Risk of nonsteroidal anti-inflammatory drug-associated renal dysfunction among neonates diagnosed with patent ductus arteriosus and treated with gentamicin.

OBJECTIVE: To evaluate the risk of nonsteroidal anti-inflammatory drug (NSAID) therapy-associated acute kidney injury (AKI) among neonates diagnosed with patent ductus arteriosus (PDA) who are treated with gentamicin. STUDY DESIGN: Multicenter retrospective observational study of patients ⩽44 postmenstrual weeks of age diagnosed with PDA who received gentamicin during hospitalization between January 2006 and December 2014. Patients with and without NSAID exposure were matched on covariates associated with AKI and NSAID therapy. The primary end point, AKI, was defined according to Kidney Disease Improving Global Outcomes neonatal criteria. RESULTS: The rate of AKI for the entire cohort (n=594) was 12% (n=71). Among neonates receiving NSAIDS, 14.8% (n=44) experienced an AKI as compared to 9.1% (n=27) for those who were not exposed (relative risk, 1.6; 95% confidence interval, 1.0 to 2.6). Therefore, the attributable risk of NSAID use was 5.7% (95% confidence interval, 0.5 to 11.0). CONCLUSION: Among neonates with PDA and receiving gentamicin, NSAID therapy increases the risk of AKI by about 6%.

Effects of valproic acid on organic acid metabolism in children: a metabolic profiling study.

Young children are at increased risk for valproic acid (VPA) hepatotoxicity. Urinary organic acid profiles, as a surrogate of mitochondrial function, were obtained in children 1.9 to 17.3 years of age (n = 52) who were undergoing treatment with VPA for seizure disorders. Age-matched patients receiving treatment with carbamazepine (CBZ; n = 50) and healthy children not undergoing treatment (n = 22) served as controls. Age-related changes in organic acid profiles were observed in all three groups. Although the untreated and CBZ control groups were indistinguishable from each other with respect to the principal-component analysis (PCA) score plots of the subjects, a distinct boundary was apparent between the VPA and each of the control groups. Interindividual variability was observed in the VPA-induced alterations in endogenous pathways corresponding to branched-chain amino acid metabolism and oxidative stress. The data suggest that more detailed metabolomic analysis may provide novel insights into biological mechanisms and predictive biomarkers for children at highest risk for serious toxicity.

Sequence and structure continuity of evolutionary importance improves protein functional site discovery and annotation.

Protein functional sites control most biological processes and are important targets for drug design and protein engineering. To characterize them, the evolutionary trace (ET) ranks the relative importance of residues according to their evolutionary variations. Generally, top-ranked residues cluster spatially to define evolutionary hotspots that predict functional sites in structures. Here, various functions that measure the physical continuity of ET ranks among neighboring residues in the structure, or in the sequence, are shown to inform sequence selection and to improve functional site resolution. This is shown first, in 110 proteins, for which the overlap between top-ranked residues and actual functional sites rose by 8% in significance. Then, on a structural proteomic scale, optimized ET led to better 3D structure-function motifs (3D templates) and, in turn, to enzyme function prediction by the Evolutionary Trace Annotation (ETA) method with better sensitivity of (40% to 53%) and positive predictive value (93% to 94%). This suggests that the similarity of evolutionary importance among neighboring residues in the sequence and in the structure is a universal feature of protein evolution. In practice, this yields a tool for optimizing sequence selections for comparative analysis and, via ET, for better predictions of functional site and function. This should prove useful for the efficient mutational redesign of protein function and for pharmaceutical targeting.

Clinical trials in neonates: a therapeutic imperative.

The lack of study of medications in pediatric patients has been recognized since the 1960s, when Shirkey described children as "therapeutic orphans." In 1968, only 25% of approved drugs included adequate pediatric prescribing information on the label. This did not begin to improve until the 1990s, with the 1997 US Food and Drug Administration (FDA) Modernization Act, the Best Pharmaceuticals for Children Acts, and the Pediatric Research Equity Acts. By 2009, more than 300 labeling changes improved pediatric prescribing information, but newborns were seldom included.

Population pharmacokinetics of fluconazole in young infants.

