Publications by authors named "Mark Conaway"

206 Publications

Hospital Survival After Surgical Repair of Truncus Arteriosus with Interrupted Aortic Arch: Results from a Multi-institutional Database.

Pediatr Cardiol 2021 Mar 30. Epub 2021 Mar 30.

Division of Cardiology, Department of Pediatrics, University of Virginia School of Medicine, Charlottesville, VA, USA.

Truncus arteriosus (TA) is a major congenital cardiac malformation that requires surgical repair in the first few weeks of life. Interrupted aortic arch (IAA) is an associated malformation that significantly impacts the complexity of the TA operation. The aim of this study was to (1) define the comorbid conditions associated with TA and (2) determine the hospital survival and morbidity of patients with TA with and without an IAA. Data was collected from the Vizient Clinical Database/Resource Manager, formerly University HealthSystem Consortium, which encompasses more than 160 academic medical centers in the United States. The database was queried for patients admitted from 2002 to 2016 who were ≤ 4 months of age at initial admission, diagnosed with TA, and underwent complete surgical repair during that hospitalization. Of the 645 patients with TA who underwent surgery, 98 (15%) had TA with an interrupted aortic arch (TA-IAA). Both TA and TA-IAA were associated with a high prevalence of comorbidities, including DiGeorge syndrome, prematurity, and other congenital malformations. There was no difference in mortality between TA and TA-IAA (13.7-18.4%, p value = 0.227). No comorbid conditions were associated with an increased mortality in either group. However, patients with TA-IAA had a longer post-operative length of stay (LOS) compared to those without IAA (30 versus 40.3 days, p value = 0.001) and this effect was additive with each additional comorbid condition. In conclusion, the addition of IAA to TA is associated with an increased post-operative LOS, but does not increase in-hospital mortality.
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http://dx.doi.org/10.1007/s00246-021-02582-5DOI Listing
March 2021

Timing of Introduction of Complementary Foods and Beverages to Infants of Low-Income Women.

Breastfeed Med 2021 Mar 30. Epub 2021 Mar 30.

Department of Pediatrics, University of Virginia, Charlottesville, Virginia, USA.

Although rates of complementary food and beverage (CFB) consumption among infants under 4 to 6 months of age have been declining, they remain well above the American Academy of Pediatrics (AAPs) recommendations. It is unclear if women with low income in the United States are more likely than other women to introduce CFBs early. We examined timing of introduction of CFBs to infants of mothers with low income to further illuminate infant feeding practices in this potentially vulnerable population. We analyzed infant feeding data collected prospectively from 443 mother-infant dyads. Data were obtained by interview at 1, 3, and 6 months postpartum. We used Kaplan-Meier curves to show time to introduction of CFBs overall and by type of CFB, and log-rank tests to compare timing by demographic and clinical characteristics. Participants were mostly non-Hispanic black or white, with a high school education or less. By month 3, 48% of infants were fed at least one CFB, increasing to over 83% by month 5. Women who did not work outside the home introduced CFBs significantly earlier than those who worked, as did women who smoked compared with those who did not. Timing did not differ by other participant characteristics. Introduction of CFBs before 4-6 months was common. Clinical guidance and intervention programs should support mothers toward the goal of improving infant diets in this at-risk population.
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http://dx.doi.org/10.1089/bfm.2020.0352DOI Listing
March 2021

Electroencephalogram Background Predicts Time to Full Oral Feedings in Hypoxic-Ischemic Encephalopathy.

Am J Perinatol 2021 Mar 3. Epub 2021 Mar 3.

Department of Pediatrics, University of Virginia, Charlottesville, Virginia.

Objective:  Infants with a history of neonatal hypoxic-ischemic encephalopathy (HIE) are at risk for oral motor dysfunction. Previous studies have associated the need for gastrostomy tube at neonatal intensive care unit discharge with brainstem injury on magnetic resonance imaging (MRI). However, the factors associated with time to full oral feeds in this population have not been previously described. This study aimed to study factors associated with time to full oral feeds in this population.

Study Design:  This is a single-center, retrospective study that examined these factors using Cox regression.

Results:  A total of 150 infants who received therapeutic hypothermia from 2011 to 2017 were included in this study. The single clinical factor significantly associated with time to full oral feeds was the severity of background abnormality on electroencephalogram in the first 24 hours of age (severe vs. mild 95% confidence interval [CI]: 0.34-0.74; moderate vs. mild 95% CI: 0.19-0.45). Brainstem injury on MRI was the factor most highly associated with need for gastrostomy tube placement ( = 0.028), though the overall incidence of need for gastrostomy tube feeds in this population was low (5%).

Conclusion:  These findings may help clinicians counsel families on what to expect in neonates with HIE and make decisions on the need for and timing to pursue gastrostomy tube in this population.

Key Points: · The overall incidence of the need for assisted feeding at NICU discharge is low in this population.. · MRI brainstem injury was most highly associated with need for gastrostomy tube placement.. · Worsening severity of background abnormality on EEG was associated with longer time to oral feeds..
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http://dx.doi.org/10.1055/s-0041-1725161DOI Listing
March 2021

Differential expression of CD49a and CD49b determines localization and function of tumor-infiltrating CD8+ T cells.

Cancer Immunol Res 2021 Feb 22. Epub 2021 Feb 22.

Carter Immunology Center and Department of Microbiology, Immunology, and Cancer Biology, University of Virginia School of Medicine

CD8+ T-cell infiltration and effector activity in tumors are correlated with better overall survival of patients, suggesting that the ability of T cells to enter and remain in contact with tumor cells supports tumor control. CD8+ T cells express the collagen-binding integrins CD49a and CD49b, but little is known about their function or how their expression is regulated in the tumor microenvironment (TME). Here, we found that tumor-infiltrating CD8+ T cells initially expressed CD49b, gained CD49a, and then lost CD49b over the course of tumor outgrowth. This differentiation sequence was driven by antigen-independent elements in the TME, although T-cell receptor (TCR) stimulation further increased CD49a expression. Expression of exhaustion markers and CD49a associated temporally, but not mechanistically. Intratumoral CD49a-expressing CD8+ T cells failed to upregulate TCR-dependent Nur77 expression, while CD69 was constitutively expressed, consistent with both a lack of productive antigen engagement and a tissue-resident memory-like phenotype. Imaging T cells in live tumor slices revealed that CD49a increased their motility, especially of those in close proximity to tumor cells, suggesting that it may interfere with T-cell recognition of tumor cells by distracting them from productive engagement, although we were not able to augment productive engagement by short-term CD49a blockade. CD49b also promoted relocalization of T cells at a greater distance from tumor cells. Thus, our results demonstrate that expression of these integrins impacts T-cell trafficking and localization in tumors via distinct mechanisms, and suggests a new way in which the TME, and likely collagen, could promote tumor-infiltrating CD8+ T-cell dysfunction.
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http://dx.doi.org/10.1158/2326-6066.CIR-20-0427DOI Listing
February 2021

Adapting isotonic dose-finding to a dynamic set of drug combinations with application to a phase I leukemia trial.

