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Neuro-Oncology  2014;16(Suppl 2):ii10.
BACKGROUND: Fluorescence-guided resection of glioblastoma improves surgical cytoreduction. Intra-operative carmustine wafers may enhance survival in patients with good surgical resection. The objective of this study was to establish the safety and tolerability of combining fluorescence-guided surgical resection (5-ALA) with intra–operative chemotherapy (carmustine wafers) in patients with primary glioblastoma (GBM) prior to standard treatment with radiotherapy and temozolomide. METHODS: A single arm design with the following inclusion criteria:
• Age 18+ years
• Patient reviewed at a specialist neuro-oncology MDT
• Imaging evaluated by a neuro-radiologist and judged to be a GBM
• Radical resection judged to be realistic by the neurosurgeons (i.e. NICE criteria for the use of Carmustine wafers can be met)
• WHO performance status 0 or 1 on clinical review.
RESULTS: Seventy-two patients were recruited from 8 UK sites between July 2011 and May 2013; 64 patients received carmustine wafer implants and 59 patients were found to be eligible after surgery. Thirteen patients were found to be ineligible due to: wafers not inserted (n = 8); GBM not diagnosed post-operatively (n = 4); simultaneous diagnosis of unrelated cutaneous sebaceous carcinoma (n = 1). There were 8 surgical complications reported in 6 patients: wound infections were reported in 5 patients (8%) and cerebrospinal fluid leakage in 3 patients (5%). One patient was not able to begin chemoRT (1/33, 3%), and 4 patients (4/33, 12%) were not able to begin chemoRT within 6 weeks of surgery, due to surgical complications. After a median follow-up of 10.8 months, 25 patients (42%) are alive without progression, 16 patients (27%) are alive having progressed and 18 patients (31%) have died. Thirty-three patients (56%) have reported 68 adverse events of grade 3 or higher, 5 of these were reported as being ‘possibly’ related to the combination of 5-ALA and carmustine wafers: sepsis (n = 2), wound infection (n = 2), seizure (n = 1). CONCLUSION: The combination of 5-ALA and carmustine wafers is safe and tolerable in the surgical management of primary glioblastoma. A phase III randomised controlled trial is being designed to evaluate efficacy.
PMCID: PMC4185716
2.  A systematic review of randomized controlled trials for the prevention of bronchopulmonary dysplasia in infants 
Bronchopulmonary dysplasia (BPD) is the most common cause of pulmonary morbidity in premature infants and is associated with life-long morbidities. Developing drugs for the prevention of BPD would improve public health. We sought to determine characteristics of favorable randomized controlled trials (RCTs) of drugs for BPD prevention.
Evidence review
We searched MEDLINE and EMBASE from 1992–2014 using the MeSH terms “BPD” and “respiratory distress syndrome, newborn.” We included a Cochrane Library search to ensure inclusion of all available RCTs. We identified RCTs with BPD as a primary or secondary outcome and determined the definition of BPD used by the study. We determined whether a phase I or phase II study—to determine drug safety, efficacy, or optimal dose—was performed prior to the RCT. Finally, we searched the Cochrane Library for meta-analyses for each drug and used the results of available meta-analyses to define a favorable versus unfavorable RCT.
We identified 2026 articles; 47 RCTs met our inclusion criteria encompassing 21 drugs; 5 of the drugs reduced the incidence of BPD. We found data from phase I or II studies for 16 of the drugs, but only 1 demonstrated a reduction of BPD.
Conclusions and relevance
The majority of the drugs studied in RCTs failed to reduce the incidence of BPD. Performing early-phase studies prior to phase III trials might provide necessary information on drugs and drug doses capable of preventing BPD, thus informing the development of future RCTs.
PMCID: PMC4152555  PMID: 25010224
bronchopulmonary dysplasia; randomized controlled trials; infant; newborn; FDA; labeling
3.  Late-Onset Bloodstream Infections in Hospitalized Term Infants 
The epidemiology and incidence of late-onset bloodstream infections (BSIs) in premature infants has been described, but studies describing late-onset BSI in term infants are sparse. We sought to describe the pathogens, incidence, risk factors, and mortality of late-onset BSI in hospitalized term infants.
A cohort study was conducted of infants ≥37 weeks gestational age and ≤120 days old discharged from Pediatrix Medical Group neonatal intensive care units from 1997–2010. We examined all cultures obtained from day of life (DOL) 4–120 and used multivariable regression to assess risk factors for late-onset BSI.
We found a total of 206,019 infants cared for between DOL 4 and 120, and the incidence of late-onset BSI was 2.7/1000 admissions. We identified Gram-positive organisms in 64% of the cultures and Gram-negative organisms in 26%. We found a decreased risk of late-onset BSI in infants with the following characteristics: small for gestational age, delivery by Cesarean section, antenatal antibiotic use, and discharged in the later years of the study. Late-onset BSI increased the risk of death after controlling for confounders (odds ratio 8.43 [95% confidence interval 4.42, 16.07]).