Fluconazole is being increasingly used to prevent and treat invasive candidiasis in neonates, yet dosing is largely empirical due to the lack of adequate pharmacokinetic (PK) data. We performed a multicenter population PK study of fluconazole in 23- to 40-week-gestation infants less than 120 days of age. We developed a population PK model using nonlinear mixed effect modeling (NONMEM) with the NONMEM algorithm. Covariate effects were predefined and evaluated based on estimation precision and clinical significance. We studied fluconazole PK in 55 infants who at enrollment had a median (range) weight of 1.02 (0.440 to 7.125) kg, a gestational age at birth (BGA) of 26 (23 to 40) weeks, and a postnatal age (PNA) of 2.3 (0.14 to 12.6) weeks. The final data set contained 357 samples; 217/357 (61%) were collected prospectively at prespecified time intervals, and 140/357 (39%) were scavenged from discarded clinical specimens. Fluconazole population PK was best described by a one-compartment model with covariates normalized to median values. The population mean clearance (CL) can be derived for this population by the equation CL (liter/h) equals 0.015 . (weight/1)(0.75) . (BGA/26)(1.739) . (PNA/2)(0.237) . serum creatinine (SCRT)(-4.896) (when SCRT is >1.0 mg/dl), and using a volume of distribution (V) (liter) of 1.024 . (weight/1). The relative standard error around the fixed effects point estimates ranged from 3 to 24%. CL doubles between birth and 28 days of age from 0.008 to 0.016 and from 0.010 to 0.022 liter/kg/h for typical 24- and 32-week-gestation infants, respectively. This population PK model of fluconazole discriminated the impact of BGA, PNA, and creatinine on drug CL. Our data suggest that dosing in young infants will require adjustment for BGA and PNA to achieve targeted systemic drug exposures.

Management of stress urinary incontinence.

Stress urinary incontinence (SUI) is a common disorder that does not require treatment unless bothersome to the patient. The evaluation includes a thorough history and physical in order to evaluate for other bladder and pelvic floor disorders. Multichannel urodynamics are not necessary for the diagnosis of SUI, but may be helpful when choosing among appropriate treatment options and for patient counseling. Behavioral and physical therapies are appropriate first-line treatments and should be discussed with all patients, even those desiring surgical treatment. Conservative treatments include the use of pessaries to improve urethral support. Multiple surgical options exist. While mid-urethral slings are commonly used today, there is a still a role for traditional pubovaginal slings and the Burch retropubic urethropexy.

Basic and translational research in neonatal pharmacology.

Pharmacologic study is needed in the extremely immature newborns who currently survive. Study is needed of both the drug treatment previously established in more mature neonates and of novel drug therapy. Carefully controlled studies are needed to identify accurately both beneficial and harmful drug therapy and the mechanisms of that toxicity. Careful pharmacologic study of drug disposition and its mechanisms might lead to dosing paradigms or patient selection that minimize toxicity and maximize efficacy. In vivo, translational models of neonatal diseases are limited, but can be used to identify novel treatments and study mechanisms of established, successful therapy. Findings from such studies can generate hypotheses for study in humans leading to a continuing scientific interchange from bedside to bench to bedside. Similarly, clinical observations can generate hypotheses for study in translational models where more invasive analyses are possible. Specific areas of drug treatment should focus on neonatal disorders with long-term, adverse outcomes, such as chronic lung disease, that is amenable to translational study with animal models. National data show a progressive decrease in the clinician-scientist pool entering biomedical research. The future of neonatal pharmacology studies requires an increase in training programs for the physician-scientist whose clinical education in neonatology can be complemented by rigorous basic-science training. Success as a clinician-scientist will require collaboration with full-time basic scientists who can continue studies during periods of clinical work and provide critical study methodology to the overall study design. Such a work environment must be supported by academic institutions and may require more flexibility in the promotion and tenure schedule and process, such as the nature of what it rewards. To complement this, the NIH could modify its grant reporting process to identify co-investigators in studies who may provide unique input to the study concepts and design, such as clinical correlations or clinical investigations.

Viscosity of rice flour: a rheological and biological study.

