University of Virginia Children's Hospital

OBJECTIVE: The goal was to create a functional status outcome measure for large outcome studies that is well defined, quantitative, rapid, reliable, minimally dependent on subjective assessments, and applicable to hospitalized pediatric patients across a wide range of ages and inpatient environments. METHODS: Functional Status Scale (FSS) domains of functioning included mental status, sensory functioning, communication, motor functioning, feeding, and respiratory status, categorized from normal (score = 1) to very severe dysfunction (score = 5). The Adaptive Behavior Assessment System II (ABAS II) established construct validity and calibration within domains. Seven institutions provided PICU patients within 24 hours before or after PICU discharge, high-risk non-PICU patients within 24 hours after admission, and technology-dependent children. Primary care nurses completed the ABAS II. Statistical analyses were performed. RESULTS: A total of 836 children, with a mean FSS score of 10.3 (SD: 4.4), were studied. Eighteen percent had the minimal possible FSS score of 6, 44% had FSS scores of >or=10, 14% had FSS scores of >or=15, and 6% had FSS scores of >or=20. Each FSS domain was associated with mean ABAS II scores (P < .0001). Cells in each domain were collapsed and reweighted, which improved correlations with ABAS II scores (P < .001 for improvements). Discrimination was very good for moderate and severe dysfunction (ABAS II categories) and improved with FSS weighting. Intraclass correlations of original and weighted total FSS scores were 0.95 and 0.94, respectively. CONCLUSIONS: The FSS met our objectives and is well suited for large outcome studies.

Malformations of cortical development containing dysplastic neuronal and glial elements, including hemimegalencephaly and focal cortical dysplasia, are common causes of intractable paediatric epilepsy. In this study we performed multiplex targeted sequencing of 10 genes in the PI3K/AKT pathway on brain tissue from 33 children who underwent surgical resection of dysplastic cortex for the treatment of intractable epilepsy. Sequencing results were correlated with clinical, imaging, pathological and immunohistological phenotypes. We identified mosaic activating mutations in PIK3CA and AKT3 in this cohort, including cancer-associated hotspot PIK3CA mutations in dysplastic megalencephaly, hemimegalencephaly, and focal cortical dysplasia type IIa. In addition, a germline PTEN mutation was identified in a male with hemimegalencephaly but no peripheral manifestations of the PTEN hamartoma tumour syndrome. A spectrum of clinical, imaging and pathological abnormalities was found in this cohort. While patients with more severe brain imaging abnormalities and systemic manifestations were more likely to have detected mutations, routine histopathological studies did not predict mutation status. In addition, elevated levels of phosphorylated S6 ribosomal protein were identified in both neurons and astrocytes of all hemimegalencephaly and focal cortical dysplasia type II specimens, regardless of the presence or absence of detected PI3K/AKT pathway mutations. In contrast, expression patterns of the T308 and S473 phosphorylated forms of AKT and in vitro AKT kinase activities discriminated between mutation-positive dysplasia cortex, mutation-negative dysplasia cortex, and non-dysplasia epilepsy cortex. Our findings identify PI3K/AKT pathway mutations as an important cause of epileptogenic brain malformations and establish megalencephaly, hemimegalencephaly, and focal cortical dysplasia as part of a single pathogenic spectrum.

OBJECTIVE: After prolonged opioid exposure, children develop opioid-induced hyperalgesia, tolerance, and withdrawal. Strategies for prevention and management should be based on the mechanisms of opioid tolerance and withdrawal. PATIENTS AND METHODS: Relevant manuscripts published in the English language were searched in Medline by using search terms "opioid," "opiate," "sedation," "analgesia," "child," "infant-newborn," "tolerance," "dependency," "withdrawal," "analgesic," "receptor," and "individual opioid drugs." Clinical and preclinical studies were reviewed for data synthesis. RESULTS: Mechanisms of opioid-induced hyperalgesia and tolerance suggest important drug- and patient-related risk factors that lead to tolerance and withdrawal. Opioid tolerance occurs earlier in the younger age groups, develops commonly during critical illness, and results more frequently from prolonged intravenous infusions of short-acting opioids. Treatment options include slowly tapering opioid doses, switching to longer-acting opioids, or specifically treating the symptoms of opioid withdrawal. Novel therapies may also include blocking the mechanisms of opioid tolerance, which would enhance the safety and effectiveness of opioid analgesia. CONCLUSIONS: Opioid tolerance and withdrawal occur frequently in critically ill children. Novel insights into opioid receptor physiology and cellular biochemical changes will inform scientific approaches for the use of opioid analgesia and the prevention of opioid tolerance and withdrawal.

