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1.  Rifampin Use and Safety in Hospitalized Infants 
American journal of perinatology  2015;32(6):565-570.
Objective
To examine the use and safety of rifampin in hospitalized infants.
Study Design
Observational study of clinical and laboratory adverse events among infants exposed to rifampin from 348 neonatal intensive care units managed by the Pediatrix Medical Group between 1997 and 2012.
Result
2500 infants received 4279 courses of rifampin; mean gestational age was 27 weeks (5th, 95th %tile; 23, 36) and mean birth weight was 1125 g (515, 2830). Thrombocytopenia (121/1000 infant days) and conjugated hyperbilirubinemia (25/1000 infant days) were the most common laboratory adverse events. The most common clinical adverse events were medical necrotizing enterocolitis (64/2500 infants, 3%) and seizure (60/2500 infants, 2%).
Conclusion
The overall incidence of adverse events among infants receiving rifampin appears low; however, additional studies to further evaluate safety and dosing of rifampin in this population are needed.
doi:10.1055/s-0034-1543955
PMCID: PMC4433596  PMID: 25594217
rifampin; broad-spectrum antibiotic; infectious disease; neonatal intensive care unit
2.  Psychosocial Predictors of Mortality Following Lung Transplantation 
Lung transplantation has become an increasingly common treatment for patients with end-stage lung disease. Few studies have examined psychosocial risk factors for mortality in transplant recipients, despite evidence suggesting that elevated levels of negative affect are associated with greater mortality following major cardiac surgery. We therefore examined the relationship between negative affect early after lung transplantation and long-term survival in a sample of 132 lung transplant recipients (28 cystic fibrosis, 64 chronic obstructive pulmonary disease, 26 idiopathic pulmonary fibrosis, 14 other) followed for up to 13.5 years (median 7.4 years) following transplantation. Patients underwent both medical and psychosocial assessments 6 months following transplantation, which included the Beck Depression Inventory–II (BDI-II), Spielberger Anxiety Inventory, and General Health Questionnaire (GHQ). Over the course of follow-up, 80 (61%) participants died. Controlling for demographic factors, native lung disease, disease severity, family income, education level, social support, and frequency of posttransplant rejection, elevated symptoms of depression (BDI-II: HR = 1.31, p = 0.011) and distress (GHQ: HR = 1.28, p = 0.003) were associated with increased mortality. Higher levels of depression and general distress, but not anxiety, measured 6 months following lung transplantation are associated with increased mortality, independent of background characteristics and medical predictors.
doi:10.1111/ajt.13447
PMCID: PMC4830128  PMID: 26366639
3.  No Survival Benefit with Empirical Vancomycin Therapy for Coagulase-negative Staphylococcal Bloodstream Infections in Infants 
Background
Coagulase-negative Staphylococcus (CoNS) is the most common cause of bloodstream infections (BSI) in hospitalized infants. CoNS BSI is most reliably treated with vancomycin; however, concerns about side effects and promoting resistance often delay empirical vancomycin therapy until culture results become available.
Methods
All infants with CoNS BSI discharged from 348 neonatal intensive care units managed by the Pediatrix Medical Group from 1997–2012 were identified. Empirical vancomycin therapy was defined as vancomycin exposure on the day of the first positive blood culture. Delayed vancomycin therapy was defined as vancomycin exposure 1–3 days after the first positive blood culture. We used multivariable logistic regression with random effects for site to evaluate the association between the use of empirical vancomycin therapy vs. delayed vancomycin therapy and 30-day mortality, controlling for gestational age, small-for-gestational age status, postnatal age on the day of the first positive culture, oxygen requirement, ventilator support, and inotropic support on the day the first positive culture was obtained.
Results
Of the 4364 infants with CoNS BSI, 2848 (65%) were treated with empirical vancomycin. The median postnatal age at first positive culture was 14 days (interquartile range: 9, 21). Unadjusted 30-day mortality was similar for infants treated with empirical vancomycin and infants treated with delayed vancomycin therapy (166/2848 [6%] vs. 69/1516 [4%]; p=0.08). There was no significant difference in 30-day mortality on multivariable analysis (odds ratio: 1.14 [0.84, 1.56]). The median duration of bacteremia was 1 day longer for infants with delayed vancomycin therapy (4 days [interquartile range 2, 6] vs. 3 days [2, 5]; p<0.0001).
