Efficacy of Epicutaneous Immunotherapy in Children With Milk-Induced Eosinophilic Esophagitis.

BACKGROUND & AIMS: Eosinophilic esophagitis (EoE) is caused by an immune response to specific food allergens. There are no approved therapies beyond avoidance of the allergen(s) or treatment of inflammation. Epicutaneous immunotherapy (EPIT) reduces features of eosinophilic gastrointestinal disease in mice and pigs. We performed randomized, placebo-controlled study to determine the safety and efficacy of EPIT with Viaskin milk in children with milk-induced EoE. METHODS: In a double-blind study, 20 children (4-17 years old) with milk-induced EoE were randomly assigned to groups given EPIT with Viaskin milk (n = 15) or placebo (n = 5) for 9 months during a milk-free period, followed by milk-containing diet for 2 months with EPIT. Then, subjects underwent upper endoscopy analysis, biopsies were collected, and maximum esophageal eosinophil counts were determined and was the primary endpoint. After upper endoscopy, patients were given open-label EPIT for 11 months (open-label phase). The subjects were allowed to consume milk if they had maximum values of fewer than 10 eosinophils/high-power field (eos/hpf); otherwise, they remained on a milk-free diet until the last 2 months of the open-label phase. RESULTS: In the intent to treat population, there was no significant difference between the Viaskin milk group in mean eos/hpf (50.1 ± 43.97 eos/hpf) vs the placebo group (48.20 ± 56.98 eos/hpf). However, in the per-protocol population (7 patients given Viaskin milk and 2 patients given placebo), patients given Viaskin milk patients had a significantly lower mean eos/hpf count (25.57 ± 31.19) than patients given placebo (95.00 ± 63.64) (p = .038). At the end of the open-label phase, 9 of 19 evaluable subjects had mean values of fewer than 15 eos/hpf (47% response). The number of adverse events did not differ significantly between the Viaskin milk and placebo groups; there was 1 serious adverse event in the placebo group. CONCLUSIONS: In a pilot study of pediatric patients with EoE given EPIT with Viaskin milk or placebo for 11 months, we found no significant difference between groups for the maximum eosinophil count at the end of the study. However, findings from a per-protocol analysis indicate that Viaskin milk can reduce eos/hpf. At study completion, 47% of patients who continued open-label Viaskin milk for an additional 11 months had mean values of fewer than 15 eos/hpf. ClinicalTrials.gov no: NCT02579876.

Persistent Basal Cell Hyperplasia Is Associated With Clinical and Endoscopic Findings in Patients With Histologically Inactive Eosinophilic Esophagitis.

BACKGROUND & AIMS: Although eosinophil count is the standard used to monitor disease activity in patients with eosinophilic esophagitis (EoE), there are often disparities between patient-reported symptoms and eosinophil counts. We examined the prevalence of epithelial alterations, namely basal cell hyperplasia (BCH) and spongiosis, among patients with inactive EoE (eosinophil counts below 15 following therapy) and aimed to determine whether maintenance of these changes in epithelial morphology are associated with persistent clinical findings. METHODS: Esophageal biopsies of 243 patients (mean age, 16.9 years) undergoing routine endoscopy at the University of Pennsylvania were evaluated for epithelial BCH and spongiosis. Univariable analysis was used to calculate the association between epithelial changes and symptoms as well as endoscopic findings and peak eosinophil count. We validated our findings using data from a cohort of patients at the University of North Carolina. RESULTS: The discovery and validation cohorts each included patients with inactive EoE, based on histologic factors, but ongoing BCH and spongiosis. Ongoing BCH, but not spongiosis, in patients with inactive EoE was associated with symptoms (odds ratio, 2.14; 95% CI, 1.03-4.42; P = .041) and endoscopic findings (odds ratio, 7.10; 95% CI, 3.12-16.18; P < .001). CONCLUSIONS: In patients with EoE, the presence of BCH might indicate ongoing disease activity, independent of eosinophil count. This might account for the persistent symptoms in patients who are considered to be in remission based on histologic factors.

Surviving Sepsis in a Referral Neonatal Intensive Care Unit: Association between Time to Antibiotic Administration and In-Hospital Outcomes.

