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Introduction: Variation exists in the timing of surgery for balanced complete atrioventricular septal defect repair. We sought to explore associations between timing of repair and resource utilisation and clinical outcomes in the first year of life., Methods: In this retrospective single-centre cohort study, we included patients who underwent complete atrioventricular septal defect repair between 2005 and 2019. Patients with left or right ventricular outflow tract obstruction and major non-cardiac comorbidities (except trisomy 21) were excluded. The primary outcome was days alive and out of the hospital in the first year of life., Results: Included were 79 infants, divided into tertiles based on age at surgery (1st = 46 to 137 days, 2nd = 140 - 176 days, 3rd = 178 - 316 days). There were no significant differences among age tertiles for days alive and out of the hospital in the first year of life by univariable analysis (tertile 1, median 351 days; tertile 2, 348 days; tertile 3, 354 days; p = 0.22). No patients died. Fewer post-operative ICU days were used in the oldest tertile relative to the youngest, but days of mechanical ventilation and hospitalisation were similar. Clinical outcomes after repair and resource utilisation in the first year of life were similar for unplanned cardiac reinterventions, outpatient cardiology clinic visits, and weight-for-age z-score at 1 year., Conclusions: Age at complete atrioventricular septal defect repair is not associated with important differences in clinical outcomes or resource utilisation in the first year of life.

Background: Infants undergoing cardiac surgery with cardiopulmonary bypass (CPB) frequently receive intraoperative methylprednisolone (MP) to suppress CPB-related inflammation; however, the optimal dosing strategy and efficacy of MP remain unclear., Methods: We retrospectively analyzed all infants under 90 days-old who received intra-operative MP for cardiac surgery with CPB from 2014-2017 at our institution. We combined real-world dosing data from the electronic health record (EHR) and two previously developed population pharmacokinetic/pharmacodynamic models to simulate peak concentration (Cmax) and area under the concentration-time curve for 24 h (AUC24) for MP and the inflammatory cytokines interleukin-6 (IL-6) and interleukin-10 (IL-10). We evaluated the relationships between post-operative, safety, and other clinical outcomes obtained from the EHR with each predicted exposure using non-parametric tests., Results: A total of 142 infants with median post-natal age 8 (interquartile range [IQR]: 5, 37) days received a total dose of 30 (19, 49) mg/kg of MP. Twelve (8%) died, 37 (26%) met the composite post-operative outcome, 114 (80%) met the composite safety outcome, and 23 (16%) had a major complication. Predicted median Cmax and AUC24 IL-6 exposure was significantly higher for infants meeting the composite post-operative outcome and those with major complications. Predicted median Cmax and AUC24 MP exposure was significantly higher for infants requiring insulin. No exposure was associated with death or other safety outcomes., Conclusions: Pro-inflammatory IL-6, but not MP exposure, was associated with post-operative organ dysfunction, suggesting current MP dosing may not adequately suppress IL-6 or increase IL-10 to impact clinical outcomes. Prospective study will be required to define the optimal exposure-efficacy and exposure-safety profiles in these infants., Competing Interests: Conflicts of Interest: The authors declare that they have no conflicts of interest to report regarding the present study.

Objective: The objective of the study was to evaluate the relationship between a panel of candidate plasma biomarkers and (1) death or severe brain injury on magnetic resonance imaging (MRI) and (2) dysfunctional cerebral pressure autoregulation as a measure of evolving encephalopathy., Study Design: Neonates with moderate-to-severe hypoxic-ischemic encephalopathy (HIE) at 2 level IV neonatal intensive care units were enrolled into this observational study. Patients were treated with therapeutic hypothermia (TH) and monitored with continuous blood pressure monitoring and near-infrared spectroscopy. Cerebral pressure autoregulation was measured by the hemoglobin volume phase (HVP) index; a higher HVP index indicates poorer autoregulation. Serial blood samples were collected during TH and assayed for Tau, glial fibrillary acidic protein, and neurogranin. MRIs were assessed using National Institutes of Child Health and Human Development scores. The relationships between the candidate biomarkers and (1) death or severe brain injury on MRI (defined as a National Institutes of Child Health and Human Development score of ≥ 2B) and (2) autoregulation were evaluated using bivariate and adjusted logistic regression models., Results: Sixty-two patients were included. Elevated Tau levels on days 2-3 of TH were associated with death or severe injury on MRI (aOR: 1.06, 95% CI: 1.03-1.09; aOR: 1.04, 95% CI: 1.01-1.06, respectively). Higher Tau was also associated with poorer autoregulation (higher HVP index) on the same day (P = .022)., Conclusions: Elevated plasma levels of Tau are associated with death or severe brain injury by MRI and dysfunctional cerebral autoregulation in neonates with HIE. Larger-scale validation of Tau as a biomarker of brain injury in neonates with HIE is warranted., (Published by Elsevier Inc.)

Background: The Breast Reconstruction Evaluation of Acellular Dermal Matrix as a Sling Trial (BREASTrial) is a blinded, randomized trial comparing the outcomes of tissue expander breast reconstruction using AlloDerm or DermaMatrix. In this final stage of the trial, outcomes 3 months to 2 years after definitive reconstruction are reported along with patient satisfaction data., Methods: A randomized trial was conducted to compare complication rates between groups of patients who underwent reconstruction with AlloDerm and DermaMatrix. Regression models were used to analyze the impact of matrix type, age, chemotherapy, radiation therapy, and reconstructive type on complication rates. Premastectomy and postmastectomy questionnaires were used to assess patient satisfaction and were also analyzed using regression models., Results: Of the 128 patients (199 breasts) who were randomized in the trial, 108 patients (167 breasts) were available for analysis in stage III. There was no difference in the overall complication rates between the AlloDerm and DermaMatrix groups (6% versus 13.2%; P = 0.3) or the severity of those complications ( P = 0.7). Obesity was a positive predictor for complications, regardless of reconstruction group ( P = 0.02). Patient satisfaction was positive overall and did not grossly vary between AlloDerm and DermaMatrix groups., Conclusions: Findings from the BREASTrial conclude that AlloDerm and DermaMatrix exhibit similar histologic and clinical outcomes. Patient satisfaction is also similar between matrices. Obesity is a predictor of complications, and acellular dermal matrices should be used with caution in these patients. As the largest head-to-head trial comparing two acellular dermal matrices, the BREASTrial contributes to the fund of knowledge regarding acellular dermal matrix supplementation in breast reconstruction., Clinical Question/level of Evidence: Therapeutic, II., Competing Interests: Disclosure : The BREASTrial is an investigator-initiated study funded by grants from the University of Utah, Lifecell, Synthes, and the Musculoskeletal Transplant Foundation to Author Dr. Agarwal. Dr. Mendenhall is an educational consultant for PolyNovo and receives research funding from CoNextions Medical. No funding was received for this article. The remaining authors have no other financial conflicts of interest to declare in relation to this study ., (Copyright © 2022 by the American Society of Plastic Surgeons.)

Assisted reproductive technology (ART) includes fertility treatment in which either eggs or embryos are handled outside a female's body to promote successful pregnancies and healthy offspring. Current ART procedures encompass in vitro fertilization with or without intracytoplasmic sperm injection. The most common complication of ART is related to the consequences of multiple pregnancy, which can be prevented or minimized by reducing the number of embryos transferred to the uterus, commonly single embryo transfer. ART has been shown to be variably associated with adverse short- and long-term perinatal outcomes, including cerebral palsy, autism, neurodevelopmental imprinting disorders, and cancer. However, there is uncertainty as to whether reported problems are related to the ART procedure itself, to factors related to infertility, to other medical and environmental factors, or a combination thereof. From a pathophysiological perspective, whether ART alters epigenetic mechanisms of gene expression, leading to later developmental, medical, and behavioral disorders, is an area of active investigation. With the meticulously conducted short- and long-term outcome studies completed so far, overall, and after controlling for multiple gestations and preterm delivery, the results suggest that ART is a safe procedure, offering hope to many parent(s) wishing for a healthy child. This paper highlights ART methods and the risk factors and confounders in the interpretation of short- and long-term outcome data, providing the reader with a means to evaluate findings and conclusions of outcome studies. WHAT THIS PAPER ADDS: Assisted reproductive technology (ART) is a relatively safe procedure. Single embryo implantation optimizes outcome. Informed consent, including the risks and benefits of ART, should be required. Ongoing longitudinal studies are necessary to fully understand ART outcomes., (© 2022 The Authors. Developmental Medicine & Child Neurology published by John Wiley & Sons Ltd on behalf of Mac Keith Press.)

