Publications by authors named "David Zurakowski"

870 Publications

rAAV-Mediated Overexpression Improves the Repair of Osteochondral Defects in a Clinically Relevant Large Animal Model Over Time In Vivo and Reduces Perifocal Osteoarthritic Changes.

Am J Sports Med 2021 Oct 13:3635465211049414. Epub 2021 Oct 13.

Center of Experimental Orthopaedics, Saarland University Medical Center, Homburg, Germany.

Background: Gene transfer of the transcription factor SOX9 with clinically adapted recombinant adeno-associated virus (rAAV) vectors offers a powerful tool to durably enhance the repair process at sites of osteochondral injuries and counteract the development of perifocal osteoarthritis (OA) in the adjacent articular cartilage.

Purpose: To examine the ability of an rAAV construct to improve the repair of focal osteochondral defects and oppose perifocal OA development over time in a large translational model relative to control gene transfer.

Study Design: Controlled laboratory study.

Methods: Standardized osteochondral defects created in the knee joints of adult sheep were treated with rAAV-FLAG-h relative to control (reporter) rAAV- gene transfer. Osteochondral repair and degenerative changes in the adjacent cartilage were monitored using macroscopic, histological, immunohistological, and biochemical evaluations after 6 months. The microarchitecture of the subchondral bone was assessed by micro-computed tomography.

Results: Effective, prolonged overexpression via rAAV was significantly achieved in the defects after 6 months versus rAAV- treatment. The application of rAAV-FLAG-h improved the individual parameters of defect filling, matrix staining, cellular morphology, defect architecture, surface architecture, subchondral bone, and tidemark as well as the overall score of cartilage repair in the defects compared with rAAV-. The overexpression of led to higher levels of proteoglycan production, stronger type II collagen deposition, and reduced type I collagen immunoreactivity in the - versus -treated defects, together with decreased cell densities and DNA content. rAAV-FLAG-h enhanced semiquantitative histological subchondral bone repair, while the microstructure of the incompletely restored subchondral bone in the defects was not different from that in the defects. The articular cartilage adjacent to the -treated defects showed reduced histological signs of perifocal OA changes versus rAAV-.

Conclusion: rAAV-mediated gene transfer enhanced osteochondral repair in sheep after 6 months and reduced perifocal OA changes. These results underline the potential of rAAV-FLAG-h as a therapeutic tool to treat cartilage defects and afford protection against OA.

Clinical Relevance: The delivery of therapeutic rAAV to sites of focal injuries may offer a novel, convenient tool to enhance the repair of osteochondral defects involving both the articular cartilage and the underlying subchondral bone and provide a protective role by reducing the extent of perifocal OA.
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http://dx.doi.org/10.1177/03635465211049414DOI Listing
October 2021

Rhythmic Change of Cortical Hemodynamic Signals Associated with Ongoing Nociception in Awake and Anesthetized Individuals: An Exploratory Functional Near Infrared Spectroscopy Study.

Anesthesiology 2021 Nov;135(5):877-892

From the Center for Pain and the Brain, Harvard Medical School, Boston, Massachusetts; Boston Children's Hospital, and Department of Psychiatry and Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.

Background: Patients undergoing surgical procedures are vulnerable to repetitive evoked or ongoing nociceptive barrage. Using functional near infrared spectroscopy, the authors aimed to evaluate the cortical hemodynamic signal power changes during ongoing nociception in healthy awake volunteers and in surgical patients under general anesthesia. The authors hypothesized that ongoing nociception to heat or surgical trauma would induce reductions in the power of cortical low-frequency hemodynamic oscillations in a similar manner as previously reported using functional magnetic resonance imaging for ongoing pain.

Methods: Cortical hemodynamic signals during noxious stimuli from the fontopolar cortex were evaluated in two groups: group 1, a healthy/conscious group (n = 15, all males) where ongoing noxious and innocuous heat stimulus was induced by a contact thermode to the dorsum of left hand; and group 2, a patient/unconscious group (n = 13, 3 males) receiving general anesthesia undergoing knee surgery. The fractional power of low-frequency hemodynamic signals was compared across stimulation conditions in the healthy awake group, and between patients who received standard anesthesia and those who received standard anesthesia with additional regional nerve block.

Results: A reduction of the total fractional power in both groups-specifically, a decrease in the slow-5 frequency band (0.01 to 0.027 Hz) of oxygenated hemoglobin concentration changes over the frontopolar cortex-was observed during ongoing noxious stimuli in the healthy awake group (paired t test, P = 0.017; effect size, 0.70), and during invasive procedures in the surgery group (paired t test, P = 0.003; effect size, 2.16). The reduction was partially reversed in patients who received a regional nerve block that likely diminished afferent nociceptive activity (two-sample t test, P = 0.002; effect size, 2.34).

Conclusions: These results suggest common power changes in slow-wave cortical hemodynamic oscillations during ongoing nociceptive processing in conscious and unconscious states. The observed signal may potentially promote future development of a surrogate signal to assess ongoing nociception under general anesthesia.

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http://dx.doi.org/10.1097/ALN.0000000000003986DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8511051PMC
November 2021

Impact of Cardiopulmonary Bypass on Neurogenesis and Cortical Maturation.

Ann Neurol 2021 Sep 29. Epub 2021 Sep 29.

Children's National Heart Institute, Center for Neuroscience Research, Sheikh Zayed Institute for Pediatric Surgical Innovation, Children's National Hospital, Washington, DC.

Objective: Neurodevelopmental delays and frontal lobe cortical dysmaturation are widespread among children with congenital heart disease (CHD). The subventricular zone (SVZ) is the largest pool of neural stem/progenitor cells in the postnatal brain. Our aim is to determine the effects of cardiopulmonary bypass (CPB) on neurogenesis and cortical maturation in piglets whose SVZ development is similar to human infants.

Methods: Three-week-old piglets (n = 29) were randomly assigned to control (no surgery), mild-CPB (34°C full flow for 60 minutes) and severe-CPB groups (25°C circulatory-arrest for 60 minutes). The SVZ and frontal lobe were analyzed with immunohistochemistry 3 days and 4 weeks postoperatively. MRI of the frontal lobe was used to assess cortical development.

Results: SVZ neurogenic activity was reduced up to 4 weeks after both mild and severe CPB-induced insults. CPB also induced decreased migration of young neurons to the frontal lobe, demonstrating that CPB impairs postnatal neurogenesis. MRI 4 weeks after CPB displayed a decrease in gyrification index and cortical volume of the frontal lobe. Cortical fractional anisotropy was increased after severe CPB injury, indicating a prolonged deleterious impact of CPB on cortical maturation. Both CPB-induced insults displayed a significant change in densities of three major inhibitory neurons, suggesting excitatory-inhibitory imbalance in the frontal cortex. In addition, different CPB insults altered different subpopulations of inhibitory neurons.

