Lung Re-transplantation after prolonged veno-venous extracorporeal membrane oxygenation (ECMO) in a child with chronic lung allograft dysfunction.

BACKGROUND: Extracorporeal Membrane Oxygenation (ECMO) may be used as a bridge to lung transplantation in selected patients with end-stage respiratory failure. Historically, ECMO use in this setting has been associated with poor outcomes Puri V et.al, J Thorac Cardiovasc Surg, 140:427. More recently, technical advances and the implementation of rehabilitation and ambulation while awaiting transplantation on ECMO have led to improved surgical and post-transplant outcomes Kirkby S et.al, J Thorac Dis, 6:1024. METHODS: We illustrate the case of a 6-year-old child who received prolonged ECMO support as a bridge to lung re-transplantation secondary to Chronic Lung Allograft Dysfunction (CLAD). RESULTS: Early rehabilitation was key in improving the overall pre-transplant conditioning during ECMO. CONCLUSIONS: Despite challenges associated with awake/ambulatory ECMO, the use of this strategy as a bridge to lung transplantation is feasible and has resulted in improved pre-transplant conditioning and post-transplant outcomes.

Early, Persistent Lymphopenia Is Associated With Prolonged Multiple Organ Failure and Mortality in Septic Children.

OBJECTIVES: Sepsis-associated immune suppression correlates with poor outcomes. Adult trials are evaluating immune support therapies. Limited data exist to support consideration of immunomodulation in pediatric sepsis. We tested the hypothesis that early, persistent lymphopenia predicts worse outcomes in pediatric severe sepsis. DESIGN: Observational cohort comparing children with severe sepsis and early, persistent lymphopenia (absolute lymphocyte count < 1,000 cells/µL on 2 d between study days 0-5) to children without. The composite outcome was prolonged multiple organ dysfunction syndrome (MODS, organ dysfunction beyond day 7) or PICU mortality. SETTING: Nine PICUs in the National Institutes of Health Collaborative Pediatric Critical Care Research Network between 2015 and 2017. PATIENTS: Children with severe sepsis and indwelling arterial and/or central venous catheters. INTERVENTIONS: Blood sampling and clinical data analysis. MEASUREMENTS AND MAIN RESULTS: Among 401 pediatric patients with severe sepsis, 152 (38%) had persistent lymphopenia. These patients were older, had higher illness severity, and were more likely to have underlying comorbidities including solid organ transplant or malignancy. Persistent lymphopenia was associated with the composite outcome prolonged MODS or PICU mortality (66/152, 43% vs 45/249, 18%; p < 0.01) and its components prolonged MODS (59/152 [39%] vs 43/249 [17%]), and PICU mortality (32/152, 21% vs 12/249, 5%; p < 0.01) versus children without. After adjusting for baseline factors at enrollment, the presence of persistent lymphopenia was associated with an odds ratio of 2.98 (95% CI [1.85-4.02]; p < 0.01) for the composite outcome. Lymphocyte count trajectories showed that patients with persistent lymphopenia generally did not recover lymphocyte counts during the study, had lower nadir whole blood tumor necrosis factor-α response to lipopolysaccharide stimulation, and higher maximal inflammatory markers (C-reactive protein and ferritin) during days 0-3 ( p < 0.01). CONCLUSIONS: Children with severe sepsis and persistent lymphopenia are at risk of prolonged MODS or PICU mortality. This evidence supports testing therapies for pediatric severe sepsis patients risk-stratified by early, persistent lymphopenia.

Midlatitude Ozone Depletion and Air Quality Impacts from Industrial Halogen Emissions in the Great Salt Lake Basin.

We report aircraft observations of extreme levels of HCl and the dihalogens Cl2, Br2, and BrCl in an industrial plume near the Great Salt Lake, Utah. Complete depletion of O3 was observed concurrently with halogen enhancements as a direct result of photochemically produced halogen radicals. Observed fluxes for Cl2, HCl, and NOx agreed with facility-reported emissions inventories. Bromine emissions are not required to be reported in the inventory, but are estimated as 173 Mg year-1 Br2 and 949 Mg year-1 BrCl, representing a major uncounted oxidant source. A zero-dimensional photochemical box model reproduced the observed O3 depletions and demonstrated that bromine radical cycling was principally responsible for the rapid O3 depletion. Inclusion of observed halogen emissions in both the box model and a 3D chemical model showed significant increases in oxidants and particulate matter (PM2.5) in the populated regions of the Great Salt Lake Basin, where winter PM2.5 is among the most severe air quality issues in the U.S. The model shows regional PM2.5 increases of 10%-25% attributable to this single industrial halogen source, demonstrating the impact of underreported industrial bromine emissions on oxidation sources and air quality within a major urban area of the western U.S.

Hyperferritinemic sepsis, macrophage activation syndrome, and mortality in a pediatric research network: a causal inference analysis.