Conclusions
The median duration of bacteremia was 1 day longer in infants with CoNS BSI who received delayed vancomycin therapy. Despite this finding, empirical vancomycin therapy for CoNS BSI was not associated with improved mortality.
doi:10.1097/INF.0000000000000573
PMCID: PMC4357312  PMID: 25760564
late-onset sepsis; NICU
4.  The Epidemiology and Diagnosis of Invasive Candidiasis Among Premature Infants 
Clinics in perinatology  2014;42(1):105-117.
Invasive candidiasis is a leading infectious cause of morbidity and mortality in premature infants. Improved recognition of modifiable risk factors and antifungal prophylaxis have contributed to the recent decline in the incidence of this infection among infants. Invasive candidiasis typically occurs in the first six weeks of life and presents with non-specific signs of sepsis. Definitive diagnosis relies on growth of Candida in blood culture or cultures from other normally sterile sites, but this may identify fewer than half of cases. Improved diagnostics are needed to guide initiation of antifungal therapy in premature infants.
doi:10.1016/j.clp.2014.10.008
PMCID: PMC4328135  PMID: 25677999
neonatal candidiasis; Candida; premature infants; risk factors
5.  Dynamics and function of the tear film in relation to the blink cycle 
Great strides have recently been made in quantitative measurements of tear film thickness and thinning, mathematical modeling thereof and linking these to sensory perception. This paper summarizes recent progress in these areas and reports on new results. The complete blink cycle is used as a framework that attempts to unify the results that are currently available. Understanding of tear film dynamics is aided by combining information from different imaging methods, including fluorescence, retroillumination and a new high-speed stroboscopic imaging system developed for studying the tear film during the blink cycle. During the downstroke of the blink, lipid is compressed as a thick layer just under the upper lid which is often released as a narrow thick band of lipid at the beginning of the upstroke. “Rippling” of the tear film/air interface due to motion of the tear film over the corneal surface, somewhat like the flow of water in a shallow stream over a rocky streambed, was observed during lid motion and treated theoretically here. New mathematical predictions of tear film osmolarity over the exposed ocular surface and in tear breakup are presented; the latter is closely linked to new in vivo observations. Models include the effects of evaporation, osmotic flow through the cornea and conjunctiva, quenching of fluorescence, tangential flow of aqueous tears and diffusion of tear solutes and fluorescein. These and other combinations of experiment and theory increase our understanding of the fluid dynamics of the tear film and its potential impact on the ocular surface.
doi:10.1016/j.preteyeres.2014.11.001
PMCID: PMC4364449  PMID: 25479602
Tear film; Tear film dynamics; Lipid layer; Tear break-up; Tear hyperosmolarity
6.  Dietary Factors and Cognitive Decline 
Cognitive decline is an increasingly important public health problem, with more than 100 million adults worldwide projected to develop dementia by 2050. Accordingly, there has been an increased interest in preventive strategies that diminish this risk. It has been recognized that lifestyle factors including dietary patterns, may be important in the prevention of cognitive decline and dementia in later life. Several dietary components have been examined, including antioxidants, fatty acids, and B vitamins. In addition, whole dietary eating plans, including the Mediterranean diet (MeDi), and the Dietary Approaches to Stop Hypertension (DASH) diet, with and without weight loss, have become areas of increasing interest. Although prospective epidemiological studies have observed that antioxidants, fatty acids, and B vitamins are associated with better cognitive functioning, randomized clinical trials have generally failed to confirm the value of any specific dietary component in improving neurocognition. Several randomized trials have examined the impact of changing ‘whole’ diets on cognitive outcomes. The MeDi and DASH diets offer promising preliminary results, but data are limited and more research in this area is needed.
doi:10.14283/jpad.2015.71
PMCID: PMC4758517  PMID: 26900574
Dietary patterns; nutrition; cognitive function; dementia
7.  Gingival Wound Healing 
Journal of Dental Research  2015;94(3):395-402.
