, 115 patients (62%) were male, 135 (73%) had previously been healthy, 131 (70%) were positive for SARS-CoV-2 by RT-PCR or antibody testing, and 164 (88%) were hospitalized after April 16, 2020. Organ-system involvement included the gastrointestinal system in 171 patients (92%), cardiovascular in 149 (80%), hematologic in 142 (76%), mucocutaneous in 137 (74%), and respiratory in 131 (70%). The median duration of hospitalization was 7 days (interquartile range, 4 to 10); 148 patients (80%) received intensive care, 37 (20%) received mechanical ventilation, 90 (48%) received vasoactive support, and 4 (2%) died. Coronary-artery aneurysms (z scores ≥2.5) were documented in 15 patients (8%), and Kawasaki’s disease–like features were documented in 74 (40%). Most patients (171 [92%]) had elevations in at least four biomarkers indicating inflammation. The use of immunomodulating therapies was common: intravenous immune globulin was used in 144 (77%), glucocorticoids in 91 (49%), and interleukin-6 or 1RA inhibitors in 38 (20%). Conclusions Multisystem inflammatory syndrome in children associated with SARS-CoV-2 led to serious and life-threatening illness in previously healthy children and adolescents. (Funded by the Centers for Disease Control and Prevention.)

Rationale: Few data exist to guide early adjunctive therapy use in pediatric acute respiratory distress syndrome (PARDS).Objectives: To describe contemporary use of adjunctive therapies for early PARDS as a framework for future investigations.Methods: This was a preplanned substudy of a prospective, international, cross-sectional observational study of children with PARDS from 100 centers over 10 study weeks.Measurements and Main Results: We investigated six adjunctive therapies for PARDS: continuous neuromuscular blockade, corticosteroids, inhaled nitric oxide (iNO), prone positioning, high-frequency oscillatory ventilation (HFOV), and extracorporeal membrane oxygenation. Almost half (45%) of children with PARDS received at least one therapy. Variability was noted in the median starting oxygenation index of each therapy; corticosteroids started at the lowest oxygenation index (13.0; interquartile range, 7.6-22.0) and HFOV at the highest (25.7; interquartile range, 16.7-37.3). Continuous neuromuscular blockade was the most common, used in 31%, followed by iNO (13%), corticosteroids (10%), prone positioning (10%), HFOV (9%), and extracorporeal membrane oxygenation (3%). Steroids, iNO, and HFOV were associated with comorbidities. Prone positioning and HFOV were more common in middle-income countries and less frequently used in North America. The use of multiple ancillary therapies increased over the first 3 days of PARDS, but there was not an easily identifiable pattern of combination or order of use.Conclusions: The contemporary description of prevalence, combinations of therapies, and oxygenation threshold for which the therapies are applied is important for design of future studies. Region of the world, income, and comorbidities influence adjunctive therapy use and are important variables to include in PARDS investigations.

Supplemental Digital Content is available in the text., Objectives: Pediatric acute respiratory distress syndrome is heterogeneous, with a paucity of risk stratification tools to assist with trial design. We aimed to develop and validate mortality prediction models for patients with pediatric acute respiratory distress syndrome. Design: Leveraging additional data collection from a preplanned ancillary study (Version 1) of the multinational Pediatric Acute Respiratory Distress syndrome Incidence and Epidemiology study, we identified predictors of mortality. Separate models were built for the entire Version 1 cohort, for the cohort excluding neurologic deaths, for intubated subjects, and for intubated subjects excluding neurologic deaths. Models were externally validated in a cohort of intubated pediatric acute respiratory distress syndrome patients from the Children’s Hospital of Philadelphia. Setting: The derivation cohort represented 100 centers worldwide; the validation cohort was from Children’s Hospital of Philadelphia. Patients: There were 624 and 640 subjects in the derivation and validation cohorts, respectively. Interventions: None. Measurements and Main Results: The model for the full cohort included immunocompromised status, Pediatric Logistic Organ Dysfunction 2 score, day 0 vasopressor-inotrope score and fluid balance, and Pao2/Fio2 6 hours after pediatric acute respiratory distress syndrome onset. This model had good discrimination (area under the receiver operating characteristic curve 0.82), calibration, and internal validation. Models excluding neurologic deaths, for intubated subjects, and for intubated subjects excluding neurologic deaths also demonstrated good discrimination (all area under the receiver operating characteristic curve ≥ 0.84) and calibration. In the validation cohort, models for intubated pediatric acute respiratory distress syndrome (including and excluding neurologic deaths) had excellent discrimination (both area under the receiver operating characteristic curve ≥ 0.85), but poor calibration. After revision, the model for all intubated subjects remained miscalibrated, whereas the model excluding neurologic deaths showed perfect calibration. Mortality models also stratified ventilator-free days at 28 days in both derivation and validation cohorts. Conclusions: We describe predictive models for mortality in pediatric acute respiratory distress syndrome using readily available variables from day 0 of pediatric acute respiratory distress syndrome which outperform severity of illness scores and which demonstrate utility for composite outcomes such as ventilator-free days. Models can assist with risk stratification for clinical trials.

OBJECTIVES: To describe mechanical ventilation management and factors associated with nonadherence to lung-protective ventilation principles in pediatric acute respiratory distress syndrome.DESIGN: A planned ancillary study to a prospective international observational study. Mechanical ventilation management (every 6 hr measurements) during pediatric acute respiratory distress syndrome days 0-3 was described and compared with Pediatric Acute Lung Injury Consensus Conference tidal volume recommendations (< 7 mL/kg in children with impaired respiratory system compliance, < 9 mL/kg in all other children) and the Acute Respiratory Distress Syndrome Network lower positive end-expiratory pressure/higher FIO2 grid recommendations.SETTING: Seventy-one international PICUs.PATIENTS: Children with pediatric acute respiratory distress syndrome.INTERVENTIONS: None.MEASUREMENTS AND MAIN RESULTS: Analyses included 422 children. On pediatric acute respiratory distress syndrome day 0, median tidal volume was 7.6 mL/kg (interquartile range, 6.3-8.9 mL/kg) and did not differ by pediatric acute respiratory distress syndrome severity. Plateau pressure was not recorded in 97% of measurements. Using delta pressure (peak inspiratory pressure - positive end-expiratory pressure), median tidal volume increased over quartiles of median delta pressure (p = 0.007). Median delta pressure was greater than or equal to 18 cm H2O for all pediatric acute respiratory distress syndrome severity levels. In severe pediatric acute respiratory distress syndrome, tidal volume was greater than or equal to 7 mL/kg 62% of the time, and positive end-expiratory pressure was lower than recommended by the positive end-expiratory pressure/FIO2 grid 70% of the time. In multivariable analysis, tidal volume nonadherence was more common with severe pediatric acute respiratory distress syndrome, fewer PICU admissions/yr, non-European PICUs, higher delta pressure, corticosteroid use, and pressure control mode. Adherence was associated with underweight stature and cuffed endotracheal tubes. In multivariable analysis, positive end-expiratory pressure/FIO2 grid nonadherence was more common with higher pediatric acute respiratory distress syndrome severity, ventilator decisions made primarily by the attending physician, pre-ICU cardiopulmonary resuscitation, underweight stature, and age less than 2 years. Adherence was associated with respiratory therapist involvement in ventilator management and longer time from pediatric acute respiratory distress syndrome diagnosis. Higher nonadherence to tidal volume and positive end-expiratory pressure recommendations were independently associated with higher mortality and longer duration of ventilation after adjustment for confounding variables. In stratified analyses, these associations were primarily influenced by children with severe pediatric acute respiratory distress syndrome.CONCLUSIONS: Nonadherence to lung-protective ventilation principles is common in pediatric acute respiratory distress syndrome and may impact outcome. Modifiable factors exist that may improve adherence.