Background: Although perioperative prophylactic glucocorticoids have been used for decades, whether they improve outcomes in infants after heart surgery with cardiopulmonary bypass is unknown., Methods: We conducted a multicenter, prospective, randomized, placebo-controlled, registry-based trial involving infants (<1 year of age) undergoing heart surgery with cardiopulmonary bypass at 24 sites participating in the Society of Thoracic Surgeons Congenital Heart Surgery Database. Registry data were used in the evaluation of outcomes. The infants were randomly assigned to receive prophylactic methylprednisolone (30 mg per kilogram of body weight) or placebo, which was administered into the cardiopulmonary-bypass pump-priming fluid. The primary end point was a ranked composite of death, heart transplantation, or any of 13 major complications. Patients without any of these events were assigned a ranked outcome based on postoperative length of stay. In the primary analysis, the ranked outcomes were compared between the trial groups with the use of odds ratios adjusted for prespecified risk factors. Secondary analyses included an unadjusted odds ratio, a win ratio, and safety outcomes., Results: A total of 1263 infants underwent randomization, of whom 1200 received either methylprednisolone (599 infants) or placebo (601 infants). The likelihood of a worse outcome did not differ significantly between the methylprednisolone group and the placebo group (adjusted odds ratio, 0.86; 95% confidence interval [CI], 0.71 to 1.05; P = 0.14). Secondary analyses (unadjusted for risk factors) showed an odds ratio for a worse outcome of 0.82 (95% CI, 0.67 to 1.00) and a win ratio of 1.15 (95% CI, 1.00 to 1.32) in the methylprednisolone group as compared with the placebo group, findings suggestive of a benefit with methylprednisolone; however, patients in the methylprednisolone group were more likely than those in the placebo group to receive postoperative insulin for hyperglycemia (19.0% vs. 6.7%, P<0.001)., Conclusions: Among infants undergoing surgery with cardiopulmonary bypass, prophylactic use of methylprednisolone did not significantly reduce the likelihood of a worse outcome in an adjusted analysis and was associated with postoperative development of hyperglycemia warranting insulin in a higher percentage of infants than placebo. (Funded by the National Center for Advancing Translational Sciences and others; STRESS ClinicalTrials.gov number, NCT03229538.)., (Copyright © 2022 Massachusetts Medical Society.)

The importance of nutrition in managing critically ill infants with congenital heart disease (CHD) is foundational to optimizing short- and long-term health outcomes. Growth failure and malnutrition are common in infants with CHD. The etiology of growth failure in this population is often multifactorial and may be related to altered metabolic demands, compromised blood flow to the intestine leading to nutrient malabsorption, cellular hypoxia, inadequate energy intake, and poor oral-motor skills. A dearth of high-quality studies and gaps in previously published guidelines have led to wide variability in nutrition practices that are locally driven. This review provides recommendations from the nutrition subgroup of the Neonatal Cardiac Care Collaborative for best evidence-based practices in the provision of nutritional support in infants with CHD. The review of evidence and recommendations focused on 6 predefined areas of clinical care for a target population of infants &lt;6 months with CHD admitted to the ICU or inpatient ward. These areas include energy needs, nutrient requirements, enteral nutrition, feeding practice, parenteral nutrition, and outcomes. Future progress will be directed at quality improvement efforts to optimize perioperative nutrition management with an increasing emphasis on individualized care based on nutritional status, cardiorespiratory physiology, state of illness, and other vulnerabilities., (Copyright © 2022 by the American Academy of Pediatrics.)

Importance: Intraventricular hemorrhage (IVH) occurs in 15-45% of all very low birth weight (VLBW) preterm infants. Despite improvements in the perinatal care, the incidence of IVH remains high. As more preterm infants survive, there will be a larger burden of neurodevelopmental abnormalities borne by former preterm infants., Objective: The objective of this study was to develop a predictive clinical model of IVH risk within the first few hours of life in an effort to augment perinatal counseling and guide the timing of future targeted therapies aimed at preventing or slowing the progression of disease., Design: This is a prospective observational cohort study of VLBW infants born in the NICU at John's Hopkins Children's Center from 2011 to 2019. The presence and severity of IVH was defined on standard head ultrasound screening (HUS) using the modified Papile classification. Clinical variables were identified as significant using absolute risk regression from a general linear model. The model predictors included clinically meaningful variables that were not collinear., Setting: This study took place at the Johns Hopkins Children's Center Level IV NICU., Participants: The study sample included VLBW infants treated in the neonatal intensive care unit (NICU) at John's Hopkins Children's Center from 2011 to 2019. A total of 683 infants included in the study had no or grade I IVH, and 115 infants had grades II through IV IVH. Exclusion criteria included admission to the JHH NICU after 24 h of age, BW &gt; 1500 g, and failure to consent., Main Outcome: The main outcome of this study was the presence of grades II-IV IVH on standard head ultrasound screening using the modified Papile classification [1]., Results: A total of 798 VLBW infants were studied in this cohort and 14.4% had moderate to severe IVH. Fifty four percent of the cohort was black, 33% white, and half of the cohort was male. A higher gestational age, 5-min Apgar score, hematocrit, and platelet count were significantly associated with decreased incidence of IVH in a multi-predictor model (ROC 0.826)., Conclusion and Relevance: In the face of continued lack of treatments for IVH, prevention is still a primary goal to avoid long-term developmental sequela. This model can be used for perinatal counseling and may provide important information during the narrow therapeutic window for targeted prevention therapies., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background Clinical risk factors in neonatal cardiac surgery do not fully capture discrepancies in outcomes. Targeted metabolomic analysis of plasma from neonates undergoing heart surgery with cardiopulmonary bypass was performed to determine associations with clinical outcomes. Methods and Result Samples and clinical variables from 149 neonates enrolled in the Corticosteroid Therapy in Neonates Undergoing Cardiopulmonary Bypass trial with surgical treatment for congenital heart disease between 2012 and 2016 were included. Blood samples were collected before skin incision, immediately after cardiopulmonary bypass, and 12 hours after surgery. Outcomes include composite morbidity/mortality (death, extracorporeal membrane oxygenation, cardiac arrest, acute kidney injury, and/or hepatic injury) and a cardiac composite (extracorporeal membrane oxygenation, cardiac arrest, or increase in lactate level), hepatic injury, and acute kidney injury. Targeted metabolite levels were determined by high-resolution tandem liquid chromatography and mass spectrometry. Principal component and regression analyses were used to assess associations between metabolic profiles and outcomes, with 2 models created: a base clinical model and a base model+metabolites. Of the 193 metabolites examined, 40 were detected and quantified. The first principal component, principal component 1, was composed mostly of preoperative metabolites and was significantly associated with the composite morbidity/mortality, cardiac composite, and hepatic injury outcomes. In regression models, individual metabolites also improved model performance for the composite morbidity/mortality, cardiac composite, and hepatic injury outcomes. Significant disease pathways included myocardial injury (false discovery rate, 0.00091) and heart failure (false discovery rate, 0.041). Conclusions In neonatal cardiac surgery, perioperative metabolites were associated with postoperative outcomes and improved clinical model outcome associations. Preoperative metabolite levels alone may improve risk models and provide a basis for optimizing perioperative care.