Our data highlight the importance of late-onset BSI in hospitalized term infants. We identified Gram-positive organisms as the most common pathogen, and late-onset BSI was an independent risk factor for death.
PMCID: PMC4160433  PMID: 24618934
sepsis; infant; term birth; infection
4.  Frequency of Anomalies and Hospital Outcomes in Infants with Gastroschisis and Omphalocele 
Early human development  2014;90(8):421-424.
Gastroschisis and omphalocele are the most common anterior abdominal wall defects affecting infants. There are few large cohort studies describing the frequency of associated anomalies in infants with these 2 conditions. We describe associated anomalies and outcomes in infants with these defects using a large, multi-center clinical database.
We identified all infants with gastroschisis or omphalocele from a prospectively collected database of infants discharged from 348 neonatal intensive care units in North America from 1997–2012. Maternal and patient demographic data, associated anomalies, and outcome data were compared between infants with gastroschisis and omphalocele.
A total of 4687 infants with gastroschisis and 1448 infants with omphalocele were identified. Infants with omphalocele were more likely to be diagnosed with at least 1 other anomaly compared with infants with gastroschisis (35% vs. 8%, p<0.001). Infants with omphalocele were more likely to develop pulmonary hypertension compared with those with gastroschisis (odds ratio [OR] 7.78; 95% confidence interval 5.81, 10.41) and had higher overall mortality (OR 6.81 [5.33, 8.71]).
Infants with omphalocele were more likely to have other anomalies, be diagnosed with pulmonary hypertension, and have higher mortality than infants with gastroschisis.
PMCID: PMC4119722  PMID: 24951080
gastroschisis; omphalocele; anomalies; outcomes
5.  Impact of KRAS codon subtypes from a randomised phase II trial of selumetinib plus docetaxel in KRAS mutant advanced non-small-cell lung cancer 
British Journal of Cancer  2015;113(2):199-203.
Selumetinib (AZD6244, ARRY-142886)+docetaxel increases median overall survival (OS) and significantly improves progression-free survival (PFS) and objective response rate (ORR) compared with docetaxel alone in patients with KRAS mutant, stage IIIB/IV non-small-cell lung cancer (NSCLC; NCT00890825).
Retrospective analysis of OS, PFS, ORR and change in tumour size at week 6 for different sub-populations of KRAS codon mutations.
In patients receiving selumetinib+docetaxel and harbouring KRAS G12C or G12V mutations there were trends towards greater improvement in OS, PFS and ORR compared with other KRAS mutations.
Different KRAS mutations in NSCLC may influence selumetinib/docetaxel sensitivity.
PMCID: PMC4506393  PMID: 26125448
selumetinib; docetaxel; KRAS; mutation; codon; non-small-cell lung cancer
6.  Impact of a Palliative Care Program on End-of-life Care in a Neonatal Intensive Care Unit 
Evaluate changes in end-of-life care following initiation of a Palliative Care Program in a neonatal intensive care unit.
Study Design
Retrospective study comparing infant deaths before and after implementation of a Palliative Care Program comprised of medication guidelines, an individualized order set, a nursing care plan, and staff education.
82 infants died before (Era 1) and 68 infants died after implementation of the program (Era 2). Morphine use was similar [88% vs. 81%; p=0.17], while benzodiazepines use increased in Era 2 [26% vs. 43%; p=0.03]. Withdrawal of life support (73% vs. 63%; p=0.17) and do-not-resuscitate orders (46% vs. 53%; p=0.42) were similar. Do-not-resuscitate orders and family meetings were more frequent among Era 2 infants with activated palliative care orders (n=21) compared to infants without activated orders (n=47).
End-of-life family meetings and benzodiazepine use increased following implementation of our program, likely reflecting adherence to guidelines and improved communication.
PMCID: PMC4491914  PMID: 25341195
7.  Defective Wound-healing in Aging Gingival Tissue 
Journal of Dental Research  2014;93(7):691-697.
Aging may negatively affect gingival wound-healing. However, little is known about the mechanisms underlying this phenomenon. The present study examined the cellular responses associated with gingival wound-healing in aging. Primary cultures of human gingival fibroblasts were obtained from healthy young and aged donors for the analysis of cell proliferation, cell invasion, myofibroblastic differentiation, and collagen gel remodeling. Serum from young and old rats was used to stimulate cell migration. Gingival repair was evaluated in Sprague-Dawley rats of different ages. Data were analyzed by the Mann-Whitney and Kruskal-Wallis tests, with a p value of .05. Fibroblasts from aged donors showed a significant decrease in cell proliferation, migration, Rac activation, and collagen remodeling when compared with young fibroblasts. Serum from young rats induced higher cell migration when compared with serum from old rats. After TGF-beta1 stimulation, both young and old fibroblasts demonstrated increased levels of alpha-SMA. However, alpha-SMA was incorporated into actin stress fibers in young but not in old fibroblasts. After 7 days of repair, a significant delay in gingival wound-healing was observed in old rats. The present study suggests that cell migration, myofibroblastic differentiation, collagen gel remodeling, and proliferation are decreased in aged fibroblasts. In addition, altered cell migration in wound-healing may be attributable not only to cellular defects but also to changes in serum factors associated with the senescence process.