A complication of severe brain injury is a syndrome of intermittent agitation, diaphoresis, hyperthermia, hypertension, tachycardia, tachypnea, and extensor posturing. To capture the main features of this syndrome, derived through literature review and our own case series, we propose the term paroxysmal autonomic instability with dystonia. We reviewed reports of autonomic dysregulation after brain injury and extracted essential features. From the clinical features, consistent themes emerge regarding signs and symptoms, differential diagnosis, and pharmacological therapies. We used these findings to make recommendations regarding diagnosis and treatment. Paroxysmal autonomic instability with dystonia appears to be a distinctive syndrome after brain injury that can mimic other life-threatening conditions. Early recognition may lead to fewer diagnostic tests and a rational approach to management. Prospective trials of specific drugs are needed to determine optimal efficacy.

BACKGROUND: Although breastfeeding is touted as providing many health benefits to infants, some aspects of this relationship remain poorly understood. METHODS: The Environmental Determinants of Diabetes in the Young (TEDDY) is a prospective longitudinal study that follows children from birth through childhood, and collects data on illness events, breastfeeding duration, and time to introduction of formula or foods at 3 month intervals up until 4 years of age and at 6 months intervals thereafter. Exclusive and non-exclusive breastfeeding is examined in relation to the 3-month odds of a respiratory or gastrointestinal infection for 6861 children between the ages of 3-18 months, and 5666 children up to the age of 4 years. Analysis was performed using logistic regression models with generalized estimating equation methodology. All models were adjusted for potential confounding variables. RESULTS: At 3-6 months of age, breastfeeding was found to be inversely associated with the odds of respiratory infections with fever (OR = 0.82, 95% CI = 0.70-0.95), otitis media (OR = 0.76, 95% CI = 0.62-0.94), and infective gastroenteritis (OR = 0.55, 95% CI = 0.46-0.70), although the inverse association with respiratory illnesses was observed only for girls during the winter months. Between 6 and 18 months of age, breastfeeding within any 3 month period continued to be inversely associated with the odds of ear infection and infective gastroenteritis, and additionally with the odds of conjunctivitis, and laryngitis and tracheitis, over the same 3 month period within this age range. However, breastfeeding in this group was associated with increased reports of common cold. Duration of exclusive breastfeeding was inversely associated with the odds of otitis media up to 48 months of age (OR = 0.97, 95% CI = 0.95-0.99) after breastfeeding had stopped. CONCLUSIONS: This study demonstrates that breastfeeding can be protective against multiple respiratory and gastrointestinal acute illnesses in some children up to at least 6 months of age, with duration of exclusive breastfeeding being somewhat protective of otitis media even after breastfeeding has stopped. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00279318 . Date of registration: January 17, 2006 (proactively registered). First Posted: January 19, 2006.

PURPOSE: The pathophysiology, evaluation, description and clinical implications of renal damage associated with vesicoureteral reflux remain controversial. We summarized the current understanding of this important aspect of clinical vesicoureteral reflux. MATERIALS AND METHODS: We performed a detailed review of the literature on clinical, pathological and experimental data related to congenital vesicoureteral reflux and bladder dynamics. We also reviewed the clinical context and imaging evaluation with underlying experimental data related to post-infectious reflux nephropathy. RESULTS: Congenital reflux nephropathy is a pattern of impaired renal function and development with renal dysplasia as the most severe but not the only form. Mechanisms of developmental disruption are potentially related to vesicoureteral reflux dynamics during gestation and associated bladder dynamics, which may continue into postnatal life. Acquired renal injury associated with infection is related to particular bacterial and host factors that determine infection virulence, host inflammatory response and tissue recovery. As best seen on dimercapto-succinic acid scan, acute changes may resolve but may also persist as permanent renal scarring. Specific risk factors for acute pyelonephritis and renal scarring in patients with vesicoureteral reflux include higher reflux grade, dysfunctional voiding/elimination, recurrent pyelonephritic episodes and delayed initiation of antibiotic therapy. Low pressure sterile reflux is not a cause of reflux nephropathy. CONCLUSIONS: Renal damage associated with vesicoureteral reflux may be congenital or acquired and the respective pathophysiological mechanisms are likely different. Congenital damage is often dysplasia, which may be a result of disordered renal development secondary to significant alterations in bladder dynamics. These processes may continue into the newborn period while kidney maturation continues. Recognizing the clinical potential for ongoing effects on renal function and the role of bladder development are important for clinical care. Post-pyelonephritic acquired damage is the result of a complex interaction of host and bacterial factors that leads to acute alterations in renal function, and may lead to permanent renal scarring. Strategies for timely intervention as well as prevention are essential to limit the risk of permanent renal injury, which may predispose to hypertension and renal insufficiency in some patients.