BACKGROUND: One of five global deaths are attributable to sepsis. Hyperferritinemic sepsis (> 500 ng/mL) is associated with increased mortality in single-center studies. Our pediatric research network's objective was to obtain rationale for designing anti-inflammatory clinical trials targeting hyperferritinemic sepsis. METHODS: We assessed differences in 32 cytokines, immune depression (low whole blood ex vivo TNF response to endotoxin) and thrombotic microangiopathy (low ADAMTS13 activity) biomarkers, seven viral DNAemias, and macrophage activation syndrome (MAS) defined by combined hepatobiliary dysfunction and disseminated intravascular coagulation, and mortality in 117 children with hyperferritinemic sepsis (ferritin level > 500 ng/mL) compared to 280 children with sepsis without hyperferritinemia. Causal inference analysis of these 41 variables, MAS, and mortality was performed. RESULTS: Mortality was increased in children with hyperferritinemic sepsis (27/117, 23% vs 16/280, 5.7%; Odds Ratio = 4.85, 95% CI [2.55-9.60]; z = 4.728; P-value < 0.0001). Hyperferritinemic sepsis had higher C-reactive protein, sCD163, IL-22, IL-18, IL-18 binding protein, MIG/CXCL9, IL-1ß, IL-6, IL-8, IL-10, IL-17a, IFN-γ, IP10/CXCL10, MCP-1/CCL2, MIP-1α, MIP-1ß, TNF, MCP-3, IL-2RA (sCD25), IL-16, M-CSF, and SCF levels; lower ADAMTS13 activity, sFasL, whole blood ex vivo TNF response to endotoxin, and TRAIL levels; more Adenovirus, BK virus, and multiple virus DNAemias; and more MAS (P-value < 0.05). Among these variables, only MCP-1/CCL2 (the monocyte chemoattractant protein), MAS, and ferritin levels were directly causally associated with mortality. MCP-1/CCL2 and hyperferritinemia showed direct causal association with depressed ex vivo whole blood TNF response to endotoxin. MCP-1/CCL2 was a mediator of MAS. MCP-1/CCL2 and MAS were mediators of hyperferritinemia. CONCLUSIONS: These findings establish hyperferritinemic sepsis as a high-risk condition characterized by increased cytokinemia, viral DNAemia, thrombotic microangiopathy, immune depression, macrophage activation syndrome, and death. The causal analysis provides rationale for designing anti-inflammatory trials that reduce macrophage activation to improve survival and enhance infection clearance in pediatric hyperferritinemic sepsis.

Measuring Social Health Following Pediatric Critical Illness: A Scoping Review and Conceptual Framework.

OBJECTIVE: Social health is an important component of recovery following critical illness as modeled in the pediatric Post-Intensive Care Syndrome framework. We conducted a scoping review of studies measuring social outcomes (measurable components of social health) following pediatric critical illness and propose a conceptual framework of the social outcomes measured in these studies. DATA SOURCES: PubMed, EMBASE, PsycINFO, CINAHL, and the Cochrane Registry. STUDY SELECTION: We identified studies evaluating social outcomes in pediatric intensive care unit (PICU) survivors or their families from 1970-2017 as part of a broader scoping review of outcomes after pediatric critical illness. DATA EXTRACTION: We identified articles by dual review and dual-extracted study characteristics, instruments, and instrument validation and administration information. For instruments used in studies evaluating a social outcome, we collected instrument content and described it using qualitative methods adapted to a scoping review. DATA SYNTHESIS: Of 407 articles identified in the scoping review, 223 (55%) evaluated a social outcome. The majority were conducted in North America and the United Kingdom, with wide variation in methodology and population. Among these studies, 38 unique instruments were used to evaluate a social outcome. Specific social outcomes measured included individual (independence, attachment, empathy, social behaviors, social cognition, and social interest), environmental (community perceptions and environment), and network (activities and relationships) characteristics, together with school and family outcomes. While many instruments assessed more than one social outcome, no instrument evaluated all areas of social outcome. CONCLUSIONS: The full range of social outcomes reported following pediatric critical illness were not captured by any single instrument. The lack of a comprehensive instrument focused on social outcomes may contribute to under-appreciation of the importance of social outcomes and their under-representation in PICU outcomes research. A more comprehensive evaluation of social outcomes will improve understanding of overall recovery following pediatric critical illness.

Interventions for acute non-arteritic central retinal artery occlusion.