PMCID: PMC4293726  PMID: 24776985
gingiva; fibroblasts; myofibroblast; granulation tissue; regeneration; actin cytoskeleton
8.  Surgical Treatment of Moderate Ischemic Mitral Regurgitation 
The New England journal of medicine  2014;371(23):2178-2188.
Ischemic mitral regurgitation is associated with increased mortality and morbidity. For surgical patients with moderate regurgitation, the benefits of adding mitral-valve repair to coronary-artery bypass grafting (CABG) are uncertain.
We randomly assigned 301 patients with moderate ischemic mitral regurgitation to CABG alone or CABG plus mitral-valve repair (combined procedure). The primary end point was the left ventricular end-systolic volume index (LVESVI), a measure of left ventricular remodeling, at 1 year. This end point was assessed with the use of a Wilcoxon rank-sum test in which deaths were categorized as the lowest LVESVI rank.
At 1 year, the mean LVESVI among surviving patients was 46.1±22.4 ml per square meter of body-surface area in the CABG-alone group and 49.6±31.5 ml per square meter in the combined-procedure group (mean change from baseline, −9.4 and −9.3 ml per square meter, respectively). The rate of death was 6.7% in the combined-procedure group and 7.3% in the CABG-alone group (hazard ratio with mitral-valve repair, 0.90; 95% confidence interval, 0.38 to 2.12; P = 0.81). The rank-based assessment of LVESVI at 1 year (incorporating deaths) showed no significant between-group difference (z score, 0.50; P = 0.61). The addition of mitral-valve repair was associated with a longer bypass time (P<0.001), a longer hospital stay after surgery (P = 0.002), and more neurologic events (P = 0.03). Moderate or severe mitral regurgitation was less common in the combined-procedure group than in the CABG-alone group (11.2% vs. 31.0%, P<0.001). There were no significant between-group differences in major adverse cardiac or cerebrovascular events, deaths, readmissions, functional status, or quality of life at 1 year.
In patients with moderate ischemic mitral regurgitation, the addition of mitral-valve repair to CABG did not result in a higher degree of left ventricular reverse remodeling. Mitral-valve repair was associated with a reduced prevalence of moderate or severe mitral regurgitation but an increased number of untoward events. Thus, at 1 year, this trial did not show a clinically meaningful advantage of adding mitral-valve repair to CABG. Longer-term follow-up may determine whether the lower prevalence of mitral regurgitation translates into a net clinical benefit. (Funded by the National Institutes of Health and the Canadian Institutes of Health Research; number, NCT00806988.)
PMCID: PMC4303577  PMID: 25405390
9.  Effects of a Novel Dental Gel on Plaque and Gingivitis: A Comparative Study 
The goal of this prospective, randomized, controlled, double-blinded study was to evaluate the effects of a novel dental gel on plaque and gingival health. The dental gel was designed to (1) break up and prevent re-accumulation of microbial biofilm, and (2) inhibit metal mediated inflammation.
Materials and Methods
Twenty-five subjects with moderate gingival inflammation (Löe and Silness Gingival Index ≥2) and pocket depths <4 were randomly assigned to brush twice daily for 21 days with the test or the control dental gel. On Days 0, 7, 14 and 21, plaque levels (Quigley-Hein, Turesky Modification Plaque Index), gingival inflammation (Löe and Silness Gingival Index) and gingival bleeding (modified Sulcus Bleeding Index) were determined by one blinded, investigator using a pressure sensitive probe.
After 3 weeks, all 3 clinical indices were significantly improved in both groups (P<0.05) and significantly lower in the test group (P<0.05).
The novel dental gel formulation was provided effective plaque control and reduced gingival inflammation.
Clinical Relevance
A novel dentifrice formulation may be an effective tool for plaque removal and maintaining gingival health.
PMCID: PMC4454341  PMID: 26052472
Plaque; Gingival inflammation; Dentifrice; Oral hygiene; Biofilm
10.  Effect of fluconazole prophylaxis on candidiasis and mortality in premature infants: A randomized clinical trial 
Invasive candidiasis in premature infants causes mortality and neurodevelopmental impairment. Fluconazole prophylaxis reduces candidiasis, but its effect on mortality and the safety of fluconazole is unknown.
To evaluate the efficacy and safety of fluconazole in preventing death or invasive candidiasis in extremely low-birth-weight infants.
This study was a randomized, blinded, placebo-controlled trial of fluconazole in premature infants. Infants weighing less than 750 g at birth (N = 361) from 32 neonatal intensive care units (NICUs) in the United States were randomly assigned to receive either fluconazole or placebo twice weekly for 42 days. Surviving infants were evaluated at 18 to 22 months corrected age for neurodevelopmental outcomes. The study was conducted between November 2008 and February 2013.
Fluconazole (6 mg/kg of body weight) or placebo.