SUMMARY The Gross Motor Function Measure (GMFM) and computerized gait analysis are commonly used to assess patients with cerebral palsy (CP). The authors investigated correlations between the GMFM and gait parameters in 32 children aged 3 to 18 (mean 8.9) years with spastic CP. Of the gait parameters, cadence and normalized velocity correlated most strongly with the GMFM score, and hip and knee excursion and percentage single support also correlated directly with the GMFM. In a stepwise multiple regression, cadence alone was a significant predictor of GMFM score. Time and distance parameters, hip and knee excursion in the sagittal plane and GMFM values all moved consistently further from pediatric norms as functional severity increased. The study confirms that gait is representative of general motor status in CP and that the GMFM and gait analysis are complementary measures in the functional assessment of these children. RÉSUMÉ Relations entre l'analyse de la démarche et le trouble moteur global dans l'IMC Une évaluation du trouble moteur global (GMFM) et une analyse de la demarche par ordinateur a été pratiquée systématiquement pour caractériser des IMC (CP). Lés auteurs ont recherche les corrélations entre le GMFM et les paramètres de la démarche chez 32 enfants âgés de 3 à 18 ans (moyenne 8,9) préscntant une IMC spastique. Parmi les paramétres de la démarche, les corrélations les plus élevées avec le GMFM concernaient la cadence et la vitesse normalisée: l'excursion de la hanche ct du genouet le pourcentage de support unipodal présentaient également une corrélation directe avec le GMFM. Dans une analyse de variance à régression multiple, la cadence à elle seule était prédictive du score GMFM. Les paramétres de distance et de temps, l'excursion de la hanche et du genou dans un plan sagittal et les valeurs GMFM s'éloignaient des normes pédiatriques avec la gravité fonctionnelle. Cette étude confirme que la démarche est un reflet de l'état moteur global dans l'IMC et que le GMFM et l'analyse de la démarche sont des mesures complémentaires dans l'évaluation fonctionnelle des enfants examinés. ZUSAMMENFASSUNG Beziehung zwischen Ganganalyse und grobmotorischer Funktion bei Cerebralparese Der Gross Motor Function Measure (GMFM) und die Komputerganganalyse werden in der Regel zur Beurteilung von Patienten mit Cerebralparese (CP) herangezogen. Die Autoren untersuchten die Zusammenhänge zwischen dem GMFM und Gangparametern bei 32 Kindern mit spastischer CP im Alter 3 und 18 (im Mittel 8,9) Jahren. Von den Gangparametern korrelierten Kadenz und geregelte Geschwindigkeit am stärksten mit dem GMFM Score und auch der Hüft‐ und Knieexcursion und der Anteil des single support korrelierten direkt mit dem GMFM. Nach einer schrittweisen multiplen Regressionsanalyse blieb nur noch die Kadenz als signifikanter Parameter für den GMFM. Zeit und Entfernungsparametcr, Hüft‐ und Knieexcursion in einer sagittalen Ebene und GMFM Werte entfernten sich mit zunehmendcr Funktionsverschlcchterung von den pädiatrischen Normalwerten. Die Studie bestütigt, daś der Gang fur den allgemeinen motorischen Status bei Cerebralparese repräsentativ ist und daß der GMFM und die Ganganalyse komplementäre Methoden für die funktionellc Beurteilung dieser Kinder sind. RESUMEN Relatión del análisis de la marcha con la fitneión nwtora grosera en la parálisis cerebral La Medición de la Función Motora Grosera (MFMG) y el análisis computarizado de la marcha se usan corrientemente para cvaluar los pacicntes con parálisis cerebral (PC). Los auiores investigaron las correlaciones cntre la MFMG y los parámetros de la marcha en 32 niños de 3 a 18 años (promedio 8,9) con PC espástica. De los parámetros de la marcha, la cadencia y la velocidad normalizadas sc correlacionaban muy fuertementc con el puntagc de MFMG; el recorrido de la cadera y la rodilla y el porcentage de soporte simple apoyan también la correlación directa con el puntage MFMG. En una regresión múltiple del paso, la cadencia sola era un predictor significativo del puntage MFMG. Los parámetros de tiempo y distancia, la excursión de cadera y rodilla en un piano sagital y los valores de MFMG todos son factores añadidos a las normas pediátricas con mayor valor al aumcntar la gravedad funcional. El estudio confirma que la marcha es representativa del estado motor general en la PC y que el análisis MFMG y de la marcha constituyen medicioncs complementarias en la evaluación funcional de estos niños.