Gingival wound healing comprises a series of sequential responses that allow the closure of breaches in the masticatory mucosa. This process is of critical importance to prevent the invasion of microbes or other agents into tissues, avoiding the establishment of a chronic infection. Wound healing may also play an important role during cell and tissue reaction to long-term injury, as it may occur during inflammatory responses and cancer. Recent experimental data have shown that gingival wound healing is severely affected by the aging process. These defects may alter distinct phases of the wound-healing process, including epithelial migration, granulation tissue formation, and tissue remodeling. The cellular and molecular defects that may explain these deficiencies include several biological responses such as an increased inflammatory response, altered integrin signaling, reduced growth factor activity, decreased cell proliferation, diminished angiogenesis, reduced collagen synthesis, augmented collagen remodeling, and deterioration of the proliferative and differentiation potential of stem cells. In this review, we explore the cellular and molecular basis of these defects and their possible clinical implications.
doi:10.1177/0022034514563750
PMCID: PMC4814024  PMID: 25527254
gingiva; gerontology; cell biology; myofibroblast; extracellular matrix; cytokines
8.  The interaction between artemether-lumefantrine and lopinavir/ritonavir-based antiretroviral therapy in HIV-1 infected patients 
Background
Artemether-lumefantrine is currently the most widely recommended treatment of uncomplicated malaria. Lopinavir–based antiretroviral therapy is the commonly recommended second-line HIV treatment. Artemether and lumefantrine are metabolised by cytochrome P450 isoenzyme CYP3A4, which lopinavir/ritonavir inhibits, potentially causing clinically important drug-drug interactions.
Methods
An adaptive, parallel-design safety and pharmacokinetic study was conducted in HIV-infected (malaria-negative) patients: antiretroviral-naïve and those stable on lopinavir/ritonavir-based antiretrovirals. Both groups received the recommended six-dose artemether-lumefantrine treatment. The primary outcome was day-7 lumefantrine concentrations, as these correlate with antimalarial efficacy. Adverse events were solicited throughout the study, recording the onset, duration, severity, and relationship to artemether-lumefantrine.
Results
We enrolled 34 patients. Median day-7 lumefantrine concentrations were almost 10-fold higher in the lopinavir than the antiretroviral-naïve group [3170 versus 336 ng/mL; p = 0.0001], with AUC(0-inf) and Cmax increased five-fold [2478 versus 445 μg.h/mL; p = 0.0001], and three-fold [28.2 versus 8.8 μg/mL; p < 0.0001], respectively. Lumefantrine Cmax, and AUC(0-inf) increased significantly with mg/kg dose in the lopinavir, but not the antiretroviral-naïve group. While artemether exposure was similar between groups, Cmax and AUC(0-8h) of its active metabolite dihydroartemisinin were initially two-fold higher in the lopinavir group [p = 0.004 and p = 0.0013, respectively]. However, this difference was no longer apparent after the last artemether-lumefantrine dose. Within 21 days of starting artemether-lumefantrine there were similar numbers of treatment emergent adverse events (42 vs. 35) and adverse reactions (12 vs. 15, p = 0.21) in the lopinavir and antiretroviral-naïve groups, respectively. There were no serious adverse events and no difference in electrocardiographic QTcF- and PR-intervals, at the predicted lumefantrine Tmax.
Conclusion
Despite substantially higher lumefantrine exposure, intensive monitoring in our relatively small study raised no safety concerns in HIV-infected patients stable on lopinavir-based antiretroviral therapy given the recommended artemether-lumefantrine dosage. Increased day-7 lumefantrine concentrations have been shown previously to reduce the risk of malaria treatment failure, but further evidence in adult patients co-infected with malaria and HIV is needed to assess the artemether-lumefantrine risk : benefit profile in this vulnerable population fully. Our antiretroviral-naïve patients confirmed previous findings that lumefantrine absorption is almost saturated at currently recommended doses, but this dose-limited absorption was overcome in the lopinavir group.