Clin Trials 2021 Jan 10:1740774520983484. Epub 2021 Jan 10.

Department of Public Health Sciences, Division of Translational Research & Applied Statistics, University of Virginia, Charlottesville, VA, USA.

Background/aims: This article describes the proposed design of a phase I study evaluating the safety of ceramide nanoliposome and vinblastine among an initial set of 19 possible dose combinations in patients with relapsed/refractory acute myeloid leukemia and patients with untreated acute myeloid leukemia who are not candidates for intensive induction chemotherapy.

Methods: Extensive collaboration between statisticians and clinical investigators revealed the need to incorporate several adaptive features into the design, including the flexibility of adding or eliminating certain dose combinations based on safety criteria applied to multiple dose pairs. During the design stage, additional dose levels of vinblastine were added, increasing the dimension of the drug combination space and thus the complexity of the problem. Increased complexity made application of existing drug combination dose-finding methods unsuitable in their current form.

Results: Our solution to these challenges was to adapt a method based on isotonic regression to meet the research objectives of the study. Application of this adapted method is described herein, and a simulation study of the design's operating characteristics is conducted.

Conclusion: The aim of this article is to bring to light examples of novel design applications as a means of augmenting the implementation of innovative designs in the future and to demonstrate the flexibility of adaptive designs in satisfying changing design conditions.
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http://dx.doi.org/10.1177/1740774520983484DOI Listing
January 2021

Glycemic excursion minimization in the management of type 2 diabetes: a novel intervention tested in a randomized clinical trial.

BMJ Open Diabetes Res Care 2020 12;8(2)

Department of Medicine, University of Virginia School of Medicine, Charlottesville, Virginia, USA.

Introduction: This study of adults with type 2 diabetes employed a non-inferiority hypothesis to investigate whether an innovative lifestyle focused on minimizing postnutrient blood glucose (BG) excursions (glycemic excursion minimization (GEM)) would be equivalent or superior to conventional weight loss (WL) therapy in regard to reducing HbA1c, and superior to WL when investigating physical, behavioral and psychological secondary outcomes. The impact of BG feedback on GEM efficacy was also investigated.

Research Design And Methods: 178 adults with type 2 diabetes for ≤10 years, HbA1c ≥6.8%, and not using insulin were randomized to WL (n=40) or one of three versions of GEM. Didactic (GEM-D, n=39) taught participants to choose low-glycemic load foods, reduce sedentary time and increase moderate routine physical activity. GEM-S (n=51) received GEM-D and systematically measured BG before and after meals and physical activity to educate and motivate food and activity choices. GEM-C (n=48) received GEM-D with continuous glucose monitoring feedback. All participants received 6 hours of group training and BG and activity monitors. Before and 3 months after treatment, participants were assessed for HbA1c, lipids, weight, routine physical activity, nutrition, depression, diabetes empowerment and distress.

Results: GEM versions did not differ in primary or secondary outcomes, so they were combined for analyses. While WL reduced body mass index (BMI) (p=0.005), GEM demonstrated a greater reduction in HbA1c (p=0.005), BMI (p=0.013), carbohydrate intake (p=0.001), BG response to a glucose challenge (p=0.02), and cardiovascular risk (p=0.003). Only GEM participants significantly improved diabetes empowerment, diabetes distress, depressive symptoms, steps/day, and active hours and reduced calories/day. Neither intervention had negative side effects.

Conclusions: GEM is an effective alternative to WL with respect to physical, behavioral and psychosocial outcomes.

Trial Registration Number: NCT03196895.
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http://dx.doi.org/10.1136/bmjdrc-2020-001795DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7745682PMC
December 2020

Minimizing Glucose Excursions (GEM) With Continuous Glucose Monitoring in Type 2 Diabetes: A Randomized Clinical Trial.

J Endocr Soc 2020 Nov 18;4(11):bvaa118. Epub 2020 Aug 18.

University of Virginia School of Medicine, Endocrinology and Metabolism, Charlottesville, VA.

This study aimed to compare conventional medication management of type 2 diabetes (T2D) to medication management in conjunction with a lifestyle intervention using continuous glucose monitoring to minimize glucose excursions. Thirty adults (63% female; mean age, 53.3 years) who were diagnosed with T2D for less than 11 years (mean, 5.6 years), had glycated A (HbA) ≥ 7.0% (51 mmol/mol) (mean 8.8%, [73 mmol/mol]), and were not using insulin, were randomly assigned in a 1:2 ratio to routine care (RC) or 4 group sessions of glycemic excursion minimization plus real-time CGM (GEM). Assessments at baseline and 5 months included a physical exam, metabolic and lipid panels, a review of diabetes medications, and psychological questionnaires. For the week following assessments, participants wore a blinded activity monitor and completed 3 days of 24-hour dietary recall. A subgroup also wore a blinded CGM. GEM participants significantly improved HbA (from 8.9% to 7.6% [74-60 mmol/mol] compared with 8.8% to 8.7% [73-72 mmol/mol] for RC ( = .03). Additionally, GEM reduced the need for diabetes medication ( = .01), reduced carbohydrate consumption ( = .009), and improved diabetes knowledge ( = .001), quality of life ( = .01) and diabetes distress ( = .02), and trended to more empowerment ( = .05) without increasing dietary fat, lipids, or hypoglycemia. Confirming our prior research, GEM appears to be a safe, effective lifestyle intervention option for adults with suboptimally controlled T2D who do not take insulin.
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http://dx.doi.org/10.1210/jendso/bvaa118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7566397PMC
November 2020

Magnetic resonance imaging accurately tracks kidney pathology and heterogeneity in the transition from acute kidney injury to chronic kidney disease.

Kidney Int 2021 01 8;99(1):173-185. Epub 2020 Sep 8.

Department of Radiology, Washington University in St. Louis, St. Louis, Missouri, USA.