Interpretation: Our results provide novel insights into cellular mechanisms contributing to CHD-induced neurological impairments. Further refinement of CPB hardware and techniques is necessary to improve long-term frontal cortical dysmaturation observed in children with CHD. ANN NEUROL 2021.
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http://dx.doi.org/10.1002/ana.26235DOI Listing
September 2021

A role for abdominal ultrasound in discriminating suspected necrotizing enterocolitis in congenital heart disease patients.

Pediatr Surg Int 2021 Sep 28. Epub 2021 Sep 28.

Department of Surgery, Boston Children's Hospital/Harvard Medical School, 300 Longwood Avenue - Fegan 3, Boston, MA, 02115, USA.

Purpose: We evaluated the diagnostic utility of abdominal ultrasound (AUS), an adjunct to abdominal X-ray (AXR), for necrotizing enterocolitis (NEC) in congenital heart disease (CHD) patients.

Methods: 86 patients with suspected NEC from 2009 to 2018 were classified as with CHD (n = 18) if they required cardiac intervention versus without CHD (n = 68). Clinical and radiological data were collected, including AXR and AUS concordance. Wilcoxon rank-sum test and Fisher's exact test were performed.

Results: CHD patients had higher birth weights (p < 0.001) and gestational ages (p < 0.001) than non-CHD patients. CHD patients presented more frequently with hypotension (p = 0.041) and less frequently with bilious emesis (p < 0.001). Overall, CHD patients were less likely to have AUS findings of pneumatosis (33.3 vs. 72.1%; p = 0.005) and decreased mural flow (0 vs. 20.6%; p = 0.035) compared to non-CHD patients. On concordance analysis, CHD patients had 3.9-fold more discordant studies with pneumatosis on AXR but not on AUS (33.3 vs. 8.8%; p = 0.016) compared to non-CHD patients. Urgent surgery was required in 5.6% of CHD patients versus 16.2% of non-CHD patients.

Conclusion: CHD patients with suspected NEC represent a distinct clinical population. AUS has particular utility in assessing findings of bowel viability in the CHD NEC population, reflecting reduced rates of surgical NEC.
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http://dx.doi.org/10.1007/s00383-021-05025-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8477364PMC
September 2021

Comparing standard and non-standard videolaryngoscopes in children: methodological issues. Response to Br J Anaesth 2021; 127: e52-e4.

Br J Anaesth 2021 Nov 10;127(5):e172-e173. Epub 2021 Sep 10.

Department of Anesthesiology, Critical Care, and Pain Medicine, Boston Children's Hospital, Boston, MA, USA; Department of Anaesthesia, Harvard Medical School, Boston, MA, USA.

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http://dx.doi.org/10.1016/j.bja.2021.08.013DOI Listing
November 2021

Predictors of anti-reflux procedure failure in complex esophageal atresia patients.

J Pediatr Surg 2021 Aug 14. Epub 2021 Aug 14.

Department of General Surgery, Boston Children's Hospital, Boston, MA USA. Electronic address:

Background: Anti-reflux procedures (ARP) in esophageal atresia (EA) patients can be challenging and prone to failure. These challenges become more evident with increasing complexity of EA. We sought to determine predictors of ARP failure in complex EA patients.

Methods: Single-institution retrospective review of complex EA patients (e.g. long-gap EA, esophageal strictures, hiatal hernia, and reoperative ARP) who underwent an ARP from 2002 to 2019. ARP failure was defined as hiatal hernia recurrence, wrap migration/loosening, or need for reoperation. Predictors of failure were evaluated using univariate and multivariable time-to-event analysis.

Results: 121 patients underwent 140 ARP at a median age of 13.5 months (IQR 7, 26.5). Nissen fundoplication (89%) was the most common ARP. Mesh (bovine pericardium) reinforcement was used in 41% of the patients. Median follow-up was 3.2 years (IQR 0.9, 5.8); 44 instances of ARP failure occurred (31%), though only 20 (14%) required reoperation. Median time to failure was 8.7 months (IQR 3.2, 25). Though fewer mesh-reinforced ARP failed (21% with vs 39% without, p = 0.02), on multivariable analysis only partial fundoplication (aHR 2.22 [95% CI 1.01-4.78]) and minimally invasive repair (aHR 2.57 [95% CI 1.12-6.01]) were significant predictors of ARP failure.

Conclusion: In our practice of complex EA patients, where ARP fail in nearly one third of cases, a Nissen fundoplication performed via laparotomy provided the lowest risk of ARP failure.
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http://dx.doi.org/10.1016/j.jpedsurg.2021.08.005DOI Listing
August 2021

Unselected CD117 expression in amniotic and placental mesenchymal stem cells.

J Pediatr Surg 2021 Jul 31. Epub 2021 Jul 31.

Department of Surgery, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA. Electronic address:

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http://dx.doi.org/10.1016/j.jpedsurg.2021.07.022DOI Listing
July 2021

Predictors of Neurological Outcome Following Infant Cardiac Surgery Without Deep Hypothermic Circulatory Arrest.

Pediatr Cardiol 2021 Aug 17. Epub 2021 Aug 17.

Division of Pediatric Neurology, University of Maryland Medical Center, University of Maryland, School of Medicine, Baltimore, MD, 21201, USA.

The aim of this study is to describe the clinical characteristics, perioperative course and neuroimaging abnormalities of infants with congenital heart disease (CHD) undergoing heart surgery without deep hypothermic circulatory arrest (DHCA) and identify variables associated with neurological outcome. Infants with CHD undergoing open-heart surgery without DHCA between 2009 and 2017 were identified from a cardiac surgery database. Full-term infants < 10 weeks of age at the time of surgery who had both a pre- and postoperative brain magnetic resonance imaging exam (MRI) were included. Clinical characteristics and perioperative variables were collected from the electronic medical record. Brain Injury Scores (BIS) were assigned to pre- and postoperative brain MRIs. Variables were examined for association with neurological outcome at 12 months of age or greater. Forty-two infants were enrolled in the study, of whom 69% (n = 29) had a neurological assessment ≥ to 12 months of age. Adverse neurological outcome was associated with longer intensive care unit (ICU) stay (P = 0.003), lengthier mechanical ventilation (P = 0.031), modified Blalock-Taussig (MBT) shunt procedure (P = 0.005) and postoperative seizures (P = 0.005). Total BIS scores did not predict outcome but postoperative infarction and/or intraparenchymal hemorrhage (IPH) was associated with worse outcome by multivariable analysis (P = 0.018). Infants with CHD undergoing open-heart surgery without DHCA are at increased risk of worse neurological outcome when their ICU stay is prolonged, mechanical ventilation is extended, MBT shunt is performed or when postoperative seizures are present. Cerebral infarctions and IPH on postoperative MRI are also associated with worse outcome.
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http://dx.doi.org/10.1007/s00246-021-02693-zDOI Listing
August 2021

Nutrition delivery and growth outcomes in infants with long-gap esophageal atresia who undergo the Foker process.