Trial registration
Clinical Trial Registration number NCT00869700. Registered on clinicaltrials.gov 25 March 2009
Electronic supplementary material
The online version of this article (doi:10.1186/s12879-016-1345-1) contains supplementary material, which is available to authorized users.
doi:10.1186/s12879-016-1345-1
PMCID: PMC4728832  PMID: 26818566
HIV; Malaria; Artemether; Lumefantrine; Lopinavir; Ritonavir; Drug interaction; Safety; Pharmacokinetic; Dose-related exposure
9.  Safety of Sildenafil in Infants* 
Objective
In view of the recent U.S. Food and Drug Administration’s warning against the use of sildenafil in pediatric patients, we aimed to provide an updated overview of the dosing and safety of sildenafil in infants and to explore the relevance of the present safety concerns to the infant population.
Data Source
The National Library of Medicine PubMed and Cochrane Database of Systematic Reviews were searched using the following terms: Sildenafil AND (infant OR infants OR newborn OR newborns OR child OR children OR childhood OR pediatric OR pediatrics OR paediatric OR paediatrics).
Study Selection
Studies presenting original clinical data regarding the dosing, use, or safety of sildenafil in infants with pulmonary hypertension would be included.
Data Extraction
Of the 49 included studies, case reports and case series were the most common type of publications (n = 25). The identified trials included 625 children, with more than 140 infants. Persistent pulmonary hypertension of the newborn and pulmonary hypertension associated with other conditions were the most common underlying diagnoses.
Conclusion
There is currently no evidence of serious adverse event in infants exposed to sildenafil. Present safety concerns regarding the use of sildenafil in pediatric patients should be further explored before being applied to infant population. Sildenafil remains a valuable option for the treatment of pulmonary hypertension in young infants. Prospective studies should be designed in such a way that they include a safety assessment to evaluate potential adverse outcomes of sildenafil therapy in this population.
doi:10.1097/PCC.0000000000000077
PMCID: PMC4709254  PMID: 24583505
adverse events; infants; off-label; pulmonary hypertension; safety; sildenafil
10.  Chyle leak following right axillary lymph node dissection: A case report and review of current literature 
Highlights
•Chyle leak is an uncommon complication of axillary node dissection.•The majority of reported cases occur on the left side, however several instances of right sided chyle leaks are reported.•The majority of chyle leaks respond to conservative management with: diet modification, pressure and drainage.•Diagnosis is based on clinical appearance for drainage, laboratory evaluation and lymphscintigraphy.
This report discusses the case of a chyle leak following a right axillary lymph node dissection for breast cancer. This presented as a sudden change in drainage character from a right axillary surgical drain from serous to milky white shortly after restarting a diet. The diagnosis of chyle leak was confirmed by laboratory testing of the fluid and managed with closed suction drainage. Chyle leak is a rare, but increasingly recognized complication following axillary clearance for breast cancer and melanoma.
doi:10.1016/j.ijscr.2015.12.044
PMCID: PMC4818284  PMID: 26826928
Chyle leak; Axillary node dissection; Axillary lymphadenectomy; Mastectomy
11.  Dosing in neonates: Special considerations in physiology and trial design 
Pediatric research  2014;77(0):2-9.
Determining the right dose for drugs used to treat neonates is critically important. Neonates have significant differences in physiology affecting drug absorption, distribution, metabolism, and elimination that makes extrapolating dosages from adults and older children inappropriate. In spite of recent legislative efforts requiring drug studies in this population, most drugs given to neonates remain insufficiently studied. Many ethical and logistical concerns make designing studies in this age group difficult. Fortunately, specialized analytical techniques, such as the use of dried blood spots, scavenged sampling, population pharmacokinetics analyses, and sparse sampling, have helped investigators better define doses that maximize efficacy and safety. Through the use of these methods, successful clinical trials have resulted in recent changes to drug dosing in this population.
doi:10.1038/pr.2014.143
PMCID: PMC4268272  PMID: 25268145
12.  Anaerobic Antimicrobial Therapy After Necrotizing Enterocolitis in VLBW Infants 
Pediatrics  2015;135(1):e117-e125.
OBJECTIVE:
To evaluate the effect of anaerobic antimicrobial therapy for necrotizing enterocolitis (NEC) on clinical outcomes in very low birth weight (≤1500 g) infants.