OBJECTIVE: To determine if time to antibiotic administration is associated with mortality and in-hospital outcomes in a neonatal intensive care unit (NICU) population. STUDY DESIGN: We conducted a prospective evaluation of infants with suspected sepsis between September 2014 and February 2018; sepsis was defined as clinical concern prompting blood culture collection and antibiotic administration. Time to antibiotic administration was calculated from time of sepsis identification, defined as the order time of either blood culture or an antibiotic, to time of first antibiotic administration. We used linear models with generalized estimating equations to determine the association between time to antibiotic administration and mortality, ventilator-free and inotrope-free days, and NICU length of stay in patients with culture-proven sepsis. RESULTS: Among 1946 sepsis evaluations, we identified 128 episodes of culture-proven sepsis in 113 infants. Among them, prolonged time to antibiotic administration was associated with significantly increased risk of mortality at 14 days (OR, 1.47; 95% CI, 1.15-1.87) and 30 days (OR, 1.47; 95% CI, 1.11-1.94) as well as fewer inotrope-free days (incidence rate ratio, 0.91; 95% CI, 0.84-0.98). No significant associations with ventilator-free days or NICU length of stay were demonstrated. CONCLUSIONS: Among infants with sepsis, delayed time to antibiotic administration was an independent risk factor for death and prolonged cardiovascular dysfunction. Further study is needed to define optimal timing of antimicrobial administration in high-risk NICU populations.

Development of the Serum α-Fetoprotein Reference Range in Patients with Beckwith-Wiedemann Spectrum.

OBJECTIVE: To establish reference ranges for serum α-fetoprotein (AFP) at various ages in patients with Beckwith-Wiedemann spectrum (BWSp), to better predict the risk for hepatoblastoma in this population. STUDY DESIGN: A retrospective analysis of AFP measurements collected from patients with BWSp was performed. Factors including sex, prematurity, molecular diagnosis of patients, and performing laboratory were evaluated for significant differences. In total, 1372 AFP values were collected from 147 patients and the predictive AFP values at various ages were calculated to establish reference ranges. Mixed-effects polynomial regression models were used to study various potential factors affecting log(AFP) values. RESULTS: Overall, predicted AFP values declined to normal range for age (<10 ng/mL) by 14 months old. Patient sex and performing laboratory were found not to influence values. A significant difference was demonstrated between premature and nonpremature patients, and separate reference values were established. Significant differences in the predicted AFP value were not broadly apparent between molecular subtypes; however, interpretation was limited due to the small sample size of some of these subtypes. CONCLUSIONS: Predictive AFP values were created for premature and nonpremature patients with BWSp to aid with interpretation and monitoring of the risk for hepatoblastoma. Further analysis is needed to determine whether AFP values differ within the less common molecular subtypes of patients with BWSsp.

Efficacy, Safety, and Durability of Voretigene Neparvovec-rzyl in RPE65 Mutation-Associated Inherited Retinal Dystrophy: Results of Phase 1 and 3 Trials.

PURPOSE: To report the durability of voretigene neparvovec-rzyl (VN) adeno-associated viral vector-based gene therapy for RPE65 mutation-associated inherited retinal dystrophy (IRD), including results of a phase 1 follow-on study at year 4 and phase 3 study at year 2. DESIGN: Open-label phase 1 follow-on clinical trial and open-label, randomized, controlled phase 3 clinical trial. PARTICIPANTS: Forty subjects who received 1.5×1011 vector genomes (vg) of VN per eye in at least 1 eye during the trials, including 11 phase 1 follow-on subjects and 29 phase 3 subjects (20 original intervention [OI] and 9 control/intervention [CI]). METHODS: Subretinal injection of VN in the second eye of phase 1 follow-on subjects and in both eyes of phase 3 subjects. MAIN OUTCOME MEASURES: End points common to the phase 1 and phase 3 studies included change in performance on the Multi-Luminance Mobility Test (MLMT) within the illuminance range evaluated, full-field light sensitivity threshold (FST) testing, and best-corrected visual acuity (BCVA). Safety end points included adverse event reporting, ophthalmic examination, physical examination, and laboratory testing. RESULTS: Mean (standard deviation) MLMT lux score change was 2.4 (1.3) at 4 years compared with 2.6 (1.6) at 1 year after administration in phase 1 follow-on subjects (n = 8), 1.9 (1.1) at 2 years, and 1.9 (1.0) at 1 year post-administration in OI subjects (n = 20), and 2.1 (1.6) at 1 year post-administration in CI subjects (n = 9). All 3 groups maintained an average improvement in FST, reflecting more than a 2 log10(cd.s/m2) improvement in light sensitivity at 1 year and subsequent available follow-up visits. The safety profile was consistent with vitrectomy and the subretinal injection procedure, and no deleterious immune responses occurred. CONCLUSIONS: After VN gene augmentation therapy, there was a favorable benefit-to-risk profile with similar improvement demonstrated in navigational ability and light sensitivity among 3 groups of subjects with RPE65 mutation-associated IRD, a degenerative disease that progresses to complete blindness. The safety profile is consistent with the administration procedure. These data suggest that this effect, which is nearly maximal by 30 days after VN administration, is durable for 4 years, with observation ongoing.