Hypoxic-ischemic encephalopathy (HIE) is the most common cause of neonatal acquired brain injury. Although conventional MRI may predict neurodevelopmental outcomes, accurate prognostication remains difficult. As diffusion tensor imaging (DTI) may provide an additional diagnostic and prognostic value over conventional MRI, we aimed to develop a composite DTI (cDTI) score to relate to short-term neurological function. Sixty prospective neonates treated with therapeutic hypothermia (TH) for HIE were evaluated with DTI, with a voxel size of 1 × 1 × 2 mm. Fractional anisotropy (FA) and mean diffusivity (MD) from 100 neuroanatomical regions (FA/MD * 100 = 200 DTI parameters in total) were quantified using an atlas-based image parcellation technique. A least absolute shrinkage and selection operator (LASSO) regression was applied to the DTI parameters to generate the cDTI score. Time to full oral nutrition [short-term oral feeding (STO) score] was used as a measure of short-term neurological function and was correlated with extracted DTI features. Seventeen DTI parameters were selected with LASSO and built into the final unbiased regression model. The selected factors included FA or MD values of the limbic structures, the corticospinal tract, and the frontotemporal cortices. While the cDTI score strongly correlated with the STO score (rho = 0.83, p = 2.8 × 10 -16 ), it only weakly correlated with the Sarnat score (rho = 0.27, p = 0.035) and moderately with the NICHD-NRN neuroimaging score (rho = 0.43, p = 6.6 × 10 -04 ). In contrast to the cDTI score, the NICHD-NRN score only moderately correlated with the STO score (rho = 0.37, p = 0.0037). Using a mixed-model analysis, interleukin-10 at admission to the NICU (p = 1.5 × 10 -13 ) and tau protein at the end of TH/rewarming ( p = 0.036) and after rewarming ( p = 0.0015) were significantly associated with higher cDTI scores, suggesting that high cDTI scores were related to the intensity of the early inflammatory response and the severity of neuronal impairment after TH. In conclusion, a data-driven unbiased approach was applied to identify anatomical structures associated with some aspects of neurological function of HIE neonates after cooling and to build a cDTI score, which was correlated with the severity of short-term neurological functions., Competing Interests: KOi is a consultant for “AnatomyWorks” and “Corporate-M.” This arrangement is being managed by the Johns Hopkins University in accordance with its conflict-of-interest policies. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Onda, Catenaccio, Chotiyanonta, Chavez-Valdez, Meoded, Soares, Tekes, Spahic, Miller, Parker, Parkinson, Vaidya, Graham, Stafstrom, Everett, Northington and Oishi.)

Background: The Pulvertaft weave continues as a staple technique for tendon coaptations. Many have proposed minor alterations to the original technique to improve its strength, although a lack of consensus exists. The authors' aim was to explore how the number of weaves and suture characteristics contribute to the overall strength of the coaptation., Methods: A comprehensive electronic search was conducted using the PubMed, Cochrane Library, and Scopus databases. Criteria for inclusion consisted of cadaveric human or animal biomechanical studies evaluating ultimate failure load (in newtons) and the number of weaves, suture characteristics, tendon source, and number of coaptations. Weaves with minimum averages of 75 N were deemed successful, and those with greater than 120 N were considered high performing., Results: A total of 347 tendon coaptations from 15 studies met inclusion criteria. Average strength by number of weaves was 36.4 N ( n = 52) for one weave, 54.2 N ( n = 58) for two weaves, 115.9 N ( n = 174) for three weaves, and 81.7 N ( n = 63) for four weaves. Statistical differences were observed between one and two weaves ( p < 0.0001); two and three weaves ( p < 0.0001); three and four weaves ( p < 0.003); and two and four weaves ( p < 0.0001). High-performing tendon transfers used three weaves, 3-0 or 4-0 braided sutures, and figure-of-eight or mattress core sutures., Conclusions: Contrary to the current dogma of "the more the better," the authors' findings show that Pulvertaft weave strength is optimized when three weaves are used to combine donor and recipient tendons. Braided sutures with either figure-of-eight or mattress sutures were associated with the highest strength of repair., (Copyright © 2022 by the American Society of Plastic Surgeons.)

Objective: To measure plasma levels of vascular endothelial growth factor (VEGF) and several cytokines (Interleukin [IL]-6 IL-8, IL-10) during the first week of life to examine the relationship between protein expression and likelihood of developing respiratory distress syndrome (RDS) and bronchopulmonary dysplasia (BPD)., Study Design: Levels of IL-6, IL-8, IL-10, and VEGF were measured from plasma obtained from preterm patients during the first week of life. Newborns were recruited from a single center between April 2009 and April 2019. Criteria for the study included being inborn, birth weight of less than 1500 grams, and a gestational age of less than 32 weeks at birth., Results: The development of RDS in preterm newborns was associated with lower levels of VEGF during the first week of life. Higher plasma levels of IL-6 and IL-8 plasma were associated with an increased likelihood and increased severity of BPD at 36 weeks postmenstrual age. In contrast, plasma levels of VEGF, IL-6, IL-8, and IL-10 obtained during the first week of life were not associated with respiratory symptoms and acute care use in young children with BPD in the outpatient setting., Conclusions: During the first week of life, lower plasma levels of VEGF was associated with the diagnosis of RDS in preterm infants. Preterm infants with higher levels of IL-6 and IL-8 during the first week of life were also more likely to be diagnosed with BPD. These biomarkers may help to predict respiratory morbidities in preterm newborns during their initial hospitalization., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Neurodevelopmental impairment is an important consequence for survivors of surgery for critical congenital heart disease. This study sought to determine whether intraoperative methylprednisolone during neonatal cardiac surgery is associated with neurodevelopmental outcomes at 12 months of age and to identify early prognostic variables associated with neurodevelopmental outcomes., Methods: We performed a planned secondary analysis of a 2-center, double-blind, randomized, placebo-controlled trial of intraoperative methylprednisolone in neonates undergoing cardiac surgery. A brain injury biomarker was measured during surgery. Bayley Scales of Infant and Toddler Development-III (BSID-III) were performed at 12 months of age. Two-sample t tests and generalized linear models were used., Results: There were 129 participants (n = 61 methylprednisolone; n = 68 placebo). There were no significant differences in BSID-III scores and brain injury biomarker levels between treatment groups. Participants who underwent a palliative (versus corrective) procedure had lower mean BSID-III cognitive (101 ± 15 versus 106 ± 14; P = .03) and motor scores (85 ± 18 versus 94 ± 16; P < .01). Longer ventilation time was associated with lower motor scores. Longer cardiac intensive care unit stay was associated with lower cognitive, language, and motor scores. Cardiopulmonary bypass time, aortic cross-clamp time, and deep hypothermic circulatory arrest were not associated with BSID-III scores., Conclusions: Neurodevelopmental outcomes were not associated with intraoperative methylprednisolone or intraoperative variables. Participants who underwent a neonatal palliative (versus corrective) procedure had longer cardiac intensive care unit stays and worse neurodevelopmental outcomes at 1 year. This work suggests that interventions focused solely on the operative period may not be associated with a long-term neurodevelopmental benefit., (Copyright © 2022 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Congenital cytomegalovirus (CMV) infection is a significant cause of neonatal hearing loss. However, at the cochlear level, the anatomical lesions and pathophysiological mechanisms that underlie hearing loss are still not clearly understood. In murine models of CMV infection, we have observed early damage to the capillary networks in stria vascularis, as well as hearing loss manifested in ABR threshold elevations. Our experimental hypothesis is that strial damage causes a reduced endocochlear potential (EP) resulting in impaired haircell activation and consequent hearing loss. We have studied strial damage, EP, and ABR threshold elevations in two mouse models (BALB/c and C57BL6 strains) infected with murine CMV. Neonatal (P3) pups were inoculated with murine CMV (2µl of 200pfu) by intra cerebral injection. Control mice were saline injected. At 6 weeks, ABR thresholds to tonal stimuli at 8, 16 and 32 kHz were determined for each ear. At 8 weeks a sub-group of treated and control animals was prepared for study of cochlear capillary networks using scanning electron microscopy of corrosion cast specimens. In a second group, at 8 weeks, EP measurements from both cochleas were made. We report that in both mouse strains, CMV infection caused capillary loss in the stria vascularis, initially at the cochlear apex, and extending to lower cochlear turns in some subjects. After CMV infection, in both BALB/c and C57BL6 mice, reduced EPs and ABR threshold elevations were observed, and there was a within-animal correlation between loss of EP and ABR threshold elevations across the sound frequencies tested. These results suggest that CMV induced damage to stria vascularis results in EP reduction that is correlated with ABR threshold elevations. Extrapolating to the human condition, we suggest that strial damage and its physiological consequences may contribute to the initial hearing loss in congenital CMV infection. The early involvement of cochlear capillary damage may encourage a focus on therapeutic interventions that can prevent vascular damage, or subsequently promote vascular healing or angiogenesis., Competing Interests: Declarations of interest None., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: The Breast Reconstruction Evaluation of Acellular Dermal Matrix as a Sling Trial is a single-center, blinded, prospective, randomized, controlled trial established to compare outcomes using two popular types of acellular dermal matrices, AlloDerm and DermaMatrix, in tissue expander breast reconstruction. This study used the acellular dermal matrix biopsy specimens from the trial to evaluate how adjuvant therapy influences inflammation, neovascularization, and capsule formation of the acellular dermal matrix., Methods: Punch biopsy specimens were taken at the time of expander exchange and were analyzed by a blinded pathologist. The inflammatory response was quantified by the number of fibroblasts, giant cells, and lymphocytes. Neovascularization and capsule formation were similarly quantified by the number of new capillaries and capsule presence and thickness, respectively., Results: Histology specimens were collected from 109 patients (170 breasts). In the absence of adjuvant therapy, there was no significant difference between AlloDerm and DermaMatrix in terms of inflammation, neovascularization, or capsule thickness. Both acellular dermal matrices showed a significant decrease in inflammation and neovascularization with adjuvant therapy. When chemotherapy and radiation therapy were used, the decrease in inflammation was greatest for the group reconstructed with DermaMatrix (p < 0.039)., Conclusions: Adjuvant therapy influences the inflammatory response, neovascularization, and capsule formation in both acellular dermal matrices. Adjuvant therapy has a protective effect on the inflammatory response toward both acellular dermal matrices in breast reconstruction. In the setting of chemotherapy and radiation therapy, DermaMatrix produced the greatest reduction in inflammation., Clinical Question/level of Evidence: Therapeutic, II., Competing Interests: Disclosure:BREASTrial is an investigator-initiated study funded by grants from the University of Utah, LifeCell, Synthes, and the Musculoskeletal Transplant Foundation to J.P.A. S.M. is an educational consultant for PolyNovo, which is unrelated to this study. The authors have no other financial conflicts of interest related to this study., (Copyright © 2022 by the American Society of Plastic Surgeons.)