METHODS:
We identified very low birth weight infants with NEC from 348 US NICUs from 1997 to 2012. Anaerobic antimicrobial therapy was defined by antibiotic exposure on the first day of NEC. We matched (1:1) infants exposed to anaerobic antimicrobial therapy with infants who were not exposed by using a propensity score stratified by NEC severity (medical and surgical). The primary composite outcome was in-hospital death or intestinal stricture. We assessed the relationship between anaerobic antimicrobial therapy and outcome by using a conditional logistic regression on the matched cohort.
RESULTS:
A total of 1390 infants exposed to anaerobic antimicrobial therapy were matched with 1390 infants not exposed. Mean gestational age and birth weight were 27 weeks and 946 g, respectively, and were similar in both groups. We found no significant difference in the combined outcome of death or strictures, but strictures as a single outcome were more common in the anaerobic antimicrobial therapy group (odds ratio 1.73; 95% confidence interval, 1.11–2.72). Among infants with surgical NEC, mortality was less common with anaerobic antimicrobial therapy (odds ratio 0.71; 95% confidence interval, 0.52–0.95).
CONCLUSIONS:
Anaerobic antimicrobial therapy was not associated with the composite outcome of death or strictures but was associated with an increase in intestinal strictures. This higher incidence of intestinal strictures may be explained by the fact that death is a competing outcome for intestinal strictures, and mortality was slightly lower in the anaerobic cohort. Infants with surgical NEC who received anaerobic antimicrobial therapy had lower mortality.
doi:10.1542/peds.2014-2141
PMCID: PMC4279070  PMID: 25511117
necrotizing enterocolitis; very low birth weight infants; anaerobes; antibiotics; mortality; intestinal strictures
13.  Diuretic exposure in premature infants from 1997–2011 
Objective
Diuretics are often prescribed off-label to premature infants, particularly to prevent or treat bronchopulmonary dysplasia (BPD). We examined their use and safety in this group.
Study Design
Retrospective cohort study of infants <32 weeks gestation and <1500 g birth weight exposed to diuretics in 333 neonatal intensive care units from 1997–2011. We examined use of acetazolamide, amiloride, bumetanide, chlorothiazide, diazoxide, ethacrynic acid, furosemide, hydrochlorothiazide, mannitol, metolazone, or spironolactone combination. Respiratory support and FiO2 on the first day of each course of diuretic use were identified.
Results
Thirty-seven percent (39,357/107,542) of infants were exposed to at least 1 diuretic; furosemide was the most commonly used (93% with ≥1 recorded dose), followed by spironolactone, chlorothiazide, hydrochlorothiazide, bumetanide, and acetazolamide. Seventy-four percent were exposed to 1 diuretic at a time, 19% to 2 diuretics simultaneously, and 6% to 3 diuretics simultaneously. The most common combination was furosemide/spironolactone, followed by furosemide/chlorothiazide and chlorothiazide/spironolactone. Many infants were not receiving mechanical ventilation on the first day of each new course of furosemide (47%), spironolactone (69%), chlorothiazide (61%), and hydrochlorothiazide (68%). Any adverse event occurred on 42 per 1000 infant-days for any diuretic and 35 per 1000 infant-days for furosemide. Any serious adverse event occurred in 3.8 for any diuretic and 3.2 per 1000 infant-days for furosemide. The most common laboratory abnormality associated with diuretic exposure was thrombocytopenia.
Conclusion
Despite no FDA indication and little safety data, over one third of premature infants in our population were exposed to a diuretic, many with minimal respiratory support.
doi:10.1055/s-0034-1373845
PMCID: PMC4223004  PMID: 24801161
bronchopulmonary dysplasia; diuretic; safety; drug
14.  Safety of milrinone use in neonatal intensive care units 
Early human development  2014;91(1):31-35.
Background
Milrinone use in the neonatal intensive care unit has increased over the last 10 years despite a paucity of published safety data in infants. We sought to determine the safety of milrinone therapy among infants in the neonatal intensive care unit.
Methods
We conducted a retrospective data analysis, identifying all infants exposed to milrinone discharged from 322 neonatal intensive care units managed by the Pediatrix Medical Group from 1997–2010. We identified adverse events (AEs) during milrinone exposure. The unit of observation for clinical AEs was the first course of milrinone and for laboratory AEs was an infant-day of exposure to milrinone.