Ultrasonographic Guidance to Improve First-Attempt Success in Children With Predicted Difficult Intravenous Access in the Emergency Department: A Randomized Controlled Trial.

STUDY OBJECTIVE: We determine whether ultrasonographically guided intravenous line placement improves the rate of first-attempt success by 20% for children with predicted difficult intravenous access. Secondary objectives included determining whether ultrasonographically guided intravenous line placement reduces the attempt number, improves time to access or parental satisfaction, or affects intravenous line survival and complications. METHODS: This was a prospective, randomized controlled trial conducted in an urban tertiary care pediatric emergency department that enrolled a convenience sample of children requiring an intravenous line and who were predicted to have difficult intravenous access according to a previously validated score. Participants were randomized to traditional or ultrasonographically guided intravenous line placement on first attempt and stratified by aged 0 to 3 versus older than 3 years. RESULTS: One hundred sixty-seven patients were enrolled and randomized to traditional intravenous line or to a care bundle with a multidisciplinary team trained to place ultrasonographically guided intravenous lines. First-attempt success was increased in the ultrasonographically guided intravenous line placement arm (n=83) compared with the traditional intravenous line arm (n=84) (85.4% versus 45.8%; relative risk 1.9; 95% confidence interval [CI] 1.5 to 2.4). There were fewer attempts in the ultrasonographically guided intravenous line placement arm than in the traditional intravenous line arm (median 1 versus 2; median difference 1; 95% CI 0.8 to 1.2) and a shorter time from randomization to intravenous line flush (median 14 minutes [interquartile range 11 to 20] versus 28 minutes [interquartile range 16 to 42]). A Kaplan-Meier survival analysis demonstrated that ultrasonographically guided intravenous lines survived longer than traditional ones (median 7.3 days [95% CI 3.7 to 9.5] versus 2.3 days [95% CI 1.8 to 3.3]). There was no difference in complications between the groups. Parents were more satisfied with ultrasonographically guided intravenous line placement. CONCLUSION: Ultrasonographically guided intravenous line placement in children with predicted difficult intravenous access improved first-attempt success and intravenous line longevity when conducted by a team of trained providers.

Determinants of Exercise Performance in Children and Adolescents with Repaired Tetralogy of Fallot Using Stress Echocardiography.

Exercise performance is variable and often impaired in patients with repaired tetralogy of Fallot (rTOF). We sought to identify factors associated with exercise performance by comparing high to low performers on cardiopulmonary exercise testing (CPET) in patients with rTOF. We conducted a cross-sectional study of subjects presenting for CPET who underwent echocardiograms at rest and peak exercise. Patients with pacemakers and arrhythmias were excluded. Right ventricular (RV) global longitudinal strain was used as a measure of systolic function. Pulmonary insufficiency (PI) was assessed with the diastolic systolic ratio and the diastolic systolic time-velocity integral ratio by Doppler interrogation of the pulmonary artery. CPET measures included percent-predicted maximum [Formula: see text][Formula: see text], percent-predicted maximum work and oxygen pulse. High versus low performers were identified as those achieving [Formula: see text] of at least 80% or falling below, respectively. Differences in echocardiographic parameters from rest to peak exercise were examined using mixed-effects regression models. Compared to the low performers (n = 17), high performers (n = 12) were younger (12.8 ± 3.3 years vs. 18.3 ± 4.8 years), had normal chronotropic response (peak heart rate > 185 bpm) with greater heart rate reserve and superior physical working capacity. High performers also had a greater reduction in PI at peak exercise, despite greater PI severity at rest. Oxygen pulse was comparable between groups. For both groups, there was no association of PI severity and RV systolic function at rest with exercise parameters. There was no group difference in the magnitude of change in RV strain and diastolic parameters from rest to peak exercise. Chronotropic response to exercise appears to be an important parameter with which to assess exercise performance in rTOF. Chronotropic health should be taken into consideration in this population, particularly given that RV function and PI severity at rest were not associated with exercise performance.

Red cell transfusion practices after stage 1 palliation: a survey of practitioners from the Pediatric Cardiac Intensive Care Society.