The mechanisms responsible for the elevated levels of circulating GH observed in diabetes mellitus (DM) remain incompletely defined. To assess the episodic fluctuations in serum GH as a reflection of hypothalamic-pituitary activity, we accumulated GH concentration-time series in a total of 48 adult men and women with and without insulin-dependent DM by obtaining serum samples at 10-min intervals over 24 h. Significant pulses of GH release were subsequently identified and characterized by an objective, statistically based pulse detection algorithm (Cluster) and fixed circadian (24-h) periodicities of secretory activity, resolved using Fourier expansion time-series analysis. Compared to those in age-matched controls, integrated 24-h concentrations of GH were 2- to 3.5-fold higher in diabetic men (P = 0.002) and women (P = 0.0005). Both men and women with DM had over 50% more GH pulses per 24 h than their non-DM counterparts. In addition, maximal GH pulse amplitude was markedly elevated in the men and women with DM (P = 0.0019 and 0.0189, respectively). That the increase in maximal pulse amplitude was accounted for by greater baseline levels was documented by a higher interpulse valley mean GH concentration in the diabetics compared to the controls (P = 0.0437 and 0.0056, men and women, respectively) and the absence of any difference in incremental pulse amplitude for either sex (P greater than 0.05). DM men had larger GH pulse areas (P = 0.039) than control men, apparently accounted for by greater pulse width (P = 0.0037). Pulse areas in DM and non-DM women were indistinguishable. Time-series analysis revealed that the 24-h (circadian) rhythms of serum GH concentrations exhibited significantly increased amplitudes in the diabetic group as a whole (compared to the controls, P = 0.011). However, the times of maximal GH concentrations (acrophases) were not significantly different. As a group, serum insulin-like growth factor-I was lower in DM vs. non-DM individuals (P = 0.0014), although when separated by sex this difference did not reach statistical significance in women (P = 0.317). The present data confirm the higher circulating levels of GH previously reported to occur in individuals with poorly controlled DM. The altered frequency of GH pulses together with enhanced interpulse GH concentrations and an amplified circadian GH rhythm are compatible with hypothalamic dysfunction associated with dysregulation of somatostatin and/or GHRH secretion.(ABSTRACT TRUNCATED AT 400 WORDS)

Pain frequency and its association with participation, function, and health-related quality of life were evaluated in a sample of 198 children (58% male; mean age 10 years 7 months, SD 3 years 11 months; range 5 to 18 years) with moderate to severe cerebral palsy (CP). Gross Motor Functional Classification System (GMFCS) levels were III to V (23% level III, 23% level IV, 31% level V without a gastrostomy tube, and 23% were level V with a gastrostomy tube). Assessment was carried out using the parent-report Child Health Questionnaire (CHQ) and questions assessing health, medical utilization, and medication use. Pain frequency ranged from 'none' to 'every day'. Eleven percent of parents reported pain almost every day (z score=-0.38, p<0.001). Pain was related to severity of motor impairment and the presence of a gastrostomy; parents of the most severely affected children reported the highest pain frequency (p=0.05). Pain was correlated with school days missed (p=0.03) and days in bed (p=0.01). Children taking gastrointestinal medications were reported to have greater pain frequency (p<0.001). The Parental Impact--Emotional subscale of the CHQ was correlated with reported pain (r=0.38, p<0.001). Pain was frequent in children with moderate or severe CP. Pain was more prevalent with more severe impairment and was associated with educational and social consequences.