J Pediatr Surg 2021 Jul 24. Epub 2021 Jul 24.

Department of Surgery, Boston Children's Hospital, 300 Longwood Avenue, Fegan 3, Boston, MA 02115, United States. Electronic address:

Background: Predictors of growth outcomes in patients with long-gap esophageal atresia (LGEA) are not known. We examined nutrition and growth in-hospital and post-discharge in LGEA patients who underwent the Foker Process (FP).

Methods: Single-center, retrospective cohort study of infants with LGEA undergoing primary (non-rescue) FP from 2014 to 2020. Weight-for-age z scores (WAZ, 0 = average), macronutrient prescription, anthropometry, and clinical variables were collected. Longitudinal median regression evaluated differences in WAZ over time. Multivariable median regression examined variables associated with change in WAZ at 1 year.

Results: 45 patients met criteria, with median (IQR) age at repair of 4 (2, 5.8) months and WAZ of -0.96 (-1.55, -0.40). On admission, 11% were moderately (WAZ < -2) and 9% were severely (WAZ < -3) malnourished. Lower admission WAZ was significantly associated with improvement in WAZ at 1-year follow-up (p = 0.002); EA type (59% type A), esophageal leak (16%), median days paralyzed (13), ventilated (21), on parenteral nutrition (35), or to full enteral nutrition (35) were not associated with change in WAZ. Median WAZ remained stable while in-hospital, and patients maintained their growth curves through 3-year follow-up.

Conclusion: Throughout infancy, most primary FP LGEA patients have weight for age that is below average. Using targeted nutritional intervention, those who present with malnutrition can still achieve adequate growth despite prolonged and complicated hospital courses.
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http://dx.doi.org/10.1016/j.jpedsurg.2021.07.014DOI Listing
July 2021

Statistical Development and Validation of Clinical Prediction Models.

Anesthesiology 2021 09;135(3):396-405

Summary: Clinical prediction models in anesthesia and surgery research have many clinical applications including preoperative risk stratification with implications for clinical utility in decision-making, resource utilization, and costs. It is imperative that predictive algorithms and multivariable models are validated in a suitable and comprehensive way in order to establish the robustness of the model in terms of accuracy, predictive ability, reliability, and generalizability. The purpose of this article is to educate anesthesia researchers at an introductory level on important statistical concepts involved with development and validation of multivariable prediction models for a binary outcome. Methods covered include assessments of discrimination and calibration through internal and external validation. An anesthesia research publication is examined to illustrate the process and presentation of multivariable prediction model development and validation for a binary outcome. Properly assessing the statistical and clinical validity of a multivariable prediction model is essential for reassuring the generalizability and reproducibility of the published tool.
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http://dx.doi.org/10.1097/ALN.0000000000003871DOI Listing
September 2021

Time to achieve delivery of nutrition targets is associated with clinical outcomes in critically ill children.

Am J Clin Nutr 2021 Jul 28. Epub 2021 Jul 28.

Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.

Background: Optimal nutrition in critically ill children involves a complex interplay between the doses, route, and timing of macronutrient delivery.

Objectives: We aimed to examine the association between the time to achieve delivery of 60% of the prescribed energy and protein targets and clinical outcomes in mechanically ventilated children.

Methods: We conducted a prospective, observational cohort study of mechanically ventilated children admitted to pediatric intensive care units (PICUs) worldwide. Daily energy and protein delivery were recorded for up to 10 d in the PICU. We calculated "adequacy" as the percentage of the prescribed energy or protein goal delivered by enteral nutrition (EN), parenteral nutrition (PN), and total nutrition (EN + PN). Based on the days required to reach 60% energy or protein adequacy after PICU admission, we categorized patients into 3 groups: early (≤3 d), pragmatic (4 to 7 d), and late (more than 7 d). The primary outcome was 60-d all-cause mortality; secondary outcomes were the incidence of acquired infections and 28-d ventilator-free days (VFDs).

Results: From 77 participating PICUs, 1844 patients, with a median age of 1.64 y (IQR, 0.47-7.05), were included; the 60-d mortality rate was 5.3% (n = 97). The average adequacies of delivery via EN + PN was 49% (IQR, 26-70) for energy and 66% (IQR, 44-89) for protein. In multivariable models adjusted for confounders, mortality was significantly lower in patients who achieved targets within 7 d, for energy (adjusted HR, 0.48; 95% CI: 0.28-0.82; P = 0.007) or protein (adjusted HR, 0.55; 95% CI: 0.33-0.94; P = 0.027) delivery. There were no clinically significant differences in infections or VFDs between groups.

Conclusions: Achieving 60% of energy or protein delivery targets within the first 7 d after PICU admission is associated with lower 60-d mortality in mechanically ventilated children, and is not associated with a greater incidence of infections or a reduction in VFDs compared to later achievement of targets. This trial was registered at clinicaltrials.gov as NCT03223038.
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http://dx.doi.org/10.1093/ajcn/nqab244DOI Listing
July 2021

Renal Tc-DMSA pharmacokinetics in pediatric patients.

EJNMMI Phys 2021 Jul 20;8(1):53. Epub 2021 Jul 20.

The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University, School of Medicine, Baltimore, MD, USA.

Tc-DMSA is one of the most commonly used pediatric nuclear medicine imaging agents. Nevertheless, there are no pharmacokinetic (PK) models for Tc-DMSA in children, and currently available pediatric dose estimates for Tc-DMSA use pediatric S values with PK data derived from adults. Furthermore, the adult PK data were collected in the mid-70's using quantification techniques and instrumentation available at the time. Using pediatric imaging data for DMSA, we have obtained kinetic parameters for DMSA that differ from those applicable to adults.

Methods: We obtained patient data from a retrospective re-evaluation of clinically collected pediatric SPECT images of Tc-DMSA in 54 pediatric patients from Boston's Children Hospital (BCH), ranging in age from 1 to 16 years old. These were supplemented by prospective data from twenty-three pediatric patients (age range: 4 months to 6 years old).

Results: In pediatric patients, the plateau phase in fractional kidney uptake occurs at a fractional uptake value closer to 0.3 than the value of 0.5 reported by the International Commission on Radiological Protection (ICRP) for adult patients. This leads to a 27% lower time-integrated activity coefficient in pediatric patients than in adults. Over the age range examined, no age dependency in uptake fraction at the clinical imaging time was observed. Female pediatric patients had a 17% higher fractional kidney uptake at the clinical imaging time than males (P < 0.001).

Conclusions: Pediatric Tc-DMSA kinetics differ from those reported for adults and should be considered in pediatric patient dosimetry. Alternatively, the differences obtained in this study could reflect improved quantification methods and the need to re-examine DMSA kinetics in adults.
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http://dx.doi.org/10.1186/s40658-021-00401-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8292521PMC
July 2021

Patch augmentation of small ascending aorta during stage I procedure reduces the risk of morbidity and mortality.