Rice breeders frequently use rapid visco analysis (RVA) as in index of rice quality. Potentially, viscosity curves could also be used to predict the sensory properties of a sample of rice or the processing properties of rice when used as an ingredient. The aim of this study is to determine the contribution of the main components of rice flour-starch and protein polymers and lipids-to the viscosity curve, accounting for biological and rheological contributions, and interactions with water. By deconstructing the rice flour, resistance to shear is generally the primary factor that affects rheological processes in the RVA, often masking the physical processes of cooking. Thus, higher concentrations of water reveal more about the true biological and physical processes of the transition from a powder to paste. Proteins contribute to peak height, offset thixotropy, and contribute to the final viscosity. Starch-lipid complexes can mask differences in the molecular structures of amylose and amylopectin, and removing lipids alters the structure of the paste significantly, which consequently alters viscosity curves.

Difficulties in the study of adverse fetal and neonatal effects of drug therapy during pregnancy.

This article reviews the difficulties in studying adverse effects of drugs during pregnancy on the fetus and newborn. A study design should strive for prospective recording of drug intake during pregnancy, comparison to appropriate control groups adjusted for inherited traits, and single drug exposures for evaluation of specific syndromic causation, such as the Fetal Hydantoin Syndrome. Animal models are best used in mechanistic study of adverse drug effects on the fetus rather than for screening for adverse effects. Careful conclusions about causation of drug-induced adverse effects are needed to avoid false associations while providing appropriate safeguards to the fetus and newborn.

Albuterol delivery in a neonatal ventilated lung model: Nebulization versus chlorofluorocarbon- and hydrofluoroalkane-pressurized metered dose inhalers.

The aim of this study was to compare albuterol delivery in a neonatal ventilated lung model, using three delivery methods: 1) jet nebulizer; 2) chlorofluorocarbon-pressurized metered dose inhaler (CFC-MDI) actuated into an ACE(R) spacer; and 3) hydrofluoroalkane-pressurized MDI (HFA-MDI) actuated into an ACE(R) spacer. The bench model consisted of a mechanically ventilated infant test lung with ventilator settings to simulate a very low birth weight neonate with moderate lung disease. Albuterol solution (0.5%) was nebulized at the humidifier and temperature port, 125 cm and 30 cm from the Y-piece, respectively. Albuterol metered dose inhalers (MDIs) were actuated into an ACE(R) spacer that was tested in two positions: 1) inline between the endotracheal (ET) tube and the Y-piece; and 2) attached to the ET tube and administered by manual ventilation. Albuterol was collected on a filter at the distal end of the ET tube and was quantitatively analyzed by high performance liquid chromatography. Albuterol delivery by CFC-MDI (position 1, 4.8 +/- 1.0%, vs. position 2, 3.8 +/- 1.6%, P > 0.05) and HFA-MDI (position 1, 5.7 +/- 1.6%, vs. position 2, 5.5 +/- 2.4%, P > 0.05) were significantly greater than delivery by nebulization at 30 cm (0.16 +/- 0.07%) and 125 cm (0.15 +/- 0.03%) from the Y-piece (P < 0.001). A single actuation of albuterol MDI delivered the equivalent of nebulizing 2.5-3.7 mg of albuterol solution. We conclude that albuterol administered by MDI and ACE(R) spacer resulted in more efficient delivery than by nebulization in this mechanically ventilated neonatal lung model. There was no significant difference in drug delivery between CFC-MDI and HFA-MDI; nor did the placement of the spacer significantly affect drug delivery.

Ten guiding principles for teaching children and adolescents about medicines. US Pharmacopeia.

In 1996, an open conference sponsored by the US Pharmacopeia (USP) and attended by more than 100 health care professionals established the need and rationale for teaching children and adolescents about medicines. After the conference, a public, iterative, consensus-development process including participation by 35 health-professional organizations was undertaken. This process resulted in a USP position statement, "Ten Guiding Principles for Teaching Children and Adolescents About Medicines," which supports the right of children and adolescents to receive developmentally appropriate information and direct communications about medicines that are consistent with their health status, capabilities, and culture. The position statement is intended to stimulate activities that will help children become active participants in the process of appropriate use of medicines and prepare them for the day they begin to use medicines independently.