INTRODUCTION: Neonates may require increased red cell mass to optimise oxygen content after stage 1 palliation; however, data informing transfusion practices are limited. We hypothesise there is a patient-, provider-, and institution-based heterogeneity in red cell transfusion decision-making after stage 1 palliation. METHODS: We conducted an online survey of Pediatric Cardiac Intensive Care Society practitioners in 2016. Respondents answered scenario-based questions that defined transfusion indications and identified haematocrit transfusion thresholds. Respondents were divided into restrictive and liberal groups based on a haematocrit score. Fisher's exact test was used to determine the associations between transfusion likelihood and patient, provider, and institutional characteristics. Bonferroni correction was applied to adjust the p-value to 0.004 for multiple comparisons. RESULTS: There was a 21% response rate (116 responses). Most were male (58.6%), attending physicians (85.3%) with >5 year of intensive care experience (88.7%) and subspeciality training in critical care medicine (47.4%). The majority of institutions were academic (96.6%), with a separate cardiac ICU (86.2%), and performed >10 stage 1 palliation cases annually (68.1%). After Bonferroni correction, there were no significant patient, respondent, or institutional differences between the restrictive and liberal groups. No respondent or institutional characteristics influenced transfusion decision-making after stage 1 palliation. CONCLUSIONS: Decision-making around red cell transfusion after stage 1 palliation is heterogeneous. We found no clear relationships between patient, respondent, or institutional characteristics and transfusion decision-making among surveyed respondents. Given the lack of existing data informing red cell transfusion after stage 1 palliation, further studies are necessary to inform evidence-based guidelines.

A Vibrating Cold Device to Reduce Pain in the Pediatric Emergency Department: A Randomized Clinical Trial.

OBJECTIVE: Pain of intravenous (IV) catheter insertion can be mitigated with appropriate analgesia, thereby avoiding unnecessary distress. Our objective was to compare the self-reported pain of IV catheter insertion in children when using a vibrating cold device (VCD) versus standard of care 4% topical lidocaine cream (TL). METHODS: This was a 2-arm randomized controlled noninferiority trial with a convenience sample of 4- to 18-year-olds requiring nonemergent IV catheter insertion. Self-reported pain was measured with the Faces Pain Scale-Revised, anxiety with the Child's Rating of Anxiety scale, and observed pain with the Face, Legs, Activity, Crying, Consolability scale. Caregivers and nurses completed satisfaction surveys. RESULTS: Two hundred twenty-four children were included in the analysis: 114 (90%) of 127 in the VCD group and 110 (89%) of 124 in the TL group. Faces Pain Scale-Revised scores for both groups were equivalent (median, 2.0 cm; interquartile range, 0-5 cm; linear regression difference, 0 [95% confidence interval, -0.82 to 0.82]), as were median Face, Legs, Activity, Crying, Consolability scale scores (difference, 0.33 [95% confidence interval, -0.01 to 0.68]). The time of completion for the IV procedure was significantly shorter for the VCD group compared with the TL group (median, 3.0 vs 40.5 minutes; P < 0.0001). There were no significant differences between groups for self-reported state or trait anxiety, success of IV catheter insertion on first attempt, or satisfaction of caregivers or staff. CONCLUSIONS: A VCD and TL showed equal effectiveness in reducing pain and distress for children undergoing IV catheter insertion. The VCD has the added benefit of quick onset time and an acceptable alternative for caregivers and nurses.

Neurological Injury and Cerebral Blood Flow in Single Ventricles Throughout Staged Surgical Reconstruction.

BACKGROUND: Patients with a single ventricle experience a high rate of brain injury and adverse neurodevelopmental outcome; however, the incidence of brain abnormalities throughout surgical reconstruction and their relationship with cerebral blood flow, oxygen delivery, and carbon dioxide reactivity remain unknown. METHODS: Patients with a single ventricle were studied with magnetic resonance imaging scans immediately prior to bidirectional Glenn (pre-BDG), before Fontan (BDG), and then 3 to 9 months after Fontan reconstruction. RESULTS: One hundred sixty-eight consecutive subjects recruited into the project underwent 235 scans: 63 pre-BDG (mean age, 4.8±1.7 months), 118 BDG (2.9±1.4 years), and 54 after Fontan (2.4±1.0 years). Nonacute ischemic white matter changes on T2-weighted imaging, focal tissue loss, and ventriculomegaly were all more commonly detected in BDG and Fontan compared with pre-BDG patients (P<0.05). BDG patients had significantly higher cerebral blood flow than did Fontan patients. The odds of discovering brain injury with adjustment for surgical stage as well as ≥2 coexisting lesions within a patient decreased (63%-75% and 44%, respectively) with increasing amount of cerebral blood flow (P<0.05). In general, there was no association of oxygen delivery (except for ventriculomegaly in the BDG group) or carbon dioxide reactivity with neurological injury. CONCLUSIONS: Significant brain abnormalities are commonly present in patients with a single ventricle, and detection of these lesions increases as children progress through staged surgical reconstruction, with multiple coexisting lesions more common earlier than later. In addition, this study demonstrated that BDG patients had greater cerebral blood flow than did Fontan patients and that an inverse association exists of various indexes of cerebral blood flow with these brain lesions. However, CO2 reactivity and oxygen delivery (with 1 exception) were not associated with brain lesion development. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02135081.