Eur J Cardiothorac Surg 2021 Jul 16. Epub 2021 Jul 16.

Department of Cardiovascular Surgery, Boston Children's Hospital, Boston, MA, USA.

Objectives: Hypoplastic left heart syndrome (HLHS) with aortic atresia (AA) patients are prone to coronary insufficiency due to a small ascending aorta. Prophylactic patch augmentation of the small ascending aorta during the stage I procedure (S1P) may reduce the risk of coronary insufficiency as marked by ventricular dysfunction, need for extracorporeal membrane oxygenator (ECMO) support or mortality.

Methods: Retrospective analysis of patients with HLHS with AA who underwent an S1P was completed. Baseline ascending aorta size, right ventricular (RV) function and outcome variables of transplant-free survival, ECMO support after the stage 1 operation and RV function at the time of the bidirectional Glenn and latest follow-up were collected.

Results: Between January 2010 and April 2020, 11 patients underwent prophylactic ascending aorta augmentation at the time of the S1P as a planned portion of the procedure. A total of 125 patients underwent S1P during this period as a comparison. Overall survival was 100% for the augmented group and 74% for the control group (P = 0.66). A composite end point of transplant-free survival, no post-S1P ECMO and less than moderate RV dysfunction was created. At the time of BDG, this composite end point was 100% for the augmented group and 61.8% for the control group (P = 0.008) and at most recent follow-up was 100% for the augmented group and 59.3% for control (P = 0.007). Eight patients required a rescue procedure for the clinical evidence of coronary insufficiency following S1P that included ascending aorta patch augmentation or stent placement. When comparing these rescue versus prophylactic ascending aortic augmentations, there were also differences in the composite outcome 100% for augmented and 60% for rescue (P = 0.009) and at the time of most recent follow-up 100% for augmented and 50% for rescue (P = 0.029).

Conclusions: Prophylactic patch augmentation of the ascending aorta in HLHS patients with AA may reduce the risk of mortality, ECMO and reduced RV function. Patients not initially undergoing augmentation but then requiring a rescue procedure have particularly poor outcomes. Patch augmentation for smaller ascending aortic diameters should be considered and further clinical experience may help delineate aorta diameter threshold for augmentation.
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http://dx.doi.org/10.1093/ejcts/ezab312DOI Listing
July 2021

Virtual reality prototype for binocular therapy in older children and adults with amblyopia.

J AAPOS 2021 08 8;25(4):217.e1-217.e6. Epub 2021 Jul 8.

Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts. Electronic address:

Purpose: To evaluate the best-corrected visual acuity and stereoacuity gains in children >7 years of age and adults with unilateral amblyopia treated with a prototype virtual reality-based binocular amblyopia therapy.

Methods: In this randomized, double masked, cross-in clinical trial, patients at Boston Children's Hospital with unilateral anisometropic and/or strabismic amblyopia and history of prior amblyopia treatment failure were randomized to either a full-treatment group (8 weeks of binocular treatment using therapeutic software application in virtual reality headset) or a sham-crossover group (4 weeks of sham treatment followed by 4 weeks of binocular treatment). Amblyopic eye visual acuity and stereoacuity were evaluated at 4, 8, and 16 weeks' follow-up.

Results: The study cohort included 20 participants (10 females), with a median age of 9 years (range, 7-38 years). In the full-treatment group (11 patients), the mean amblyopic eye logMAR visual acuity at 16 weeks was 0.49 ± 0.26, compared with 0.47 ± 0.20 at baseline. In the sham-crossover group, it was 0.51 ± 0.18 at 16 weeks, compared with 0.53 ± 0.21 at baseline. Stereoacuity (log arcsec) was significantly improved, from 7.3 ± 2 at baseline to 6.6 ± 2.3 at 8 weeks (P < 0.001) and 6.7 ± 2.6 at 16 weeks (P < 0.001). No significant adverse events (diplopia, asthenopia, or worsening strabismus) were noted in either group.

Conclusions: Although the virtual reality-based prototype for binocular amblyopia therapy did not significantly improve visual acuity in the amblyopic eyes of older children and adults, stereoacuity did significantly improve compared with baseline; improvements were clinically minute. However, larger studies are required to confirm the results.
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http://dx.doi.org/10.1016/j.jaapos.2021.03.008DOI Listing
August 2021

Synergy in Nanomedicine: What It Is Not, and What It Might Be.

Nano Lett 2021 07 29;21(13):5457-5460. Epub 2021 Jun 29.

Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children's Hospital, Harvard Medical School, Boston Massachusetts 02115, United States.

Interactions between nanoformulations delivering two or more drugs-or a drug and some other therapeutic modality-are often described as synergistic. In fact, synergy is a specific term of art, with important therapeutic implications. The term is often misused in the nanoscience literature. Here we discuss what synergy is and an approach to demonstrating it rigorously.
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http://dx.doi.org/10.1021/acs.nanolett.1c01894DOI Listing
July 2021

The Liver Retransplantation Risk Score: a prognostic model for survival after adult liver retransplantation.

Transpl Int 2021 Oct 16;34(10):1928-1937. Epub 2021 Jul 16.

Division of HPB Surgery and Liver Transplantation, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

High-risk combinations of recipient and graft characteristics are poorly defined for liver retransplantation (reLT) in the current era. We aimed to develop a risk model for survival after reLT using data from the European Liver Transplantation Registry, followed by internal and external validation. From 2006 to 2016, 85 067 liver transplants were recorded, including 5581 reLTs (6.6%). The final model included seven predictors of graft survival: recipient age, model for end-stage liver disease score, indication for reLT, recipient hospitalization, time between primary liver transplantation and reLT, donor age, and cold ischemia time. By assigning points to each variable in proportion to their hazard ratio, a simplified risk score was created ranging 0-10. Low-risk (0-3), medium-risk (4-5), and high-risk (6-10) groups were identified with significantly different 5-year survival rates ranging 56.9% (95% CI 52.8-60.7%), 46.3% (95% CI 41.1-51.4%), and 32.1% (95% CI 23.5-41.0%), respectively (P < 0.001). External validation showed that the expected survival rates were closely aligned with the observed mortality probabilities. The Retransplantation Risk Score identifies high-risk combinations of recipient- and graft-related factors prognostic for long-term graft survival after reLT. This tool may serve as a guidance for clinical decision-making on liver acceptance for reLT.
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http://dx.doi.org/10.1111/tri.13956DOI Listing
October 2021

Predictors of progression in radiation-induced versus nonradiation-induced pediatric meningiomas: a large single-institution surgical experience.

J Neurosurg Pediatr 2021 Jun 11:1-7. Epub 2021 Jun 11.

1Department of Neurosurgery, Boston Children's Hospital.

Objective: The goal in this study was to outline unique differences between radiation-induced and nonradiation-induced pediatric meningiomas and to identify independent risk factors of tumor recurrence/progression.