Cisapride: a survey of the frequency of use and adverse events in premature newborns.

OBJECTIVE: This survey estimated the frequency of use and adverse events associated with cisapride treatment of premature newborns in intensive care units. It was initiated in response to a warning issued in Canada cautioning against cisapride treatment of premature infants of <36 weeks' gestation and <3 months of age. METHODOLOGY: Surveys were mailed to 105 neonatology training program directors to obtain the total number of neonatal intensive care unit (NICU) admissions, the number of admissions of infants of <36 weeks' gestation, the number of years that cisapride had been used, the estimated percent/number of premature patients treated with cisapride per year, and the frequency and nature of arrhythmias or other adverse events associated with cisapride treatment. Of 105 programs, 46 responded to a single mailing of the first survey. A second survey mailed to the 45 respondents to the first survey sought to determine the indications, diagnostic tests, and dosages used with cisapride treatment of premature newborns. Of the 45 programs, 26 responded to the second survey. RESULTS: More than 58 000 premature newborns of <36 weeks' gestation were admitted to the NICUs we surveyed, and approximately 19% were treated with cisapride. No deaths attributable to cisapride were reported among >11 000 preterm newborns treated. Three nonfatal arrhythmias were reported; two associated with 10-fold dosing errors and one with co-treatment with erythromycin, a macrolide antibiotic that reduces the metabolism of cisapride. Diarrhea was reported in 12 patients, and reversible liver enzyme changes were noted in one patient. Typically, cisapride treatment was started in dosages of 0.1 to 0.2 mg/kg/dose, repeated every 6 to 8 hours. Treatment usually was begun empirically, without a preceding study to document gastroesophageal reflux. The most frequent indications for cisapride treatment were choking or gagging, with associated apnea, bradycardia, and desaturation. Approximately 50% of patients had discontinued cisapride treatment before discharge. Eighty-four percent of clinicians judged cisapride to be effective for the problems being treated. CONCLUSIONS: Cisapride treatment of premature infants of <36 weeks' gestation and <3 months of age in NICUs appears to be widespread in the United States. Complications and adverse events were seen when cisapride was administered in excessive dosages or in combination with a drug that inhibits its metabolism and leads to increased serum concentrations. Severe toxicities such as arrhythmias were reported with a frequency of <1/11 000 NICU admissions. However, in a retrospective survey, episodes of toxicity, including mortality, attributable to cisapride may not have been recognized or reported.

Congenital malformations presenting during the neonatal period.

Discharge of the newborn within 24 to 48 hours after birth makes it more difficult to detect some congenital malformations and increases the need for careful examination and review of the history of the pregnancy, delivery, and nursery course. Progressive physiologic changes after birth, especially in the cardiovascular system, precede the development of signs indicative of disease for certain congenital malformations. Discharge before these changes occur may delay their detection because the newborn is not being monitored by medical or nursing caregivers. The AAP Committee on the Fetus and Newborn has published guidelines for criteria for safe discharge and follow-up evaluation to help create a safe situation for such early discharges. Some specific observations at birth may lead to earlier diagnosis. Careful attention to subtle differences between the initial and follow-up examination, such as a changing cardiac murmur or quality of pulses or abdominal fullness, may provide clues to the diagnosis of congenital malformations. Coordinated suck and swallow with successful feeding and passage of stool and urine within 24 hours after birth should occur before discharge. Reports of feeding difficulties should be reviewed. Although a thorough examination is facilitated by a sleeping infant, documentation of a normal pitched cry helps in the evaluation of the upper airway. Parents should be counseled about signs of illness that warrant medical attention, and early follow-up is needed to detect problems early enough to intervene effectively. In addition, although passage of a feeding tube through each nare and to the stomach with aspiration and measurement of gastric volume is not a routine procedure in the well, term newborn, this may be a useful early diagnostic tool in infants with signs or a maternal or nursery history suggestive of nasal or GI obstruction.

Visual search for a tilted target: tests of spatial uncertainty models.