The primary end point was a composite of death or definite or probable invasive candidiasis prior to study day 49 (1 week after completion of study drug). Secondary and safety outcomes included invasive candidiasis, liver function, bacterial infection, length of stay, intracranial hemorrhage, periventricular leukomalacia, chronic lung disease, patent ductus arteriosus requiring surgery, retinopathy of prematurity requiring surgery, necrotizing enterocolitis, spontaneous intestinal perforation, and neurodevelopmental outcomes—defined as a Bayley-III cognition composite score of less than 70, blindness, deafness, or cerebral palsy at 18–22-months corrected age.
Among infants receiving fluconazole, the composite primary end point of death or invasive candidiasis was 16% (95% CI, 11%–22%) vs 21% in the placebo group (95% CI, 15%–28%; odds ratio 0.73 [95% CI 0.43–1.23]; P=.24; treatment difference −5% [95% CI, −13%–3%]). Invasive candidiasis occurred less frequently in the fluconazole group (3% [95% CI, 1%–6%] vs the placebo group (9% [95% CI, 5%–14%]; P=.02; treatment difference −6% [95% CI, −11%–−1%]). The cumulative incidences of other secondary outcomes were not statistically different between groups. Neurodevelopmental impairment did not differ between the groups (fluconazole 31% [95% CI, 21–41%] vs placebo, 27% [95% CI, 18–37%]; P=.60; treatment difference 4% [95% CI, −10–17%]).
Among infants with a birth weight of less 750 g, 42 days of fluconazole prophylaxis compared with placebo did not result in a lower incidence of the composite of death or invasive candidiasis. These findings do not support the universal use of prophylactic fluconazole in extremely-low-birth-weight infants.
PMCID: PMC4110724  PMID: 24794367
11.  Feasibility of Autologous Cord Blood Cells for Infants with Hypoxic-Ischemic Encephalopathy 
The Journal of pediatrics  2013;164(5):973-979.e1.
To assess feasibility and safety of providing autologous umbilical cord blood (UCB) cells to neonates with hypoxic-ischemic encephalopathy (HIE).
Study design
We enrolled infants in the Intensive Care Nursery who were cooled for HIE and had available UCB in an open-label study of non-cyropreserved autologous volume- and red blood cell-reduced UCB cells (up to four doses adjusted for volume and RBC content,1 – 5 × 107cells/dose). We recorded UCB collection and cell infusion characteristics, and pre- and post- infusion vital signs. As exploratory analyses we compared cell recipients’ hospital outcomes (mortality, oral feeds at discharge) and one year survival with Bayley III scores ≥ 85 in 3 domains (cognitive, language, and motor development) with cooled infants who did not have available cells.
Twenty-three infants were cooled and received cells. Median collection and infusion volumes were 36 and 4.3 milliliters. Vital signs including oxygen saturation were similar before and after infusions in the first 48 postnatal hours. Cell recipients and concurrent cooled infants had similar hospital outcomes. Thirteen of 18 (74%) cell recipients and 19 of 46 (41%) concurrent cooled infants with known 1 year outcomes survived with scores ≥ 85.
Collection, preparation and infusion of fresh autologous UCB cells for use in infants with HIE is feasible. A randomized double-blind study is needed.
PMCID: PMC3992180  PMID: 24388332
Asphyxia; Neonatal encephalopathy; Umbilical cord blood; Neonate
12.  Trends in Caffeine Use and Association between Clinical Outcomes and Timing of Therapy in Very-Low-Birth-Weight Infants 
The Journal of pediatrics  2014;164(5):992-998.e3.
To examine the effect of early initiation of caffeine therapy on neonatal outcomes and characterized the use of caffeine therapy in very-low-birth-weight (VLBW) infants.
Study design
We analyzed a cohort of 62,056 VLBW infants discharged between 1997 and 2010 who received caffeine. We compared outcomes between infants receiving early caffeine therapy (initial dose <3 days of life) and late caffeine therapy (initial dose ≥3 days of life) through propensity scoring using baseline and early clinical variables. The primary outcome was the association between the timing of caffeine initiation and the incidence of bronchopulmonary dysplasia (BPD) or death.
We propensity score-matched 29,070 VLBW infants in a 1:1 ratio. Of infants receiving early caffeine therapy, 3681 (27.6%) died or developed BPD compared with 4591 (34.0%) infants receiving late caffeine therapy (odds ratio [OR]=0.74; 99% confidence interval 0.69–0.80). The incidence of BPD was lower in infants receiving early caffeine (early, 23.1%; late, 30.7%; OR=0.68; 0.63–0.73), and the incidence of death was higher (early, 4.5%; late, 3.7%; OR=1.23; 1.05–1.43). Infants receiving early caffeine therapy had decreased treatment of a patent ductus arteriosus (OR=0.60; 0.55–0.65) and a shorter duration of mechanical ventilation (mean difference of 6 days; P<0.001).
Early caffeine initiation is associated with a decreased incidence of BPD. Randomized trials are needed to determine the efficacy and safety of early caffeine prophylaxis in VLBW infants.