BACKGROUND: Acute non-arteritic central retinal artery occlusion (CRAO) occurs as a sudden interruption of the blood supply to the retina and typically results in severe loss of vision in the affected eye. Although many therapeutic interventions have been proposed, there is no generally agreed upon treatment regimen. OBJECTIVES: To assess the effects of treatments for acute non-arteritic CRAO. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Trials Register) (2022, Issue 2); Ovid MEDLINE; Embase.com; PubMed; Latin American and Caribbean Health Sciences Literature Database (LILACS); ClinicalTrials.gov; and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP). We did not use any date or language restrictions in the electronic search for trials. We last searched the electronic databases on 15 February 2022. SELECTION CRITERIA: We included randomized controlled trials (RCTs) comparing any interventions with another treatment in participants with acute non-arteritic CRAO in one or both eyes.  DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodology and graded the certainty of the body of evidence for primary (mean change in best-corrected visual acuity [BCVA]) and secondary (quality of life and adverse events) outcomes using the GRADE classification. MAIN RESULTS: We included six RCTs with 223 total participants with acute non-arteritic CRAO; the studies ranged in size from 10 to 84 participants. The included studies varied geographically: one in Australia, one in Austria and Germany, two in China, one in Germany, and one in Italy. We were unable to conduct any meta-analyses due to study heterogeneity. None of the included studies compared the same pair of interventions: 1) tissue plasminogen activator (t-PA) versus intravenous saline; 2) t-PA versus isovolemic hemodilution, eyeball massage, intraocular pressure reduction, and anticoagulation; 3) nitroglycerin, methazolamide, mecobalamin tablets, vitamin B1 and B12 injections, puerarin and compound anisodine (also known as 654-2) along with oxygen inhalation, eyeball massage, tube expansion, and anticoagulation compared with and without intravenous recombinant tissue plasminogen activator (rt-PA); 4) transcorneal electrical stimulation (TES) with 0 mA versus with 66% of the participant's individual electrical phosphene threshold (EPT) at 20 Hz (66%) versus with 150% of the participant's individual EPT (150%) at 20 Hz; 5) ophthalmic artery branch retrograde thrombolysis versus superselective ophthalmic artery thrombolysis; and 6) pentoxifylline versus placebo. There was no evidence of an important difference in visual acuity between participants treated with t-PA versus intravenous saline (mean difference [MD] at 1 month -0.15 logMAR, 95% confidence interval [CI] -0.48 to 0.18; 1 study, 16 participants; low certainty evidence); t-PA versus isovolemic hemodilution, eyeball massage, intraocular pressure reduction, and anticoagulation (MD at 1 month -0.00 logMAR, 95% CI -0.24 to 0.23; 1 study, 82 participants; low certainty evidence); and TES with 0 mA versus TES with 66% of EPT at 20 Hz versus TES with 150% of EPT at 20 Hz. Participants treated with t-PA experienced higher rates of serious adverse effects. The other three comparisons did not report statistically significant differences. Other studies reported no data on secondary outcomes (quality of life or adverse events).  AUTHORS' CONCLUSIONS: The current research suggests that proposed interventions for acute non-arteritic CRAO may not be better than observation or treatments of any kind such as eyeball massage, oxygen inhalation, tube expansion, and anticoagulation, but the evidence is uncertain. Large, well-designed RCTs are necessary to determine the most effective treatment for acute non-arteritic CRAO.

Acute Disorders of Consciousness in Pediatric Severe Sepsis and Organ Failure: Secondary Analysis of the Multicenter Phenotyping Sepsis-Induced Multiple Organ Failure Study.

OBJECTIVES: Acute disorders of consciousness (DoC) in pediatric severe sepsis are associated with increased risk of morbidity and mortality. We sought to examine the frequency of and factors associated with DoC in children with sepsis-induced organ failure. DESIGN: Secondary analysis of the multicenter Phenotyping Sepsis-Induced Multiple Organ Failure Study (PHENOMS). SETTING: Nine tertiary care PICUs in the United States. PATIENTS: Children less than 18 years old admitted to a PICU with severe sepsis and at least one organ failure during a PICU stay. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The primary outcome was frequency of DoC, defined as Glasgow Coma Scale (GCS) less than 12 in the absence of sedatives during an ICU stay, among children with severe sepsis and the following: single organ failure, nonphenotypeable multiple organ failure (MOF), MOF with one of the PHENOMS phenotypes (immunoparalysis-associated MOF [IPMOF], sequential liver failure-associated MOF, thrombocytopenia-associated MOF), or MOF with multiple phenotypes. A multivariable logistic regression analysis was performed to evaluate the association between clinical variables and organ failure groups with DoC. Of 401 children studied, 71 (18%) presented with DoC. Children presenting with DoC were older (median 8 vs 5 yr; p = 0.023), had increased hospital mortality (21% vs 10%; p = 0.011), and more frequently presented with both any MOF (93% vs 71%; p < 0.001) and macrophage activation syndrome (14% vs 4%; p = 0.004). Among children with any MOF, those presenting with DoC most frequently had nonphenotypeable MOF and IPMOF (52% and 34%, respectively). In the multivariable analysis, older age (odds ratio, 1.07; 95% CI, 1.01-1.12) and any MOF (3.22 [1.19-8.70]) were associated with DoC. CONCLUSIONS: One of every five children with severe sepsis and organ failure experienced acute DoC during their PICU stay. Preliminary findings suggest the need for prospective evaluation of DoC in children with sepsis and MOF.

Noninvasive Ventilation for Pediatric Acute Respiratory Distress Syndrome: Experience From the 2016/2017 Pediatric Acute Respiratory Distress Syndrome Incidence and Epidemiology Prospective Cohort Study.

OBJECTIVES: The worldwide practice and impact of noninvasive ventilation (NIV) in pediatric acute respiratory distress syndrome (PARDS) is unknown. We sought to describe NIV use and associated clinical outcomes in PARDS. DESIGN: Planned ancillary study to the 2016/2017 prospective Pediatric Acute Respiratory Distress Syndrome Incidence and Epidemiology study. SETTING: One hundred five international PICUs. PATIENTS: Patients with newly diagnosed PARDS admitted during 10 study weeks. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Children were categorized by their respiratory support at PARDS diagnosis into NIV or invasive mechanical ventilation (IMV) groups. Of 708 subjects with PARDS, 160 patients (23%) received NIV at PARDS diagnosis (NIV group). NIV failure rate (defined as tracheal intubation or death) was 84 of 160 patients (53%). Higher nonrespiratory pediatric logistic organ dysfunction (PELOD-2) score, Pa o2 /F io2 was less than 100 at PARDS diagnosis, immunosuppression, and male sex were independently associated with NIV failure. NIV failure was 100% among patients with nonrespiratory PELOD-2 score greater than 2, Pa o2 /F io2 less than 100, and immunosuppression all present. Among patients with Pa o2 /F io2 greater than 100, children in the NIV group had shorter total duration of NIV and IMV, than the IMV at initial diagnosis group. We failed to identify associations between NIV use and PICU survival in a multivariable Cox regression analysis (hazard ratio 1.04 [95% CI, 0.61-1.80]) or mortality in a propensity score matched analysis ( p = 0.369). CONCLUSIONS: Use of NIV at PARDS diagnosis was associated with shorter exposure to IMV in children with mild to moderate hypoxemia. Even though risk of NIV failure was high in some children, we failed to identify greater hazard of mortality in these patients.