OBJECTIVES: Interventional trials aimed at pediatric acute respiratory distress syndrome prevention require accurate identification of high-risk patients. In this study, we aimed to characterize the frequency and outcomes of children meeting "at risk for pediatric acute respiratory distress syndrome" criteria as defined by the Pediatric Acute Lung Injury Consensus Conference.DESIGN: Planned substudy of the prospective multicenter, international Pediatric Acute Respiratory Distress Syndrome Incidence and Epidemiology study conducted during 10 nonconsecutive weeks (May 2016-June 2017).SETTING: Thirty-seven international PICUs.PATIENTS: Three-hundred ten critically ill children meeting Pediatric Acute Lung Injury Consensus Conference "at-risk for pediatric acute respiratory distress syndrome" criteria.INTERVENTIONS: None.MEASUREMENTS AND MAIN RESULTS: We evaluated the frequency of children at risk for pediatric acute respiratory distress syndrome and rate of subsequent pediatric acute respiratory distress syndrome diagnosis and used multivariable logistic regression to identify factors associated with subsequent pediatric acute respiratory distress syndrome. Frequency of at risk for pediatric acute respiratory distress syndrome was 3.8% (95% CI, 3.4-5.2%) among the 8,122 critically ill children who were screened and 5.8% (95% CI, 5.2-6.4%) among the 5,334 screened children on positive pressure ventilation or high-flow oxygen. Among the 310 at-risk children, median age was 2.1 years (interquartile range, 0.5-7.3 yr). Sixty-six children (21.3%) were subsequently diagnosed with pediatric acute respiratory distress syndrome, a median of 22.6 hours (interquartile range, 9.8-41.0 hr) later. Subsequent pediatric acute respiratory distress syndrome was associated with increased mortality (21.2% vs 3.3%; p < 0.001) and longer durations of invasive ventilation and PICU care. Subsequent pediatric acute respiratory distress syndrome rate did not differ by respiratory support modality at the time of meeting at risk criteria but was independently associated with lower initial saturation:FIO2 ratio, progressive tachycardia, and early diuretic administration.CONCLUSIONS: The Pediatric Acute Lung Injury Consensus Conference "at-risk for pediatric acute respiratory distress syndrome" criteria identify critically ill children at high risk of pediatric acute respiratory distress syndrome and poor outcomes. Interventional trials aimed at pediatric acute respiratory distress syndrome prevention should target patients early in their illness course and include patients on high-flow oxygen and positive pressure ventilation.

Many animals migrate to take advantage of temporal and spatial variability in resources. These benefits are offset with costs like increased energetic expenditure and travel through unfamiliar areas. Differences in the cost-benefit ratio for individuals may lead to partial migration with one portion of a population migrating while another does not. We investigated migration dynamics and winter site fidelity for a long-distance partial migrant, barren ground caribou (Rangifer tarandus granti) of the Teshekpuk Caribou Herd in northern Alaska. We used GPS telemetry for 76 female caribou over 164 annual movement trajectories to identify timing and location of migration and winter use, proportion of migrants, and fidelity to different herd wintering areas. We found within-individual variation in movement behavior and wintering area use by the Teshekpuk Caribou Herd, adding caribou to the growing list of ungulates that can exhibit migratory plasticity. Using a first passage time–net squared displacement approach, we classified 78.7% of annual movement paths as migration, 11.6% as residency, and 9.8% as another strategy. Timing and distance of migration varied by season and wintering area. Duration of migration was longer for fall migration than for spring, which may relate to the latter featuring more directed movement. Caribou utilized four wintering areas, with multiple areas used each year. This variation occurred not just among different individuals, but state sequence analyses indicated low fidelity of individuals to wintering areas among years. Variability in movement behavior can have fitness consequences. As caribou face the pressures of a rapidly warming Arctic and ongoing human development and activities, further research is needed to investigate what factors influence this diversity of behaviors in Alaska and across the circumpolar Arctic.

ObjectivesTo evaluate the associations between early cumulative fluid balance (CFB) and outcomes among critically ill pediatric allogeneic hematopoietic cell transplant (HCT) recipients with acute respiratory failure, and determine if these associations vary by treatment with renal replacement therapy (RRT).MethodsWe performed a secondary analysis of a multicenter retrospective cohort of patients (1mo - 21yrs) post-allogeneic HCT with acute respiratory failure treated with invasive mechanical ventilation (IMV) from 2009 to 2014. Fluid intake and output were measured daily for the first week of IMV (day 0 = day of intubation). The exposure, day 3 CFB (CFB from day 0 through day 3 of IMV), was calculated using the equation [Fluid in – Fluid out] (liters)/[PICU admission weight](kg)*100. We measured the association between day 3 CFB and PICU mortality with logistic regression, and the rate of extubation at 28 and 60 days with competing risk regression (PICU mortality = competing risk).Results198 patients were included in the study. Mean % CFB for the cohort was positive on day 0 of IMV, and increased further on days 1-7 of IMV. For each 1% increase in day 3 CFB, the odds of PICU mortality were 3% higher (adjusted odds ratio (aOR) 1.03, 95% CI 1.00-1.07), and the rate of extubation was 3% lower at 28 days (adjusted subdistribution hazard ratio (aSHR) 0.97, 95% CI 0.95-0.98) and 3% lower at 60 days (aSHR 0.97, 95% CI 0.95-0.98). When day 3 CFB was dichotomized, 161 (81%) had positive and 37 (19%) had negative day 3 CFB. Positive day 3 CFB was associated with higher PICU mortality (aOR 3.42, 95% CI 1.48-7.87) and a lower rate of extubation at 28 days (aSHR 0.30, 95% CI 0.18-0.48) and 60 days (aSHR 0.30, 95% 0.19-0.48). On stratified analysis, the association between positive day 3 CFB and PICU mortality was significantly stronger in those not treated with RRT (no RRT: aOR 9.11, 95% CI 2.29-36.22; RRT: aOR 1.40, 95% CI 0.42-4.74).ConclusionsAmong critically ill pediatric allogeneic HCT recipients with acute respiratory failure, positive and increasing early CFB were independently associated with adverse outcomes.