PMCID: PMC3992195  PMID: 24461786
methylxanthines; outcomes; bronchopulmonary dysplasia; chronic lung disease; premature infants; neonatal care
13.  Pharmacokinetics and safety of recently approved drugs used to treat methicillin-resistant Staphylococcus aureus infections in infants, children, and adults 
Methicillin-resistant Staphylococcus aureus (MRSA) remains a significant cause of morbidity in hospitalized infants. Over the past 15 years, several drugs have been approved for the treatment of S. aureus infections in adults (linezolid, quinupristin/dalfopristin, daptomycin, telavancin, tigecycline, and ceftaroline). The use of there majority of these drugs has extended into the treatment of MRSA infections in infants, frequently with minimal safety or dosing information. Only linezolid is approved for use in infants, and pharmacokinetic data in infants are limited to linezolid and daptomycin. Pediatric trials are underway for ceftaroline, telavancin, and daptomycin; however, none of these studies includes infants. Here, we review current pharmacokinetic, safety, and efficacy data of these drugs with a specific focus in infants.
PMCID: PMC4032771  PMID: 24716805
linezolid; daptomycin; quinupristin; dalfopristin; ceftaroline; tigecycline; neonate; sepsis
14.  Feeding Practices and Other Risk Factors for Developing Transfusion-Associated Necrotizing Enterocolitis 
Early human development  2014;90(5):237-240.
Determine the incidence of and risk factors for necrotizing enterocolitis (NEC) and transfusion-associated NEC (TANEC) in very-low-birth-weight (VLBW) infants pre/post implementation of a peri-transfusion feeding protocol.
Study Design
A retrospective cohort study was conducted including all inborn VLBW infants admitted to the Duke intensive care nursery from 2002–10. We defined NEC using Bell’s modified criteria IIA and higher and TANEC as NEC occurring within 48 hours of a packed red blood cell (pRBC) transfusion. We compared demographic and laboratory data for TANEC vs. other NEC infants and the incidence of TANEC pre/post implementation of our peri-transfusion feeding protocol. We also assessed the relationship between pre-transfusion hematocrit and pRBC unit age with TANEC.
A total of 148/1380 (10.7%) infants developed NEC. Incidence of NEC decreased after initiating our peri-transfusion feeding protocol: 126/939 (12%) to 22/293 (7%), P=0.01. The proportion of TANEC did not change: 51/126 (41%) vs. 9/22 (41%), P>0.99. TANEC infants were smaller, more likely to develop surgical NEC, and had lower mean pre-transfusion hematocrits prior to their TANEC transfusions compared with all other transfusions before their NEC episode: 28% vs. 33%, P<0.001. Risk of TANEC was inversely related to pre-transfusion hematocrit: odds ratio 0.87 (0.79–0.95).
Pre-transfusion hematocrit is inversely related to risk of TANEC, which suggests that temporally maintaining a higher baseline hemoglobin in infants most at risk of NEC may be protective. The lack of difference in TANEC pre-/post-implementation of our peri-transfusion feeding protocol, despite an overall temporal decrease in NEC, suggests other unmeasured interventions may account for the observed decreased incidence of NEC.
PMCID: PMC4050434  PMID: 24598173
16.  Right Ventricular Mechanics using a Novel Comprehensive Three-View Echocardiographic Strain Analysis in a Normal Population 
While quantitative RV strain analysis may be useful in congenital and acquired heart disease populations with RV failure, a comprehensive, standardized approach is lacking. An 18 segment RV strain analysis obtained from 3 standardized RV apical echo images was used to determine the feasibility, normal values and reproducibility of the method in normal adults.
Forty healthy, prospectively-enrolled volunteers with no cardiac history and normal QRS duration received an echo optimized for strain analysis including 3 RV apical views. 2D speckle tracking longitudinal strain analysis was performed on EchoPAC software. Eleven retrospectively-identified subjects with RV disease were included as a pilot population. All had been imaged using the same protocol including the 3 RV apical views.
All control subjects had normal anatomic morphology and function by echo. Feasibility of the RV strain analysis was good (adequate tracking in 696/720 (97%) of segments). RV global peak systolic strain was −23 ± 2%. Peak strain was highest in the RV free wall and lowest in the septum. Dyssynchrony indices demonstrated no dyssynchrony using LV criteria. Reproducibility of most strain measures was acceptable. This methodology identified important disease not seen in the 4-chamber apical view alone in the pilot population of 11 patients with RV disease. Strain pattern and values were different from the control population indicating differences do exist from normal.
The 18 segment RV strain analysis is feasible with strain measures falling into discrete ranges in this normal population. Those with RV disease illustrate the potential utility of this approach. These data indicate that this model can be utilized for more detailed studies evaluating abnormal RV populations where its full potential can be assessed.
PMCID: PMC4052609  PMID: 24508364
17.  Cardiopulmonary Bypass is Associated with Hemolysis and Acute Kidney Injury in Neonates, Infants and Children 
This pilot study assesses the degree of hemolysis induced by cardiopulmonary bypass (CPB) and determines its association with acute kidney injury (AKI) in pediatric patients. Further, it evaluates the degree to which the use of urinary biomarkers neutrophil gelatinase-associated lipocalin (NGAL) and cystatin C correlate with the presence of AKI and hemolysis following CPB.