Caring for Critically Ill Children With the ICU Liberation Bundle (ABCDEF): Results of the Pediatric Collaborative.

OBJECTIVES: Assess clinical outcomes following PICU Liberation ABCDEF Bundle utilization. DESIGN: Prospective, multicenter, cohort study. SETTING: Eight academic PICUs. PATIENTS: Children greater than 2 months with expected PICU stay greater than 2 days and need for mechanical ventilation (MV). INTERVENTIONS: ABCDEF Bundle implementation. MEASUREMENT AND MAIN RESULTS: Over an 11-month period (3-mo baseline, 8-mo implementation), Bundle utilization was measured for 622 patients totaling 5,017 PICU days. Risk of mortality was quantified for 532 patients (4,275 PICU days) for correlation between Bundle utilization and MV duration, PICU length of stay (LOS), delirium incidence, and mortality. Utilization was analyzed as subject-specific (entire PICU stay) and day-specific (single PICU day). Median overall subject-specific utilization increased from 50% during the 3-month baseline to 63.9% during the last four implementation months ( p < 0.001). Subject-specific utilization for elements A and C did not change; utilization improved for B (0-12.5%; p = 0.007), D (22.2-61.1%; p < 0.001), E (17.7-50%; p = 0.003), and F (50-79.2%; p = 0.001). We observed no association between Bundle utilization and MV duration, PICU LOS, or delirium incidence. In contrast, on adjusted analysis, every 10% increase in subject-specific utilization correlated with mortality odds ratio (OR) reduction of 34%, p < 0.001; every 10% increase in day-specific utilization correlated with a mortality OR reduction of 1.4% ( p = 0.006). CONCLUSIONS: ABCDEF Bundle is applicable to children. Although enhanced Bundle utilization correlated with decreased mortality, increased utilization did not correlate with duration of MV, PICU LOS, or delirium incidence. Additional research in the domains of comparative effectiveness, implementation science, and human factors engineering is required to understand this clinical inconsistency and optimize PICU Liberation concept integration into clinical practice.

Prevalence of Pathogenic and Potentially Pathogenic Inborn Error of Immunity Associated Variants in Children with Severe Sepsis.

PURPOSE: Our understanding of inborn errors of immunity is increasing; however, their contribution to pediatric sepsis is unknown. METHODS: We used whole-exome sequencing (WES) to characterize variants in genes related to monogenic immunologic disorders in 330 children admitted to intensive care for severe sepsis. We defined candidate variants as rare variants classified as pathogenic or potentially pathogenic in QIAGEN's Human Gene Mutation Database or novel null variants in a disease-consistent inheritance pattern. We investigated variant correlation with infection and inflammatory phenotype. RESULTS: More than one in two children overall and three of four African American children had immunodeficiency-associated variants. Children with variants had increased odds of isolating a blood or urinary pathogen (blood: OR 2.82, 95% CI: 1.12-7.10, p = 0.023, urine: OR: 8.23, 95% CI: 1.06-64.11, p = 0.016) and demonstrating increased inflammation with hyperferritinemia (ferritin [Formula: see text] ng/mL, OR: 2.16, 95% CI: 1.28-3.66, p = 0.004), lymphopenia (lymphocyte count < 1000/µL, OR: 1.66, 95% CI: 1.06 - 2.60, p = 0.027), thrombocytopenia (platelet count < 150,000/µL, OR: 1.76, 95% CI: 1.12-2.76, p = 0.013), and CRP greater than 10 mg/dl (OR: 1.71, 95% CI: 1.10-2.68, p = 0.017). They also had increased odds of requiring extracorporeal membrane oxygenation (ECMO, OR: 4.19, 95% CI: 1.21-14.5, p = 0.019). CONCLUSION: Herein, we describe the genetic findings in this severe pediatric sepsis cohort and their microbiologic and immunologic significance, providing evidence for the phenotypic effect of these variants and rationale for screening children with life-threatening infections for potential inborn errors of immunity.

Machine learning derivation of four computable 24-h pediatric sepsis phenotypes to facilitate enrollment in early personalized anti-inflammatory clinical trials.