Background The assessment of real-world effectiveness of immunomodulatory medications for multisystem inflammatory syndrome in children (MIS-C) may guide therapy. Methods We analyzed surveillance data on inpatients younger than 21 years of age who had MIS-C and were admitted to 1 of 58 U.S. hospitals between March 15 and October 31, 2020. The effectiveness of initial immunomodulatory therapy (day 0, indicating the first day any such therapy for MIS-C was given) with intravenous immune globulin (IVIG) plus glucocorticoids, as compared with IVIG alone, was evaluated with propensity-score matching and inverse probability weighting, with adjustment for baseline MIS-C severity and demographic characteristics. The primary outcome was cardiovascular dysfunction (a composite of left ventricular dysfunction or shock resulting in the use of vasopressors) on or after day 2. Secondary outcomes included the components of the primary outcome, the receipt of adjunctive treatment (glucocorticoids in patients not already receiving glucocorticoids on day 0, a biologic, or a second dose of IVIG) on or after day 1, and persistent or recurrent fever on or after day 2. Results A total of 518 patients with MIS-C (median age, 8.7 years) received at least one immunomodulatory therapy; 75% had been previously healthy, and 9 died. In the propensity-score–matched analysis, initial treatment with IVIG plus glucocorticoids (103 patients) was associated with a lower risk of cardiovascular dysfunction on or after day 2 than IVIG alone (103 patients) (17% vs. 31%; risk ratio, 0.56; 95% confidence interval [CI], 0.34 to 0.94). The risks of the components of the composite outcome were also lower among those who received IVIG plus glucocorticoids: left ventricular dysfunction occurred in 8% and 17% of the patients, respectively (risk ratio, 0.46; 95% CI, 0.19 to 1.15), and shock resulting in vasopressor use in 13% and 24% (risk ratio, 0.54; 95% CI, 0.29 to 1.00). The use of adjunctive therapy was lower among patients who received IVIG plus glucocorticoids than among those who received IVIG alone (34% vs. 70%; risk ratio, 0.49; 95% CI, 0.36 to 0.65), but the risk of fever was unaffected (31% and 40%, respectively; risk ratio, 0.78; 95% CI, 0.53 to 1.13). The inverse-probability-weighted analysis confirmed the results of the propensity-score–matched analysis. Conclusions Among children and adolescents with MIS-C, initial treatment with IVIG plus glucocorticoids was associated with a lower risk of new or persistent cardiovascular dysfunction than IVIG alone. (Funded by the Centers for Disease Control and Prevention.)

CDC, the Food and Drug Administration (FDA), state and local health departments, and public health and clinical stakeholders are investigating a nationwide outbreak of e-cigarette, or vaping, product use-associated lung injury (EVALI) (1). CDC has published recommendations for health care providers regarding EVALI (2-4). Recently, researchers from Utah and New York published proposed diagnosis and treatment algorithms for EVALI (5,6). EVALI remains a diagnosis of exclusion because, at present, no specific test or marker exists for its diagnosis, and evaluation should be guided by clinical judgment. Because patients with EVALI can experience symptoms similar to those associated with influenza or other respiratory infections (e.g., fever, cough, headache, myalgias, or fatigue), it might be difficult to differentiate EVALI from influenza or community-acquired pneumonia on initial assessment; EVALI might also co-occur with respiratory infections. This report summarizes recommendations for health care providers managing patients with suspected or known EVALI when respiratory infections such as influenza are more prevalent in the community than they have been in recent months (7). Recommendations include 1) asking patients with respiratory, gastrointestinal, or constitutional symptoms about the use of e-cigarette, or vaping, products; 2) evaluating those suspected to have EVALI with pulse oximetry and obtaining chest imaging, as clinically indicated; 3) considering outpatient management for clinically stable EVALI patients who meet certain criteria; 4) testing patients for influenza, particularly during influenza season, and administering antimicrobials, including antivirals, in accordance with established guidelines; 5) using caution when considering prescribing corticosteroids for outpatients, because this treatment modality has not been well studied among outpatients, and corticosteroids could worsen respiratory infections; 6) recommending evidence-based treatment strategies, including behavioral counseling, to help patients discontinue using e-cigarette, or vaping, products; and 7) emphasizing the importance of annual influenza vaccination for all persons aged ≥6 months, including patients who use e-cigarette, or vaping products.

CDC, the Food and Drug Administration (FDA), state and local health departments, and public health and clinical partners are investigating a multistate outbreak of lung injury associated with the use of electronic cigarette (e-cigarette), or vaping, products. In late August, CDC released recommendations for health care providers regarding e-cigarette, or vaping, product use associated lung injury (EVALI) based on limited data from the first reported cases (1,2). This report summarizes national surveillance data describing clinical features of more recently reported cases and interim recommendations based on these data for U.S. health care providers caring for patients with suspected or known EVALI. It provides interim guidance for 1) initial clinical evaluation; 2) suggested criteria for hospital admission and treatment; 3) patient follow-up; 4) special considerations for groups at high risk; and 5) clinical and public health recommendations. Health care providers evaluating patients suspected to have EVALI should ask about the use of e-cigarette, or vaping, products in a nonjudgmental and thorough manner. Patients suspected to have EVALI should have a chest radiograph (CXR), and hospital admission is recommended for patients who have decreased blood oxygen (O2) saturation (

In this multicenter study, we investigated the kinetics of neutrophil recovery in relation to acuity and survival among 125 children undergoing allogeneic hematopoietic cell transplantation (allo-HCT) who required invasive mechanical ventilation (IMV). Recovery of neutrophils, whether prior to or after initiation of IMV, was associated with a significantly decreased risk of death relative to never achieving neutrophil recovery. A transient increase in acuity (by oxygenation index and vasopressor requirements) occurred among a subset of the patients who achieved neutrophil recovery after initiation of IMV; 61.5% of these patients survived to discharge from the intensive care unit (ICU). Improved survival among patients who subsequently achieved neutrophil recovery on IMV was not limited to those with peri-engraftment respiratory distress syndrome. The presence of a respiratory pathogen did not affect the risk of death while on IMV but was associated with an increased length of IMV (p

SummaryWhat is already known about this topic?Community-level face mask use is encouraged as an important preventive measure against COVID-19 transmission, and evidence suggests that jurisdictions which implement face mask mandates see a subsequent decline in COVID incidence.What is added by this report?In the Greater Boston area when a face mask mandate is in effect, 95% of people observed were wearing some type of face covering. Most of which were wearing fabric/cloth coverings (51%) or single use surgical masks (40%). Of those wearing a face covering, 85% were appropriately fitted. Indoor locations have higher adherence of appropriately worn face masks, compared to outdoor locations.What are the implications for public health practice?Adherence with face mask mandates was very high, but many individuals wore fabric face masks with unknown filtration efficacy. In addition, it was common for individuals to mis-wear, adjust, or remove their masks. Public health policies requiring mask use should include messaging about appropriate type and best practices for use.