Acute kidney injury (AKI) increases the risk for chronic kidney disease (CKD). However, there are few tools to detect microstructural changes after AKI. Here, cationic ferritin-enhanced magnetic resonance imaging (CFE-MRI) was applied to examine the heterogeneity of kidney pathology in the transition from AKI to CKD. Adult male mice received folic acid followed by cationic ferritin and were euthanized at four days (AKI), four weeks (CKD-4) or 12 weeks (CKD-12). Kidneys were examined by histologic methods and CFE-MRI. In the CKD-4 and CKD-12 groups, glomerular number was reduced and atubular cortical lesions were observed. Apparent glomerular volume was larger in the AKI, CKD-4 and CKD-12 groups compared to controls. Glomerular hypertrophy occurred with ageing. Interglomerular distance and glomerular density were combined with other MRI metrics to distinguish the AKI and CKD groups from controls. Despite significant heterogeneity, the noninvasive (MRI-based) metrics were as accurate as invasive (histological) metrics at distinguishing AKI and CKD from controls. To assess the toxicity of cationic ferritin in a CKD model, CKD-4 mice received cationic ferritin and were examined one week later. The CKD-4 groups with and without cationic ferritin were similar, except the iron content of the kidney, liver, and spleen was greater in the CKD-4 plus cationic ferritin group. Thus, our study demonstrates the accuracy and safety of CFE-MRI to detect whole kidney pathology allowing for the development of novel biomarkers of kidney disease and providing a foundation for future in vivo longitudinal studies in mouse models of AKI and CKD to track nephron fate.
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http://dx.doi.org/10.1016/j.kint.2020.08.021DOI Listing
January 2021

Dose escalation study of bovine lactoferrin in preterm infants: getting the dose right.

Biochem Cell Biol 2021 Feb 26;99(1):7-13. Epub 2020 Aug 26.

Duke Human Vaccine Institute, Duke University Medical Center, Durham, North Carolina, USA.

Lactoferrin as a nutritional enteral supplement has emerged as a novel preventative therapy against serious infections in preterm infants, although neonatal studies have demonstrated variable results, in part due to the lack of pharmacokinetic data and differences in the products tested. We conducted a prospective, dose escalation (100, 200, and 300 mg·kg·day) safety study of bovine lactoferrin (Glanbia Nutritionals, USA) dissolved in sterile water (100 mg·mL) for 30 days in preterm infants with birth weight <1500 g. Safety related to adverse events (AEs), tolerability, and exposure-response of lactoferrin was assessed. We enrolled 31 patients [10, 10, and 11 patients, for the lactoferrin treatment groups (100, 200, and 300 mg·kg·day, respectively)] over a 10-month period. No AEs related to the study solution occurred, and lactoferrin was tolerated by each group. During lactoferrin supplementation, one bloodstream infection occurred in each group, but there were no incidences of urinary tract infections and no cases of necrotizing enterocolitis. Postnatal cytomegalovirus acquisition was detected in the group treated with 200 mg·kg·day ( = 2). There were no adverse effects on hepatic, renal, or hematologic function. All of the patients survived to discharge. Bovine lactoferrin at doses up to 300 mg·kg·day is safe in preterm infants. Future studies examining higher doses of lactoferrin, length of treatment, and potency of different products will aid in determining the optimal approach for the use of lactoferrin to prevent infections in preterm infants.
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http://dx.doi.org/10.1139/bcb-2020-0217DOI Listing
February 2021

The relative efficacy of the cranium and os coxa for taxonomic assessment in macaques.

Am J Phys Anthropol 2020 10 27;173(2):350-367. Epub 2020 Jun 27.

Buffalo Human Evolutionary Morphology Lab, Department of Anthropology, University at Buffalo, Buffalo, New York, USA.

Objectives: The cranium is generally considered more reliable than the postcranium for assessing primate taxonomy, although recent research suggests that pelvic shape may be equally reliable. However, little research has focused on intrageneric taxonomic discrimination. Here, we test the relative taxonomic efficacy of the cranium and os coxa for differentiating two macaque species, with and without considering sexual dimorphism.

Materials And Methods: Geometric morphometric analyses were performed on cranial and os coxa landmarks for 119 adult Macaca fascicularis, M. mulatta, and Chlorocebus pygerythrus. Among-group shape variation was examined using canonical variates analyses. Cross-validated discriminant function analysis provided rates of correct group classification. Additionally, average morphological distances were compared with neutral genetic distances.

Results: Macaque species were clearly differentiated, both cranially and pelvically, when sex was not considered. Males were more often correctly classified based on the os coxa, while female classification rates were high for both morphologies. Female crania and male os coxa were differentiated approximately the same as genetic distance, while male crania were more similar (convergent), and female os coxa were more divergent than expected based on genetic distance.

Discussion: The hypothesis that cranial and os coxal shape can be used to discriminate among macaque species was supported. The cranium was better at differentiating females, while the os coxa was better at differentiating male macaques. Hence, there is no a priori reason for preferring the cranium when assessing intragenetic taxonomic relationships, but the effects of high levels of sexual dimorphism must be corrected for to accurately assess taxonomic signatures.
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http://dx.doi.org/10.1002/ajpa.24100DOI Listing
October 2020

Prenatal consults with illustrated literature (PnCIL): a RCT studying visual aids during prenatal consults.

J Perinatol 2020 08 8;40(8):1154-1162. Epub 2020 Jun 8.

Division of Neonatology, Department of Pediatrics, University of Virginia, Charlottesville, VA, USA.

Objective: We hypothesize that addition of illustrated handouts during prenatal consultations decreases maternal anxiety and improves maternal knowledge.

Study Design: Inpatient gravid women at 25 0/7-34 6/7 weeks gestation were randomized to Standard or Illustrated consults, verbal consults supplemented with a visual handout. Post consult surveys were administered assessing maternal anxiety and knowledge acquisition.

Result: We enrolled 82 women; 54 to Standard Consult, 28 to Illustrated Consult. Consult duration was the same across arms. Anxiety and knowledge were not impacted by the intervention overall. We found higher mean knowledge by 17% for consults ≥31 min (P = 0.006; 95% CI 0.67-3.82), and 13% in primigravids (P = 0.032; 95% CI 0.15-3.21) in the intervention arm.

Conclusions: Using illustrated handouts is feasible and does not increase duration of prenatal consults. It may improve knowledge acquisition in long consults and in primigravida women, although it does not impact anxiety and knowledge overall.
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http://dx.doi.org/10.1038/s41372-020-0709-yDOI Listing
August 2020

Adenosine A2A receptor agonist (regadenoson) in human lung transplantation.

J Heart Lung Transplant 2020 06 13;39(6):563-570. Epub 2020 Feb 13.

Division of Developmental Immunology, La Jolla Institute for Immunology and Department of Pharmacology, University of California, San Diego, California.

Background: Currently, there are no clinically approved treatments for ischemia-reperfusion injury after lung transplantation. Pre-clinical animal models have demonstrated a promising efficacy of adenosine receptor (AR) agonists as a treatment option for reducing ischemia-reperfusion injury. The purpose of this human study, is to conduct a Phase I clinical trial for evaluating the safety of continuous infusion of an AR agonist in lung transplant recipients.