Neonatal cardiac performance is dependent on calcium delivery to the myocardium. Little is known about the use and impact of calcium chloride infusions in neonates who undergo cardiac surgery. We hypothesized that the use of calcium chloride infusions would decrease the doses required of traditional inotropic and vasoactive medications by supporting cardiac output in this patient population. We performed a single-institution, retrospective, cohort study. All neonates (≤ 30 days old) undergoing cardiac surgery from 06/01/2015 through 12/31/2018 were included. Patients were divided into two groups: those who received postoperative calcium chloride infusions (calcium group) and those who did not (control group). The primary outcome was the occurrence of a maximum Vasoactive Inotropic Score (VIS) > 15 in the first 24 h following surgery. One hundred and thirty-five patients met inclusion criteria. Sixty-six patients received postoperative calcium infusions and 69 patients did not. Gestational age, weight at surgery, age at surgery, surgical complexity and cardiopulmonary bypass times were similar between groups. Forty-two (70%) patients receiving calcium had a postoperative maximum VIS > 15 compared with 38 (55%) patients not on a calcium infusion (p = 0.08). There were no differences in postoperative length of ventilation, time to enteral feeding, hospital LOS, or operative mortality between groups. Calcium chloride infusions in neonates who underwent cardiac surgery did not decrease exposure to other inotropic and vasoactive agents in the first 24 post-operative hours or improve patient outcomes., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background Heart failure phenotyping in single-ventricle Fontan patients is challenging, particularly in patients with normal ejection fraction (EF). The objective of this study was to identify Fontan patients with abnormal diastolic function, who are high risk for heart failure with preserved ejection fraction (HFpEF), and characterize their cardiac mechanics, exercise function, and functional health status. Methods and Results Data were obtained from the Pediatric Heart Network Fontan Cross-sectional Study database. EF was considered abnormal if <50%. Diastolic function was defined as abnormal if the diastolic pressure:volume quotient (lateral E:e'/end-diastolic volume) was >90th percentile (≥0.26 mL -1 ). Patients were divided into: controls=normal EF and diastolic function; systolic dysfunction (SD) = abnormal EF with normal diastolic function; diastolic dysfunction (DD) = normal EF with abnormal diastolic pressure:volume quotient. Exercise function was quantified as percent predicted peak VO 2 . Physical Functioning Summary Score (FSS) was reported from the Child Health Questionnaire. A total of 239 patients were included, 177 (74%) control, 36 (15%) SD, and 26 (11%) DD. Median age was 12.2 (5.4) years. Arterial elastance, a measure of arterial stiffness, was higher in DD (3.6±1.1 mm Hg/mL) compared with controls (2.5±0.8 mm Hg/mL), P <0.01. DD patients had lower predicted peak VO 2 compared with controls (52% [20] versus 67% [23], P <0.01). Physical FSS was lower in DD (45±13) and SD (44±13) compared with controls (50±7), P <0.01. Conclusions Fontan patients with abnormal diastolic function and normal EF have decreased exercise tolerance, decreased functional health status, and elevated arterial stiffness. Identification of patients at high risk for HFpEF is feasible and should be considered when evaluating Fontan patients.

Objective: Perinatal ischemic stroke is estimated to occur in 1/2300-1/5000 live births, but early differential diagnosis from global hypoxia-ischemia is often difficult. In this study, we tested the ability of a hand-held transcranial photoacoustic (PA) imaging probe to non-invasively detect a focal photothrombotic stroke (PTS) within 2 h of stroke onset in a gyrencephalic piglet brain., Approach: About 17 stroke lesions of approximately 1 cm 2 area were introduced randomly in anterior or posterior cortex via the light/dye PTS technique in anesthetized neonatal piglets ( n = 11). The contralateral non-ischemic region served as control tissue for discrimination contrast for the PA hemoglobin metrics: oxygen saturation, total hemoglobin (tHb), and individual quantities of oxygenated and deoxygenated hemoglobin (HbO 2 and HbR)., Main Results: The PA-derived tissue oxygen saturation at 2 h yielded a significant separation between control and affected regions-of-interest ( p < 0.0001), which were well matched with 24 h post-stroke cerebral infarction confirmed in the triphenyltetrazolium chloride-stained image. The quantity of HbO 2 also displayed a significant contrast ( p = 0.021), whereas tHb and HbR did not. The analysis on receiver operating characteristic curves and multivariate data analysis also agreed with the results above., Significance: This study shows that a hand-held transcranial PA neuroimaging device can detect a regional thrombotic stroke in the cerebral cortex of a neonatal piglet. In particular, we conclude that the oxygen saturation metric can be used alone to identify regional stroke lesions. The lack of change in tHb may be related to arbitrary hand-held imaging configuration and/or entrapment of red blood cells within the thrombotic stroke., (© 2022 IOP Publishing Ltd.)

A noninvasive monitor for concurrent evaluation of placental and fetal sagittal sinus sO 2 for both antepartum surveillance at the late 2nd and 3rd trimesters and intrapartum monitoring would be a great advantage over current methods. A PA fetal brain and placental monitor has potential value to rapidly identify the fetus at risk for developing hypoxia and ischemia of a sufficient degree that brain injury or death may develop, which may be prevented by intervention with delivery and other follow-up treatments., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: To determine the changes due to therapeutic hypothermia (TH) exposure in the strength of association between traditional clinical and biochemical indicators of severity of neonatal hypoxic-ischemic encephalopathy (HIE) and serum biomarkers. We hypothesized that culmination of TH changes the strength of the relationships between traditional indicators of severity of HIE and serum biomarkers. Methods: This was a single-center observational cohort study of 178 neonates with HIE treated with TH and followed with serum biomarkers: (i) brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF) (neurotrophins); (ii) tau and glial fibrillary acidic protein (GFAP) (neural cell injury); and (iii) interleukin 6 (IL-6), IL-8, and IL-10 (cytokines), during their first week of life. Adjusted mixed-effect models tested associations with HIE indicators in relation to TH exposure. Results: At admission, lower Apgar scores and base excess (BE) and higher lactate and nucleated red blood cell (NRBC) count correlated with higher Sarnat scores. These indicators of worse HIE severity, including higher Sarnat score, correlated with lower VEGF and higher tau, GFAP, and IL-10 levels at different time points. Within the first 24 h of life, patients with a Sarnat score >2 had lower VEGF levels, whereas only those with score of 3 also had higher GFAP and IL-10 levels. Tau levels increased during TH in patients with Sarnat score of 3, whereas tau and GFAP increased after TH in those with scores of 2. After adjustments, lower VEGF levels during TH and higher tau, GFAP, and IL-10 levels during and after TH were associated with worse Sarnat scores. Tau and GFAP relationship with Sarnat score became stronger after TH. Conclusion: Therapeutic hypothermia exerts an independent modulatory effect in the relationships between traditional indicators of severity of HIE and serum biomarkers after adjustments. Thus, the timing of biomarker testing in relation to TH exposure must be carefully considered if biomarkers are proposed for patient stratification in novel clinical trials., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Chavez-Valdez, Miller, Spahic, Vaidya, Parkinson, Dietrick, Brooks, Gerner, Tekes, Graham, Northington and Everett.)