Efficacy and safety of voretigene neparvovec (AAV2-hRPE65v2) in patients with RPE65-mediated inherited retinal dystrophy: a randomised, controlled, open-label, phase 3 trial.

BACKGROUND: Phase 1 studies have shown potential benefit of gene replacement in RPE65-mediated inherited retinal dystrophy. This phase 3 study assessed the efficacy and safety of voretigene neparvovec in participants whose inherited retinal dystrophy would otherwise progress to complete blindness. METHODS: In this open-label, randomised, controlled phase 3 trial done at two sites in the USA, individuals aged 3 years or older with, in each eye, best corrected visual acuity of 20/60 or worse, or visual field less than 20 degrees in any meridian, or both, with confirmed genetic diagnosis of biallelic RPE65 mutations, sufficient viable retina, and ability to perform standardised multi-luminance mobility testing (MLMT) within the luminance range evaluated, were eligible. Participants were randomly assigned (2:1) to intervention or control using a permuted block design, stratified by age (<10 years and ≥10 years) and baseline mobility testing passing level (pass at ≥125 lux vs <125 lux). Graders assessing primary outcome were masked to treatment group. Intervention was bilateral, subretinal injection of 1·5 × 1011 vector genomes of voretigene neparvovec in 0·3 mL total volume. The primary efficacy endpoint was 1-year change in MLMT performance, measuring functional vision at specified light levels. The intention-to-treat (ITT) and modified ITT populations were included in primary and safety analyses. This trial is registered with ClinicalTrials.gov, number NCT00999609, and enrolment is complete. FINDINGS: Between Nov 15, 2012, and Nov 21, 2013, 31 individuals were enrolled and randomly assigned to intervention (n=21) or control (n=10). One participant from each group withdrew after consent, before intervention, leaving an mITT population of 20 intervention and nine control participants. At 1 year, mean bilateral MLMT change score was 1·8 (SD 1·1) light levels in the intervention group versus 0·2 (1·0) in the control group (difference of 1·6, 95% CI 0·72-2·41, p=0·0013). 13 (65%) of 20 intervention participants, but no control participants, passed MLMT at the lowest luminance level tested (1 lux), demonstrating maximum possible improvement. No product-related serious adverse events or deleterious immune responses occurred. Two intervention participants, one with a pre-existing complex seizure disorder and another who experienced oral surgery complications, had serious adverse events unrelated to study participation. Most ocular events were mild in severity. INTERPRETATION: Voretigene neparvovec gene replacement improved functional vision in RPE65-mediated inherited retinal dystrophy previously medically untreatable. FUNDING: Spark Therapeutics.

22q11.2 Deletion Status and Perioperative Outcomes for Tetralogy of Fallot with Pulmonary Atresia and Multiple Aortopulmonary Collateral Vessels.

Deletion of 22q11.2 (del22q11) is associated with adverse outcomes in patients with tetralogy of Fallot (TOF). We sought to investigate its contribution to perioperative outcome in patients with a severe form of TOF characterized by pulmonary atresia (PA) or severe pulmonary stenosis (PS) and major aortopulmonary collateral arteries (MAPCAS). We conducted a retrospective review of patients with TOF/MAPCAS who underwent staged surgical reconstruction between 1995 and 2006. Groups were compared according to 22q11.2 deletion status using t-tests or the Wilcoxon Rank sum test. We included 26 subjects, 24 of whom survived the initial operation. Of those, 21 subjects had known deletion status and constitute the group for this analysis [15 with no deletion present (ND) and 6 del22q11 subjects]. There was no difference with respect to occurrence of palliative procedure prior to initial operation, or to timing of closure of the ventricular septal defect (VSD). Other than higher prevalence of prematurity (50%) in the del22q11 group versus no prematurity in the ND, the groups were comparable in terms of pre-operative characteristics. The intra- and post-operative course outcomes (length of cardiopulmonary bypass, use of vasopressors, duration of intensive care and length of hospital stay, tube-feeding) were also comparable. Although the del22q11 had longer mechanical ventilation than the ND, this difference was not significant [68 h (range 4-251) vs. 45 h (range 3-1005), p = 0.81]. In this detailed comparison of a small patient cohort, 22q11.2 deletion syndrome was not associated with adverse perioperative outcomes in patients with TOF, PA, and MAPCAS when compared to those without 22q11.2 deletion syndrome. These results are relevant to prenatal and neonatal pre-operative counseling and planning.