OBJECTIVE: Hospital care for children with viral lower respiratory illness (VLRI) is highly variable, and its relationship to severity and impact on outcome is unclear. Using the Pediatric Comprehensive Severity Index, we analyzed the correlation of institutional practice variation with severity and resource utilization in 10 children's medical centers. METHODS: Demographics, clinical information, laboratory results, interventions, and outcomes were extracted from the charts of consecutive infants with VLRI from 10 children's medical centers. Pediatric Component of the Comprehensive Severity Index scoring was performed at admission and at maximum during hospitalization. The correlation of patient variables, interventions, and resource utilization at the patient level was compared with their correlation at the aggregate institutional level. RESULTS: Of 601 patients, 1 died, 6 were discharged to home health care, 4 were discharged to rehabilitative care, and 2 were discharged to chronic nursing care. Individual patient admission severity score correlated positively with patient hospital costs (r = 0.48), but institutional average patient severity was negatively correlated with average institutional costs (r = -0.26). Maximal severity score correlated well with costs (r = 0.66) and length of stay (LOS; r = 0.64) at the patient level but poorly at the institutional level (r = 0.07 costs; r = 0.40 LOS). The institutional intensity of therapy was negatively correlated with admission severity (r = -0.03) but strongly correlated with costs (r = 0.84) and LOS (r = 0.83). CONCLUSIONS: Institutional differences in care practices for children with VLRI were not explained by differences in patient severity and did not affect the children's recovery but correlated significantly with hospital costs and LOS.

PURPOSE To improve the outcomes of patients with T-cell acute lymphoblastic leukemia (T-ALL) and lymphoblastic lymphoma (T-LL), the proteasome inhibitor bortezomib was examined in the Children's Oncology Group phase III clinical trial AALL1231, which also attempted to reduce the use of prophylactic cranial radiation (CRT) in newly diagnosed T-ALL. PATIENTS AND METHODS Children and young adults with T-ALL/T-LL were randomly assigned to a modified augmented Berlin-Frankfurt-Münster chemotherapy regimen with/without bortezomib during induction and delayed intensification. Multiple modifications were made to the augmented Berlin-Frankfurt-Münster backbone used in the predecessor trial, AALL0434, including using dexamethasone instead of prednisone and adding two extra doses of pegaspargase in an attempt to eliminate CRT in most patients. RESULTS AALL1231 accrued 824 eligible and evaluable patients from 2014 to 2017. The 4-year event-free survival (EFS) and overall survival (OS) for arm A (no bortezomib) versus arm B (bortezomib) were 80.1% ± 2.3% versus 83.8% ± 2.1% (EFS, P = .131) and 85.7% ± 2.0% versus 88.3% ± 1.8% (OS, P = .085). Patients with T-LL had improved EFS and OS with bortezomib: 4-year EFS (76.5% ± 5.1% v 86.4% ± 4.0%; P = .041); and 4-year OS (78.3% ± 4.9% v 89.5% ± 3.6%; P = .009). No excess toxicity was seen with bortezomib. In AALL0434, 90.8% of patients with T-ALL received CRT. In AALL1231, 9.5% of patients were scheduled to receive CRT. Evaluation of comparable AALL0434 patients who received CRT and AALL1231 patients who did not receive CRT demonstrated no statistical differences in EFS ( P = .412) and OS ( P = .600). CONCLUSION Patients with T-LL had significantly improved EFS and OS with bortezomib on the AALL1231 backbone. Systemic therapy intensification allowed elimination of CRT in more than 90% of patients with T-ALL without excess relapse.