Methods: This is a retrospective cohort study of all pediatric meningiomas diagnosed and surgically treated at the authors' institution between 1993 and 2017. Multivariable Cox regression was applied to identify independent risk factors for tumor recurrence/progression.

Results: Thirty-five patients were identified. The primary etiology was nonradiation-induced (n = 24: n = 3 with neurofibromatosis type 2) or radiation-induced (n = 11: acute lymphoblastic leukemia [n = 5], medulloblastoma [n = 4], germ cell tumor [n = 1], and primitive neuroectodermal tumor [n = 1]) meningioma. The mean age at time of diagnosis was 10.7 ± 5.7 years for nonradiation-induced and 17.3 ± 3.5 years for radiation-induced meningiomas. Overall, 8/24 patients with nonradiation-induced meningioma experienced either recurrence or progression of the tumor. Of the 8 patients with tumor recurrence or progression, the pathological diagnosis was clear cell meningioma (n = 3: 2 recurrent and 1 progressive); grade I (n = 2 progressive); grade I with atypical features (n = 2: 1 recurrent and 1 progressive); or atypical meningioma (n = 1 recurrent). None of the patients with radiation-induced meningioma experienced recurrence or progression. Predictors of tumor recurrence/progression by univariate analysis included age at time of diagnosis ≤ 10 years (p = 0.002), histological subtype clear cell meningioma (p = 0.003), and primary etiology nonradiation-induced meningioma (p = 0.04), and there was a notable trend with elevated MIB-1 staining index (SI) (p = 0.09). There was no significant difference between nonradiation-induced and radiation-induced meningiomas (p = 0.258), although there was a trend between recurrent and nonrecurrent meningiomas (p = 0.09). Multivariate Cox regression, adjusted for length of follow-up, identified younger age at diagnosis (p = 0.004) and a higher MIB-1 SI (p = 0.044) as independent risk factors for recurrence. Elevated MIB-1 SI statistically correlated with atypia (p < 0.001). However, there was no significant statistical correlation between tumor recurrence/progression and atypia (p = 0.2).

Conclusions: Younger patient age and higher MIB-1 SI are independent risk factors for recurrence. Atypia was not a predictor of recurrence.
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http://dx.doi.org/10.3171/2021.1.PEDS20819DOI Listing
June 2021

Magnetic Resonance Imaging Features and Clinical Findings in Pediatric Idiopathic Intracranial Hypertension: A Case-Control Study.

Life (Basel) 2021 May 27;11(6). Epub 2021 May 27.

Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.

The purpose of this study is to identify salient magnetic resonance imaging (MRI) findings of pediatric IIH, to determine the relevance of these findings with regard to disease pathogenesis, and to relate these findings to the clinical presentation towards identification of risk factors of disease. A retrospective, a case-control study of 38 pediatric patients with and 24 pediatric patients without IIH from the ophthalmology department at a tertiary care center was performed. Clinical data, including ophthalmic findings and lumbar puncture results, were recorded. Neuroimaging, including both MRI and magnetic resonance venography (MRV), was evaluated for perioptic subarachnoid space diameter enlargement, posterior globe flattening, optic nerve head protrusion, empty or partially empty sella turcica, dural venous sinus abnormalities, skull base crowding, and prominent arachnoid granulations. Compared with controls, IIH patients had larger perioptic subarachnoid space diameters, higher incidences of posterior globe flattening, protrusion of the optic nerve heads, an empty sella turcica, and dural venous sinus abnormalities. A perioptic subarachnoid space diameter of ≥5.2 mm was identified as an independent predictor of IIH ( < 0.001) with sensitivity of 87% and specificity of 67%. Several significant MRI findings in pediatric IIH were identified. Using a model that uniquely incorporated clinical and MRI findings at presentation, we provide a framework for risk stratification for the diagnosis of pediatric IIH which may be utilized to facilitate diagnosis. Future prospective work is needed to further validate the model developed in this study.
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http://dx.doi.org/10.3390/life11060487DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8230318PMC
May 2021

Outcomes of a multicomponent safe surgery intervention in Tanzania's Lake Zone: a prospective, longitudinal study.

Int J Qual Health Care 2021 Jun;33(2)

Assist International, 800 South Stockton Avenue, Ripon, CA 95366, USA.

Background: Evidence-based strategies for improving surgical quality and patient outcomes in low-resource settings are a priority.

Objective: To evaluate the impact of a multicomponent safe surgery intervention (Safe Surgery 2020) on (1) adherence to safety practices, teamwork and communication, and documentation in patient files, and (2) incidence of maternal sepsis, postoperative sepsis, and surgical site infection.

Methods: We conducted a prospective, longitudinal study in 10 intervention and 10 control facilities in Tanzania's Lake Zone, across a 3-month pre-intervention period in 2018 and 3-month post-intervention period in 2019. SS2020 is a multicomponent intervention to support four surgical quality areas: (i) leadership and teamwork, (ii) evidence-based surgery, anesthesia and equipment sterilization practices, (iii) data completeness and (iv) infrastructure. Surgical team members received training and mentorship, and each facility received up to a $10 000 infrastructure grant. Inpatients undergoing major surgery and postpartum women were followed during their stay up to 30 days. We assessed adherence to 14 safety and teamwork and communication measures through direct observation in the operating room. We identified maternal sepsis (vaginal or cesarean delivery), postoperative sepsis and SSIs prospectively through daily surveillance and assessed medical record completeness retrospectively through chart review. We compared changes in surgical quality outcomes between intervention and control facilities using difference-in-differences analyses to determine areas of impact.

Results: Safety practices improved significantly by an additional 20.5% (95% confidence interval (CI), 7.2-33.7%; P = 0.003) and teamwork and communication conversations by 33.3% (95% CI, 5.7-60.8%; P = 0.02) in intervention facilities compared to control facilities. Maternal sepsis rates reduced significantly by 1% (95% CI, 0.1-1.9%; P = 0.02). Documentation completeness improved by 41.8% (95% CI, 27.4-56.1%; P < 0.001) for sepsis and 22.3% (95% CI, 4.7-39.8%; P = 0.01) for SSIs.

Conclusion: Our findings demonstrate the benefit of the SS2020 approach. Improvement was observed in adherence to safety practices, teamwork and communication, and data quality, and there was a reduction in maternal sepsis rates. Our results support the emerging evidence that improving surgical quality in a low-resource setting requires a focus on the surgical system and culture. Investigation in diverse contexts is necessary to confirm and generalize our results and to understand how to adapt the intervention for different settings. Further work is also necessary to assess the long-term effect and sustainability of such interventions.
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http://dx.doi.org/10.1093/intqhc/mzab087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8240014PMC
June 2021

Timing of Ocular Hypertension After Pediatric Closed-Globe Traumatic Hyphema: Implications for Surveillance.

Am J Ophthalmol 2021 May 12. Epub 2021 May 12.