Methods: An adaptive, two-stage continual reassessment trial was designed to evaluate the safety of regadenoson (AR agonist) in the setting of lung transplantation. Continuous infusion of regadenoson was administered to lung transplant recipients that was started at the time of skin incision. Adverse events and dose-limiting toxicities, as pre-determined by a study team and assessed by a clinical team and an independent safety monitor, were the primary end-points for safety in this trial.

Results: Between January 2018 and March 2019, 14 recipients were enrolled in the trial. Of these, 10 received the maximum infused dose of 1.44 µg/kg/min for 12 hours. No dose-limiting toxicities were observed. The steady-state plasma regadenoson levels sampled before the reperfusion of the first lung were 0.98 ± 0.46 ng/ml. There were no mortalities within 30 days.

Conclusions: Regadenoson, an AR agonist, can be safely infused in the setting of lung transplantation with no dose-limiting toxicities or drug-related mortality. Although not powered for the evaluation of secondary end-points, the results of this trial and the outcome of pre-clinical studies warrant further investigation with a Phase II randomized controlled trial.
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http://dx.doi.org/10.1016/j.healun.2020.02.003DOI Listing
June 2020

Looking past PD-L1: expression of immune checkpoint TIM-3 and its ligand galectin-9 in cervical and vulvar squamous neoplasia.

Mod Pathol 2020 06 6;33(6):1182-1192. Epub 2020 Mar 6.

Department of Pathology, University of Virginia, Charlottesville, VA, USA.

Immunotherapies targeting the PD-1/PD-L1 pathway have shown some success in cervical and vulvar squamous cell carcinomas, but little is known about the potential vulnerability of these tumors to other checkpoint inhibitors. TIM-3 is a checkpoint molecule that exerts immunosuppressive function via its interaction with Gal-9. TIM-3 and Gal-9 have been identified on a variety of malignancies but have not been studied in cervical and vulvar cancers, nor has their relationship to PD-L1 been established. Sixty-three cervical and vulvar invasive (n = 34) and intraepithelial lesions (n = 29) were assessed for TIM-3, Gal-9, and PD-L1 in tumor/lesional cells and associated immune cells. Tumoral TIM-3 expression was identified in 85% of squamous cell carcinomas but only 21% of intraepithelial lesions (p < 0.0001). When immune cells were also accounted for, 97% of invasive and 41% of intraepithelial lesions had a TIM-3 combined positive score (CPS) ≥ 1 (p < 0.0001). Tumoral membranous expression of Gal-9 was seen in 82% of squamous cell carcinomas and 31% of intraepithelial lesions (p = 0.0001); nearly all cases had Gal-9-positive immune cells. Tumoral PD-L1 was seen in 71% of squamous cell carcinomas and 10% of intraepithelial lesions (p < 0.0001), while the PD-L1 CPS was ≥1 in 82 and 21%, respectively (p < 0.0001). There were no significant differences in TIM-3, GAL-9, or PD-L1 expression in cervical vs. vulvar neoplasms, nor was HPV status significantly associated with any of the three markers. Dual TIM-3/Gal-9 expression was present in the majority (86%) of PD-L1-positive cases including 100% of PD-L1-positive squamous cell carcinomas, suggesting a possible role for TIM-3 checkpoint inhibition in concert with anti-PD-1/PD-L1.
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http://dx.doi.org/10.1038/s41379-019-0433-3DOI Listing
June 2020

Understanding the asthmatic response to an experimental rhinovirus infection: Exploring the effects of blocking IgE.

J Allergy Clin Immunol 2020 09 1;146(3):545-554. Epub 2020 Feb 1.

Department of Pediatric Infectious Diseases, University of Virginia, Charlottsville, Va.

Background: Rhinovirus frequently causes asthma exacerbations among children and young adults who are allergic. The interaction between allergen and rhinovirus-induced symptoms and inflammation over time is unclear.

Objective: Our aim was to compare the response to an experimental inoculation with rhinovirus-16 in allergic asthmatics with the response in healthy controls and to evaluate the effects of administrating omalizumab before and during the infection.

Methods: Two clinical trials were run in parallel. In one of these trials, the response to an experimental inoculation with rhinovirus-16 among asthmatics with high levels of total IgE was compared to the response in healthy controls. The other trial compared the effects of administering omalizumab versus placebo to asthmatics in a randomized, double-blind placebo-controlled investigation. The primary outcome for both trials compared lower respiratory tract symptoms (LRTSs) between study groups over the first 4 days of infection.

Results: Frequent comparisons of symptoms, lung function, and blood eosinophil counts revealed differences that were more pronounced among allergic asthmatics than among controls by days 2 and 3 after virus inoculation. Additionally, an augmentation of upper respiratory tract symptom scores and LRTS scores occurred among the atopic asthmatics versus the controls during the resolution of symptoms (P < .01 for upper respiratory symptom tract scores and P < .001 for LRTS scores). The beneficial effects of administering omalizumab on reducing LRTSs and improving lung function were strongest over the first 4 days.

Conclusions: LRTSs and blood eosinophil counts were augmented and lung function was reduced among allergic asthmatics early after rhinovirus inoculation but increased late in the infection during symptom resolution. The effect of administering omalizumab on the response to rhinovirus was most pronounced during the early/innate phase of the infection.
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http://dx.doi.org/10.1016/j.jaci.2020.01.035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7733370PMC
September 2020

Picking up the Pace: Decreasing Platelet Administration Safely and Effectively.

J Pediatr Nurs 2020 May - Jun;52:1-4. Epub 2020 Jan 31.

University of Virginia Medical Center, Charlottesville, VA, USA; University of Virginia School of Nursing, VA, USA. Electronic address:

Background: Hematology-oncology patients often require blood and blood product transfusions, including platelets (PLTs), to maintain stability. Administering PLTs in a shorter timeframe may prove beneficial by possibly raising platelet counts to a higher level faster, and allowing patients to be disconnected from IV pumps sooner.

Objective: To evaluate the optimal (safe and effective) transfusion time by comparing standard administration of PLTs over 2-4 h to the investigational administration of PLTs over 30-45 min in the pediatric hematology-oncology inpatient population.

Methodology: A pilot trial was conducted using a convenience sample of hematology-oncology children. Children prescribed a PLT transfusion while admitted to an inpatient unit were eligible. If randomized to the intervention group, the nurse administered the PLTs over 30-45 min. If randomized to the standard group, the nurse administered the PLTs over 2-4 h. Post transfusion PLTcount was drawn 30 min after completion. The child was monitored closely for adverse reactions.