Safety and durability of effect of contralateral-eye administration of AAV2 gene therapy in patients with childhood-onset blindness caused by RPE65 mutations: a follow-on phase 1 trial.

BACKGROUND: Safety and efficacy have been shown in a phase 1 dose-escalation study involving a unilateral subretinal injection of a recombinant adeno-associated virus (AAV) vector containing the RPE65 gene (AAV2-hRPE65v2) in individuals with inherited retinal dystrophy caused by RPE65 mutations. This finding, along with the bilateral nature of the disease and intended use in treatment, prompted us to determine the safety of administration of AAV2-hRPE65v2 to the contralateral eye in patients enrolled in the phase 1 study. METHODS: In this follow-on phase 1 trial, one dose of AAV2-hRPE65v2 (1.5 × 10(11) vector genomes) in a total volume of 300 µL was subretinally injected into the contralateral, previously uninjected, eyes of 11 children and adults (aged 11-46 years at second administration) with inherited retinal dystrophy caused by RPE65 mutations, 1.71-4.58 years after the initial subretinal injection. We assessed safety, immune response, retinal and visual function, functional vision, and activation of the visual cortex from baseline until 3 year follow-up, with observations ongoing. This study is registered with ClinicalTrials.gov, number NCT01208389. FINDINGS: No adverse events related to the AAV were reported, and those related to the procedure were mostly mild (dellen formation in three patients and cataracts in two). One patient developed bacterial endophthalmitis and was excluded from analyses. We noted improvements in efficacy outcomes in most patients without significant immunogenicity. Compared with baseline, pooled analysis of ten participants showed improvements in mean mobility and full-field light sensitivity in the injected eye by day 30 that persisted to year 3 (mobility p=0.0003, white light full-field sensitivity p<0.0001), but no significant change was seen in the previously injected eyes over the same time period (mobility p=0.7398, white light full-field sensitivity p=0.6709). Changes in visual acuity from baseline to year 3 were not significant in pooled analysis in the second eyes or the previously injected eyes (p>0.49 for all time-points compared with baseline). INTERPRETATION: To our knowledge, AAV2-hRPE65v2 is the first successful gene therapy administered to the contralateral eye. The results highlight the use of several outcome measures and help to delineate the variables that contribute to maximal benefit from gene augmentation therapy in this disease. FUNDING: Center for Cellular and Molecular Therapeutics at The Children's Hospital of Philadelphia, Spark Therapeutics, US National Institutes of Health, Foundation Fighting Blindness, Institute for Translational Medicine and Therapeutics, Research to Prevent Blindness, Center for Advanced Retinal and Ocular Therapeutics, Mackall Foundation Trust, F M Kirby Foundation, and The Research Foundation-Flanders.

Effect of Oral Lipid Matrix Supplement on Fat Absorption in Cystic Fibrosis: A Randomized Placebo-Controlled Trial.

Pancreatic enzyme therapy does not normalize dietary fat absorption in patients with cystic fibrosis and pancreatic insufficiency. Efficacy of LYM-X-SORB (LXS), an easily absorbable lipid matrix that enhances fat absorption, was evaluated in a 12-month randomized, double-blinded, placebo-controlled trial with plasma fatty acids (FA) and coefficient of fat absorption (CFA) outcomes. A total of 110 subjects (age 10.4 ±â€Š3.0 years) were randomized. Total FA increased with LXS at 3 and 12 months (+1.58, +1.14 mmol/L) and not with placebo (P = 0.046). With LXS, linoleic acid (LA) increased at 3 and 12 months (+298, +175 nmol/mL, P ≤ 0.046), with a 6% increase in CFA (P < 0.01). LA increase was significant in LXS versus placebo (445 vs 42 nmol/mL, P = 0.038). Increased FA and LA predicted increased body mass index Z scores. In summary, the LXS treatment improved dietary fat absorption compared with placebo as indicated by plasma FA and LA and was associated with better growth status.

Choline Supplementation With a Structured Lipid in Children With Cystic Fibrosis: A Randomized Placebo-Controlled Trial.

