Multicenter Validation of the Vasoactive-Ventilation-Renal Score as a Predictor of Prolonged Mechanical Ventilation After Neonatal Cardiac Surgery

Objectives: We sought to validate the Vasoactive-Ventilation-Renal score, a novel disease severity index, as a predictor of outcome in a multicenter cohort of neonates who underwent cardiac surgery. Design: Retrospective chart review. Setting: Seven tertiary-care referral centers. Patients: Neonates defined as age less than or equal to 30 days at the time of cardiac surgery. Interventions: Ventilation index, Vasoactive-Inotrope Score, serum lactate, and Vasoactive-Ventilation-Renal score were recorded for three postoperative time points: ICU admission, 6 hours, and 12 hours. Peak values, defined as the highest of the three measurements, were also noted. Vasoactive-Ventilation-Renal was calculated as follows: ventilation index + Vasoactive-Inotrope Score + Δ creatinine (change in creatinine from baseline × 10). Primary outcome was prolonged duration of mechanical ventilation, defined as greater than 96 hours. Receiver operative characteristic curves were generated, and abilities of variables to correctly classify prolonged duration of mechanical ventilation were compared using area under the curve values. Multivariable logistic regression modeling was also performed. Measurements and Main Results: We reviewed 275 neonates. Median age at surgery was 7 days (25th–75th percentile, 5–12 d), 86 (31%) had single ventricle anatomy, and 183 (67%) were classified as Society of Thoracic Surgeons-European Association for Cardio-Thoracic Surgery Congenital Heart Surgery Mortality Category 4 or 5. Prolonged duration of mechanical ventilation occurred in 89 patients (32%). At each postoperative time point, the area under the curve for prolonged duration of mechanical ventilation was significantly greater for the Vasoactive-Ventilation-Renal score as compared to the ventilation index, Vasoactive-Inotrope Score, and serum lactate, with an area under the curve for peak Vasoactive-Ventilation-Renal score of 0.82 (95% CI, 0.77–0.88). On multivariable analysis, peak Vasoactive-Ventilation-Renal score was independently associated with prolonged duration of mechanical ventilation, odds ratio (per 1 unit increase): 1.08 (95% CI, 1.04–1.12). Conclusions: In this multicenter cohort of neonates who underwent cardiac surgery, the Vasoactive-Ventilation-Renal score was a reliable predictor of postoperative outcome and outperformed more traditional measures of disease complexity and severity

Expanded genetic screening in Caenorhabditis elegans identifies new regulators and an inhibitory role for NAD+ in axon regeneration.

The mechanisms underlying axon regeneration in mature neurons are relevant to the understanding of normal nervous system maintenance and for developing therapeutic strategies for injury. Here, we report novel pathways in axon regeneration, identified by extending our previous function-based screen using the C. elegans mechanosensory neuron axotomy model. We identify an unexpected role of the nicotinamide adenine dinucleotide (NAD+) synthesizing enzyme, NMAT-2/NMNAT, in axon regeneration. NMAT-2 inhibits axon regrowth via cell-autonomous and non-autonomous mechanisms. NMAT-2 enzymatic activity is required to repress regrowth. Further, we find differential requirements for proteins in membrane contact site, components and regulators of the extracellular matrix, membrane trafficking, microtubule and actin cytoskeleton, the conserved Kelch-domain protein IVNS-1, and the orphan transporter MFSD-6 in axon regrowth. Identification of these new pathways expands our understanding of the molecular basis of axonal injury response and regeneration

Extubation Failure after Neonatal Cardiac Surgery: A Multicenter Analysis

Objectives To describe the epidemiology of extubation failure and identify risk factors for its occurrence in a multicenter population of neonates undergoing surgery for congenital heart disease. Study design We conducted a prospective observational study of neonates ≤30 days of age who underwent cardiac surgery at 7 centers within the US in 2015. Extubation failure was defined as reintubation within 72 hours of the first planned extubation. Risk factors were identified with the use of multivariable logistic regression analysis and reported as OR with 95% CIs. Multivariable logistic regression analysis was conducted to examine the relationship between extubation failure and worse clinical outcome, defined as hospital length of stay in the upper 25% or operative mortality. Results We enrolled 283 neonates, of whom 35 (12%) failed their first extubation at a median time of 7.5 hours (range 1-70 hours). In a multivariable model, use of uncuffed endotracheal tubes (OR 4.6; 95% CI 1.8-11.6) and open sternotomy of 4 days or more (OR 4.8; 95% CI 1.3-17.1) were associated independently with extubation failure. Accordingly, extubation failure was determined to be an independent risk factor for worse clinical outcome (OR 5.1; 95% CI 2-13). Conclusions In this multicenter cohort of neonates who underwent surgery for congenital heart disease, extubation failure occurred in 12% of cases and was associated independently with worse clinical outcome. Use of uncuffed endotracheal tubes and prolonged open sternotomy were identified as independent and potentially modifiable risk factors for the occurrence of this precarious complication

Expanded Genetic Screening in \u3cem\u3eCaenorhabditis elegans\u3c/em\u3e Identifies New Regulators and an Inhibitory Role for NAD\u3csup\u3e+\u3c/sup\u3e in Axon Regeneration