Results
Overall, 1446 of 716,821 (0.2%) infants received milrinone for a total of 6894 infant-days. The proportion of infants exposed to milrinone increased from 0 in 1997 to 4/1000 infant cases in 2010. Persistent pulmonary hypertension (40%) was the most commonly reported diagnosis at the start of milrinone administration. Overall, 606/1446 (42%) of infants had at least 1 clinical AE recorded during milrinone therapy. Hypotension requiring pressors and thrombocytopenia (<100,000/mm3) were the most commonly reported clinical and laboratory AEs, respectively. Death was reported in 8% of infants during the first course of milrinone therapy.
Conclusion
Among infants hospitalized in the neonatal intensive care unit, there was an increase in the use of milrinone over the past 13 years. The safety, dosing, and efficacy of milrinone in infants should be determined in prospective clinical trials.
doi:10.1016/j.earlhumdev.2014.10.007
PMCID: PMC4302030  PMID: 25460254
milrinone; infants; safety; adverse events; neonatal intensive care unit; persistent pulmonary hypertension
15.  Clinical outcomes in very low birth weight infants with major congenital heart defects 
Early human development  2014;90(12):791-795.
Background
The combination of major congenital heart disease (CHD) and prematurity is associated with poor prognosis, but previous studies have not fully characterized morbidity and mortality in this population. We conducted a retrospective cohort study of very low birth weight (VLBW) infants with major CHD to describe outcomes, including mortality, over time.
Methods
We included all infants <1500 g birth weight with major CHD discharged from Pediatrix Medical Group neonatal intensive care units from 1997–2012. We report incidences of major CHD in VLBW infants and compare mortality and morbidity by infant birth weight, type of major CHD, and time period.
Results
Of 105,539 VLBW infants, 299 (0.3%) were diagnosed with 15 different major CHDs. Coarctation of the aorta (n=67, 22%), atrioventricular septal defect (n=58, 19%), and tetralogy of Fallot (n=53, 18%) were the most common major CHDs identified. Overall mortality was 163/299 (55%). Mortality was ≥70% for 10 lesions and <30% for isolated aortic valve stenosis (6/30, 20%). Mortality in infants with major CHD did not significantly change over time: 76/133 (57%) in 1997–2005, 49/95 (52%) in 2006–2009, and 38/71 (54%) in 2010–2012 (p=0.70). The majority of infants suffered ≥1 comorbidity or died (218/299, 73%).
Conclusion
Major CHD is associated with high morbidity and mortality. While mortality varies by lesion, overall survival and incidence of major morbidity have not improved over time.
doi:10.1016/j.earlhumdev.2014.09.006
PMCID: PMC4312193  PMID: 25463822
prematurity; very low birth weight; congenital heart defect; morbidity; mortality
16.  The acute psychobiological impact of the intensive care experience on relatives 
Psychology, Health & Medicine  2015;21(1):20-26.
There is a growing awareness amongst critical care practitioners that the impact of intensive care medicine extends beyond the patient to include the psychological impact on close family members. Several studies have addressed the needs of relatives within the intensive care context but the psychobiological impact of the experience has largely been ignored. Such impact is important in respect to health and well-being of the relative, with potential to influence patient recovery. The current feasibility study aimed to examine the acute psychobiological impact of the intensive care experience on relatives. Using a mixed methods approach, quantitative and qualitative data were collected simultaneously. Six relatives of patients admitted to the intensive care unit (ICU) of a District General Hospital, were assessed within 48 h of admission. Qualitative data were provided from semi-structured interviews analysed using interpretative phenomenological analysis. Quantitative data were collected using a range of standardised self-report questionnaires measuring coping responses, emotion, trauma symptoms and social support, and through sampling of diurnal salivary cortisol as a biomarker of stress. Four themes were identified from interview: the ICU environment, emotional responses, family relationships and support. Questionnaires identified high levels of anxiety, depression and trauma symptoms; the most commonly utilised coping techniques were acceptance, seeking support through advice and information, and substance use. Social support emerged as a key factor with focused inner circle support relating to family and ICU staff. Depressed mood and avoidance were linked to greater mean cortisol levels across the day. Greater social network and coping via self-distraction were related to lower evening cortisol, indicating them as protective factors in the ICU context. The experience of ICU has a psychological and physiological impact on relatives, suggesting the importance of identifying cost-effective interventions with evaluations of health benefits to both relatives and patients.
doi:10.1080/13548506.2014.997763
PMCID: PMC4662102  PMID: 25572144
social support; coping; stress; intensive care; relatives
17.  Between-Hospital Variation in Treatment and Outcomes in Extremely Preterm Infants 
The New England journal of medicine  2015;372(19):1801-1811.