SUMMARY The purpose of this cross‐sectional study was to determine correlates of linear growth in children with cerebral palsy (CP). 171 children with CP were measured and their charts reviewed, z scores were calculated for weight (Wz) and height (Hz). Hz correlated positively with Wz and head circumference, and negatively with age, the presence of spastic quadriplegia, non‐ambulation and seizures. The correlation between Hz and age was stronger when non‐ambulatory children were analysed separately. Multiple linear regression resulted in only Wz and age contributing significantly to the variance in stature as measured by Hz. These results provide preliminary evidence that nutritional status is a major correlate of growth in CP. The finding that linear growth worsens with age independent of nutrition suggests that other factors also influence growth in CP. RÉSUMÉ Corrélations cliniques de la croissance en laille chez l'enfant IMC Le but de cette étude transversale était d'établir des corrélations de croissance linéaire chez les enfants IMC. Des mesures fürent effectuees chez 171 IMC et les résultats fürent analysés. Des scores z fürent calculés pour le poids (Wz) et la taille (Hz). Hz était corrélée positivement avec Wz et le tour de tête, et négativement avec l'âge, la présence d'une quadriplégic spastique, l'absence de marchc et la comitialité. La corrélation entrc Hz et l'âge se montra plus élevée lorsquc les enfants ne marchant pas fürent étudiés séparément. La régression linéaire multiple montra que seuls Wz et l'âge contribuaient significativement à la variance de la taille mesurée. Ces résultats favorisent l'idée que l'état nutritionnel est un facteur majeur de croissance chez l'IMC. Le fait que la croissance linéaire s'altère avec l'âge indépendamment de l'alimentation suggère que d'autres facteurs influencent également la croissance chez l'IMC. ZUSAMMENFASSUNG Klinische Parameter des linearen Wachstums bei Kindern mil Cerebralparese Es war das Ziel dieser Querschnittsstudie, die Parameter des linearen Wachstums bei Kindern mil Cerebralparese (CP) zu untersuchen. 171 Kinder mit Cerebralparese wurden untersucht und ihre Meßkarten ausgewcrtet. Es wurden z Scores für Gewicht (Wz) und Größe (Hz) bestimmt. Hz korrelierte positiv mit Wz und Kopfumfang und negativ mit Alter, spastischer Tetraplegie, Gehunfähigkeit und Anfällen. Die Korrelation zwischen Hz und Alter war stärker, wenn die nicht gehfähigen Kinder getrennt analysiert wurden. Multiple lineare Regressionsberechnungen ergaben, daß nur Wz und Alter signifikant zur Veränderung der Statur, gemessen durch Hz, beitrugen. Diese Ergebnisse sind ein vorläufiger Beweis dafür, daß der Emahrungsstatus ein wichtiger Wachstumsfaktor bei CP ist. Der Befund, daß das lineare Wachstum unabhängig von der‐ Ernährung mit dem Alter schlechter wird, bedeuiet, daß noch andere Faktoren das Wachstum bei Patienten mit CP beeinflussen. RESUMEN Correlatión clínica del crecimiento lineal en niños con parálisis cerebral El propósito de este estudio transverso fue el determinar la c'orrelación del crecimiento lineal en niños con parálisis cerebral (PC). 171 niños con PC fueron tallados y sus gráficos revisados. Se calcularon z puntajes para el peso (Pz) y estatura (Ez). Ez se correlacionaba positivamente con Pz y con el perímetro craneal y negativamente con la edad, la presencia de una cuatriplejia espástica, la no ambulatión y las convulsiones. La correlatión entre Ez y la edad era mayor si se analizaban separadamente los niños que no andaban. Una regresión lineal múltiple sólo se dio en Pz y edad lo que contribuía significativamente a la varianza de la estatura medida en forma de Ez. Estos resultados proporcionan una evidencia preliminar de que el estado nutritivo es un importante correlativo del crecimiento en la PC. El hallazgo de que el crecimiento lineal empeora con la edad con independencia de la nutrición, sugiere que hay otros factors que influencian también el crecimiento en la PC.

The study was designed to determine the strategies used by diplegic subjects to change walking speed. Two groups, limited community ambulators and community ambulators, were compared with controls to determine if ability to increase speed would decrease as a function of motor impairment. Compared with matched controls, diplegic subjects were slower and relied more on cadence to increase speed. The ability to change velocity and stride length was significantly less in the diplegic groups than in controls and accounted for the wider difference in their fast walking velocity. Velocity and stride length decreased, whereas stance time increased as a function of motor involvement. In the limited community ambulators, pelvic excursion was increased, whereas hip and knee excursion was reduced. By assessing fast speed, differences between controls and diplegic groups became more apparent.

Summary The study was designed to determine the strategies used by diplegic subjects to change walking speed. Two groups, limited community ambulators and community ambulators, were compared with controls to determine if ability to increase speed would decrease as a function of motor impairment. Compared with matched controls, diplegic subjects were slower and relied more on cadence to increase speed. The ability to change velocity and stride length was significantly less in the diplegic groups than in controls and accounted for the wider difference in their fast walking velocity. Velocity and stride length decreased, whereas stance time increased as a function of motor involvement. In the limited community ambulators, pelvic excursion was increased, whereas hip and knee excursion was reduced. By assessing fast speed, differences between controls and diplegic groups became more apparent.

AggR is a transcriptional regulator of enteroaggregative Escherichia coli (EAEC) and has been proposed as the defining factor for typical EAEC strains. Expression of multiple putative virulence factors, including the aggregative adherence fimbriae (AAF), dispersin, the dispersin translocator Aat, and the Aai type VI secretion system, have been found to be regulated by AggR. Here, we confirm the existence of at least 44 AggR-regulated genes using DNA microarray and real-time quantitative reverse transcription-PCR (qRT-PCR); these genes include chromosomal and plasmid-borne loci and 19 previously unsuspected genes. Two previously uncharacterized virulence plasmid-encoded open reading frames (ORFs) (designated ORF3 and ORF4) exhibit significant identity with isoprenoid biosynthesis genes of Bacteria and Archaea. The predicted ORF4 product is closely related to isopentenyl isomerase (IDI) enzymes, whereas the predicted product of the adjacent ORF3 exhibits an aspartate-rich region that is common among trans-isoprenyl phosphate synthases. We show that mutations in these ORFs confer changes in bacterial surface properties. AggR coordinately controls expression of a large number of EAEC genes.