Introduction: Leadership positions occupied by women within academic emergency medicine have remained stagnant despite increasing numbers of women with faculty appointments. We distributed a multi-institutional survey to women faculty and residents to evaluate categorical characteristics contributing to success and differences between the two groups., Methods: An institutional review board-approved electronic survey was distributed to women faculty and residents at eight institutions and were completed anonymously. We created survey questions to assess multiple categories: determination; resiliency; career support and obstacles; career aspiration; and gender discrimination. Most questions used a Likert five-point scale. Responses for each question and category were averaged and deemed significant if the average was greater than or equal to 4 in the affirmative, or less than or equal to 2 in the negative. We calculated proportions for binary questions., Results: The overall response rate was 55.23% (95/172). The faculty response rate was 54.1% (59/109) and residents' response rate was 57.1% (36/63). Significant levels of resiliency were reported, with a mean score of 4.02. Childbearing and rearing were not significant barriers overall but were more commonly reported as barriers for faculty over residents (P <0.001). Obstacles reported included a lack of confidence during work-related negotiations and insufficient research experience. Notably, 68.4% (65/95) of respondents experienced gender discrimination and 9.5% (9/95) reported at least one encounter of sexual assault by a colleague or supervisor during their career., Conclusion: Targeted interventions to promote female leadership in academic emergency medicine include coaching on negotiation skills, improved resources and mentorship to support research, and enforcement of safe work environments. Female emergency physician resiliency is high and not a barrier to career advancement.

Background: Corticosteroids suppress the inflammatory response to cardiopulmonary bypass in children undergoing cardiac surgery. What is less clear is the impact of corticosteroids on the postoperative course., Methods: A systematic review and meta-analysis was made of prospective randomized blinded placebo-controlled trials of pediatric patients who received corticosteroids or saline placebo before surgery was performed. Ten studies met inclusion criteria for a total of 768 patients. In a prespecified subgroup analysis, studies that either were limited to The Society of Thoracic Surgeons-European Association for Cardio-Thoracic Surgery congenital heart surgery mortality categories 1 and 2 or excluded neonates were eliminated and a secondary analysis was conducted, which consisted of seven studies and 555 patients., Results: Corticosteroids were associated with a significant improvement in fluid balance at 24 and 36 hours after surgery, with a mean difference of -15.2 mL/kg (95% confidence interval, 25.3 to -5.1 mL/kg; P < .01) and -5.7 mL/kg (95% confidence interval, -9.8 to -1.6 mL/kg; P < .01), respectively. Corticosteroids had no impact on the incidence of infection or mortality. With the secondary analysis, corticosteroids were associated with a trend toward significance in shortening the duration of mechanical ventilation (mean difference -0.7 days; 95% confidence interval, -1.7 to 0.1; P = .08)., Conclusions: Corticosteroids were found to have a favorable impact on postoperative fluid balance and may be associated with shortening the duration of mechanical ventilation. Although corticosteroids had no impact on mortality, they may be beneficial particularly for neonates and patients undergoing highly complex surgery., (Copyright © 2021 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Introduction: The efficacy of a specialized pediatric cardiac rapid response team is unknown. We hypothesized that a specialized cardiac rapid response team would facilitate team-wide communication between the cardiac stepdown unit and cardiac intensive care unit (ICU) teams and improve patient care., Materials and Methods: A specialized pediatric cardiac rapid response team was implemented in June 2015. All pediatric cardiac rapid response team activations and outcomes from implementation through December 2018 were reviewed. Cardiac arrests and unplanned transfers to the cardiac ICU were indexed to 1000 patient-days to account for inpatient volume trends and evaluated over time., Results: There were 202 cardiac rapid response team activations in 108 unique patients during the study period. After implementation of the pediatric cardiac rapid response team, unplanned transfers from the cardiac stepdown unit to the cardiac ICU decreased from 16.8 to 7.1 transfers per 1000 patient days (p = 0.012). The stepdown unit cardiac arrest rate decreased from 1.2 to 0.0 arrests per 1000 patient-days (p = 0.015). There was one death on the cardiac stepdown unit in the 5 years since the implementation of the cardiac rapid response team, compared to four deaths in the previous 5 years., Conclusions: A reduction in unplanned cardiac ICU transfers, cardiac arrests, and mortality on the cardiac stepdown unit has been observed since the implementation of a specialized pediatric cardiac rapid response team. A specialized cardiac rapid response team may improve communication and empower the interdisciplinary care team to escalate care for patients experiencing clinical decline.

Objective: To determine if blood biomarkers measured at delivery and shortly after birth can identify growth-restricted infants at risk for developing severe brain injury., Study Design: In a cohort of very low birth weight neonates, fetal growth restricted (FGR) (birth weight <10%) were compared to non-FGR neonates, and within the FGR group those with brain injury were compared to those without. Biomarkers were measured in cord blood at delivery, and daily for the 1st 5 days of life., Result: FGR was associated with significantly higher levels of interleukin (IL)-6, IL-8, IL-10, and lower levels of vascular endothelial growth factor (VEGF). FGR and brain injury were associated with significantly higher levels of IL-6, IL-8, IL-10, and glial fibrillary acidic protein (GFAP)., Conclusion: Interleukins may be involved in a common pathway contributing to both the development of growth restriction and brain injury, and GFAP may help identify brain injury within this growth-restricted group., (© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Clefts of the lip and/or palate are the most prevalent orofacial birth defects occurring in about 1:700 live human births worldwide. Early postnatal surgical interventions are extensive and staged to bring about optimal growth and fusion of palatal shelves. Severe cleft defects pose a challenge to correct with surgery alone, resulting in complications and sequelae requiring life-long, multidisciplinary care. Advances made in materials science innovation, including scaffold-based delivery systems for precision tissue engineering, now offer new avenues for stimulating bone formation at the site of surgical correction for palatal clefts. In this study, we review the present scientific literature on key developmental events that can go awry in palate development and the common surgical practices and challenges faced in correcting cleft defects. How key osteoinductive pathways implicated in palatogenesis inform the design and optimization of constructs for cleft palate correction is discussed within the context of translation to humans. Finally, we highlight new osteogenic agents and innovative delivery systems with the potential to be adopted in engineering-based therapeutic approaches for the correction of palatal defects. Impact statement Tissue-engineered scaffolds supplemented with osteogenic growth factors have attractive, largely unexplored possibilities to modulate molecular signaling networks relevant to driving palatogenesis in the context of congenital anomalies (e.g., cleft palate). Constructs that address this need may obviate current use of autologous bone grafts, thereby avoiding donor-site morbidity and other regenerative challenges in patients afflicted with palatal clefts. Combinations of biomaterials and drug delivery of diverse regenerative cues and biologics are currently transforming strategies exploited by engineers, scientists, and clinicians for palatal cleft repair.

Objective: To determine if neonatal serum biomarkers representing different pathways of injury differ for cases of HIE of unknown cause to gain insight into timing and mechanism of injury., Study Design: In this cohort of all neonates with HIE admitted to our NICU, newborns with sentinel events were compared to those without during the 1st 3 days of life. Discard neonatal blood during the 1st 3 days of life was used for analysis., Results: Of 277 babies with HIE treated with whole-body hypothermia, 190 (68.6%) had blood available for biomarker analysis. In total, 71 (37.4%) were born within our system, and 119 (62.6%) were transferred in from outside hospitals. Of these babies, 77 (40.5%) had a sentinel event and 113 (59.6%) had no sentinel event. Although the degree of metabolic acidosis was similar, repeated measures analysis showed that during the initial 3 days of life neonates born with HIE in the absence of sentinel events had 41.4% decreased VEGF (p = 0.027) and 62.5% increased IL-10 serum concentrations (p = 0.005)., Conclusion: These changes indicate that neonatal HIE in the absence of sentinel events is not related to an unrecognized acute intrapartum event and is possibly related to chronic hypoxia of lower severity or recovery from a remote event.