BACKGROUND: Thrombotic microangiopathy-induced thrombocytopenia-associated multiple organ failure and hyperinflammatory macrophage activation syndrome are important causes of late pediatric sepsis mortality that are often missed or have delayed diagnosis. The National Institutes of General Medical Science sepsis research working group recommendations call for application of new research approaches in extant clinical data sets to improve efficiency of early trials of new sepsis therapies. Our objective is to apply machine learning approaches to derive computable 24-h sepsis phenotypes to facilitate personalized enrollment in early anti-inflammatory trials targeting these conditions. METHODS: We applied consensus, k-means clustering analysis to our extant PHENOtyping sepsis-induced Multiple organ failure Study (PHENOMS) dataset of 404 children. 24-hour computable phenotypes are derived using 25 available bedside variables including C-reactive protein and ferritin. RESULTS: Four computable phenotypes (PedSep-A, B, C, and D) are derived. Compared to all other phenotypes, PedSep-A patients (n = 135; 2% mortality) were younger and previously healthy, with the lowest C-reactive protein and ferritin levels, the highest lymphocyte and platelet counts, highest heart rate, and lowest creatinine (p < 0.05); PedSep-B patients (n = 102; 12% mortality) were most likely to be intubated and had the lowest Glasgow Coma Scale Score (p < 0.05); PedSep-C patients (n = 110; mortality 10%) had the highest temperature and Glasgow Coma Scale Score, least pulmonary failure, and lowest lymphocyte counts (p < 0.05); and PedSep-D patients (n = 56, 34% mortality) had the highest creatinine and number of organ failures, including renal, hepatic, and hematologic organ failure, with the lowest platelet counts (p < 0.05). PedSep-D had the highest likelihood of developing thrombocytopenia-associated multiple organ failure (Adj OR 47.51 95% CI [18.83-136.83], p < 0.0001) and macrophage activation syndrome (Adj OR 38.63 95% CI [13.26-137.75], p < 0.0001). CONCLUSIONS: Four computable phenotypes are derived, with PedSep-D being optimal for enrollment in early personalized anti-inflammatory trials targeting thrombocytopenia-associated multiple organ failure and macrophage activation syndrome in pediatric sepsis. A computer tool for identification of individual patient membership ( www.pedsepsis.pitt.edu ) is provided. Reproducibility will be assessed at completion of two ongoing pediatric sepsis studies.

Non-steroidal anti-inflammatory agents for treating cystoid macular edema following cataract surgery.

BACKGROUND: Cataract surgery is the most common ambulatory incisional surgery performed in the USA. Cystoid macular edema (CME), the accumulation of fluid in the central retina due to leakage from dilated capillaries, is the most common cause of vision impairment following cataract surgery. Acute CME, defined as CME of less than four months' duration, often resolves spontaneously. CME that persists for four months or longer is termed chronic CME. Non-steroidal anti-inflammatory drugs (NSAIDs) have been used to treat CME. This update adds new evidence and analyses to the previously published review. OBJECTIVES: To examine the effectiveness of NSAIDs in the treatment of CME following cataract surgery. SEARCH METHODS: We searched the CENTRAL (2022, Issue 3); Ovid MEDLINE; Embase; PubMed; LILACS; mRCT (discontinued in 2014, last searched August 2011), ClinicalTrials.gov, and WHO ICTRP databases. We did not use any date or language restrictions in the electronic search for trials. We last searched the electronic databases on 20 March 2022.   SELECTION CRITERIA: We included randomized controlled trials evaluating the effects of NSAIDs for CME following cataract surgery. DATA COLLECTION AND ANALYSIS: Two review authors independently screened all titles and abstracts, reviewed full-text publications against eligibility criteria, independently extracted data from newly included trials and assessed risk of bias for each included trial. We contacted trial authors for clarification or to request missing information. We provided a narrative synthesis of all included trials and their results. For continuous and dichotomous outcomes, we separately performed pooled analysis and reported mean difference (MD) and risk ratio (RR) as well as the associated 95% confidence interval (CI) whenever feasible. Two review authors independently graded the overall certainty of the evidence for each outcome using the GRADE approach. MAIN RESULTS: We included nine trials with a total of 390 participants (393 eyes). Study participants' mean age was 72.2 years (interquartile range [IQR] 68.8 to 73.6) and 72% were women (IQR 69% to 74%). Three trials included participants with acute CME, and four included participants with chronic CME; the remaining two trials enrolled both participants with acute and chronic CME or participants with unknown CME duration. We assessed trials as having unclear (33%) or high risk of bias (67%). Visual improvement of two or more lines at the end of treatment  Data from one trial in participants with acute CME show no treatment effect of topical ketorolac compared to placebo (RR 2.00, 95% CI 0.46 to 8.76; 22 participants). Data from a three-arm trial in participants with acute CME demonstrate that, when compared with topical prednisolone, topical ketorolac (RR 1.33, 95% CI 0.58 to 3.07; 17 participants) or topical ketorolac and prednisolone combination therapy (RR 1.78, 95% CI 0.86 to 3.69; 17 participants) may have little or no effect on visual improvement. Results of subgroup analysis from two studies in participants with chronic CME suggest that, after treatment for 90 days or longer, NSAIDs may increase participants' likelihood of visual improvement by 1.87 fold (RR 2.87, 95% CI 1.58 to 5.22; I2 = 33%; 2 trials, 121 participants) relative to placebo. However, there was no evidence of treatment effects in the subgroup with two months of treatment or less (RR 0.72, 95% CI 0.30 to 1.73; P = 0.19, I2 = 41%; 2 trials, 34 participants). Overall, this evidence is very low certainty.  A single-study estimate in patients with mixed CME indicates that topical diclofenac may increase the likelihood of visual improvement by 40% when compared to topical ketorolac (RR 1.40, 95% CI 1.02 to 1.94; 68 participants). However, the same trial reported no difference between the groups in mean final visual acuity in Snellen lines (MD 0.40, 95% CI -0.93 to 1.73). A three-arm trial in patients with mixed CME reporting visual changes in ETDRS letters in comparisons between ketorolac and diclofenac (34 participants) or bromfenac (34 participants) suggests no evidence of effects. Overall, NSAIDs may slightly improve visual acuity in participants with mixed CME but the evidence is very uncertain. Persistence of improvement of vision one month after discontinuation of treatment One trial of participants with chronic CME tested oral indomethacin (RR 0.40, 95% CI 0.10 to 1.60; 20 participants) and the other compared topical ketorolac to placebo (RR 4.00, 95% CI 0.51 to 31.1; 26 participants). While there is no evidence of treatment effects, evidence suggests substantial between-group heterogeneity (P = 0.07, I2 = 69.9%; very low-certainty evidence). None of the trials in patients with acute or mixed CME reported this outcome. Proportion of participants with improvement in leakage on fundus fluorescein angiography One three-arm trial in participants with acute CME shows that, when compared with topical prednisolone, there is no treatment benefit of topical ketorolac (RR 1.11, 95% CI 0.45 to 2.75; 17 participants) or topical ketorolac and topical prednisolone combination therapy (RR 1.56, 95% CI 0.72 to 3.38; 17 participants). This evidence is very low certainty. The combined estimate from two trials in participants with chronic CME indicates NSAIDs have little to no effect over placebo on improving leakage (RR 1.93, 95% CI 0.62 to 6.02; 40 participants; very low-certainty evidence). Neither of the trials in patients with mixed CME reported this outcome. Proportion of participants with improved contrast sensitivity Very low-certainty evidence from one trial in participants with acute CME shows no treatment benefit of ketorolac (RR 1.11, 95% CI 0.45 to 2.75; 17 participants) or ketorolac and prednisolone combination therapy (RR 1.78, 95% CI 0.86 to 3.69; 17 participants) compared with topical prednisolone. None of the trials in patients with chronic or mixed CME reported this outcome. Proportion of participants with improved central macular thickness on optical coherence tomography; measures of quality of life No included trial reported these outcomes. Adverse effects Most trials observed no differences in ocular adverse events, such as corneal toxicity or elevated intraocular pressure, between comparison groups. AUTHORS' CONCLUSIONS: Evidence on effects of NSAIDs in patients with CME is very uncertain and further investigation is warranted. Our findings are limited by small sample sizes, and heterogeneity in interventions, assessments, and reporting of clinically important outcomes.