Prospective observational study
A 13-bed pediatric cardiac intensive care unit in a university hospital
Children undergoing cardiac surgery with the use of CPB
Measurements and Main Results
Blood and urine samples were obtained at multiple time points before and after CPB. Hemolysis was assessed by measuring levels of plasma hemoglobin and haptoglobin. AKI was defined as a doubling in serum creatinine from preoperative baseline and by using the pediatric-modified RIFLE criteria. Urinary NGAL and Cystatin C levels were measured. A total of 40 patients (range: 3 days to 4.8 years) were enrolled. Plasma hemoglobin levels increased markedly on separation from CPB with a concurrent decrease in haptoglobin. This was associated with an increase in protein oxidation in the plasma. Hemolysis was more evident in younger patients with a longer duration of bypass and in those requiring a blood-primed circuit. 40% of patients had a doubling in serum creatinine and 88% of patients developed acute kidney injury when defined by the pediatric-modified RIFLE criteria. Controlling for CPB time, persistently elevated levels of plasma hemoglobin were associated with a 5 fold increase in AKI. Further, urinary NGAL measured 2 hours after separation from CPB was associated with AKI and with elevations in plasma hemoglobin.
CPB in pediatric patients results in significant hemolysis, which is associated with the development of AKI. The biomarker NGAL correlates with both AKI and hemolysis in this population.
PMCID: PMC3951557  PMID: 24394997
cardiopulmonary bypass; hemolysis; neutrophil gelatinase-associated lipocalin; cystatin C; acute kidney injury; pediatrics
18.  Notifications for child safeguarding from an acute hospital in response to presentations to healthcare by parents 
Child  2014;41(2):186-193.
Consideration of child safeguarding is routine within maternity services but less common in other health services for adults. We audited notifications for child safeguarding from an acute general hospital where the policy includes questioning adults presenting with violence, mental health problems or drug or alcohol misuse to any department within the hospital about children at home and notifying to the local authority children's social care services if there are safeguarding concerns.
Cross-sectional audit of notifications for child safeguarding, including abuse, neglect or victimization, from all departments in one hospital to the local authority children's social care department during 12 months (2010/11).
Of 681 notifications (57 per month), 40% (270/681) were triggered by parents' presentation to acute hospital services. Of these, 37% (100/270; 12 teenage mothers) presented for maternity care and 60% (162/270; 8 teenage parents) presented to the emergency department (ED). Of the 60% (411/681) of notifications prompted by children presenting for healthcare, most originated from the ED (358/411; 87%): two-thirds of these presented with injury (250/358; 70%).
Given a policy to ask adults about children at home, a substantial proportion of children notified for child safeguarding were recognized through presentations to acute healthcare by their parents. Further research and development of this policy needs to ensure that questioning results in effective interventions for the children and their parents.
PMCID: PMC4340040  PMID: 24635011
child maltreatment; child safeguarding; paediatric emergency; social care; victimization
19.  Baseline Urinary Glucose Tetrasaccharide Concentrations in Patients with Infantile- and Late-Onset Pompe Disease Identified by Newborn Screening 
JIMD Reports  2015;19:67-73.
Purpose: The urinary glucose tetrasaccharide, Glcα1-6Glcα1-4Glcα1-4Glc (Glc4), is a biomarker of glycogen accumulation and tissue damage and is elevated in patients with Pompe disease. We report baseline urinary Glc4 concentrations for patients with classic infantile-onset or late-onset Pompe disease, and those with a pseudodeficiency of acid alpha-glucosidase (GAA), identified through newborn screening (NBS) in Taiwan.
Methods: Infants identified through NBS with (1) classic infantile-onset Pompe disease (NBS-IOPD) (n = 7) defined as patients with evidence for hypertrophic cardiomyopathy by EKG, X-ray, and echocardiogram, (2) a late-onset phenotype (NBS-LOPD) (n = 13) defined as patients without evidence for cardiomyopathy, (3) a GAA pseudodeficiency (n = 58), and (4) one patient with LOPD diagnosed in infancy due to family history were consented to the study. Four infants diagnosed after the onset of clinical symptoms (CLIN-IOPD) were included for comparison. Glc4 concentrations in dried urine samples on filter paper were determined using tandem mass spectrometry.
Results: Baseline Glc4 concentrations were at or above the 90th centile of the age-matched reference range for the NBS-IOPD cohort. The median Glc4 level for this group was lower than that of the CLIN-IOPD group, although not at the level of significance (p = 0.07), but was significantly higher than that of the NBS-LOPD group (p < 0.05). Baseline Glc4 was not elevated for the NBS-LOPD and GAA pseudodeficiency cohorts and remained low for late-onset patients that did not require treatment before the age of three years.
Conclusion: Baseline urinary Glc4 is elevated in neonates with infantile-onset Pompe disease identified through NBS.
Electronic supplementary material
The online version of this chapter (doi:10.1007/8904_2014_366) contains supplementary material, which is available to authorized users.