IMPORTANCE: Refinement of criteria for multisystem inflammatory syndrome in children (MIS-C) may inform efforts to improve health outcomes. OBJECTIVE: To compare clinical characteristics and outcomes of children and adolescents with MIS-C vs those with severe coronavirus disease 2019 (COVID-19). SETTING, DESIGN, AND PARTICIPANTS: Case series of 1116 patients aged younger than 21 years hospitalized between March 15 and October 31, 2020, at 66 US hospitals in 31 states. Final date of follow-up was January 5, 2021. Patients with MIS-C had fever, inflammation, multisystem involvement, and positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reverse transcriptase–polymerase chain reaction (RT-PCR) or antibody test results or recent exposure with no alternate diagnosis. Patients with COVID-19 had positive RT-PCR test results and severe organ system involvement. EXPOSURE: SARS-CoV-2. MAIN OUTCOMES AND MEASURES: Presenting symptoms, organ system complications, laboratory biomarkers, interventions, and clinical outcomes. Multivariable regression was used to compute adjusted risk ratios (aRRs) of factors associated with MIS-C vs COVID-19. RESULTS: Of 1116 patients (median age, 9.7 years; 45% female), 539 (48%) were diagnosed with MIS-C and 577 (52%) with COVID-19. Compared with patients with COVID-19, patients with MIS-C were more likely to be 6 to 12 years old (40.8% vs 19.4%; absolute risk difference [RD], 21.4% [95% CI, 16.1%-26.7%]; aRR, 1.51 [95% CI, 1.33-1.72] vs 0-5 years) and non-Hispanic Black (32.3% vs 21.5%; RD, 10.8% [95% CI, 5.6%-16.0%]; aRR, 1.43 [95% CI, 1.17-1.76] vs White). Compared with patients with COVID-19, patients with MIS-C were more likely to have cardiorespiratory involvement (56.0% vs 8.8%; RD, 47.2% [95% CI, 42.4%-52.0%]; aRR, 2.99 [95% CI, 2.55-3.50] vs respiratory involvement), cardiovascular without respiratory involvement (10.6% vs 2.9%; RD, 7.7% [95% CI, 4.7%-10.6%]; aRR, 2.49 [95% CI, 2.05-3.02] vs respiratory involvement), and mucocutaneous without cardiorespiratory involvement (7.1% vs 2.3%; RD, 4.8% [95% CI, 2.3%-7.3%]; aRR, 2.29 [95% CI, 1.84-2.85] vs respiratory involvement). Patients with MIS-C had higher neutrophil to lymphocyte ratio (median, 6.4 vs 2.7, P

Supplemental Digital Content is available in the text., Objectives: To identify and compare serum and lower respiratory tract fluid biomarkers of lung injury using well-characterized mouse models of lung injury. To explore the relationship between these preclinical biomarkers and clinical outcomes in a discovery cohort of pediatric patients with acute respiratory failure from pneumonia. Design: Prospective, observational cohort study. Setting: A basic science laboratory and the PICU of a tertiary-care children’s hospital. Patients: PICU patients intubated for respiratory failure from a suspected respiratory infection. Interventions: Prospective enrollment and collection of lower respiratory tract fluid samples. Measurements and Main Results: C57BL6/J mice were intranasally inoculated with escalating doses of influenza A virus or toll-like receptor agonists to simulate varying degrees of lung injury. Serum and bronchoalveolar lavage fluid were measured for the presence of cytokines using commercially available multiplex cytokine assays. Elevated levels of C-C motif chemokine ligand 7 at the peak of inflammation in both bronchoalveolar lavage fluid and serum correlated with lethality, with the bronchoalveolar lavage fluid ratio of C-C motif chemokine ligand 7:C-C motif chemokine ligand 22 providing the best prediction in the mouse models. These preclinical biomarkers were examined in the plasma and lower respiratory tract fluid of a discovery cohort of pediatric patients with acute respiratory failure from pneumonia. The primary clinical outcome measure was ventilator-free days, with secondary outcomes of pediatric acute respiratory distress syndrome severity and mortality. Elevation in peak lower respiratory tract fluid C-C motif chemokine ligand 7:C-C motif chemokine ligand 22 ratios demonstrated a significant negative correlation with ventilator-free days (r = –0.805; p < 0.02). Conclusions: This study provides evidence that lung immune profiling via lower respiratory tract fluid cytokine analysis is feasible and may provide insight into clinical outcomes. Further validation of markers, including the C-C motif chemokine ligand 7:C-C motif chemokine ligand 22 ratio in this limited study, in a larger cohort of patients is necessary.

INTRODUCTION: The effectiveness of high-frequency oscillatory ventilation (HFOV) in the pediatric hematopoietic cell transplant patient has not been established. We sought to identify current practice patterns of HFOV, investigate parameters during HFOV and their association with mortality, and compare the use of HFOV to conventional mechanical ventilation in severe pediatric ARDS. METHODS: This is a retrospective analysis of a multi-center database of pediatric and young adult allogeneic hematopoietic cell transplant subjects requiring invasive mechanical ventilation for critical illness from 2009 through 2014. Twelve United States pediatric centers contributed data. Continuous variables were compared using a Wilcoxon rank-sum test or a Kruskal-Wallis analysis. For categorical variables, univariate analysis with logistic regression was performed. RESULTS: The database contains 222 patients, of which 85 subjects were managed with HFOV. Of this HFOV cohort, the overall pediatric ICU survival was 23.5% (n = 20). HFOV survivors were transitioned to HFOV at a lower oxygenation index than nonsurvivors (25.6, interquartile range 21.1–36.8, vs 37.2, interquartile range 26.5–52.2, P = .046). Survivors were transitioned to HFOV earlier in the course of mechanical ventilation, (day 0 vs day 2, P = .002). No subject survived who was transitioned to HFOV after 1 week of invasive mechanical ventilation. We compared subjects with severe pediatric ARDS treated only with conventional mechanical ventilation versus early HFOV (within 2 d of invasive mechanical ventilation) versus late HFOV. There was a trend toward difference in survival (conventional mechanical ventilation 24%, early HFOV 30%, and late HFOV 9%, P = .08). CONCLUSIONS: In this large database of pediatric allogeneic hematopoietic cell transplant subjects who had acute respiratory failure requiring invasive mechanical ventilation for critical illness with severe pediatric ARDS, early use of HFOV was associated with improved survival compared to late implementation of HFOV, and the subjects had outcomes similar to those treated only with conventional mechanical ventilation.

Objective Heated and humidified high flow nasal cannula (HFNC) is an increasingly used form of noninvasive respiratory support with the potential to generate significant tracheal pressure. The aim of this study was to quantify the pressure generated by HFNC within the trachea in anatomically correct, pediatric airway models. Methods 3D-printed upper airway models of a preterm neonate, term neonate, toddler, and small child were connected to a spontaneous breathing computerized lung model at age-appropriate ventilation settings. Two commercially available HFNC systems were applied to each airway model at increasing flows and the positive end-expiratory pressure (PEEP) was recorded at the level of the trachea. Results Increasing HFNC flow produced a quadratically curved increase in tracheal pressure in closed-mouth models. The maximum flow tested in each model generated a tracheal pressure of 7 cm H2O in the preterm neonate, 10 cm H2O in the term neonate, 9 cm H2O in the toddler, and 24 cm H2O in the small child. Tracheal pressure decreased by at least 50% in open-mouth models. Conclusions HFNC was found to demonstrate a predictable flow-pressure relationship that achieved sufficient distending pressure to consider treatment of pediatric obstructive sleep apnea and tracheomalacia in the closed-mouth models tested.