Results: Eleven participants were enrolled in the study and 20 PLT infusions administered. No adverse events were noted. There was not a significant difference in changes in PLT counts by group (post minus pre), p = 0.082. There was not a significant difference in post infusion PLT counts, p = 0.727. There was a significant difference in the rate of change in PLT counts by groups, p = 0.003.

Nursing Implications: This pilot study provides preliminary evidence that PLTs may be safely and effectively administered over 30-45 min in pediatric hematology-oncology patients. With quicker PLT administration, patients can be disconnected from IV pumps sooner.
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http://dx.doi.org/10.1016/j.pedn.2020.01.014DOI Listing
January 2020

Coherence principles in interval-based dose finding.

Pharm Stat 2020 03 6;19(2):137-144. Epub 2019 Nov 6.

Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA.

This paper studies the notion of coherence in interval-based dose-finding methods. An incoherent decision is either (a) a recommendation to escalate the dose following an observed dose-limiting toxicity or (b) a recommendation to deescalate the dose following a non-dose-limiting toxicity. In a simulated example, we illustrate that the Bayesian optimal interval method and the Keyboard method are not coherent. We generated dose-limiting toxicity outcomes under an assumed set of true probabilities for a trial of n=36 patients in cohorts of size 1, and we counted the number of incoherent dosing decisions that were made throughout this simulated trial. Each of the methods studied resulted in 13/36 (36%) incoherent decisions in the simulated trial. Additionally, for two different target dose-limiting toxicity rates, 20% and 30%, and a sample size of n=30 patients, we randomly generated 100 dose-toxicity curves and tabulated the number of incoherent decisions made by each method in 1000 simulated trials under each curve. For each method studied, the probability of incurring at least one incoherent decision during the conduct of a single trial is greater than 75%. Coherency is an important principle in the conduct of dose-finding trials. Interval-based methods violate this principle for cohorts of size 1 and require additional modifications to overcome this shortcoming. Researchers need to take a closer look at the dose assignment behavior of interval-based methods when using them to plan dose-finding studies.
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http://dx.doi.org/10.1002/pst.1974DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7065921PMC
March 2020

Delayed Umbilical Cord Clamping is Not Associated with Acute Kidney Injury in Very Low Birth Weight Neonates.

Am J Perinatol 2020 01 13;37(2):210-215. Epub 2019 Oct 13.

Department of Pediatrics, University of Virginia, Charlottesville, Virginia.

Objective: This study aimed to determine if delayed cord clamping (DCC) is associated with a reduction in neonatal acute kidney injury (AKI).

Study Design: A retrospective single-center cohort study of 278 very low birth weight (VLBW) neonates was performed to compare the incidence of AKI in the following groups: immediate cord clamping (ICC), DCC, and umbilical cord milking. AKI was diagnosed by the modified neonatal Kidney Diseases and Improving Global Outcomes (KDIGO) definition.

Results: The incidence of AKI in the first week was 20.1% with no difference between groups ( = 0.78). After adjustment for potential confounders, the odds of developing AKI, following DCC, compared with ICC was 0.93 (confidence interval [CI]: 0.46-1.86) with no reduction in the stage of AKI between groups.

Conclusion: In this study, DCC was not associated with a reduced rate of AKI in VLBW neonates. However, the data suggest that DCC is also not harmful to the kidneys, further supporting the safety of DCC in VLBW neonates.
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http://dx.doi.org/10.1055/s-0039-1697671DOI Listing
January 2020

A MULTICENTER STUDY EVALUATING PERCEPTIONS AND KNOWLEDGE OF INPATIENT GLYCEMIC CONTROL AMONG RESIDENT PHYSICIANS: ANALYZING THEMES TO INFORM AND IMPROVE CARE.

Endocr Pract 2019 Dec 14;25(12):1295-1303. Epub 2019 Aug 14.

In this descriptive study, we evaluated perceptions and knowledge of inpatient glycemic control among resident physicians. We performed this study at four academic medical centers: the University of Mississippi Medical Center, University of Virginia Health System, University of Louisville Health Sciences Center, and Emory University. We designed a questionnaire, and Institutional Review Board approval was granted at each institution prior to study initiation. We then administered the questionnaire to Internal Medicine and Medicine-Pediatric resident physicians. A total of 246 of 438 (56.2%) eligible resident physicians completed the Inpatient Glycemic Control Questionnaire (IGCQ). Most respondents (85.4%) reported feeling comfortable treating and managing inpatient hyperglycemia, and a majority (66.3%) agreed they had received adequate education. Despite self-reported comfort with knowledge, only 51.2% of respondents could identify appropriate glycemic targets in critically ill patients. Only 45.5% correctly identified appropriate inpatient random glycemic target values in noncritically ill patients, and only 34.1% of respondents knew appropriate preprandial glycemic targets in noncritically ill patients. A small majority (54.1%) were able to identify the correct fingerstick glucose value that defines hypoglycemia. System issues were the most commonly cited barrier to successful inpatient glycemic control. Most respondents reported feeling comfortable managing inpatient hyperglycemia but had difficulty identifying appropriate inpatient glycemic target values. Future interventions could utilize the IGCQ as a pre- and postassessment tool and focus on early resident education along with improving system environments to aid in successful inpatient glycemic control. = diabetes mellitus; = Emory University Healthcare; = inpatient glycemic control; = Inpatient Glycemic Control Questionnaire; = Institutional Review Board; = postgraduate year; = University of Mississippi Medical Center; = University of Virginia Health System; = University of Louisville Health Sciences Center.
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http://dx.doi.org/10.4158/EP-2019-0299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7286353PMC
December 2019

Trajectory of right ventricular indices is an early predictor of outcomes in hypoplastic left heart syndrome.

Congenit Heart Dis 2019 Nov 8;14(6):1185-1192. Epub 2019 Aug 8.

Division of Cardiology, Department of Pediatrics, University of Virginia, Charlottesville, Virginia.

Background: Children with hypoplastic left heart syndrome (HLHS) have risk for mortality and/or transplantation. Previous studies have associated right ventricular (RV) indices in a single echocardiogram with survival, but none have related serial measurements to outcomes. This study sought to determine whether the trajectory of RV indices in the first year of life was associated with transplant-free survival to stage 3 palliation (S3P).

Methods: HLHS patients at a single center who underwent stage 1 palliation (S1P) between 2000 and 2015 were reviewed. Echocardiographic indices of RV size and function were obtained before and following S1P and stage 2 palliation (S2P). The association between these indices and transplant-free survival to S3P was examined.