Background: Many factors affect outcomes after congenital cardiac surgery., Objectives: The RLS (Residual Lesion Score) study explored the impact of severity of residual lesions on post-operative outcomes across operations of varying complexity., Methods: In a prospective, multicenter, observational study, 17 sites enrolled 1,149 infants undergoing 5 common operations: tetralogy of Fallot repair (n = 250), complete atrioventricular septal defect repair (n = 249), arterial switch operation (n = 251), coarctation or interrupted arch with ventricular septal defect (VSD) repair (n = 150), and Norwood operation (n = 249). The RLS was assigned based on post-operative echocardiography and clinical events: RLS 1 (trivial or no residual lesions), RLS 2 (minor residual lesions), or RLS 3 (reintervention for or major residual lesions before discharge). The primary outcome was days alive and out of hospital within 30 post-operative days (60 for Norwood). Secondary outcomes assessed post-operative course, including major medical events and days in hospital., Results: RLS 3 (vs. RLS 1) was an independent risk factor for fewer days alive and out of hospital (p ≤ 0.008) and longer post-operative hospital stay (p ≤ 0.02) for all 5 operations, and for all secondary outcomes after coarctation or interrupted arch with VSD repair and Norwood (p ≤ 0.03). Outcomes for RLS 1 versus 2 did not differ consistently. RLS alone explained 5% (tetralogy of Fallot repair) to 20% (Norwood) of variation in the primary outcome., Conclusions: Adjusting for pre-operative factors, residual lesions after congenital cardiac surgery impacted in-hospital outcomes across operative complexity with greatest impact following complex operations. Minor residual lesions had minimal impact. These findings may provide guidance for surgeons when considering short-term risks and benefits of returning to bypass to repair residual lesions., Competing Interests: Funding Support and Author Disclosures This study was supported by grants (U24HL135691, U10HL068270, HL109818, HL109778, HL109816, HL109743, HL109741, HL109673, HL068270, HL109781, HL135665, HL135680) from the National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH). Drs. Nathan and Anderson were supported by K23 grants (NHLBI/NIH HL119600and HL133454, respectively). The views expressed in this paper are those of the authors and do not necessarily represent the views of the NHLBI, NIH, or U.S. Department of Health and Human Services. The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 American College of Cardiology Foundation. All rights reserved.)

Jane Austen died 200 years ago at the age of 41 and authors have attributed her premature death to a wide variety of causes, which include Addison's disease and lymphoma.We have reviewed all of her available letters and extricated relevant medical information which reveal rheumatism, facial skin lesions, fever and marked fluctuation of these symptoms. The severity of these symptoms increased, leading to her death within a year.This range of clinical features fulfils the most recent classification criteria for systemic lupus erythematosus.

Repurposing biological samples collected for required diagnostic purposes into suitable biobanking projects is a particularly useful method for enabling research in vulnerable populations. This approach is especially appropriate for the neonate in the neonatal intensive care unit (NICU), where blood volume reductions can quickly increase beyond minimal risk for adverse events, such as iatrogenic anemia, and proxy consent provided by parents or guardians is required. The method described in this study provides a framework to prospectively collect and store blood-derived clinical samples after all clinical and regulatory requirements are fulfilled. The consent approach incorporated a 30-day window to allow parents and guardians ample consideration time with follow-up involvement with NICU embedded study team members. The study enrolled 875 participants over a 3-year period. This established a critically needed biobank to support investigator-initiated research with explicit study aims requiring samples at defined day of life frequencies within the NICU and created a normative control reference bank for case comparisons for premature and full-term neonates with brain injury.

Partial hand amputations are the most common upper extremity amputations and affect individuals across a spectrum of socioeconomic and geographic backgrounds. Prosthetic devices can provide straightforward solutions to the devastating aesthetic, functional, psychological, and social deficits caused by these injuries. However, because of the recent development of multiple partial hand prosthetic devices, many hand providers remain unaware of their applicability in practice. This article highlights the various classes of partial hand prostheses currently available, including passive functional, body-powered, and externally powered options. Familiarity with these partial hand prostheses will better enable providers to care for partial hand amputees., Competing Interests: Disclosure D.J. Atkins is a former consultant at Össur and Touch Bionics. C.C. Duncan is partially funded by a National Science Foundation grant. S.D. Mendenhall is a consultant for PolyNovo. The other authors have no disclosures., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The discovery of multi-species synchronous spawning of scleractinian corals on the Great Barrier Reef in the 1980s stimulated an extraordinary effort to document spawning times in other parts of the globe. Unfortunately, most of these data remain unpublished which limits our understanding of regional and global reproductive patterns. The Coral Spawning Database (CSD) collates much of these disparate data into a single place. The CSD includes 6178 observations (3085 of which were unpublished) of the time or day of spawning for over 300 scleractinian species in 61 genera from 101 sites in the Indo-Pacific. The goal of the CSD is to provide open access to coral spawning data to accelerate our understanding of coral reproductive biology and to provide a baseline against which to evaluate any future changes in reproductive phenology.

For secondary alveolar bone grafting in cleft patients, the success of bone graft take is dependent upon creating an ideal environment for both bony and soft tissue healing. This is particularly challenging in patients with existing fistulas, wide clefts, and bilateral alveolar clefts, where large soft tissue mobilization is required to get a tensionless repair, and micro-motion around the bone graft is significantly higher. Herein we describe our method for manufacture and placement of a custom postoperative maxillary splint following secondary alveolar bone grafting. Our splint encompasses the palate and alveolus to stabilize the maxillary arch and protect the incision lines during healing. We find our splint to be a useful adjunct to facilitate postoperative healing following secondary alveolar bone grafting., (Copyright © 2020 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of The American Society of Plastic Surgeons.)

The craniofacial region comprises the most complex and intricate anatomical structures in the human body. As a result of developmental defects, traumatic injury, or neoplastic tissue formation, the functional and aesthetic intricacies of the face and cranium are often disrupted. While reconstructive techniques have long been innovated in this field, there are crucial limitations to the surgical restoration of craniomaxillofacial form and function. Fortunately, the rise of regenerative medicine and surgery has expanded the possibilities for patients affected with hard and soft tissue deficits, allowing for the controlled engineering and regeneration of patient-specific defects. In particular, stem cell therapy has emerged in recent years as an adjuvant treatment for the targeted regeneration of craniomaxillofacial structures. This review outlines the current state of the art in stem cell therapies utilized for the engineered restoration and regeneration of skeletal defects in the craniofacial region.