OBJECTIVES To assess the incidence, severity, and outcomes of pediatric acute respiratory distress syndrome following trauma using Pediatric Acute Lung Injury Consensus Conference criteria. DESIGN Retrospective cohort study. SETTING Level 1 pediatric trauma center. PATIENTS Trauma patients less than or equal to 17 years admitted to the ICU from 2009 to 2017. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS We queried electronic health records to identify patients meeting pediatric acute respiratory distress syndrome oxygenation criteria for greater than or equal to 6 hours and determined whether patients met complete pediatric acute respiratory distress syndrome criteria via chart review. We estimated associations between pediatric acute respiratory distress syndrome and outcome using generalized linear Poisson regression adjusted for age, injury mechanism, Injury Severity Score, and serious brain and chest injuries. Of 2,470 critically injured children, 103 (4.2%) met pediatric acute respiratory distress syndrome criteria. Mortality was 34.0% among pediatric acute respiratory distress syndrome patients versus 1.7% among patients without pediatric acute respiratory distress syndrome (adjusted relative risk, 3.7; 95% CI, 2.0-6.9). Mortality was 50.0% for severe pediatric acute respiratory distress syndrome at onset, 33.3% for moderate, and 30.5% for mild. Cause of death was neurologic in 60.0% and multiple organ failure in 34.3% of pediatric acute respiratory distress syndrome nonsurvivors versus neurologic in 85.4% of nonsurvivors without pediatric acute respiratory distress syndrome (p = 0.001). Among survivors, 77.1% of pediatric acute respiratory distress syndrome patients had functional disability at discharge versus 30.7% of patients without pediatric acute respiratory distress syndrome patients (p < 0.001), and only 17.5% of pediatric acute respiratory distress syndrome patients discharged home without ongoing care versus 86.4% of patients without pediatric acute respiratory distress syndrome (adjusted relative risk, 1.5; 1.1-2.1). CONCLUSIONS Incidence and mortality associated with pediatric acute respiratory distress syndrome following traumatic injury are substantially higher than previously recognized, and pediatric acute respiratory distress syndrome development is associated with high risk of poor outcome even after adjustment for underlying injury type and severity.

Acute respiratory distress syndrome (ARDS) is a restrictive lung disease with severe hypoxemia and often hypercarbia. ARDS is caused by direct (alveolar epithelial) and indirect (endothelial) injuries and is conceptually divided into three phases: acute, fibroproliferative, and repair. Diffuse disruption of the alveolar epithelial-endothelial barrier (diffuse alveolar damage) resulting in noncardiogenic pulmonary edema is the main pathologic finding. The primary pathobiological mechanisms are reduction in alveolar fluid clearance, decreased production and inactivation of surfactant, inflammation, apoptosis, and coagulopathy. With multiple causes and pathobiologic mechanisms, resolving the initial injury and restoring normal lung architecture and function are complex processes that have been difficult to model experimentally. Furthermore, regulation of normal postnatal lung development overlaps with many of the pathways of the acute and repair phases of ARDS, making extrapolation of knowledge gained from adult clinical and laboratory models to children challenging.

BACKGROUND We describe organisms found in the respiratory tracts of a multicenter cohort of pediatric hematopoietic cell transplant (HCT) recipients with respiratory failure. METHODS Twelve centers contributed up to 25 pediatric allogeneic HCT recipients requiring mechanical ventilation for respiratory failure to a retrospective database. Positive respiratory pathogens and method of obtaining sample were recorded. Outcomes were assessed using Mann-Whitney U test or chi-squared analysis. RESULTS Of the 222 patients in the database, ages 1 month through 21 years, 34.6% had a positive respiratory culture. 105 pathogens were identified in 77 patients; of those, 48.6% were viral, 34.3% bacterial, 16.2% fungal, and 1% parasitic. PICU mortality with a respiratory pathogen was 68.8% compared to 54.9% for those without a respiratory pathogen (P = .045). Those with a positive respiratory pathogen had longer PICU length of stay, 20 days (IQR 14.0, 36.8) vs 15 (IQR 6.5, 32.0), P = .002, and a longer course of mechanical ventilation, 17 days (IQR 10, 29.5) vs 8 (3, 17), P

Background: Noise-induced hearing loss (NIHL) is on the rise, affecting nearly 1.1 billion young people as per the World Health Organization. It is mainly due to exposure to noise in recreational settings for prolonged duration and at high intensity resulting in unsafe listening practices. Aim and Objective: This study aims to analyze the potential risk of audio device usage and hearing loss among the students. Materials and Methods: Hearing loss among students using personal music player with headphones/earphones was assessed using a self-designed audiometry mobile application and followed by a questionnaire to those found to have hearing loss asking for their preferences of personal audio devices, usage in terms of years, duration per day, volume, content, and awareness of NIHL. Results: Among the 3000 students, 3.2% (96) of students were identified with hearing loss and 72% of the total subjects were unaware of NIHL. About 81% (78) were headphones users as compared to 19% (18) earphones users. About 50% of the subjects with hearing loss had reported usage of a personal audio device for more than 6 h per day followed by 30% who used it for 4–6 h, 16% who used it for 2–4 h followed by 4% who used it for 1–2 h per day. About 90% of students used volume settings more than 60% and 10% preferred 60–40% volume settings. About 65% of the subjects were using audio devices for more than 6 years and 16% for

Objective To establish the current respiratory practice patterns in pediatric hematopoietic stem cell transplant patients and investigate their associations with mortality across multiple centers. Design Retrospective cohort between 2009 and 2014. Setting Twelve children's hospitals in the United States. Patients Two hundred twenty-two pediatric allogeneic hematopoietic stem cell transplant recipients with acute respiratory failure using invasive mechanical ventilation. Interventions None. Measurements and main results PICU mortality of our cohort was 60.4%. Mortality at 180 days post PICU discharge was 74%. Length of PICU stay prior to initiation of invasive mechanical ventilation was significantly lower in survivors, and the odds of mortality increased for longer length of PICU stay prior to intubation. A total of 91 patients (41%) received noninvasive ventilation at some point during their PICU stay prior to intubation. Noninvasive ventilation use preintubation was associated with increased mortality (odds ratio, 2.1; 95% CI, 1.2-3.6; p = 0.010). Patients ventilated longer than 15 days had higher odds of death (odds ratio, 2.4; 95% CI, 1.3-4.2; p = 0.004). Almost 40% of patients (n = 85) were placed on high-frequency oscillatory ventilation with a mortality of 76.5% (odds ratio, 3.3; 95% CI, 1.7-6.5; p = 0.0004). Of the 20 patients who survived high-frequency oscillatory ventilation, 18 were placed on high-frequency oscillatory ventilation no later than the third day of invasive mechanical ventilation. In this subset of 85 patients, transition to high-frequency oscillatory ventilation within 2 days of the start of invasive mechanical ventilation resulted in a 76% decrease in the odds of death compared with those who transitioned to high-frequency oscillatory ventilation later in the invasive mechanical ventilation course. Conclusions This study suggests that perhaps earlier more aggressive critical care interventions in the pediatric hematopoietic stem cell transplant patient with respiratory failure requiring invasive mechanical ventilation may offer an opportunity to improve outcomes.