PMCID: PMC4501239  PMID: 25681082
Biomarker; Glucose tetrasaccharide; Newborn screening; Pompe disease; Tandem mass spectrometry
20.  Four Characteristics and a Model of an Effective Tear Film Lipid Layer (TFLL) 
The ocular surface  2013;11(4):236-245.
It is proposed that a normal, effective tear film lipid layer (TFLL) should have the following four characteristics: 1) high evaporation resistance to prevent water loss and consequent hyperosmolarity; 2) respreadability, so it will return to its original state after the compression-expansion cycle of the blink; 3) fluidity sufficient to avoid blocking secretion from meibomian glands; 4) gel-like and incompressible structure that can resist forces that may tend to disrupt it. These characteristics tend to be incompatible; for example, lipids that form good evaporation barriers tend to be disrupted by compression-expansion cycles. It is noted that clues about the function and organization of the TFLL can be obtained by comparison with other biological lipid layers, such as lung surfactant and the lipid evaporation barrier of the skin. In an attempt to satisfy the conflicting characteristics, a “multilamellar sandwich model” of the TFLL is proposed, having features in common with the skin evaporation barrier.
PMCID: PMC4313865  PMID: 24112227
blinks; evaporation resistance; evaporative dry eye; lipid layer structure; lipid monolayers; meibomian gland dysfunction; skin lipid barrier; X-ray analysis
21.  High resolution microscopy of the lipid layer of the tear film 
The ocular surface  2011;9(4):197-211.
The lipid layer of the tear film reduces evaporation and hence limits hyperosmolarity; the latter can cause ocular surface damage in dry eye conditions. The barrier to evaporation depends on the structure of the lipid layer, so that, for example, localized regions of thin lipid could cause increased evaporation. It is therefore important to study the detailed structure of the lipid layer, and high resolution microscope for this purpose is described here. To broaden the range of observations, both normal and dry eye conditions were included in this study, but a systematic comparison of the two conditions will be reserved for future reports.
The microscope incorporates the following features. First, a long working distance microscope objective is used with a high numerical aperture and resolution. Second, because such a high resolution objective has a limited depth of focus, 2000 images are recorded with a video camera over a 20 s period, with the expectation that some images will be in focus. Third, illumination is from a stroboscopic light source having a flash duration of less than 0.1 ms, to avoid blurring from movement of the lipid layer. Fourth, the image is in focus when the edge of the image is sharp – this is used to select images in good focus. Fifth, an aid is included to help align the cornea at normal incidence to the axis of the objective so that the whole lipid image can be in focus. Illustrative results are presented derived from over 10,000 images from 375 subjects.
Images could generally be described as containing localized “objects” within an extensive “background”. Backgrounds were of two types – dark (thin) “seas” and “irregular” (thicker). Sea backgrounds were less common and included irregular “islands” and round “lenses” of lipid. Irregular backgrounds included thick “droplets” and thin “dots”. Islands were fluid and on occasion turned into lenses. Dots sometimes, but not always, seem to increase in size between blinks; sometimes they had a flower-like outline. Droplets were very stable, with little change during the interblink interval. Within about 0.1 seconds after a blink, sea backgrounds were relatively more common than at later times, droplets were less common, and the lipid layer was significantly thinner; objects described as “snowflakes” and “clouds” tended to occur in this early period.
Lipid islands within a sea background show many of the characteristics of dewetting including formation of round “lakes” (holes), rupture of the lake walls to form larger irregular lakes, further rupture to form islands which eventually form circular lenses. The observation of thick, narrow ridges surrounding lakes and islands is another characteristic of dewetting. Dewetting indicates that, in this case, the lipid layer has a negative “spreading coefficient”, perhaps because of a lack of polar lipids at the interface with the aqueous layer. Conversely, when the whole surface seems to be covered in lipid, the spreading coefficient may be positive, indicating adequate polar lipids at the interface. Dots, particularly those with flower-like outlines, may be related to “lipid domains” observed in monolayers. The fact that lipid droplets within an irregular background are stable over the inter-blink interval, indicates that their origin is either due to other phases (compression, upstroke) of the blink cycle, or that they correspond to the “fat droplets” observed in Meibomian glands. The stability of irregular backgrounds could be due to solid or gel-like properties of the lipid layer, but may also be due to an absence of overall force (from surface tension and pressure gradients) on the lipid layer.
PMCID: PMC4313928  PMID: 22023815
22.  Changes in the Incidence of Candidiasis in Neonatal Intensive Care Units 
Pediatrics  2014;133(2):236-242.
Neonatal invasive candidiasis is associated with significant morbidity and mortality. We describe the association between invasive candidiasis and changes in use of antifungal prophylaxis, empirical antifungal therapy, and broad-spectrum antibacterial antibiotics over time.
We examined data from 709 325 infants at 322 NICUs managed by the Pediatrix Medical Group from 1997 to 2010. We determined the cumulative incidence of invasive candidiasis and use of antifungal prophylaxis, broad-spectrum antibacterial antibiotics, and empirical antifungal therapy by year.