Harvard Medical School, Boston, MA; Boston Children's Hospital, Boston, MA; Massachusetts Eye and Ear, Boston, MA. Electronic address:

Purpose: To evaluate the timing of ocular hypertension (OHT) after pediatric closed-globe injury (CGI) and traumatic hyphema. We hypothesize that OHT will occur at different times based on injury characteristics.

Design: Retrospective, cohort study.

Methods: SETTING: : Single-center, tertiary-care, pediatric hospital.

Participants: Subjects included patients ≤18 years of age at the time of injury who suffered CGI and traumatic hyphema between 2002 and 2019.

Observation Procedure(s): Intraocular pressure and injury demographics were abstracted for every visit after injury. OHT was defined as >21 mmHg at presentation or after a reading of ≤21 mmHg at a prior visit.

Main Outcome Measures: The primary outcome measure was the timing of OHT categorized into 4 periods: presentation, acute (day 1-7), sub-acute (day 8-28), or late (day >28). Secondary outcome measures were identification of risks factors for OHT by multivariable logistic regression.

Results: OHT occurred in 119 (39%) of the 305 subject eyes. OHT occurred in 35 patients at presentation, 69 times acutely, 35 times sub-acutely, and 36 times late. Pupil damage predicted acute-period OHT (p=0.004). OHT at presentation predicted sub-acute period OHT (p=0.004). Iridodialysis and cataract predicted late-period OHT (p=0.007 and p<0.001, respectively).

Conclusions: OHT after CGI and traumatic hyphema in pediatric patients is common. Injury demographics predict this complication. Integration of these risk factors with current literature allows proposal of a risk-stratification tool to guide efficient surveillance for OHT.
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http://dx.doi.org/10.1016/j.ajo.2021.04.033DOI Listing
May 2021

Abdominal ultrasound findings contribute to a multivariable predictive risk score for surgical necrotizing enterocolitis: A pilot study.

Am J Surg 2021 Apr 27. Epub 2021 Apr 27.

Department of Surgery, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA. Electronic address:

Background: Abdominal ultrasound (AUS) is a promising adjunct to abdominal x-ray (AXR) for evaluating necrotizing enterocolitis (NEC). We developed a multivariable risk score incorporating AUS to predict surgical NEC.

Methods: 83 patients were evaluated by AXR and AUS for suspected NEC. A subset had surgical NEC. Multivariate logistic regression determined predictors of surgical NEC, which were incorporated into a risk score.

Results: 14/83 patients (16.9%) had surgical NEC. 10/83 (12.0%) patients required acute intervention, while 4/83 (4.8%) patients only required delayed surgery. Four predictors of surgical NEC were identified: abdominal wall erythema (OR: 8.2, p = 0.048), portal venous gas on AXR (OR: 29.8, p = 0.014), and echogenic free fluid (OR: 17.2, p = 0.027) and bowel wall thickening (OR: 12.5, p = 0.030) on AUS. A multivariable risk score incorporating these predictors had excellent area-under-the-curve of 0.937 (95% CI: 0.879-0.994).

Conclusions: AUS, as an adjunct to physical exam and AXR, has utility for predicting surgical NEC.
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http://dx.doi.org/10.1016/j.amjsurg.2021.04.025DOI Listing
April 2021

Non-invasive Urinary Biomarkers in Moyamoya Disease.

Front Neurol 2021 1;12:661952. Epub 2021 Apr 1.

Vascular Biology Program, Boston Children's Hospital and Harvard Medical School, Boston, MA, United States.

A major difficulty in treating moyamoya disease is the lack of effective methods to detect novel or progressive disease prior to the onset of disabling stroke. More importantly, a tool to better stratify operative candidates and quantify response to therapy could substantively complement existing methods. Here, we present proof-of-principle data supporting the use of urinary biomarkers as diagnostic adjuncts in pediatric moyamoya patients. Urine and cerebrospinal fluid specimens were collected from pediatric patients with moyamoya disease and a cohort of age and sex-matched control patients. Clinical and radiographic data were paired with measurements of a previously validated panel of angiogenic proteins quantified by ELISA. Results were compared to age and sex-matched controls and subjected to statistical analyses. Evaluation of a specific panel of urinary and cerebrospinal fluid biomarkers by ELISA demonstrated significant elevations of angiogenic proteins in samples from moyamoya patients compared to matched controls. ROC curves for individual urinary biomarkers, including MMP-2, MMP-9, MMP-9/NGAL, and VEGF, showed excellent discrimination. The optimal urinary biomarker was MMP-2, providing a sensitivity of 88%, specificity of 100%, and overall accuracy of 91%. Biomarker levels changed in response to therapy and correlated with radiographic evidence of revascularization. We report, for the first time, identification of a panel of urinary biomarkers that predicts the presence of moyamoya disease. These biomarkers correlate with presence of disease and can be tracked from the central nervous system to urine. These data support the hypothesis that urinary proteins are useful predictors of the presence of moyamoya disease and may provide a basis for a novel, non-invasive method to identify new disease and monitor known patients following treatment.
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http://dx.doi.org/10.3389/fneur.2021.661952DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8047329PMC
April 2021

Transamniotic Stem Cell Therapy for Experimental Congenital Diaphragmatic Hernia: Structural, Transcriptional, and Cell Kinetics Analyses in the Nitrofen Model.

Fetal Diagn Ther 2021 14;48(5):381-391. Epub 2021 Apr 14.

Department of Surgery, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, USA.

Purpose: We examined select pulmonary effects and donor cell kinetics after transamniotic stem cell therapy (TRASCET) in a model of congenital diaphragmatic hernia (CDH).

Methods: Pregnant dams (n = 58) received nitrofen on gestational day 9.5 (E9) to induce fetal CDH. Fetuses (n = 681) were divided into 4 groups: untreated (n = 99) and 3 groups receiving volume-matched intra-amniotic injections on E17 of either saline (n = 142), luciferase-labeled amniotic fluid-derived mesenchymal stem cells (afMSCs; n = 299), or acellular recombinant luciferase (n = 141). Pulmonary morphometry, quantitative gene expression of pulmonary vascular tone mediators, or screening for labeled afMSCs were performed at term (E22). Statistical comparisons were by Mann-Whitney U-test, nested ANOVA, and Wald test.

Results: TRASCET led to significant downregulation of endothelial nitric oxide synthase and endothelin receptor-A expressions compared to both untreated and saline groups (both p < 0.001). TRASCET also led to a significant decrease in arteriole wall thickness compared to the untreated group (p < 0.001) but not the saline group (p = 0.180). Donor afMSCs were identified in the bone marrow and umbilical cord (p = 0.035 and 0.015, respectively, vs. plain luciferase controls).

Conclusions: The effects of TRASCET in experimental CDH appear to be centered on the pulmonary vasculature and to derive from circulating donor cells.
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http://dx.doi.org/10.1159/000515277DOI Listing
April 2021

Fetal hematogenous routing of a donor hematopoietic stem cell line in a healthy syngeneic model of transamniotic stem cell therapy.