We report that spatial cueing of a parafoveal target in the presence of distractors enhances orientational acuity for that target. When no distractors were present, orientation thresholds were in the range 1-4 degrees. For long exposure times, distractors increased threshold by the amount predicted from a winner-takes-all spatial uncertainty model. For short (100-msec) exposures followed by a random dot mask, the rise in threshold with distractors was considerably greater than that predicted from spatial uncertainty. For brief exposures the effect of distractors was greater when the target and distractors were spatially crowded rather than widely spaced. Adding a tilt to the distractors in the opposite direction to the target increased thresholds still further. Cueing the target with a spatial pointer decreased the effect of distractors, even when they were crowded. We suggest that when attention cannot be appropriately focused, discrimination is carried out by a relatively coarse texture analyser, which averages over several elements, and that focused attention permits the analysis of the target over a smaller area of space.

Genetic studies into inherited and sporadic hemolytic uremic syndrome.

Hemolytic uremic syndrome (HUS) in adults carries a high morbidity and mortality, and its cause remains unknown despite many theories. Although familial HUS is rare, it affords a unique opportunity to elucidate underlying mechanisms that may have relevance to acquired HUS. We have undertaken a genetic linkage study based on a candidate gene approach. A common area bounded by the markers D1S212 and D1S306, a distance of 26 cM located at 1q32 segregated with the disease (Z max 3.94). We demonstrate that the gene for factor H lies within the region. Subsequent mutation analysis of the factor H gene has revealed two mutations in patients with HUS. In an individual with the sporadic/relapsing form of the disease we have found a mutation comprising a deletion, subsequent frame shift and premature stop codon leading to half normal levels of serum factor H. In one of the three families there is a point mutation in exon 20 causing an arginine to glycine change, which is likely to alter structure and hence function of the factor H protein. Factor H is a major plasma protein that plays a critical regulatory role in the alternative pathway of complement activation. In light of these findings and previous reports of HUS in patients with factor H deficiency, we postulate that abnormalities of factor H may be involved in the etiology of HUS.

Acute response to inhaled nitric oxide in newborns with respiratory failure and pulmonary hypertension.

OBJECTIVE: Systemic oxygenation is improved by inhaled nitric oxide therapy in some newborns with respiratory failure and pulmonary hypertension. Our results with inhaled nitric oxide were reviewed to determine factors associated with an acute improvement in systemic oxygenation. METHODS: Newborns with oxygenation indices of 25 to 40 were prospectively randomized to receive conventional therapy with or without 20 ppm inhaled nitric oxide. All newborns with oxygenation indices greater than 40 were treated with inhaled nitric oxide. Hemodynamic, blood gas, and Doppler ultrasound measurements were performed before and after 30 to 60 minutes of observation or therapy. The severity of lung disease was classified by the chest radiograph as: (1) normal or focal disease; (2) moderate diffuse disease-diffuse lung disease with well-defined heart borders; or (3) severe diffuse disease-diffuse lung opacification with indistinct heart borders. RESULTS: Heart rate, blood pressure, and ductal diameters did not change. Blood gases and ductal shunting acutely improved only in patients treated with inhaled nitric oxide. Patients with normal lung fields or focal disease had the greatest degree of improvement in systemic oxygenation. Changes in oxygenation were not influenced by gestational age, baseline blood gases, the proportion of right-to-left ductal shunting, prior treatment with a surfactant, or the use of conventional or high-frequency jet ventilation. Collectively, blood gases and ductal shunting did not improve with inhaled nitric oxide in patients with lung hypoplasia or severe diffuse lung disease. Sustained improvement in oxygenation occurred in 87% of patients with oxygenation indices greater than 40 in whom oxygenation indices less than 40 acutely developed after exposure to nitric oxide, whereas 90% of patients in whom oxygenation indices less than 40 did not acutely develop were treated with extracorporeal membrane oxygenation or ultimately died. CONCLUSIONS: Inhaled nitric oxide acutely improves systemic oxygenation in many newborns with respiratory failure and pulmonary hypertension. The diagnosis and chest radiograph are helpful in identifying patients who will have favorable acute responses to therapy. In patients with severe hypoxemia, the need for invasive support with extracorporeal membrane oxygenation may be determined by an acute trial of inhaled nitric oxide.