BACKGROUND
Between-hospital variation in outcomes among extremely preterm infants is largely unexplained and may reflect differences in hospital practices regarding the initiation of active lifesaving treatment as compared with comfort care after birth.
METHODS
We studied infants born between April 2006 and March 2011 at 24 hospitals included in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Data were collected for 4987 infants born before 27 weeks of gestation without congenital anomalies. Active treatment was defined as any potentially lifesaving intervention administered after birth. Survival and neurodevelopmental impairment at 18 to 22 months of corrected age were assessed in 4704 children (94.3%).
RESULTS
Overall rates of active treatment ranged from 22.1% (interquartile range [IQR], 7.7 to 100) among infants born at 22 weeks of gestation to 99.8% (IQR, 100 to 100) among those born at 26 weeks of gestation. Overall rates of survival and survival without severe impairment ranged from 5.1% (IQR, 0 to 10.6) and 3.4% (IQR, 0 to 6.9), respectively, among children born at 22 weeks of gestation to 81.4% (IQR, 78.2 to 84.0) and 75.6% (IQR, 69.5 to 80.0), respectively, among those born at 26 weeks of gestation. Hospital rates of active treatment accounted for 78% and 75% of the between-hospital variation in survival and survival without severe impairment, respectively, among children born at 22 or 23 weeks of gestation, and accounted for 22% and 16%, respectively, among those born at 24 weeks of gestation, but the rates did not account for any of the variation in outcomes among those born at 25 or 26 weeks of gestation.
CONCLUSIONS
Differences in hospital practices regarding the initiation of active treatment in infants born at 22, 23, or 24 weeks of gestation explain some of the between-hospital variation in survival and survival without impairment among such patients. (Funded by the National Institutes of Health.)
doi:10.1056/NEJMoa1410689
PMCID: PMC4465092  PMID: 25946279
18.  Comparative effectiveness of digoxin and propranolol for supraventricular tachycardia in infants 
Objective
Supraventricular tachycardia (SVT) is the most common arrhythmia in infants, and antiarrhythmic medications are frequently used for prophylaxis. The optimal prophylactic antiarrhythmic medication is unknown, and prior randomized trials have been underpowered. We used data from a large clinical registry to compare efficacy and safety of digoxin and propranolol for infant SVT prophylaxis. We hypothesized that SVT recurrence is less common on digoxin compared with propranolol.
Design
Retrospective cohort study.
Setting
Pediatrix Medical Group neonatal intensive care units.
Patients
Infants discharged from 1998–2012 with SVT treated with digoxin or propranolol. We excluded infants discharged prior to completing 2 days of therapy, those with Wolff-Parkinson-White syndrome, structural heart defects (except atrial/ventricular septal defects and patent ductus arteriosus), and those started on multi-drug therapy.
Measurements
We used Cox proportional hazards to evaluate SVT recurrence, defined as need for adenosine or electrical cardioversion while exposed to digoxin vs. propranolol, controlling for infant characteristics, inotropic support, supplemental oxygen, and presence of a central line.
Results
We identified 342 infants exposed to digoxin and 142 infants exposed to propranolol. The incidence rate of treatment failure was 6.7/1000 infant-days of exposure to digoxin and 15.4/1000 infant-days of exposure to propranolol. On multivariable analysis, treatment failure was higher on propranolol compared with digoxin (hazard ratio=1.97 [95% confidence interval: 1.05, 3.71]). Hypotension was more frequent during exposure to digoxin versus propranolol (39.4 versus 11.1/1000 infant-days, p<0.001). There was no difference in frequency of other clinical adverse events.