Background:  The aim of this study was to compare postoperative elbow flexion outcomes in patients receiving functioning free muscle transplantation (FFMT) innervated by either intercostal nerve (ICN) or spinal accessory nerve (SAN) grafts., Methods:  A comprehensive systematic review on FFMT for brachial plexus reconstruction was conducted utilizing Medline/PubMed database. Analysis was designed to compare functional outcomes between (1) nerve graft type (ICN vs. SAN) and (2) different free muscle graft types to biceps tendon (gracilis vs. rectus femoris vs. latissimus dorsi)., Results:  A total of 312 FFMTs innervated by ICNs (169) or the SAN (143) are featured in 10 case series. The mean patient age was 28 years. Patients had a mean injury to surgery time of 31.5 months and an average follow-up time of 39.1 months with 18 patients lost to follow-up. Muscles utilized included the gracilis (275), rectus femoris (28), and latissimus dorsi (8). After excluding those lost to follow-up or failures due to vascular compromise, the mean success rates of FFMTs innervated by ICNs and SAN were 64.1 and 65.4%, respectively., Conclusion:  This analysis did not identify any difference in outcomes between FFMTs via ICN grafts and those innervated by SAN grafts in restoring elbow flexion in traumatic brachial plexus injury patients., Competing Interests: None declared., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Objectives: Early extubation following pediatric cardiac surgery is common, but debate exists whether location affects outcome, with some centers performing routine early extubations in the operating room (odds ratio) and others in the cardiac ICU. We aimed to define early extubation practice variation across hospitals and assess impact of location on hospital length-of-stay and other outcomes., Design: Secondary analysis of the Pediatric Cardiac Critical Care Consortium registry., Setting: Twenty-eight Pediatric Cardiac Critical Care Consortium hospitals., Patients: Patients undergoing Society of Thoracic Surgeons-European Association for Cardio-Thoracic Surgery mortality category 1-3 operations between August 2014 and February 2018., Interventions: None., Measurements and Main Results: We defined early extubation as extubation less than 6 hours after postoperative admission. Hospitals were categorized based on the proportion of their early extubation patients who underwent an odds ratio extubation. Categories included low- (< 50% of early extubation, n = 12), medium- (50%-90%, n = 8), or high- (> 90%, n = 8) frequency odds ratio early extubation centers. The primary outcome of interest was postoperative hospital length-of-stay. We analyzed 16,594 operations (9,143 early extubation, 55%). Rates of early extubation ranged from 16% to 100% across hospitals. Odds ratio early extubation rates varied from 16% to 99%. Patient characteristics were similar across hospital odds ratio early extubation categories. Early extubation rates paralleled the hospital odds ratio early extubation rates-77% patients underwent early extubation at high-frequency odds ratio extubation centers compared with 39% at low-frequency odds ratio extubation centers (p < 0.001). High- and low-frequency odds ratio early extubation hospitals had similar length-of-stay, cardiac arrest rates, and low mortality. However, high-frequency odds ratio early extubation hospitals used more noninvasive ventilation than low-frequency hospitals (15% vs. 9%; p < 0.01), but had fewer extubation failures (3.6% vs. 4.5%; p = 0.02)., Conclusions: Considerable variability exists in early extubation practices after low- and moderate-complexity pediatric cardiac surgery. In this patient population, hospital length-of-stay did not differ significantly between centers with different early extubation strategies based on location or frequency.

Objective: To assess the additional benefits of 17-hydroxyprogesterone caproate (17-OHPC) therapy in preventing recurrent spontaneous preterm birth in women with an ultrasound-indicated cerclage. Methods: Electronic databases (Medline, Scopus, ClinicalTrials.gov, PROSPERO, Embase, Scielo, and the Cochrane Central Register of Controlled Trials) were searched for studies published before September 2018. Keywords included "preterm birth", "ultrasound-indicated cerclage", "pregnancy" and "17-hydroxyprogesterone caproate". Studies comparing ultrasound-indicated cerclage alone to cerclage plus 17-OHPC were included. The primary outcome measure was preterm birth at <35 weeks of gestation. Secondary outcome measures include preterm birth <24 weeks, <28 weeks, <32 weeks and <37 weeks of gestation, necrotizing enterocolitis (NEC), fetal birth weight, and intraventricular hemorrhage (grades III and IV). Meta-analysis was performed using the random effects model of DerSimonian and Laird. Risk of bias and quality assessment was performed using the risk of bias in nonrandomized studies of interventions (ROBINS-I). Results: Four studies met inclusion criteria and were included in the final analysis. Of the 396 women who received ultrasound-indicated cerclage, 142 (35.9%) received adjuvant 17-OHPC. The primary outcome, preterm birth <35 weeks of gestation, was present in three studies and 332/396 singleton pregnancies. Though there was a trend towards a reduced risk of preterm birth, the summary estimate of effect was not statistically significant when comparing cerclage alone to cerclage plus 17-OHPC at <35 weeks (relative risk (RR) 0.95, 95% CI 0.77-1.17). Similarly, we found no differences in preterm birth at <24 weeks (RR 0.30, 95% CI 0.06-1.60), <28 weeks (RR 0.57, 95% CI 0.13-2.53), and <32 weeks (RR 0.99, 95% CI 0.44-2.27) when comparing cerclage alone to cerclage plus 17-OHPC. There were no differences in fetal birth weight, intraventricular hemorrhage and necrotizing enterocolitis comparing cerclage alone to cerclage plus 17-OHPC. Conclusion: Intramuscular 17-OHPC in combination with ultrasound-indicated cerclage in women with prior preterm birth had no additional effect in reducing spontaneous recurrent preterm birth or improving perinatal outcomes.

Background: Randomized controlled trials (RCTs) in children with heart disease are challenging and therefore infrequently performed. We sought to improve feasibility of perioperative RCTs for this patient cohort using data from a large, multicenter clinical registry. We evaluated potential enrollment and end point frequencies for various inclusion cohorts and developed a novel global rank trial end point. We then performed trial simulations to evaluate power gains with the global rank end point and with use of planned covariate adjustment as an analytic strategy., Methods: Data from the Society of Thoracic Surgery-Congenital Heart Surgery Database (STS-CHSD, 2011-2016) were used to support development of a consensus-based global rank end point and for trial simulations. For Monte Carlo trial simulations (n = 50,000/outcome), we varied the odds of outcomes for treatment versus placebo and evaluated power based on the proportion of trial data sets with a significant outcome (P < .05)., Results: The STS-CHSD study cohort included 35,967 infant index cardiopulmonary bypass operations from 103 STS-CHSD centers, including 11,411 (32%) neonatal cases and 12,243 (34%) high-complexity (Society of Thoracic Surgeons-European Association for Cardio-Thoracic Surgery mortality category ≥4) cases. In trial simulations, study power was 21% for a mortality-only end point, 47% for a morbidity and mortality composite, and 78% for the global rank end point. With covariate adjustment, power increased to 94%. Planned covariate adjustment was preferable to restricting to higher-risk cohorts despite higher event rates in these cohorts., Conclusions: Trial simulations can inform trial design. Our findings, including the newly developed global rank end point, may be informative for future perioperative trials in children with heart disease., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objectives: Current central venous catheter utilization in patients within pediatric cardiac ICUs is not well elucidated. We aim to describe current use of central venous catheters in a multi-institutional cohort and to explore the prevalence and risk factors for central line-associated thrombosis and central line-associated bloodstream infections., Design: Observational analysis., Setting: Pediatric Cardiac Critical Care Consortium hospitals., Patients: Hospitalizations with at least one cardiac ICU admission from October 2013 to July 2016., Interventions: None., Measurements and Main Results: There were 17,846 hospitalizations and 69% included greater than or equal to one central venous catheter. Central venous catheter use was higher in younger patients (86% neonates). Surgical hospitalizations included at least one central venous catheter 88% of the time compared with 35% of medical hospitalizations. The most common location for central venous catheters was internal jugular (46%). Central venous catheters were in situ a median of 4 days (interquartile range, 2-10). There were 248 hospitalizations (2% overall, 1.8% medical, and 2.1% surgical) with at least one central line-associated thrombosis (271 total thromboses). Thrombosis was diagnosed at a median of 7 days (interquartile range, 4-14) after catheter insertion. There were 127 hospitalizations (1% overall, 1.4% medical, and 1% surgical) with at least one central line-associated bloodstream infection (136 total infections) with no association with catheter type or location. Central line-associated bloodstream infection was diagnosed at a median of 19 days (interquartile range, 8-36) after catheter insertion. Significant risk factors for central line-associated thrombosis and central line-associated bloodstream infection were younger age, greater surgical complexity, and total catheter days., Conclusions: Utilization of central venous catheters in pediatric cardiac ICUs differs according to indication for hospitalization. Although thrombosis and central line-associated bloodstream infection are infrequent complications of central venous catheter use in cardiac ICU patients, these events can have important short- and long-term consequences for patients. Total central venous catheter line days were the only modifiable risk factor identified. Future study must focus on understanding central venous catheter practices in high-risk patient subgroups that reduce the prevalence of thrombosis and central line-associated bloodstream infection.