BACKGROUND: Choline depletion is seen in cystic fibrosis (CF) and pancreatic insufficiency in spite of enzyme treatment and may result in liver, fatty acid, and muscle abnormalities. This study evaluated the efficacy and safety of an easily absorbed choline-rich structured lipid (LYM-X-SORB™ [LXS]) to improve choline status. METHODS: Children with CF and pancreatic insufficiency were randomized to LXS or placebo in a 12-month double blind trial. Dietary choline intake, plasma cholines, plasma and fecal phospholipids, coefficient of fat absorption, pulmonary function, growth status, body composition, and safety measures were assessed. Magnetic resonance spectroscopy for calf muscle choline and liver fat were assessed in a subgroup and compared with a healthy comparison group matched for age, sex, and body size. RESULTS: A total of 110 subjects were enrolled (age 10.4 ±â€Š3.0 years). Baseline dietary choline, 88% recommended, increased 3-fold in the LXS group. Plasma choline, betaine, and dimethylglycine increased in the LXS but not placebo (P = 0.007). Plasma lysophosphatidylcholine and phosphatidylcholine increased, and fecal phosphatidylcholine/phosphatidylethanolamine ratio decreased (P ≤ 0.05) in LXS only, accompanied by a 6% coefficient of fat absorption increase (P = 0.001). Children with CF had higher liver fat than healthy children and depleted calf muscle choline at baseline. Muscle choline concentration increased in LXS and was associated with improvement in plasma choline status. No relevant changes in safety measures were evident. CONCLUSIONS: LXS had improved choline intake, plasma choline status, and muscle choline stores compared with placebo group. The choline-rich supplement was safe, accepted by participants, and improved choline status in children with CF.

Wise Choices: Nutrition and Exercise for Older Adults: A Community-Based Health Promotion Intervention.

Effective interventions for older adults are needed to address lifestyle behaviors linked to chronic illnesses. We implemented a 12-week group behavioral intervention for 118 racially diverse older adults at 6 community-based senior centers to improve eating and physical activity. Assessments were completed pre- and postintervention, with 85.6% retention. We documented increases in fruit, vegetable, and whole grain intake; pace of walking; number of city blocks walked; daily steps walked; functional mobility; and self-rated general health (P < .05). Findings indicate that a relatively low-intensity lifestyle intervention can effectively be implemented for community-dwelling older adults. Further development of this approach is warranted.

Hospital Charges for Pediatric Heart Failure-Related Hospitalizations from 2000 to 2009.

Scarce data exist regarding costs of pediatric heart failure-related hospitalizations (HFRH) or how costs have changed over time. Pediatric HFRH costs, due to advances in management, will have increased significantly over time. A retrospective analysis of Healthcare Cost and Utilization Project Kids' Inpatient Database was performed on all pediatric HFRH. Inflation-adjusted charges are used as a proxy for cost. There were a total of 33,189 HFRH captured from 2000 to 2009. Median charges per HFRH rose from $35,079 in 2000 to $72,087 in 2009 (p < 0.0001). The greatest median charges were incurred in patients on extracorporeal membrane oxygenation ($442,134 vs $53,998) or ventricular assist devices ($462,647 vs $55,151). Comorbidities, including sepsis ($207,511 vs $48,995), renal failure ($180,624 vs $52,812), stroke ($198,260 vs $54,974) and respiratory failure ($146,200 vs $48,797), were associated with greater charges (p < 0.0001). Comorbidities and use of mechanical support increased over time. After adjusting for these factors, later year remained associated with greater median charges per HFRH (p < 0.0001). From 2000 to 2009, there has been an almost twofold increase in pediatric HFRH charges, after adjustment for inflation. Although comorbidities and use of mechanical support account for some of this increase, later year remained independently associated with greater charges. Further study is needed to understand potential factors driving these higher costs over time and to identify more cost-effective therapies in this population.

Intraoperative dexmedetomidine reduces postoperative mechanical ventilation in infants after open heart surgery.