OBJECTIVES Acute respiratory failure is common in pediatric hematopoietic cell transplant recipients and has a high mortality. However, respiratory prognostic markers have not been adequately evaluated for this population. Our objectives are to assess respiratory support strategies and indices of oxygenation and ventilation in pediatric allogeneic hematopoietic cell transplant patients receiving invasive mechanical ventilation and investigate how these strategies are associated with mortality. DESIGN Retrospective, multicenter investigation. SETTING Twelve U.S. pediatric centers. PATIENTS Pediatric allogeneic hematopoietic cell transplant recipients with respiratory failure. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS Two-hundred twenty-two subjects were identified. PICU mortality was 60.4%. Nonsurvivors had higher peak oxygenation index (38.3 [21.3-57.6] vs 15.0 [7.0-30.7]; p < 0.0001) and oxygen saturation index (24.7 [13.8-38.7] vs 10.3 [4.6-21.6]; p < 0.0001), greater days with FIO2 greater than or equal to 0.6 (2.4 [1.0-8.5] vs 0.8 [0.3-1.6]; p < 0.0001), and more days with oxygenation index greater than 18 (1.4 [0-6.0] vs 0 [0-0.3]; p < 0.0001) and oxygen saturation index greater than 11 (2.0 [0.5-8.8] vs 0 [0-1.0]; p < 0.0001). Nonsurvivors had higher maximum peak inspiratory pressures (36.0 cm H2O [32.0-41.0 cm H2O] vs 30.0 cm H2O [27.0-35.0 cm H2O]; p < 0.0001) and more days with peak inspiratory pressure greater than 31 cm H2O (1.0 d [0-4.0 d] vs 0 d [0-1.0 d]; p < 0.0001). Tidal volume per kilogram was not different between survivors and nonsurvivors. CONCLUSIONS In this cohort of pediatric hematopoietic cell transplant recipients with respiratory failure in the PICU, impaired oxygenation and use of elevated ventilator pressures were common and associated with increased mortality.

Objectives:Although there are similarities in the pathophysiology of acute respiratory distress syndrome in adults and children, pediatric-specific practice patterns, comorbidities, and differences in outcome necessitate a pediatric-specific definition. We sought to create such a definition.Design:A

Contains fulltext : 182539.pdf (Publisher’s version ) (Closed access) Calcium/calmodulin-dependent protein kinase II (CAMK2) is one of the first proteins shown to be essential for normal learning and synaptic plasticity in mice, but its requirement for human brain development has not yet been established. Through a multi-center collaborative study based on a whole-exome sequencing approach, we identified 19 exceedingly rare de novo CAMK2A or CAMK2B variants in 24 unrelated individuals with intellectual disability. Variants were assessed for their effect on CAMK2 function and on neuronal migration. For both CAMK2A and CAMK2B, we identified mutations that decreased or increased CAMK2 auto-phosphorylation at Thr286/Thr287. We further found that all mutations affecting auto-phosphorylation also affected neuronal migration, highlighting the importance of tightly regulated CAMK2 auto-phosphorylation in neuronal function and neurodevelopment. Our data establish the importance of CAMK2A and CAMK2B and their auto-phosphorylation in human brain function and expand the phenotypic spectrum of the disorders caused by variants in key players of the glutamatergic signaling pathway.

BACKGROUND: Heated and humidified high-flow nasal cannula (HFNC) is a widely used form of respiratory support; however, data regarding optimal flows for a given patient size or disease state are lacking. A comprehensive study of the physiologic effects of HFNC is needed to better understand the mechanisms of action. The objective of the current study was to quantify the effect of HFNC settings in age-specific, anatomically correct nasal airways and spontaneously breathing lung models. We hypothesized that there is an effect of flow on pressure and ventilation. METHODS: Three-dimensionally printed upper airway models of a preterm neonate, term neonate, toddler, small child, and adult were affixed to the ASL 5000 test lung to simulate spontaneous breathing with age-appropriate normal ventilation parameters. CO2 was introduced to simulate profound hypercapneic respiratory failure with an end-tidal partial pressure of carbon dioxide (PETCO2) of 90 ± 1 mm Hg. Two commercially available HFNC systems were applied to the airway models, and PEEP, inspired CO2, and exhaled CO2 (PETCO2) were recorded for 6 min across a range of flow. RESULTS: Increasing HFNC flow provided a non-linear increase in PEEP in closed-mouth models, with maximum tested flows generating 6 cm H2O in the preterm neonate to 20 cm H2O in the small child. Importantly, PEEP decreased by approximately 50% in open-mouth models. Increasing HFNC flow improved expiratory CO2 elimination to a certain point, above which continued increases in flow had minimal additional effect. This change point ranged from 4 L/min in the preterm neonate to 10 L/min in the small child. CONCLUSIONS: These findings may help clinicians understand the effects of HFNC at different settings and may inform management guidelines for patients with respiratory failure.

We report on a fragment of the quasicrystal-bearing CV3 carbonaceous chondrite Khatyrka recovered from fine-grained, clay-rich sediments in the Koryak Mountains, Chukotka (Russia). We show higher melting-point silicate glass cross-cutting lower melting-point Al-Cu-Fe alloys, as well as unambiguous evidence of a reduction-oxidation reaction history between Al-Cu-Fe alloys and silicate melt. The redox reactions involve reduction of FeO and SiO2 to Fe and Fe-Si metal, and oxidation of metallic Al to Al2O3, occurring where silicate melt was in contact with Al-Cu-Fe alloys. In the reaction zone, there are metallic Fe and Fe-Si beads, aluminous spinel rinds on the Al-Cu-Fe alloys, and Al2O3 enrichment in the silicate melt surrounding the alloys. From this and other evidence, we demonstrate that Khatyrka must have experienced at least two distinct events: first, an event as early as 4.564 Ga in which the first Al-Cu-Fe alloys formed; and, second, a more recent impact-induced shock in space that led to transformations of and reactions between the alloys and the meteorite matrix. The new evidence firmly establishes that the Al-Cu-Fe alloys (including quasicrystals) formed in outer space in a complex, multi-stage process.

Purpose Requiring PaO2/FiO2 ratio (PF) to define ARDS may bias towards children with cardiovascular dysfunction and hypoxemia. We sought to evaluate (1) the Berlin definition of ARDS in children using PF; (2) the effect of substituting SpO2/FiO2(SF) ratio; (3) differences between patients with and without arterial blood gases; and (4) the ability of SpO2 and PaO2 indices to discriminate ICU mortality.