Results: There were 61 patients enrolled in the study with 51 undergoing S2P, 20 S3P, and 18 awaiting S3P. In the stage 1 perioperative period, indexed RV end-systolic area increased in patients who died or needed transplant following S2P, and changed little in those surviving to S3P (3.37 vs -0.04 cm /m , P = .017). Increased indexed RV end-systolic area was associated with worse transplant-free survival. (OR = 0.815, P = .042). In the interstage period, indexed RV end-diastolic area increased less in those surviving to S3P (3.6 vs 9.2, P = .03).

Conclusion: Change in indexed RV end-systolic area through the stage 1 perioperative period was associated with transplant-free survival to S3P. Neither the prestage nor poststage 1 indexed RV end-systolic area was associated with transplant-free survival to S3P. Patients with death or transplant before S3P had a greater increase in indexed RV end-diastolic area during the interstage period. This suggests earlier serial changes in RV size which may provide prognostic information beyond RV indices in a single study.
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http://dx.doi.org/10.1111/chd.12834DOI Listing
November 2019

Discovery of a novel long noncoding RNA overlapping the LCK gene that regulates prostate cancer cell growth.

Mol Cancer 2019 06 28;18(1):113. Epub 2019 Jun 28.

Departments of Microbiology Immunology, and Cancer Biology, University of Virginia, Charlottesville, Virginia, 22908, USA.

Background: Virtually all patients with metastatic prostate cancer (PCa) will relapse and develop lethal castration-resistant prostate cancer (CRPC). Long noncoding RNAs (lncRNAs) are emerging as critical regulatory elements of many cellular biological processes, and may serve as therapeutic targets for combating PCa progression. Here, we have discovered in a high-throughput RNAi screen a novel lncRNA in PCa, and assessed the oncogenic effects of this lncRNA.

Methods: Rapid amplification of cDNA ends and sequencing was utilized to identify a previously unannotated lncRNA lying within exon six and the 3'UTR of the lymphocyte-specific protein tyrosine kinase (LCK) gene. The levels of HULLK in the presence or absence of hormone and/or enzalutamide or coregulator inhibitors were measured by quantitative PCR (qPCR). The determination of HULLK transcription and localization were characterized by strand-specific qPCR and cellular fractionation followed by qPCR, respectively. The correlation between HULLK expression and prostate cancer Gleason score was analyzed by droplet digital PCR. CyQuant assays were conducted to evaluate the effects of knocking down HULLK with shRNAs or overexpressing HULLK on cell growth.

Results: In this study, a previously unannotated lncRNA lying within exon six and 3'UTR of the LCK gene was dramatically upregulated by androgen in a dose-dependent manner, and the anti-androgen enzalutamide completely blocked this hormone-induced increase. Therefore, we labeled this lncRNA "HULLK" for Hormone-Upregulated lncRNA within LCK. Binding sites for two AR coregulators p300 and Brd4 reside near the HULLK transcriptional start site (TSS), and inhibitors of these coregulators downregulated HULLK. HULLK is transcribed from the sense strand of DNA, and predominantly localizes to the cytoplasm. HULLK transcripts are not only expressed in prostate cancer cell lines, but also prostate cancer patient tissue. Remarkably, there was a significant positive correlation between HULLK expression and high-grade PCa in multiple cohorts. shRNAs targeting HULLK significantly decreased PCa cell growth. Moreover, cells overexpressing HULLK were hypersensitive to androgen stimulation.

Conclusions: HULLK is a novel lncRNA situated within the LCK gene that may serve as an oncogene in PCa. Our data enhances our understanding of lncRNA biology and may assist in the development of additional biomarkers or more effective therapeutic targets for advanced PCa.
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http://dx.doi.org/10.1186/s12943-019-1039-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6598369PMC
June 2019

Construction and preliminary evaluation of the inpatient glycemic control questionnaire (IGCQ): a survey tool assessing perceptions and knowledge of resident physicians.

BMC Med Educ 2019 Jun 24;19(1):228. Epub 2019 Jun 24.

Division of General Internal Medicine and Hypertension, Department of Medicine, University of Mississippi Medical Center, Jackson, MS, USA.

Background: Uncontrolled hyperglycemia in hospitalized patients, with or without diabetes mellitus, is associated with many adverse outcomes. Resident physicians are the primary managers of inpatient glycemic control (IGC) in many academic and community medical centers; however, no validated survey tools related to their perceptions and knowledge of IGC are currently available. As identification of common barriers to successful IGC amongst resident physicians may help foster better educational interventions (ultimately leading to improvements in IGC and patient care), we sought to construct and preliminarily evaluate such a survey tool.

Methods: We developed the IGC questionnaire (IGCQ) by using previously published but unvalidated survey tools related to physician perspectives on inpatient glycemic control as a framework. We administered the IGCQ to a cohort of resident physicians from the University of Mississippi Medical Center, University of Louisville, Emory University, and the University of Virginia. We then used classical test theory and Rasch Partial Credit Model analyses to preliminarily evaluate and revise the IGCQ. The final survey tool contains 16 total items and three answer-choice categories for most items.

Results: Two hundred forty-six of 438 (56.2%) eligible resident physicians completed the IGCQ during various phases of development.

Conclusions: We constructed and preliminarily evaluated the IGCQ, a survey tool that may be useful for future research into resident physician perceptions and knowledge of IGC. Future studies could seek to externally validate the IGCQ and then utilize the survey tool in pre- and post-intervention assessments.
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http://dx.doi.org/10.1186/s12909-019-1657-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6591905PMC
June 2019

Consequences of Performing Parallel Dose Finding Trials in Heterogeneous Groups of Patients.

JNCI Cancer Spectr 2019 Jun 7;3(2):pkz013. Epub 2019 May 7.

Division of Translational Research and Applied Statistics, Department of Public Health Sciences, University of Virginia, Charlottesville, VA.

Patient heterogeneity, in which patients can be grouped by risk of toxicity, is a design challenge in early phase dose finding trials. Carrying out independent trials for each group is a readily available approach for dose finding. However, this often leads to dose recommendations that violate the known order of toxicity risk by group, or reversals in dose recommendation. In this manuscript, trials for partially ordered groups are simulated using four approaches: independent parallel trials using the continual reassessment method (CRM), Bayesian optimal interval design, and 3 + 3 methods, as well as CRM for partially ordered groups. Multiple group order structures are considered, allowing for varying amounts of group frailty order information. These simulations find that parallel trials in the presence of partially ordered groups display a high frequency of trials resulting in reversals. Reversals occur when dose recommendations do not follow known order of toxicity risk by group, such as recommending a higher dose level in a group of patients known to have a higher risk of toxicity. CRM for partially ordered groups eliminates the issue of reversals, and simulation results indicate improved frequency of maximum tolerated dose selection as well as treating a greater proportion of trial patients at this dose compared with parallel trials. When information is available on differences in toxicity risk by patient subgroup, methods designed to account for known group ordering should be considered to avoid reversals in dose recommendations and improve operating characteristics.
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http://dx.doi.org/10.1093/jncics/pkz013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6555302PMC
June 2019

The Role of Early-Phase Design-Response.