J Pediatr Surg 2021 Jun 24;56(6):1233-1236. Epub 2021 Feb 24.

Department of Surgery, Boston Children's Hospital/ Harvard Medical School, Boston, MA 02115, USA. Electronic address:

Background/purpose: In utero administration of hematopoietic stem cells (HSCs) has a variety of actual or potential clinical applications but is hindered by invasive, morbid administration techniques. We sought to determine whether donor HSCs could reach the fetal circulation after simple intra-amniotic delivery in a syngeneic rat model of transamniotic stem cell therapy (TRASCET).

Methods: Pregnant Lewis rat dams underwent volume-matched intra-amniotic injections in all fetuses (n = 90) on gestational day 17 (E17; term=E21-22) of a suspension of commercially available syngeneic Lewis rat HSCs labeled with luciferase (n = 37 fetuses) or an acellular suspension of recombinant luciferase (n = 53). HSC phenotype was confirmed by flow cytometry. Fetuses were euthanized at term for screening of luciferase activity at select anatomical sites. Statistical comparisons were by Fisher's exact test.

Results: Among survivors (47/90; 52.2%), donor HSCs were identified selectively in the placenta (p = 0.003), umbilical cord (p < 0.001), bone marrow (p < 0.001), thymus (p = 0.009), bowel (p = 0.003), kidney (p = 0.022), and skin (p < 0.001) when compared with acellular luciferase controls.

Conclusions: Donor hematopoietic stem cells undergo hematogenous routing and can reach the fetal bone marrow after simple intra-amniotic delivery in a syngeneic rat model. Transamniotic stem cell therapy may become a practicable, minimally invasive strategy for the prenatal administration of these cells.
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http://dx.doi.org/10.1016/j.jpedsurg.2021.02.035DOI Listing
June 2021

Enhancement of transamniotic stem cell therapy for spina bifida by genetic engineering of donor mesenchymal stem cells with an Fgf2 transgene.

J Pediatr Surg 2021 Jun 24;56(6):1226-1232. Epub 2021 Feb 24.

Department of Surgery, Boston Children's Hospital/Harvard Medical School, Boston, MA 02115, USA. Electronic address:

Background/purpose: We examined whether engineered overexpression of fibroblast growth factor-2 (Fgf2) in donor mesenchymal stem cells (MSCs) could enhance spina bifida coverage induced by transamniotic stem cell therapy (TRASCET).

Methods: Pregnant Sprague-Dawley dams (n = 24) exposed to retinoic acid for induction of fetal spina bifida were divided in three groups. An untreated group had no further manipulations. Two groups received volume-matched intra-amniotic injections into all fetuses (n = 157) of either amniotic fluid-derived MSCs (afMSC; n = 85) or afMSCs transduced with an Fgf2 transgene (Fgf2-afMSC; n = 72) on gestational day 17 (term=21-22 days). Defect coverage was categorized at term by histology and pan-cytokeratin immunohistochemistry. Statistical coverage comparisons were by logistic regression.

Results: Among 84 survivors with isolated spina bifida, 71 had definitive histology. Defect coverage rates in both the afMSC (38.5%) and Fgf2-afMSC (73.3%) groups were statistically significantly higher than in the untreated group (10%; p<0.001 for both). There was a significantly higher coverage rate in the Fgf2-afMSC group compared with the afMSC group (p = 0.025).

Conclusions: Fgf2 overexpression in donor mesenchymal stem cells increases defect coverage rates in a rodent model of transamniotic stem cell therapy for spina bifida. Genetic engineering of donor cells is a promising strategy for the enhancement of this emerging therapy.
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http://dx.doi.org/10.1016/j.jpedsurg.2021.02.036DOI Listing
June 2021

Hydrogel-Guided, rAAV-Mediated IGF-I Overexpression Enables Long-Term Cartilage Repair and Protection against Perifocal Osteoarthritis in a Large-Animal Full-Thickness Chondral Defect Model at One Year In Vivo.

Adv Mater 2021 Apr 18;33(16):e2008451. Epub 2021 Mar 18.

Center of Experimental Orthopaedics, Saarland University and Saarland University Medical Center, D-66421, Homburg/Saar, Germany.

The regeneration of focal articular cartilage defects is complicated by the reduced quality of the repair tissue and the potential development of perifocal osteoarthritis (OA). Biomaterial-guided gene therapy may enhance cartilage repair by controlling the release of therapeutic sequences in a spatiotemporal manner. Here, the benefits of delivering a recombinant adeno-associated virus (rAAV) vector coding for the human insulin-like growth factor I (IGF-I) via an alginate hydrogel (IGF-I/AlgPH155) to enhance repair of full-thickness chondral defects following microfracture surgery after one year in minipigs versus control (lacZ/AlgPH155) treatment are reported. Sustained IGF-I overexpression is significantly achieved in the repair tissue of defects treated with IGF-I/AlgPH155 versus those receiving lacZ/AlgPH155 for one year and in the cartilage surrounding the defects. Administration of IGF-I/AlgPH155 significantly improves parameters of cartilage repair at one year relative to lacZ/AlgPH155 (semiquantitative total histological score, cell densities, matrix deposition) without deleterious or immune reactions. Remarkably, delivery of IGF-I/AlgPH155 also significantly reduces perifocal OA and inflammation after one year versus lacZ/AlgPH155 treatment. Biomaterial-guided rAAV gene transfer represents a valuable clinical approach to promote cartilage repair and to protect against OA.
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http://dx.doi.org/10.1002/adma.202008451DOI Listing
April 2021

Pain stickiness in pediatric complex regional pain syndrome: A role for the nucleus accumbens.

Neurobiol Pain 2021 Jan-Jul;9:100062. Epub 2021 Feb 19.

Department of Anesthesiology, Perioperative & Pain Medicine, Stanford University School of Medicine, Stanford, CA 94305, United States.

Some individuals with chronic pain experience improvement in their pain with treatment, whereas others do not. The neurobiological reason is unclear, but an understanding of brain structure and functional patterns may provide insights into pain's responsivity to treatment. In this investigation, we used magnetic resonance imaging (MRI) techniques to determine grey matter density alterations on resting functional connectivity (RFC) strengths between pain responders and nonresponders in patients with complex regional pain syndrome. Brain metrics of pediatric patients at admission to an intensive pain rehabilitative treatment program were evaluated. Pain responders reported significant pain improvement at discharge and/or follow-up whereas nonresponders reported no improvements in pain, increases in pain, or emergence of new pain symptoms. The pain (responder/nonresponder) groups were compared with pain-free healthy controls to examine predictors of pain responder status via brain metrics. Our results show: (1) on admission, pain nonresponders had decreased grey matter density (GMD) within the nucleus accumbens (NAc) and reduced RFC strength between the NAc and the dorsolateral prefrontal cortex vs. responders; (2) Connectivity strength was positively correlated with change in pain intensity from admission to discharge; (3) Compared with pain-free controls, grey matter and RFC differences emerged only among pain nonresponders; and (4) Using a discriminative model, combining GMD and RFC strengths assessed at admission showed the highest prediction estimate (87%) on potential for pain improvement, warranting testing in a de novo sample. Taken together, these results support the idea that treatment responsiveness on pain is underpinned by concurrent brain structure and resting brain activity.
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http://dx.doi.org/10.1016/j.ynpai.2021.100062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7941018PMC
February 2021

Long-term outcomes of truncus arteriosus repair: A modulated renewal competing risks analysis.