OBJECTIVE: The inclusion of dexmedetomidine in the operative and postoperative management of infants with congenital heart defects has lessened the need for opioids that may cause respiratory depression. Our objective was to show that a dexmedetomidine bolus at or about the time of sternal closure is associated with a decrease in the use of mechanical ventilation in the immediate postoperative period. DESIGN: Retrospective cohort study. SETTING: Single pediatric tertiary cardiac center. PATIENTS: Infants undergoing surgical intervention for congenital heart defects requiring cardiopulmonary bypass, age 30-365 days in a 5-year time period from June 1, 2008, to December 31, 2012. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of 1,057 total encounters, 441 met inclusion criteria and were evenly distributed over the 5-year time period. Dexmedetomidine had been given at or about the time of sternal closure in 57% of patients. When the exposed and unexposed groups were compared in terms of mechanical ventilation immediately postoperative, there was a statistically significant effect of using dexmedetomidine on the odds of receiving mechanical ventilation (p = 0.0019). This difference remained significant after adjusting for covariates affecting the decision for mechanical ventilation, including year of the procedure, age and weight of subject, cardiopulmonary bypass time, the use of deep hypothermic circulatory arrest, intraoperative fentanyl dose, and the Risk Adjustment for Congenital Heart Surgery Score 1 (p = 0.0317). The odds of receiving mechanical ventilation are estimated to be two times higher for patients who did not receive dexmedetomidine than for patients who received dexmedetomidine after adjusting for variables. CONCLUSION: The use of dexmedetomidine bolus in the operating room at the time of sternal closure in infants undergoing open heart surgery is associated with reduced need for mechanical ventilation in the immediate postoperative period.

Locally advanced squamous cell carcinoma of the head and neck: CT texture and histogram analysis allow independent prediction of overall survival in patients treated with induction chemotherapy.

PURPOSE: To determine if computed tomographic (CT) texture and histogram analysis measurements of the primary mass are independently associated with overall survival in patients with locally advanced squamous cell carcinoma of the head and neck who were previously treated with cisplatin, 5-fluorouracil, and docetaxel (TPF) induction chemotherapy. MATERIALS AND METHODS: This institutional review board-approved retrospective study included 72 patients with locally advanced squamous cell carcinoma of the head and neck who were treated with induction TPF chemotherapy in 2004-2010. CT texture and histogram analysis of the primary mass on the pretherapy CT images were performed by using TexRAD software before and after application of spatial filters at different anatomic scales ranging from fine detail to coarse features. Cox proportional hazards models were used to examine the association between overall survival and the baseline CT imaging measurements and clinical variables. RESULTS: Primary mass entropy and skewness measurements with multiple spatial filters were associated with overall survival. Multivariate Cox regression analysis incorporating clinical and imaging variables indicated that primary mass size (hazard ratio [HR], 1.58 for each 1-cm increase; P = .018), N stage (HR, 8.77 for N3 vs N0 or N1; P = .002; HR, 4.99 for N3 vs N2; P = .001), and primary mass entropy (HR, 2.10 for each 0.5-unit increase; P = .036) and skewness (HR, 3.67 for each 1.0-unit increase; P = .009) measurements with the 1.0 spatial filter were independently associated with overall survival. CONCLUSION: Independent of tumor size, N stage, and other clinical variables, primary mass CT texture and histogram analysis parameters are associated with overall survival in patients with locally advanced squamous cell carcinoma of the head and neck who were treated with induction TPF. Online supplemental material is available for this article.

The impact of self-reported psychological stress levels on changes to peripheral blood immune biomarkers in recreational marathon runners during training and recovery.

OBJECTIVE: Marathon training is both physically and psychologically stressful, both of which can lead to altered immunity. The purpose of this study was to determine if the overall immunoregulatory changes associated with the physical stress of marathon training are affected by psychological stress. METHODS: Nineteen recreational marathoners completed the Perceived Stress Scale (PSS), State-Trait Anxiety Inventory (STAI) and Penn State Worry Questionnaire (PSWQ), and had levels of T cell subpopulations and cytokine (IFNγ, IL4 and IL10) production determined 4 weeks before (baseline), 24-48 h before (prerace) and 1 week after (recovery) participation in a marathon. RESULTS: PSS scores decreased at the prerace visit compared to baseline and remained low at recovery. Compared to baseline, there were significant changes to numerous immune measures at the prerace visit, including decreases in Th1/Th2 ratio, Tc1/Tc2 ratio, Tr1 and Th3 cell populations as well as decreases in IFNγ/IL4 cytokine ratio and IL10 production. Most immune parameters had returned to near baseline values at the recovery visit. Higher levels of perceived stress, anxiety and worry exacerbated many of the alterations in immunity that were observed at the prerace visit. Higher levels of perceived stress and worry had significant effects on changes to Treg, IL4 production and the IFNγ/IL4 cytokine ratio. Stress had an additional impact on changes in IL10 production. High anxiety levels resulted in significant changes to Treg, Tr1 and Th3. CONCLUSION: These data suggest that recreational marathon runners with higher levels of psychological stress may be more at risk for the immune alterations that are common during periods of prolonged physical training.