Clin Cancer Res 2019 05;25(10):3191

Division of Translational Research and Applied Statistics, The University of Virginia Health System, Charlottesville, Virginia.

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http://dx.doi.org/10.1158/1078-0432.CCR-19-0618DOI Listing
May 2019

Reasons for Early Cessation of Breastfeeding Among Women with Low Income.

Breastfeed Med 2019 Jul/Aug;14(6):375-381. Epub 2019 Apr 17.

3 Department of Pediatrics, University of Virginia, Charlottesville, Virginia.

Most women in the United States do not meet their breastfeeding goals, and low-income women breastfeed at lower rates than the general population. While risk factors for early cessation have been documented, specific reasons for discontinuing among this population are less understood. We examined reasons for cessation among low-income mothers to inform the development of targeted strategies to address breastfeeding disparities. We performed a secondary data analysis using prospective data collected during a randomized intervention trial of Special Supplemental Nutrition Program for Women, Infants, and Children (WIC)-eligible women interviewed in the third trimester and at 1, 3, and 6 months postpartum. We included the 221 women who initiated breastfeeding and stopped by 6 months. Women's reasons for discontinuing breastfeeding were grouped by thematic category and compared by time of breastfeeding cessation. The most common reasons reported overall for breastfeeding cessation were concerns about breast milk supply and latch difficulty. Some reasons differed significantly by time of cessation. Latch difficulty was reported most often by women who breastfed for 1 month or less; supply concerns increased with increasing breastfeeding duration. Returning to work/school was uncommonly reported for those who stopped by 1 month, but more frequently reported in those with later cessation. We found that low-income women reported similar reasons for early breastfeeding cessation as have been reported for other populations of women. These results underscore the need for appropriately timed, culturally sensitive interventions to reduce disparities in duration of breastfeeding, specifically to address latch difficulty in the first few weeks and supply concerns as infants grow.
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http://dx.doi.org/10.1089/bfm.2018.0206DOI Listing
April 2020

Acid ceramidase promotes drug resistance in acute myeloid leukemia through NF-κB-dependent P-glycoprotein upregulation.

J Lipid Res 2019 06 8;60(6):1078-1086. Epub 2019 Apr 8.

Department of Medicine, Division of Hematology and Oncology University of Virginia School of Medicine, Charlottesville, VA

Acute myeloid leukemia (AML) is the most common acute leukemia in adults. More than half of older AML patients fail to respond to cytotoxic chemotherapy, and most responders relapse with drug-resistant disease. Failure to achieve complete remission can be partly attributed to the drug resistance advantage of AML blasts that frequently express P-glycoprotein (P-gp), an ATP-binding cassette transporter. Our previous work showed that elevated acid ceramidase (AC) levels in AML contribute to blast survival. Here, we investigated P-gp expression levels in AML relative to AC. Using parental HL-60 cells and drug-resistant derivatives as our model, we found that P-gp expression and efflux activity were highly upregulated in resistant derivatives. AC overexpression in HL-60 conferred resistance to the AML chemotherapeutic drugs, cytarabine, mitoxantrone, and daunorubicin, and was linked to P-gp upregulation. Furthermore, targeting AC through pharmacologic or genetic approaches decreased P-gp levels and increased sensitivity to chemotherapeutic drugs. Mechanistically, AC overexpression increased NF-κB activation whereas NF-kB inhibitors reduced P-gp levels, indicating that the NF-kappaB pathway contributes to AC-mediated modulation of P-gp expression. Hence, our data support an important role for AC in drug resistance as well as survival and suggest that sphingolipid targeting approaches may also impact drug resistance in AML.
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http://dx.doi.org/10.1194/jlr.M091876DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6547629PMC
June 2019

Body mass index trajectories in pediatric multiple sclerosis.

Dev Med Child Neurol 2019 11 5;61(11):1289-1294. Epub 2019 Apr 5.

Department of Neurology, University of Virginia, Charlottesville, VA, USA.

Aim: To characterize growth trajectories of children who develop multiple sclerosis compared to typically developing, regional peers and Centers for Disease Control (CDC) normative values.

Method: This case-control study collected weight, height, and body mass index (BMI) in 40 consecutive pediatric patients with multiple sclerosis (28 females, 12 males), in addition to 120 typically developing peers (84 females, 36 males), identified and matched for year of birth, sex, ethnicity, and socio-economic status. BMI values were converted to z-scores based on CDC reference values and were compared with respect to age between our two cohorts and by years relative to multiple sclerosis onset for cases.

Results: Median age for the clinical onset of multiple sclerosis was 15 years. BMI z-scores are significantly higher for patients with multiple sclerosis compared to typically developing, demographically-matched peers and CDC standards. These significant differences in BMI are noted from 4 years of age and onward. Height trajectories were similar among case and control individuals and CDC normative values.

Interpretation: BMI in pediatric multiple sclerosis is markedly higher, beginning in early childhood, years before the clinical-onset of the disease.

What This Paper Adds: Children with multiple sclerosis are significantly more overweight than typically developing peers at the time of diagnosis. Body mass index trajectories are significantly higher years before the clinical manifestation(s) of multiple sclerosis.
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http://dx.doi.org/10.1111/dmcn.14233DOI Listing
November 2019

Children with Hemiparesis Arm and Movement Project (CHAMP): protocol for a multisite comparative efficacy trial of paediatric constraint-induced movement therapy (CIMT) testing effects of dosage and type of constraint for children with hemiparetic cerebral palsy.

BMJ Open 2019 01 15;9(1):e023285. Epub 2019 Jan 15.

University of Virginia, Charlottesville, Virginia, USA.

Introduction: The Children with Hemiparesis Arm and Movement Project (CHAMP) addresses two pressing issues concerning paediatric constraint-induced movement therapy (CIMT): effects of two dosages and two types of constraint on functional outcomes. Systematic reviews conclude that CIMT is one of the most efficacious treatments, but wide variations in treatment protocols, outcome measures and patient characteristics have prevented conclusions about potential effects of dosage levels and constraint methods.