Mortality Risk in Pediatric Sepsis Based on C-reactive Protein and Ferritin Levels.

OBJECTIVES: Interest in using bedside C-reactive protein (CRP) and ferritin levels to identify patients with hyperinflammatory sepsis who might benefit from anti-inflammatory therapies has piqued with the COVID-19 pandemic experience. Our first objective was to identify patterns in CRP and ferritin trajectory among critically ill pediatric sepsis patients. We then examined the association between these different groups of patients in their inflammatory cytokine responses, systemic inflammation, and mortality risks. DATA SOURCES: A prospective, observational cohort study. STUDY SELECTION: Children with sepsis and organ failure in nine pediatric intensive care units in the United States. DATA EXTRACTION: Two hundred and fifty-five children were enrolled. Five distinct clinical multi-trajectory groups were identified. Plasma CRP (mg/dL), ferritin (ng/mL), and 31 cytokine levels were measured at two timepoints during sepsis (median Day 2 and Day 5). Group-based multi-trajectory models (GBMTM) identified groups of children with distinct patterns of CRP and ferritin. DATA SYNTHESIS: Group 1 had normal CRP and ferritin levels ( n = 8; 0% mortality); Group 2 had high CRP levels that became normal, with normal ferritin levels throughout ( n = 80; 5% mortality); Group 3 had high ferritin levels alone ( n = 16; 6% mortality); Group 4 had very high CRP levels, and high ferritin levels ( n = 121; 11% mortality); and Group 5 had very high CRP and very high ferritin levels ( n = 30; 40% mortality). Cytokine responses differed across the five groups, with ferritin levels correlated with macrophage inflammatory protein 1α levels and CRP levels reflective of many cytokines. CONCLUSIONS: Bedside CRP and ferritin levels can be used together to distinguish groups of children with sepsis who have different systemic inflammation cytokine responses and mortality risks. These data suggest future potential value in personalized clinical trials with specific targets for anti-inflammatory therapies.

Oxidation State and Surface Reconstruction of Cu under CO2 Reduction Conditions from In Situ X-ray Characterization.

The electrochemical CO2 reduction reaction (CO2RR) using Cu-based catalysts holds great potential for producing valuable multi-carbon products from renewable energy. However, the chemical and structural state of Cu catalyst surfaces during the CO2RR remains a matter of debate. Here, we show the structural evolution of the near-surface region of polycrystalline Cu electrodes under in situ conditions through a combination of grazing incidence X-ray absorption spectroscopy (GIXAS) and X-ray diffraction (GIXRD). The in situ GIXAS reveals that the surface oxide layer is fully reduced to metallic Cu before the onset potential for CO2RR, and the catalyst maintains the metallic state across the potentials relevant to the CO2RR. We also find a preferential surface reconstruction of the polycrystalline Cu surface toward (100) facets in the presence of CO2. Quantitative analysis of the reconstruction profiles reveals that the degree of reconstruction increases with increasingly negative applied potentials, and it persists when the applied potential returns to more positive values. These findings show that the surface of Cu electrocatalysts is dynamic during the CO2RR, and emphasize the importance of in situ characterization to understand the surface structure and its role in electrocatalysis.