In this issue of Critical Care Medicine [1], members of the Brazilian Pediatric ARDS Study Group present a prospective validation of the Berlin Definition of ARDS [2] using an observational cohort from eight pediatric intensive care units in Brazil. Much like a previous validation of the Berlin Definition for younger children [3], the authors found that stratification into mild, moderate and severe categories of ARDS based on PF ratio better classified mortality than the AECC classification, and, like the previous pediatric validation, mortality did not differ between mild and moderate ARDS, but the severe group had significantly higher mortality. This validation is important for clinical care and research as it provides pediatric specific data regarding the performance of the Berlin Definition. However, it is important to consider this validation in the context of the broader picture of pediatric ARDS, and whether ultimately the Berlin Definition is the most appropriate definition to use for pediatric ARDS [4, 5]. The methodology and choices made by the investigators in this study highlight important ambiguities and practice pattern differences between adult and pediatric providers, which may have large implications for diagnosing pediatric ARDS. First, the authors chose in this validation to select the worst PF ratio the patient attained at any point during their ICU stay to stratify risk. This is a salient, and often overlooked issue with regards to ARDS severity stratification. The main goal of different risk severity groups in the Berlin Definition surrounds potential risk benefit profiles of therapeutic interventions. Therefore, the “timing” of when ARDS severity is assessed becomes crucial. A PF ratio of < 100 several days into the course of mechanical ventilation may have substantially different implications than a PF ratio < 100 within the first 24 hours of ventilation [6-9]. The PF ratio several days into the course of mechanical ventilation, or several days after the initial diagnosis of ARDS, may be a marker of adequacy (or inadequacy) of response to therapy, and variability in ventilator management. Given the multi-center nature of this cohort study, and the lack of completely standardized approaches to ventilator management (including PEEP, FiO2, Recruitment Maneuvers), it becomes even more crucial to use early values of PF ratio (i.e. within the first 24 hours of ventilation) to stratify risk. These issues will not be unique to these 8 centers; there is significant variability in ventilator or other management across pediatric centers, which may directly influence the PF ratio, particularly several days into the course of ventilation [10, 11]. Some of these issues can be overcome by using a measure of hypoxemia less subject to variability in practice, such as oxygenation index (OI), to stratify risk [12]. To that end, a pediatric specific definition of ARDS has been proposed by the Pediatric Acute Lung Injury Consensus Conference [13], in which OI is used as the primary metric for ARDS diagnosis and risk stratification for mechanically ventilated children. Moreover, PALICC recommends that epidemiologic studies report the performance of this this risk stratification method using data from the first 24 hours of ARDS diagnosis, to minimize the potential effect of practice pattern variability [13]. Ultimately, a later measure of hypoxemia (beyond the first day) may be important for therapies considered for patients who are not “initial responders,” and this study highlights that hypoxemia severity beyond the first day of ARDS diagnosis has important prognostic implications. A second important issue surrounds practice patterns with regards to arterial blood gasses. In this study, daily arterial blood gas (ABG) measurement was routine for all mechanically ventilated patients in these 8 intensive care units. However, pediatric and adult data suggest that the increased use of noninvasive mechanical ventilation in and outside of ICUs in combination with infrequent ABG sampling results in under recognition of ARDS in children and adults [11, 14-17]. Although routine, daily ABG sampling in this study helps to avoid this problem, the ABG data is acquired at discrete, arbitrary time points that may not reflect the condition of the patient throughout the day. Second, some centers reserve ABGs or arterial catheters for patients with significant hemodynamic compromise, rather than simply hypoxemia [18]. Therefore, there is an inherent selection bias regarding ABGs for ARDS diagnosis which may be related to disease severity or may not reflect the condition of the patient throughout the day. This may, in part, explain the lower number of patients identified with mild or moderate hypoxemia, and the minimal differences in risk of mortality between those with mild or moderate hypoxemia, as these deaths may be from cardiovascular causes. However, for generalizability it becomes imperative that the diagnosis of ARDS not be dependent on clinician behavior regarding a procedure (such as an ABG). For this reason, PALICC recommendations for diagnosis of ARDS allow for pulse-oximetry based criteria (Oxygen Saturation Index (OSI) and SpO2/FiO2 (SF) Ratio) to be substituted when an ABG is not available [13]. Third, the study investigators should be applauded on their attempt to standardize interpretation of bilateral infiltrates on chest radiograph for the purposes of this study. It appears as if their common training exercise between the study investigators and a radiologist resulted in good agreement regarding the presence of pulmonary edema and bilateral infiltrates. This is one of the first pediatric studies to demonstrate that such a method could result in similar, reproducible interpretation of bilateral infiltrates [3, 19]. However, it is still unclear just how necessary bilateral infiltrates are in the definition of ARDS. While bilateral infiltrates are meant to distinguish lobar processes like pneumonia from the diffuse injury seen in ARDS, chest radiographs demonstrate only modest sensitivity and specificity to detect areas of inflammation or infiltrate [20] [21-24]. Moreover, there are conflicting data whether presence or absence of bilateral infiltrates on CXR adds any prognostic value after controlling for the degree of hypoxemia [7, 25-29]. For this reason, the PALICC recommendations for diagnosis of ARDS have simplified radiographic criteria to patients with pulmonary parenchymal disease, in an attempt to improve disease recognition. However, PALICC continues to recommend tracking bilateral infiltrates, to determine the relevance on outcome [13]. If bilateral infiltrates are important for the definition, we must determine optimal methods for standardization of interpretation, which can be used both for clinical care and research. It is possible we can learn from the investigators of this study, to mimic their methodology and apply it on a broader scale. Finally, this manuscript highlights the potential differences and ambiguities in “lung protective” ventilator settings and modes of ventilation between adult and pediatric practice. As highlighted in this study, pressure control (PC) and pressure regulated volume control (PRVC) modes of ventilation are used much more commonly in pediatrics [11, 30]. Adult data regarding settings to minimize VILI are based on the square wave flow pattern of volume control ventilation, rather than the decelerating flow of PC or PRVC [31]. Hence extrapolation of tidal volume (which is frequently the response variable) targets become difficult, particularly with a lack of pediatric data to support that tidal volume has a significant association with mortality when decelerating flow patterns are used [32]. Driving pressure may be the more relevant metric for pediatric ARDS, but there is paucity of data in pediatrics to suggest what these pressure targets should be. To that end, the concept of plateau pressure (as compared to peak pressure) has less meaning with the decelerating flow patterns of PC or PRVC, and it is unclear whether the inspiratory hold maneuvers to measure plateau pressure are done universally across institutions. The same issues are highlighted with compliance measurements, where variability in methods of assessment of tidal volume (location of measurement, circuit compensation, predicted versus actual body weight), as well as which pressure is used (peak versus plateau) influence the reproducibility and generalizability of compliance measurements in studies [33]. To this end, the PALICC group has recommended future research into reproducible and reliable methods to report compliance, tidal volume, and pressure in clinical studies, to enable direct comparison [13]. Ultimately, the authors should be applauded for providing this first pediatric specific prospective validation of the Berlin Definition, highlighting the potential for successful application of pieces of the Berlin Definition to pediatric ARDS. However, pediatric specific practice patterns and the pathophysiology of pediatric ARDS warrant a pediatric specific definition of ARDS, which can be applied universally for children taken care of across the world [13].

To provide a current overview of the epidemiology and pathophysiology of acute respiratory distress syndrome in adults and children, and to identify research questions that will address the differences between adults and children with acute respiratory distress syndrome.Narrative literature review and author-generated data.The epidemiology of acute respiratory distress syndrome in adults and children, lung morphogenesis, and postnatal lung growth and development are reviewed. The pathophysiology of acute respiratory distress syndrome is divided into eight categories: alveolar fluid transport, surfactant, innate immunity, apoptosis, coagulation, direct alveolar epithelial injury by bacterial products, ventilator-associated lung injury, and repair.Epidemiologic data suggest significant differences in the prevalence and mortality of acute respiratory distress syndrome between children and adults. Postnatal lung development continues through attainment of adult height, and there is overlap between the regulation of postnatal lung development and inflammatory, apoptotic, alveolar fluid clearance, and repair mechanisms. Therefore, there is a different biological baseline network of gene and protein expression in children as compared with adults.There are significant obstacles to performing research on children with acute respiratory distress syndrome. However, epidemiologic, clinical, and animal studies suggest age-dependent differences in the pathophysiology of acute respiratory distress syndrome. In order to reduce the prevalence and improve the outcome of patients with acute respiratory distress syndrome, translational studies of inflammatory, apoptotic, alveolar fluid clearance, and repair mechanisms are needed. Understanding the differences in pathophysiologic mechanisms in acute respiratory distress syndrome between children and adults should facilitate identification of novel therapeutic interventions to prevent or modulate lung injury and improve lung repair.