Conclusions
Digoxin was associated with fewer episodes of SVT recurrence but more frequent hypotension in hospitalized infants relative to propranolol.
doi:10.1097/PCC.0000000000000229
PMCID: PMC4221410  PMID: 25072477
supraventricular tachycardia; infants; digoxin; propranolol
19.  Medication use in the neonatal intensive care unit 
American journal of perinatology  2013;31(9):811-822.
Objective
We provide an update on medication use in infants admitted to the neonatal intensive care unit (NICU) in the United States and examine how use has changed over time.
Study Design
We performed a retrospective review (2005–2010) of a large prospectively collected administrative database.
Result
Medications most commonly administered during the study period were ampicillin, gentamicin, caffeine citrate, vancomycin, beractant, furosemide, fentanyl, dopamine, midazolam, and calfactant (56–681 exposures per 1000 infants). Those with the greatest relative increase in use included azithromycin, sildenafil, and milrinone. Medications with the greatest relative decrease in use included theophylline, metoclopramide, and doxapram.
Conclusion
Medication use in the NICU has changed substantially over time, and only 35% of the most commonly prescribed medications are FDA-approved in infants.
doi:10.1055/s-0033-1361933
PMCID: PMC4061287  PMID: 24347262
pharmacotherapy; trends over time
20.  Vancomycin Cerebrospinal Fluid Pharmacokinetics in Children with Cerebral Ventricular Shunt Infections 
This study described the cerebrospinal fluid (CSF) exposure of vancomycin in 8 children prescribed intravenous vancomycin therapy for cerebral ventricular shunt infection. Vancomycin CSF concentrations ranged from 0.06 to 9.13 mg/L and the CSF: plasma ratio ranged from 0 to 0.66. Two children out of three with a staphylococcal CSF infection had CSF concentrations > minimal inhibitory concentration at the end of the dosing interval.
doi:10.1097/INF.0000000000000385
PMCID: PMC4209191  PMID: 24776517
vancomycin; pharmacokinetics; cerebrospinal fluid; children; cerebral shunt
21.  O5.04PRELIMINARY RESULTS OF THE GALA-5 STUDY: AN EVALUATION OF THE TOLERABILITY AND FEASIBILITY OF COMBINING 5-AMINO-LEVULINIC ACID (5-ALA) WITH CARMUSTINE WAFERS (GLIADEL) IN THE SURGICAL MANAGEMENT OF PRIMARY GLIOBLASTOMA 
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.
doi:10.1093/neuonc/nou174.35
PMCID: PMC4185716
22.  A systematic review of randomized controlled trials for the prevention of bronchopulmonary dysplasia in infants 
Objective
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.
Findings
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.
doi:10.1038/jp.2014.126
PMCID: PMC4152555  PMID: 25010224
bronchopulmonary dysplasia; randomized controlled trials; infant; newborn; FDA; labeling
23.  Late-Onset Bloodstream Infections in Hospitalized Term Infants 
Background
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.
Methods
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.
Results
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]).
Conclusion
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.
doi:10.1097/INF.0000000000000322
PMCID: PMC4160433  PMID: 24618934
sepsis; infant; term birth; infection
24.  Frequency of Anomalies and Hospital Outcomes in Infants with Gastroschisis and Omphalocele 
Early human development  2014;90(8):421-424.
Background
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.
Methods
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.
Results
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]).
Conclusion
Infants with omphalocele were more likely to have other anomalies, be diagnosed with pulmonary hypertension, and have higher mortality than infants with gastroschisis.
doi:10.1016/j.earlhumdev.2014.05.006
PMCID: PMC4119722  PMID: 24951080
gastroschisis; omphalocele; anomalies; outcomes
25.  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.
Background:
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).
Methods:
Retrospective analysis of OS, PFS, ORR and change in tumour size at week 6 for different sub-populations of KRAS codon mutations.
Results:
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.
Conclusion:
Different KRAS mutations in NSCLC may influence selumetinib/docetaxel sensitivity.
doi:10.1038/bjc.2015.215
PMCID: PMC4506393  PMID: 26125448
selumetinib; docetaxel; KRAS; mutation; codon; non-small-cell lung cancer

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