Adherence to Lung-Protective Ventilation Principles in Pediatric Acute Respiratory Distress Syndrome: A Pediatric Acute Respiratory Distress Syndrome Incidence and Epidemiology Study.

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.

Pre-statistical harmonization of behavrioal instruments across eight surveys and trials.

BACKGROUND: Data harmonization is a powerful method to equilibrate items in measures that evaluate the same underlying construct. There are multiple measures to evaluate dementia related behavioral symptoms. Pre-statistical harmonization of behavioral instruments in dementia research is the first step to develop a statistical crosswalk between measures. Studies that conduct pre-statistical harmonization of behavioral instruments rarely document their methods in a structured, reproducible manner. This is a crucial step which entails careful review, documentation and scrutiny of source data to ensure sufficient comparability between items prior to data pooling. Here, we document the pre-statistical harmonization of items measuring behavioral and psychological symptoms among people with dementia. We provide a box of recommended procedure for future studies. METHODS: We identified behavioral instruments that are used in clinical practice, a national survey, and randomized trials of dementia care interventions. We rigorously reviewed question content and scoring procedures to establish sufficient comparability across items as well as item quality prior to data pooling. Additionally, we standardized coding to Stata-readable format, which allowed us to automate approaches to identify potential cross-study differences in items and low-quality items. To ensure reasonable model fit for statistical co-calibration, we estimated two-parameter logistic Item Response Theory models within each of the eight studies. RESULTS: We identified 59 items from 11 behavioral instruments across the eight datasets. We found considerable cross-study heterogeneity in administration and coding procedures for items that measure the same attribute. Discrepancies existed in terms of directionality and quantification of behavioral symptoms for even seemingly comparable items. We resolved item response heterogeneity, missingness and skewness, conditional dependency prior to estimation of item response theory models for statistical co-calibration. We used several rigorous data transformation procedures to address these issues, including re-coding and truncation. CONCLUSIONS: This study highlights the importance of each aspect involved in the pre-statistical harmonization process of behavioral instruments. We provide guidelines and recommendations for how future research may detect and account for similar issues in pooling behavioral and related instruments.

Virtual reality training for cataract surgery operating performance in ophthalmology trainees.

BACKGROUND: Cataract surgery is the most common incisional surgical procedure in ophthalmology and is important in ophthalmic graduate medical education. Although most ophthalmology training programs in the United States (US) include virtual reality (VR) training for cataract surgery, comprehensive reviews that detail the impact of VR training on ophthalmology trainee performance are lacking. OBJECTIVES: To assess the impact of VR training for cataract surgery on the operating performance of postgraduate ophthalmology trainees, measured by operating time, intraoperative complications, postoperative complications, supervising physician ratings, and VR simulator task ratings. SEARCH METHODS: We searched CENTRAL (which contains the Cochrane Eyes and Vision Trials Register), Ovid MEDLINE, Embase.com, PubMed, LILACS, ClinicalTrials.gov, and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP). We did not use any date or language restrictions in the electronic search for trials. We last searched the electronic databases on 14 June 2021. SELECTION CRITERIA: We included randomized controlled trials (RCTs) comparing VR training to any other method of training, including non-VR simulation training (e.g., wet laboratory training), didactics training, or no supplementary training in postgraduate ophthalmology trainees. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodology. Primary outcomes were operating times in the operating room and intraoperative complications. Secondary outcomes were operating times in simulated settings, simulator task ratings, and supervising physician ratings, either in the operating room or simulated settings. MAIN RESULTS: We included six RCTs with a total of 151 postgraduate ophthalmology trainees ranging from 12 to 60 participants in each study. The included studies varied widely in terms of geography: two in the US, and one study each in China, Germany, India, and Morocco. Three studies compared VR training for phacoemulsification cataract surgery on the Eyesi simulator (VRmagic, Mannheim, Germany) with wet laboratory training and two studies compared VR training with no supplementary training. One study compared trainees who received VR training with those who received conventional training for manual small incision cataract surgery on the HelpMeSee simulator (HelpMeSee, New York, NY). Industry financially supported two studies. All studies had at least three domains judged at high or unclear risks of bias. We did not conduct a meta-analysis due to insufficient data (i.e., lack of precision measurements, or studies reported only P values). All evidence was very low-certainty, meaning that any estimates were unreliable. The evidence for the benefits of VR training for trainees was very uncertain for primary outcomes. VR-trained trainees relative to those without supplementary training had shorter operating times (mean difference [MD] -17 minutes, 95% confidence interval [CI] -21.62 to -12.38; 1 study, n = 12; very low-certainty evidence). Results for operating time were inconsistent when comparing VR and wet laboratory training: one study found that VR relative to wet laboratory training was associated with longer operating times (P = 0.038); the other reported that two training groups had similar operating times (P = 0.14). One study reported that VR-trained trainees relative to those without supplementary training had fewer intraoperative complications (P < 0.001); in another study, VR and conventionally trained trainees had similar intraoperative complication rates (MD -8.31, 95% CI -22.78 to 6.16; 1 study, n = 19; very low-certainty evidence). For secondary outcomes, VR training may have similar impact on trainee performance compared to wet laboratory and greater impact compared to no supplementary training, but the evidence was very uncertain. One study reported VR-trained trainees relative to those without supplementary training had significantly reduced operating time in simulated settings (P = 0.0013). Another study reported that VR-trained relative to wet laboratory-trained trainees had shorter operating times in VR settings (MD -1.40 minutes, 95% CI -1.96 to -0.84; 1 study, n = 60) and similar times in wet laboratory settings (MD 0.16 minutes, 95% CI -0.50 to 0.82; 1 study, n = 60). This study also found the VR-trained trainees had higher VR simulator ratings (MD 5.17, 95% CI 0.61 to 9.73; 1 study, n = 60). Results for supervising physician ratings in the operating room were inconsistent: one study reported that VR- and wet laboratory-trained trainees received similar supervising physician ratings for cataract surgery (P = 0.608); another study reported that VR-trained trainees relative to those without supplementary training were less likely to receive poor ratings by supervising physicians for capsulorhexis construction (RR 0.29, 95% CI 0.15 to 0.57). In wet laboratory settings, VR-trained trainees received similar supervising physician ratings compared with wet laboratory-trained trainees (MD -1.50, 95% CI -6.77 to 3.77; n = 60) and higher supervising physician ratings compared with trainees without supplementary training (P < 0.0001). However, the results for all secondary outcomes should be interpreted with caution because of very low-certainty evidence.  AUTHORS' CONCLUSIONS: Current research suggests that VR training may be more effective than no supplementary training in improving trainee performance in the operating room and simulated settings for postgraduate ophthalmology trainees, but the evidence is uncertain. The evidence comparing VR with conventional or wet laboratory training was less consistent.