We identified 2063 (0.3%) infants with 2101 episodes of invasive candidiasis. Over the study period, the annual incidence of invasive candidiasis decreased from 3.6 episodes per 1000 patients to 1.4 episodes per 1000 patients among all infants, from 24.2 to 11.6 episodes per 1000 patients among infants with a birth weight of 750–999 g, and from 82.7 to 23.8 episodes per 1000 patients among infants with a birth weight <750 g. Fluconazole prophylaxis use increased among all infants with a birth weight <1000 g (or <1500 g), with the largest effect on birth weights <750 g, increasing from 3.8 per 1000 patients in 1997 to 110.6 per 1000 patients in 2010. The use of broad-spectrum antibacterial antibiotics decreased among all infants from 275.7 per 1000 patients in 1997 to 48.5 per 1000 patients in 2010. The use of empirical antifungal therapy increased over time from 4.0 per 1000 patients in 1997 to 11.5 per 1000 patients in 2010.
The incidence of invasive candidiasis in the NICU decreased over the 14-year study period. Increased use of fluconazole prophylaxis and empirical antifungal therapy, along with decreased use of broad-spectrum antibacterial antibiotics, may have contributed to this observation.
PMCID: PMC3904270  PMID: 24446441
invasive candidiasis; fluconazole prophylaxis; premature infants
In this paper, we investigate the dynamics of tear film and the associated temperature variation for partial blinks. We investigate the mechanism of fluid supply during partial blink cycles, and compare the film thickness with observation in vivo. We find that varying the thickness of the fluid layer beneath the moving upper lid improves the agreement for the in vivo measurement of tear film thickness after a half blink. By examining the flux of the fluid, we provide an explanation of this assumption. We also investigate the temperature dynamics both at the ocular surface and inside the simulated anterior chamber. Our simulation results suggest that the ocular surface temperature readjusts rapidly to normal temperature distribution after partial blinks.
PMCID: PMC4307865  PMID: 25635242
tear film; blinking; ocular surface temperature; spectral collocation
24.  Population Pharmacokinetics of Intravenous Acyclovir in Preterm and Term Infants 
Acyclovir is used to treat herpes infections in preterm and term infants; however, the influence of maturation on drug disposition and dosing requirements is poorly characterized in this population.
We administered intravenous acyclovir to preterm and term infants <31 days postnatal age and collected plasma samples. We performed a population pharmacokinetic analysis. The primary pharmacodynamic target was acyclovir concentration ≥3 mg/L for ≥50% of the dosing interval. The final model was simulated using infant data from a clinical database.
The analysis included 28 infants (median 30 weeks gestation). Acyclovir pharmacokinetics was described by a 1-compartment model: clearance (L/h/kg) = 0.305 × (postmenstrual age [PMA]/31.3 weeks)3.02. This equation predicts a 4.5-fold increase in clearance from 25 to 41 weeks PMA. With proposed dosing, the pharmacodynamic target was achieved in 91% of infants: 20 mg/kg every 12 hours in infants <30 weeks PMA; 20 mg/kg every 8 hours in infants 30 to <36 weeks PMA; 20 mg/kg every 6 hours in infants 36–41 weeks PMA.
Acyclovir clearance increased with infant maturation. A dosing strategy based on PMA accounted for developmental changes in acyclovir disposition to achieve the surrogate pharmacodynamic target in the majority of infants.
PMCID: PMC3904301  PMID: 24346595
herpes simplex virus; preterm infants; acyclovir
25.  Intestinal Fatty-Acid Binding Protein and Metronidazole Response in Premature Infants 
In premature infants with suspected intra-abdominal infection, biomarkers for treatment response to antimicrobial therapy are lacking. Intestinal fatty acid-binding protein (I-FABP) is specific to the enterocyte and is released in response to intestinal mucosal injury. I-FABP has not been evaluated as a surrogate marker of disease response to antimicrobial therapy. We examined the relationship between metronidazole exposure and urinary I-FABP concentrations in premature infants with suspected intra-abdominal infection.
Study design
We conducted an intravenous metronidazole pharmacokinetic study, collecting ≤3 urine samples per infant for I-FABP concentration measurements. We analyzed the relationship between I-FABP concentrations and measures of metronidazole exposure and pharmacokinetics, maturational factors, and other covariates.
Twenty-six samples from 19 premature infants were obtained during metronidazole treatment. When analyzed without regard to presence of necrotic gastrointestinal disease, there were no significant associations between predictor variables and I-FABP concentrations. However, when the sample was limited to premature infants with necrotic gastrointestinal disease, an association was found between average predicted metronidazole concentration and I-FABP concentration (p=0.006).
While a predictive association between urinary I-FABP and metronidazole systemic exposure was not observed, the data suggest the potential of this endogenous biomarker to serve as a pharmacodynamic surrogate for antimicrobial treatment of serious abdominal infections in neonates and infants.
PMCID: PMC4225165  PMID: 25318626
necrotizing enterocolitis; biomarkers; pharmacokinetics; premature infants; antimicrobial agents

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