Methods And Analysis: CHAMP is a multisite comparative efficacy randomised controlled trial of 135 children (2-8 years) with hemiparetic cerebral palsy. The 2×2 factorial design tests two dosage levels-60 hours (3.0 hours/day, 5 days/week × 4 weeks) and 30 hours (2.5 hours/day, 3 days/week × 4 weeks) and two constraint conditions-full-arm, full-time cast and part-time splint, plus usual and customary (UCT) controls, yielding five groups: (1) 60 hours CIMT+full-time cast, (2) 60 hours CIMT+part-time splint, (3) 30 hours CIMT+full-time cast, (4) 30 hours CIMT+part-time splint and (5) UCT. Trained therapists deliver the standardised ACQUIREc protocol for CIMT. Blinded assessments at baseline, end of treatment, and 6 and 12 months post treatment include the Assisting Hand Assessment, and subscales from the Peabody Developmental Motor Scales-2 and modified Quality of Upper Extremity Skills Test. Parents complete the Pediatric Motor Activity Log and Pediatric Evaluation of Disability Inventory. A new Fidelity of Implementation Rehabilitation Measure monitors treatment delivery. Data analyses involve repeated-measures multivariate analysis of co-variance controlling for selected baseline variables.

Ethics And Dissemination: Ethics boards at site universities approved the study protocol. To promote equipoise, parents of UCT controls are offered ACQUIREc after 6 months. A Data Safety and Monitoring Committee reviews results regularly, including measures of child and family stress. We will disseminate CHAMP results via peer-reviewed publications and presentations to professional and advocacy organisations.

Trial Registration Number: NCT01895660; Pre-results.
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http://dx.doi.org/10.1136/bmjopen-2018-023285DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6340418PMC
January 2019

Low Risk of Adrenal Insufficiency After Use of Low- to Moderate-Potency Topical Corticosteroids for Children With Atopic Dermatitis.

Clin Pediatr (Phila) 2019 04 29;58(4):406-412. Epub 2019 Jan 29.

1 University of Virginia, Charlottesville, VA, USA.

Our objective was to assess the risk of adrenal insufficiency (AI) with short-term use of low- to moderate-potency topical corticosteroids (TCS) for treatment of atopic dermatitis. Our systematic literature search revealed 9 studies (n = 371) that evaluated AI using adrenocorticotropic hormone stimulation testing, with measures of serum cortisol levels at baseline and following at least 2 weeks of TCS application. Biochemical AI was defined by a stimulated cortisol level of ≤18.0 µg/dL (~500 nmol/L). The overall proportion of AI with low-to-moderate TCS use was 2.7% (95% confidence interval = 1.47% to 4.89%). None of the children showed any clinical evidence of AI or adrenal crisis. Short-term use of low- to moderate-potency TCS for the treatment of atopic dermatitis is associated with a low risk of adrenal suppression. General practitioners do not need to test these patients for adrenal suppression in the absence of concerning signs and symptoms of AI.
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http://dx.doi.org/10.1177/0009922818825154DOI Listing
April 2019

Behavioral Strategies to Lower Postprandial Glucose in Those with Type 2 Diabetes May Also Lower Risk of Coronary Heart Disease.

Diabetes Ther 2019 Feb 18;10(1):277-281. Epub 2018 Dec 18.

Department of Acute and Specialty Care, University of Virginia School of Nursing, Charlottesville, VA, 22908, USA.

Introduction: Efforts to lower glycosylated hemoglobin (A1c) in patients with type 2 diabetes (T2D) are intended to reduce the risk of diabetic complications, but A1c is not the only factor contributing to this risk. Consequently, we re-analyzed published data from a broad-spectrum lifestyle intervention that lowered A1c to assess its effectiveness in lowering the overall risk of two complications of T2D, namely, coronary heart disease (CHD) and stroke.

Methods: Data from 37 adults who participated in a randomized clinical trial of a lifestyle intervention intended to reduce postprandial glucose (PPG) were re-analyzed for their pre- and post-treatment risk of CHD and stroke using the T2D-specific UK Prospective Diabetes Study (UKPDS) v2.0 risk algorithm.

Results: Compared to participants who received routine care, those using the lifestyle intervention had a significantly greater reduction in 10-year risk for CHD, but not for stroke.

Conclusion: These secondary analyses suggest that broad-spectrum lifestyle interventions that focus on lowering PPG may lower the risk of future CHD, which could guide future research.

Trial Registration: ClinicalTrials.gov ID: NCT02432391.
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http://dx.doi.org/10.1007/s13300-018-0554-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6349282PMC
February 2019

The effect of right ventricular function on survival and morbidity following stage 2 palliation: An analysis of the single ventricle reconstruction trial public data set.

Congenit Heart Dis 2019 Mar 2;14(2):274-279. Epub 2018 Dec 2.

Division of Cardiology, Department of Pediatrics, University of Virginia, Charlottesville, Virginia.

Objective: Limited information is known on how right ventricular function affects outcomes after stage 2 palliation. We evaluated the impact of different right ventricular indices prior to stage 2 palliation on morbidity and mortality.

Design: Retrospective study design.

Setting: Pediatric Heart Network Single Ventricle Reconstruction Trial Public Data Set.

Patient: Any variant of stage 1 palliation and all anatomic hypoplastic left heart syndrome variants in the trial were evaluated. Echocardiograms prior to stage 2 palliation were analyzed and compared between those who failed and those who survived.

Intervention: None.

Outcome Measures: Mortality was defined as death, listed for transplant, or transplanted after stage 2 palliation. Morbidity was evaluated as hospital length of stay and duration of intubation.

Results: A total of 283 patients met criteria for analysis. Of those, only 18 patients failed stage 2. Right ventricular fractional area change was less in those who failed (30% vs 34%, P = .039) and right ventricular indexed end-diastolic volume and end-systolic volume were larger in those who failed (142.74 mL/ BSA vs 111.29 mL/BSA , P = .023, 88.45 mL/ BSA vs 62.75 mL/ BSA , P = .025, respectively). Larger right ventricular indexed end-diastolic and systolic volumes were associated with failure (OR 1.17 [1.01-1.35] P = .021, OR 1.25 [1.03-1.52] P = .021, respectively). Every 10% increase in RV ejection fraction had a 63% decrease in length of stay and a 68% decrease in duration of intubation (P = .014, and P = .039, respectively).

Conclusion: Patients with decreased right ventricular fractional area change and larger right ventricular indexed end-diastolic and systolic volumes were more likely to fail stage 2 palliation. Those with preserved right ventricular function had a shorter hospital length of stay and duration of intubation. Echocardiographic measurements of right ventricular indices during the interstage period can be utilized to determine the prognosis following stage 2 palliation.
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http://dx.doi.org/10.1111/chd.12722DOI Listing
March 2019