Long-term urban carbon dioxide observations reveal spatial and temporal dynamics related to urban characteristics and growth.

Cities are concentrated areas of CO2 emissions and have become the foci of policies for mitigation actions. However, atmospheric measurement networks suitable for evaluating urban emissions over time are scarce. Here we present a unique long-term (decadal) record of CO2 mole fractions from five sites across Utah's metropolitan Salt Lake Valley. We examine "excess" CO2 above background conditions resulting from local emissions and meteorological conditions. We ascribe CO2 trends to changes in emissions, since we did not find long-term trends in atmospheric mixing proxies. Three contrasting CO2 trends emerged across urban types: negative trends at a residential-industrial site, positive trends at a site surrounded by rapid suburban growth, and relatively constant CO2 over time at multiple sites in the established, residential, and commercial urban core. Analysis of population within the atmospheric footprints of the different sites reveals approximately equal increases in population influencing the observed CO2, implying a nonlinear relationship with CO2 emissions: Population growth in rural areas that experienced suburban development was associated with increasing emissions while population growth in the developed urban core was associated with stable emissions. Four state-of-the-art global-scale emission inventories also have a nonlinear relationship with population density across the city; however, in contrast to our observations, they all have nearly constant emissions over time. Our results indicate that decadal scale changes in urban CO2 emissions are detectable through monitoring networks and constitute a valuable approach to evaluate emission inventories and studies of urban carbon cycles.

Best Practices for Conducting Interprofessional Team Rounds to Facilitate Performance of the ICU Liberation (ABCDEF) Bundle.

OBJECTIVES: Daily ICU interprofessional team rounds, which incorporate the ICU Liberation ("A" for Assessment, Prevention, and Manage Pain; "B" for Both Spontaneous Awakening Trials and Spontaneous Breathing Trials; "C" for Choice of Analgesia and Sedation; "D" for Delirium Assess, Prevent, and Manage; "E" for Early Mobility and Exercise; "F" for Family Engagement and Empowerment [ABCDEF]) Bundle, support both the care coordination and regular provider communication necessary for Bundle execution. This article describes evidence-based practices for conducting effective interprofessional team rounds in the ICU to improve Bundle performance. DESIGN: Best practice synthesis. METHODS: The authors, each extensively involved in the Society of Critical Care Medicine's ICU Liberation Campaign, reviewed the pertinent literature to identify how ICU interprofessional team rounds can be optimized to increase ICU Liberation adherence. RESULTS: Daily ICU interprofessional team rounds that foster ICU Liberation Bundle use support both care coordination and regular provider communication within and between teams. Evidence-based best practices for conducting effective interprofessional team rounds in the ICU include the optimal structure for ICU interprofessional team rounds; the importance of conducting rounds at patients' bedside; essential participants in rounds; the inclusion of ICU patients and their families in rounds-based discussions; and incorporation of the Bundle into the Electronic Health Record. Interprofessional team rounds in the ICU ideally employ communication strategies to foster inclusive and supportive behaviors consistent with interprofessional collaboration in the ICU. Patient care discussions during interprofessional team rounds benefit from being patient-centered and goal-oriented. Documentation of ICU Liberation Bundle elements in the Electronic Health Record may help facilitate team communication and decision-making. CONCLUSIONS: Conducting high-quality interprofessional team rounds in the ICU is a key strategy to support ICU Liberation Bundle use.