J Thorac Cardiovasc Surg 2021 Feb 12. Epub 2021 Feb 12.

Department of Cardiac Surgery, Boston Children's Hospital, Harvard Medical School, Boston, Mass. Electronic address:

Objective: In this study, we sought to identify independent risk factors for mortality and reintervention after early surgical correction of truncus arteriosus using a novel statistical method.

Methods: Patients undergoing neonatal/infant truncus arteriosus repair between January 1984 and December 2018 were reviewed retrospectively. An innovative statistical strategy was applied integrating competing risks analysis with modulated renewal for time-to-event modeling.

Results: A total of 204 patients were included in the study. Mortality occurred in 32 patients (15%). Smaller right ventricle to pulmonary artery conduit size and truncal valve insufficiency at birth were significantly associated with overall mortality (right ventricle to pulmonary artery conduit size: hazard ratio, 1.34; 95% confidence interval, 1.08-1.66, P = .008; truncal valve insufficiency: hazard ratio, 2.5; 95% confidence interval, 1.13-5.53, P = .024). truncal valve insufficiency at birth, truncal valve intervention at index repair, and number of cusps (4 vs 3) were associated with truncal valve reoperations (truncal valve insufficiency: hazard ratio, 2.38; 95%, confidence interval, 1.13-5.01, P = .02; cusp number: hazard ratio, 6.62; 95% confidence interval, 2.54-17.3, P < .001). Right ventricle to pulmonary artery conduit size 11 mm or less was associated with a higher risk of early catheter-based reintervention (hazard ratio, 1.54; 95% confidence interval, 1.04-2.28, P = .03) and reoperation (hazard ratio, 1.96; 95% confidence interval, 1.33-2.89, P = .001) on the right ventricle to pulmonary artery conduit.

Conclusions: Smaller right ventricle to pulmonary artery conduit size and truncal valve insufficiency at birth were associated with overall mortality after truncus arteriosus repair. Quadricuspid truncal valve, the presence of truncal valve insufficiency at the time of diagnosis, and truncal valve intervention at index repair were associated with an increased risk of reoperation. The size of the right ventricle to pulmonary artery conduit at index surgery is the single most important factor for early reoperation and catheter-based reintervention on the conduit.
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http://dx.doi.org/10.1016/j.jtcvs.2021.01.136DOI Listing
February 2021

Long-term ophthalmic outcomes in 120 children with unilateral coronal synostosis: a 20-year retrospective analysis.

J AAPOS 2021 04 11;25(2):76.e1-76.e5. Epub 2021 Mar 11.

Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts. Electronic address:

Background: Prior studies comparing ophthalmic outcomes after treating unicoronal synostosis (UCS) by early endoscopic strip craniectomy (ESC) versus later fronto-orbital advancement (FOA) are modest in sample size, or lack consistent age adjustment. We report long-term, age-adjusted ophthalmic outcomes for a large cohort after nonrandomized treatment by one of these two options.

Methods: The following data was retrieved from a retrospective review of the medical records of patients with treated UCS born since 2000: cycloplegic refractions, sensorimotor examinations, and strabismus procedures before craniofacial repair and postoperatively at approximately 18 and 60 months of age. V-pattern strabismus was graded as mild (absent or + 1/-1 oblique dysfunction) versus moderate-to-severe (≥+2/-2 oblique dysfunction or left to right vertical alignment change of ≥20 or ocular torticollis >15°).

Results: A total of 120 infants were included: 60 treated by FOA and 60 by ESC. By the late examination, aniso-astigmatism was present in 72% of FOA-treated patients and 46% of ESC-treated patients (P < 0.0001). By late examination, the age-adjusted odds ratio of moderate-to-severe V-pattern strabismus after treatment by FOA versus ESC was 2.65 (95% CI, 1.37-6.28; P = 0.02); strabismus surgery was performed in 26 infants treated by FOA compared with 13 treated by ESC (OR = 2.8; P = 0.02). Amblyopia developed in 60% of FOA-treated patients compared with 35% of those treated by ESC (OR 3.0; 95% CI, 1.3-6.7; P = 0.02).

Conclusions: Our age-adjusted ophthalmic results confirm better long-term outcomes after treatment of USC by endoscopic strip craniectomy. Recognition and referral of affected infants by the earliest months of life facilitates the opportunity for endoscopic repair.
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http://dx.doi.org/10.1016/j.jaapos.2020.10.013DOI Listing
April 2021

A survey of the global impact of COVID-19 on the practice of pediatric anesthesia: A study from the pediatric anesthesia COVID-19 Collaborative Group.

Paediatr Anaesth 2021 06 3;31(6):720-729. Epub 2021 May 3.

Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.

Background: Pediatric anesthesiology has been greatly impacted by COVID-19 in the delivery of care to patients and to the individual providers. With this study, we sought to survey pediatric centers and highlight the variations in care related to perioperative medicine during the COVID-19 pandemic, including the availability of protective equipment, the practice of pediatric anesthesia, and economic impact.

Aim: The aim of the survey was to determine how COVID-19 directly impacted pediatric anesthesia practices during the study period.

Methods: A survey concerning four major domains (testing, safety, clinical management/policy, economics) was developed. It was pilot tested for clarity and content by members of the Pediatric Anesthesia COVID-19 Collaborative. The survey was administered by email to all Pediatric Anesthesia COVID-19 Collaborative members on September 1, 2020. Respondents had six weeks to complete the survey and were instructed to answer the questions based on their institution's practice during September 1 - October 13, 2020.

Results: Sixty-three institutions (100% response rate) participated in the COVID-19 Pediatric Anesthesia Survey. Forty-one hospitals (65%) were from the United States, and 35% included other countries. N95 masks were available to anesthesia teams at 91% of institutions (n = 57) (95% CI: 80%-96%). COVID-19 testing criteria of anesthesia staff and guidelines to return to work varied by institution. Structured simulation training aimed at improving COVID-19 safety and patient care occurred at 62% of institutions (n = 39). Pediatric anesthesiologists were economically affected by a reduction in their employer benefits and restriction of travel due to employer imposed quarantine regulations.

Conclusion: Our data indicate that the COVID-19 pandemic has impacted the testing, safety, clinical management, and economics of pediatric anesthesia practice. Further investigation into the long-term consequences for the specialty is indicated.
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http://dx.doi.org/10.1111/pan.14174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8250770PMC
June 2021
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