In March 2010, Brazil introduced the 10-valent pneumococcal conjugate vaccine (PCV10) in the routine infant immunization program using a 4-dose schedule and catch-up for children

Objective Obese patients pose unique technical challenges for minimal-access cardiac surgery. We sought to examine the effect of body mass index on short-term outcomes in robotic-assisted coronary surgery. Methods From January 2010 to November 2011, a total of 110 consecutive patients underwent robotic-assisted coronary surgery at our institution. All patients had robotic-assisted mobilization of the left internal mammary artery. Some patients then underwent direct coronary anastomosis to the left anterior descending coronary artery via a left mini thoracotomy, whereas others had a complete robotic endoscopic procedure within the closed chest. The short-term outcomes of obese patients (n = 39), defined as body mass index greater than 30 kg/m2, were compared with those of nonobese patients (n = 71). Results Mean left internal mammary artery harvest time was longer in obese patients than in nonobese patients (51.03 vs 39.94 minutes; P = 0.007), as was overall operative time (218.15 vs 186.72 minutes; P = 0.034). There were no significant differences in mortality or major morbidity between obese and nonobese patients. Conclusions Obesity does not adversely affect short-term outcomes in robotic-assisted coronary surgery, although operative times are somewhat longer for these patients. Robotic-assisted coronary techniques can be safely pursued in obese patients.

Children have a lower incidence and mortality from acute lung injury (ALI) than adults, and infections are the most common event associated with ALI. To study the effects of age on susceptibility to ALI, we investigated the responses to microbial products combined with mechanical ventilation (MV) in juvenile (21-d-old) and adult (16-wk-old) mice. Juvenile and adult C57BL/6 mice were treated with inhaled Escherichia coli 0111:B4 lipopolysaccharide (LPS) and MV using tidal volume = 15 ml/kg. Comparison groups included mice treated with LPS or MV alone and untreated age-matched control mice. In adult animals treated for 3 hours, LPS plus MV caused synergistic increases in neutrophils (P < 0.01) and IgM in bronchoalveolar lavage fluid (P = 0.03) and IL-1β in whole lung homogenates (P < 0.01) as compared with either modality alone. Although juvenile and adult mice had similar responses to LPS or MV alone, the synergistic interactions between LPS and MV did not occur in juvenile mice. Computational analysis of gene expression array data suggest that the acquisition of synergy with increasing age results, in part, from the loss of antiapoptotic responses and the acquisition of proinflammatory responses to the combination of LPS and MV. These data suggest that the synergistic inflammatory and injury responses to inhaled LPS combined with MV are acquired with age as a result of coordinated changes in gene expression of inflammatory, apoptotic, and TGF-β pathways.

Mechanical ventilation (MV) and lipopolysaccharide (LPS) synergistically increase inflammation and lung injury. The goal of this study was to determine whether blockade of CD14 or Toll-like receptor 4 (TLR4) would reduce inflammation caused by LPS and MV. Rabbits were pretreated with anti-TLR4 or anti-CD14 monoclonal antibodies, followed by endobronchial LPS and MV. Blockade of TLR4 reduced the number of neutrophils and the amount of CXCL8 in bronchoalveolar lavage fluid. In contrast, blockade of CD14 did not significantly decrease the number of neutrophils or the amount of CXCL8. These data show that TLR4 blockade reduces pulmonary inflammation caused by the combination of LPS and Mechanical ventilation.

Hypertrophic stimuli cause transcription of the proto-oncogene c-Myc (Myc). Prior work showed that myocardial knockout of c-Myc (Myc) attenuated hypertrophy and decreased expression of metabolic genes after aortic constriction. Accordingly, we assessed the interplay between Myc, substrate oxidation and cardiac function during early pressure overload hypertrophy. Mice with cardiac specific, inducible Myc knockout (MycKO-TAC) and non-transgenic littermates (Cont-TAC) were subjected to transverse aortic constriction (TAC; n = 7/group). Additional groups underwent sham surgery (Cont-Sham and MycKO-Sham, n = 5 per group). After two weeks, function was measured in isolated working hearts along with substrate fractional contributions to the citric acid cycle by using perfusate with 13C labeled mixed fatty acids, lactate, ketone bodies and unlabeled glucose and insulin. Cardiac function was similar between groups after TAC although +dP/dT and -dP/dT trended towards improvement in MycKO-TAC versus Cont-TAC. In sham hearts, Myc knockout did not affect cardiac function or substrate preferences for the citric acid cycle. However, Myc knockout altered fractional contributions during TAC. The unlabeled fractional contribution increased in MycKO-TAC versus Cont-TAC, whereas ketone and free fatty acid fractional contributions decreased. Additionally, protein posttranslational modifications by O-GlcNAc were significantly greater in Cont-TAC versus both Cont-Sham and MycKO-TAC. In conclusion, Myc alters substrate preferences for the citric acid cycle during early pressure overload hypertrophy without negatively affecting cardiac function. Myc also affects protein posttranslational modifications by O-GlcNAc during hypertrophy, which may regulate Myc-induced metabolic changes.

Circumferential lesions to the pulmonary vein (PV) ostia to cause conduction block at the junction of the PV and left atrium could offer a new approach during catheter ablation of patients with paroxysmal (focal) atrial fibrillation. Diode laser can deliver energy through diffusing or ring fiber tips. In three pigs weighing between 60 and 65 kg, transseptal puncture was performed and a fiberoptic balloon catheter with a collapsed profile of 10 Fr was advanced through a sheath under fluoroscopic guidance to the ostium of the right and left PVs. The balloon was inflated with a 3-cc mixture of D2O (deuterium oxide) and contrast to deliver circumferential lesions with a 15-mm diameter x 3-mm ring width of light. Applications consisted of 3.2 to 3.8 W/cm for 120 seconds; the animals were sacrificed 3 hours after ablation for pathological examination. Photonic energy was delivered successfully to the ostium of five of the five targeted PVs, and was well tolerated hemodynamically in each animal without ectopy. Gross inspection revealed endocardial lesions at the ostium of four of five PVs, confined to the atrium in each and circumferential in three of five PVs. Microscopically, transmural coagulation necrosis of the atrium was present at the ostium of three of five PVs, and extended into the myocardial sleeves of two PVs. Photonic energy delivery using a fiberoptic balloon catheter can create circumferential lesions to the PV ostia, suggesting that this new form of energy delivery may be therapeutically advantageous for pulmonary vein ablation with need to pursue chronic studies.