Importance: Cyclohexanone is an industrial solvent used as a coupling agent in medical plastics. Perioperative exposure to cyclohexanone could play a role in lower scores on measures of neurodevelopmental outcomes after neonatal cardiac operations., Objective: To examine the presence and association of serum cyclohexanone level with neonatal cardiac operations and neurodevelopmental outcomes., Design, Setting, and Participants: This ad hoc secondary analysis used data from the Corticosteroid Therapy in Neonates Undergoing Cardiopulmonary Bypass randomized clinical trial. The cohort included neonates younger than 31 days and with at least 37 weeks postgestational age at surgical treatment who were enrolled at a single center between June 1, 2012, and October 31, 2016, and who had completed a neurodevelopmental assessment at age 12 months. Data were analyzed from July 8 to August 20, 2019., Exposures: Serum cyclohexanone and its metabolites were measured preoperatively (prior to skin incision), postoperatively (immediately after the surgical procedure was completed), and 12 hours postoperatively. Cyclohexanone and the molar sum of its metabolites were examined at each point and as a geometric mean of all 3 points., Main Outcomes and Measures: Neurodevelopment was assessed at age 12 months with the Bayley Scales of Infant and Toddler Development III, assessing cognitive, language, and motor function composite scores standardized to a population mean (SD) of 100 (15). Linear regression models were used to determine covariate-adjusted differences in 12-month cognitive, language, and motor composite scores per interquartile range increase in cyclohexanone level or summed metabolite molar concentrations., Results: Among 85 included neonates, mean (SD) age at surgical treatment was 9.7 (5.3) days, 49 (58%) were boys, and 54 (64%) underwent corrective repair. Mean (SD) Bayley Scales of Infant and Toddler Development III composite scores were 108.2 (12.2) for cognitive function, 104.7 (11.0) for language function, and 94.7 (15.7) for motor function. Median (interquartile range) cyclohexanone levels increased approximately 3-fold from immediately prior to surgical treatment to immediately after surgical treatment (572 [389-974] vs 1744 [1469-2291] μg/L; P = .001). In adjusted analyses, higher geometric mean cyclohexanone levels were associated with significantly lower composite scores for cognitive (-4.23; 95% CI, -7.39 to -1.06; P = .01) and language (-3.65; 95% CI, -6.41 to -0.88; P = .01) function. The difference in composite scores for motor function among infants with higher geometric mean cyclohexanone levels was not statistically significant(-3.93, 95% CI: -8.19 to 0.33, P = .07)., Conclusions and Relevance: The findings of this secondary analysis of a randomized clinical trial suggest that infants who underwent neonatal cardiac surgical treatment with cardiopulmonary bypass had substantial cyclohexanone levels, which were associated with adverse neurodevelopmental function at age 12 months., Trial Registration: ClinicalTrials.gov identifier: NCT01579513.

Thyroid hormone modifies metabolic, immune and cardiovascular functions and has been administered perioperatively to treat a relative reduction of thyroid function in children following cardiopulmonary bypass (CPB) for correction of congenital heart disease. However, it remains unclear whether its use is associated with improved outcomes. We performed a meta-analysis of studies that evaluated the impact of thyroid hormone supplementation on clinical outcomes in children undergoing repair of congenital heart disease using CPB. A systematic review of published trials was conducted to identify studies of children randomized to thyroid hormone supplementation or placebo undergoing congenital heart surgery. A meta-analysis was then conducted to determine the clinical impact of thyroid hormone replacement on cardiac function and postoperative characteristics. The following outcomes were included for the study: duration of mechanical ventilation, duration of intensive care unit (ICU) stay, duration of postoperative hospital stay, inotrope score, cardiac index at 24 hours postoperatively, and inpatient mortality. A total of 9 studies with 711 patients were included in the analyses. All included studies were prospective and patients were randomized to either thyroid hormone or placebo. There was wide variation in thyroid hormone dosing, ranging from 0.4 μg/kg up to 5 μg/kg over a 24-hour period, and duration of therapy, ranging from a single dose after cessation of CPB to continued thyroid hormone for the duration of the ICU stay. There was a significant difference in the mean inotrope score between the 2 groups of -1.249 (95% confidence interval -1.570 to -0.929, P < 0.001), with the inotrope score being significantly lower in the thyroid group. There was no difference in duration of mechanical ventilation, duration of ICU stay, duration of hospital stay, cardiac index, and mortality between groups. In this meta-analysis, routine thyroid hormone replacement with approximately 1-5 μg/kg administered over 24 hours does not significantly alter the postoperative course in children following CPB. However, given a clinically small but significant difference in respect to lower inotrope score and shorter duration of ICU and hospital stays with higher thyroid replacement additional studies are warranted., (Copyright © 2019 Elsevier Inc. All rights reserved.)

For decades, physicians have administered corticosteroids in the perioperative period to infants undergoing heart surgery with cardiopulmonary bypass (CPB) to reduce the postoperative systemic inflammatory response to CPB. Some question this practice because steroid efficacy has not been conclusively demonstrated and because some studies indicate that steroids could have harmful effects. STRESS is a randomized, placebo-controlled, double-blind, multicenter trial designed to evaluate safety and efficacy of perioperative steroids in infants (age < 1 year) undergoing heart surgery with CPB. Participants (planned enrollment = 1,200) are randomized 1:1 to methylprednisolone (30 mg/kg) administered into the CPB pump prime versus placebo. The trial is nested within the existing infrastructure of the Society of Thoracic Surgeons Congenital Heart Surgery Database. The primary outcome is a global rank score of mortality, major morbidities, and hospital length of stay with components ranked commensurate with their clinical severity. Secondary outcomes include several measures of major postoperative morbidity, postoperative hospital length of stay, and steroid-related safety outcomes including prevalence of hyperglycemia and postoperative infectious complications. STRESS will be one of the largest trials ever conducted in children with heart disease and will answer a decades-old question related to safety and efficacy of perioperative steroids in infants undergoing heart surgery with CPB. The pragmatic "trial within a registry" design may provide a mechanism for conducting low-cost, high-efficiency trials in a heretofore-understudied patient population., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Methylprednisolone is used in neonates to modulate cardiopulmonary bypass (CPB)-induced inflammation, but optimal dosing and exposure are unknown. We used plasma methylprednisolone and interleukin (IL)-6 and IL-10 concentrations from neonates enrolled in a randomized trial comparing one vs. two doses of methylprednisolone to develop indirect response population pharmacokinetic/pharmacodynamic models characterizing the exposure-response relationships. We applied the models to simulate methylprednisolone dosages resulting in the desired IL-6 and -10 exposures, known mediators of CPB-induced inflammation. A total of 64 neonates (median weight 3.2 kg, range 2.2-4.3) contributed 290 plasma methylprednisolone concentrations (range 1.07-12,700 ng/mL) and IL-6 (0-681 pg/mL) and IL-10 (0.1-1125 pg/mL). Methylprednisolone plasma exposure following a single 10 mg/kg intravenous dose inhibited IL-6 and stimulated IL-10 production when compared with placebo. Higher (30 mg/kg) or more frequent (twice) dosing did not confer additional benefit. Clinical efficacy studies are needed to evaluate the effect of optimized dosing on outcomes., (© 2019 The Authors. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of the American Society for Clinical Pharmacology and Therapeutics.)

Objectives: Acute kidney injury is a frequent complication following neonatal cardiac surgery and is associated with significant morbidity and mortality. The objectives of this study were to determine if plasma neutrophil gelatinase-associated lipocalin levels were associated with acute kidney injury and clinical outcomes in neonates with congenital heart disease undergoing cardiopulmonary bypass., Design: Retrospective single-center observational study., Setting: A pediatric cardiac ICU within a tertiary-care academic hospital., Patients: Patients age less than 30 days undergoing cardiac surgery requiring cardiopulmonary bypass., Interventions: None., Measurements and Main Results: Plasma neutrophil gelatinase-associated lipocalin peaked at 12 hours postcardiopulmonary bypass and more than doubled compared with preoperative levels. Higher preoperative and 24-hour postoperative neutrophil gelatinase-associated lipocalin levels were associated with acute kidney injury (r = 0.30, r = 0.49), longer duration of mechanical ventilation (r = 0.40, r = 0.51), ICU (r = 0.32, r = 0.33) and hospital lengths of stay (r = 0.28, r = 0.32), and total hospital charges (r = 0.35, r = 0.30; all p values < 0.05)., Conclusions: Both preoperative and 24-hour postoperative plasma neutrophil gelatinase-associated lipocalin levels are associated with acute kidney injury and worse clinical outcomes in neonates undergoing cardiac surgery. Plasma neutrophil gelatinase-associated lipocalin levels may have a role in risk stratification for predicting postoperative renal dysfunction as well as providing a potential clinical trajectory in the postoperative period.