The mechanisms underlying axon regeneration in mature neurons are relevant to the understanding of normal nervous system maintenance and for developing therapeutic strategies for injury. Here, we report novel pathways in axon regeneration, identified by extending our previous function-based screen using the C. elegans mechanosensory neuron axotomy model. We identify an unexpected role of the nicotinamide adenine dinucleotide (NAD+) synthesizing enzyme, NMAT-2/NMNAT, in axon regeneration. NMAT-2 inhibits axon regrowth via cell-autonomous and non-autonomous mechanisms. NMAT-2 enzymatic activity is required to repress regrowth. Further, we find differential requirements for proteins in membrane contact site, components and regulators of the extracellular matrix, membrane trafficking, microtubule and actin cytoskeleton, the conserved Kelch-domain protein IVNS-1, and the orphan transporter MFSD-6 in axon regrowth. Identification of these new pathways expands our understanding of the molecular basis of axonal injury response and regeneration

Addressing and Inspiring Vaccine Confidence in Black, Indigenous, and People of Color During the Coronavirus Disease 2019 Pandemic

During the coronavirus disease 2019 (COVID-19) pandemic, we have witnessed profound health inequities suffered by Black, Indigenous, and People of Color (BIPOC). These manifested as differential access to testing early in the pandemic, rates of severe disease and death 2-3 times higher than white Americans, and, now, significantly lower vaccine uptake compared with their share of the population affected by COVID-19. This article explores the impact of these COVID-19 inequities (and the underlying cause, structural racism) on vaccine acceptance in BIPOC populations, ways to establish trustworthiness of healthcare institutions, increase vaccine access for BIPOC communities, and inspire confidence in COVID-19 vaccines

Adaptive Haar wavelets for the angular discretisation of spectral wave models

A new framework for applying anisotropic angular adaptivity in spectral wave modelling is presented. The angular dimension of the action balance equation is discretised with the use of Haar wavelets, hierarchical piecewise-constant basis functions with compact support, and an adaptive methodology for anisotropically adjusting the resolution of the angular mesh is proposed. This work allows a reduction of computational effort in spectral wave modelling, through a reduction in the degrees of freedom required for a given accuracy, with an automated procedure and minimal cost

Near-Infrared Spectroscopy for Prediction of Extubation Success after Neonatal Cardiac Surgery

Introduction: Reliable predictors of extubation readiness are needed and may reduce morbidity related to extubation failure. We aimed to examine the relationship between changes in pre-extubation near-infrared spectroscopy measurements from baseline and extubation outcomes after neonatal cardiac surgery. Materials and Methods: In this retrospective cross-sectional multi-centre study, a secondary analysis of prospectively collected data from neonates who underwent cardiac surgery at seven tertiary-care children’s hospitals in 2015 was performed. Extubation failure was defined as need for re-intubation within 72 hours of the first planned extubation attempt. Near-infrared spectroscopy measurements obtained before surgery and before extubation in patients who failed extubation were compared to those of patients who extubated successfully using t-tests. Results: Near-infrared spectroscopy measurements were available for 159 neonates, including 52 with single ventricle physiology. Median age at surgery was 6 days (range: 1–29 days). A total of 15 patients (9.4 %) failed extubation. Baseline cerebral and renal near-infrared spectroscopy measurements were not statistically different between those who were successfully extubated and those who failed, but pre-extubation cerebral and renal values were significantly higher in neonates who extubated successfully. An increase from baseline to time of extubation values in cerebral oximetry saturation by ≥ 5 % had a positive predictive value for extubation success of 98.6 % (95%CI: 91.1–99.8 %). Conclusion: Pre-extubation cerebral near-infrared spectroscopy measurements, when compared to baseline, were significantly associated with extubation outcomes. These findings demonstrate the potential of this tool as a valuable adjunct in assessing extubation readiness after paediatric cardiac surgery and warrant further evaluation in a larger prospective study

Varying spin state composition by the choice of capping ligand in a family of molecular chains: detailed analysis of magnetic properties of chromium(III) horseshoes

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Higher-Order Assembly of BRCC36-KIAA0157 Is Required for DUB Activity and Biological Function

BRCC36 is a Zn²⁺-dependent deubiquitinating enzyme (DUB) that hydrolyzes lysine-63-linked ubiquitin chains as part of distinct macromolecular complexes that participate in either interferon signaling or DNA-damage recognition. The MPN⁺ domain protein BRCC36 associates with pseudo DUB MPN⁻ proteins KIAA0157 or Abraxas, which are essential for BRCC36 enzymatic activity. To understand the basis for BRCC36 regulation, we have solved the structure of an active BRCC36-KIAA0157 heterodimer and an inactive BRCC36 homodimer. Structural and functional characterizations show how BRCC36 is switched to an active conformation by contacts with KIAA0157. Higher-order association of BRCC36 and KIAA0157 into a dimer of heterodimers (super dimers) was required for DUB activity and interaction with targeting proteins SHMT2 and RAP80. These data provide an explanation of how an inactive pseudo DUB allosterically activates a cognate DUB partner and implicates super dimerization as a new regulatory mechanism underlying BRCC36 DUB activity, subcellular localization, and biological function