After completing this article, readers should be able to:Aspiration of foreign bodies by children can lead to serious illness and sometimes even death. According to National Safety Council statistics, in 1995, mechanical suffocation accounted for 5% (167) of all unintentional deaths among children in the United States younger than 4 years of age. Most of these deaths occurred in children younger than 1 year of age (81 deaths, accounting for 10% of all unintentional deaths in children younger than 1 year of age). Fortunately, the number of deaths has decreased over the past decade, which has been attributed to better education of the public and stricter guidelines for toy manufacturers. Nevertheless, foreign body aspiration continues to account for a significant number of preventable childhood deaths.Younger children are at the highest risk for accidental foreign body aspiration. This increased incidence has been attributed to several factors among younger children, including that they: 1) have the tendency to put small objects into their mouths;2) often cry, shout, run, and play with objects in their mouths; and 3) do not have molars to chew certain foods adequately. Most studies show that fewer than 15% of foreign body aspirations occur among children older than 5 years of age. Boys comprise more than 50% of all cases of foreign body aspiration. By far, the objects aspirated most frequently are organic or food matter. In North America, peanuts are most common (Table 1). Unlike aspiration in adults, there is only a slight propensity for objects to lodge on the right side in children. Some studies even demonstrate a higher incidence of foreign bodies on the left side. This observation may be explained by children having symmetric bronchial angles until about 15 years of age. It is not until that age that the aortic knob fully develops, displacing the left mainstem bronchus and creating a more obtuse angle at the carina.The most important piece of data for a clinician to have when evaluating a child who possibly has aspirated a foreign body is an accurate history provided by a witness to the event. Unfortunately, a reliable witness is not always available. Even with a good history for aspiration provided by a witness, children sometimes are asymptomatic at presentation. Therefore,it is important to evaluate the child who presents with a reliable history of aspiration thoroughly,even in the absence of physical findings.The classic history can include an acute choking episode followed by coughing, wheezing, and even stridor. A history of one or more of these symptoms is present in greater than 90% of children who aspirate foreign bodies. Often temporary perioral cyanosis can follow these initial symptoms. A fever may be present. If the child has been febrile,it is important to consider the possibility that the object may be contaminated or chemically irritating. Alternatively, the aspiration may have occurred weeks or even months earlier, causing the child to develop an obstructive pneumonia or lung abscess. It is important to entertain the diagnosis of chronic foreign body aspiration in children who present with unexplained recurrent pneumonia or lung abscesses.Physical findings include cough,tachypnea, diminished breath sounds, wheezing, stridor, dyspnea,cyanosis, and suprasternal retractions. However, the absence of any of these findings does not preclude the possibility of foreign body aspiration. Absence of breath sounds on auscultation of the chest occurs in 30% to 60% of affected children and is suggestive of total airway obstruction. However, the presence of normal bilateral breath sounds does not exclude the diagnosis. Some authors have advocated use of the two-headed stethoscope to help in assessing breath sounds. Although this device can assist in making the diagnosis, it never should be used to exclude the diagnosis of foreign body aspiration. As stated earlier, if there is a reliable history for aspiration,the child should be evaluated further.Most foreign bodies aspirated by children are radiolucent. Therefore,radiographs primarily are useful for detecting only the indirect signs of foreign body aspiration, such as air trapping or atelectasis.Common radiographagic findings are listed in Table 2. Routine diagnostic imaging consists of anteroposterior and lateral chest radiographs (Fig. 1). It is important to include the entire neck in these studies or specific neck radiographs should be obtained. The use of inspiratory and expiratory anteroposterior chest radiographs often will help lateralize the foreign body by emphasizing air trapping(Fig. 2).Left and right lateral decubitus films can be helpful in infants and younger children who cannot cooperate with inspiratory and expiratory films. The side with the foreign body usually will not deflate when placed in the dependent position.Fluoroscopy has been advocated as a more sensitive modality to evaluate movement of the mediastinum and diaphragms. Mu and colleagues(see Suggested Reading) reviewed 343 cases that were evaluated with fluoroscopy, plain chest radiography,or both prior to bronchoscopic removal of the foreign body. Positive radiographic findings were seen in 213 (62%) of the cases. The most common findings were obstructive emphysema (62%), mediastinal shift(55%), pneumonia (26%), atelectasis(18%), and radiopaque objects (3%). The authors noted that 56% of the chest radiographs obtained within 24 hours of the aspiration appeared normal. In contrast, only 33% of the chest radiographs were normal if more than 24 hours had passed since the aspiration.Most studies report normal radiographic findings in 10% to 30% of children who have documented foreign body aspiration. As many as 50% of those who have foreign bodies in the trachea can have normal findings on radiography. Therefore,the presence of normal findings on chest radiography should not exclude the diagnosis of aspiration. Other diagnostic imaging modalities,such as computed tomography, magnetic resonance imaging, and ventilation perfusion scans have a limited role in the diagnosis of foreign body aspiration.Acute management usually occurs before the child arrives in the hospital. Most children manifest forceful coughing as a reflex to clear the airway. As long as the child is able to cough, cry, or speak, no further immediate measures should be undertaken. Complete occlusion of the airway presents as the inability to make sounds or exchange air and requires immediate action. The current American Academy of Pediatrics guidelines for a choking infant and child suggest that, unlike the treatment for adults, the clinician should not perform a blind oropharyngeal finger sweep in children. Only if the object can be seen in the posterior pharynx should an attempt be made to remove it. For children younger than 1 year of age, back slaps and chest thrusts with the infant in a head-down position are the treatment of choice. For children older than 1 year, abdominal thrusts(Heimlich maneuver) are recommended. These maneuvers are designed to force the diaphragm upward, which generates increased intrathoracic pressure and results in increased intratracheal pressure that expels the foreign body. Unfortunately,these techniques are not without complication. However, it is believed that with proper application(brought about through public education),these techniques can save many more children than can be injured.Before the advent of bronchoscopy in the early 1900s, the mortality rate for foreign body aspiration approached 50%. Today, successful treatment with bronchoscopy has reduced this to less than 1%.Improvements in surgical techniques,instruments,and modern anesthesia have allowed bronchoscopy to be effective in greater than 95%of the patients,with a complication rate of less than 1%. In 2000, the standard of care for children who have aspirated foreign bodies is extraction by rigid bronchoscopy,performed under general anesthesia.Once the decision has been made to evaluate the child via bronchoscopy,he or she should be taken to the operating room quickly. Coordination with a skilled pediatric anesthesiologist is critical to the success of the procedure. It is important not to use positive pressure ventilation,which could wedge the foreign body further into the airway or cause pulmonary hyperexpansion. After inducing general anesthesia and obtaining intravenous access,the patient’s head is placed into the“sniffing” position. The surgeon then can insert the rigid, open-channel bronchoscope through which high-resolution optical telescopes and instruments may be passed. Use of the rigid bronchoscope allows the patient to be ventilated throughout the procedure and provides a larger working area through which various instruments can be passed. We believe that there is no role for flexible bronchoscopy to remove foreign bodies from the airway. On the other hand, flexible bronchoscopy occasionally can be useful for diagnostic purposes in patients who have more chronic symptoms. Following removal of the aspirated foreign body, patients are admitted for observation, aggressive pulmonary toilet, and possible antibiotic and bronchodilator treatment. Most children are discharged within 24 hours of the procedure.Rarely, some foreign bodies cannot be removed by bronchoscopy. In these instances, open thoracotomy is required. Such cases usually necessitate a bronchotomy to remove the object or resection of the lung parenchyma along with the foreign body.It should be mentioned that there is no role for “inhalation and postural drainage,” a technique of postural drainage, percussion, and isoproterenol inhalation that was introduced in the early 1970s by Burrington and Cotton. This technique was fraught with complications,including airway obstruction and cardiac arrest. Subsequent to publication of the original articles,several retraction articles were published advocating the use of rigid bronchoscopy as the treatment of choice for airway foreign bodies.Complications from airway foreign bodies are related directly to the timeliness of the diagnosis and treatment. If sudden complete airway obstruction occurs and the child does not receive immediate medical attention, cardiac arrest and death will follow shortly. However, the foreign body usually does not obstruct the airway completely;rather, it lodges in one or the other mainstem bronchus or a distal bronchus.The most common complication associated with foreign body aspiration is pulmonary infection, the pathogenesis of which is related to either partial or complete obstruction of the airway that results in retained secretions and subsequent bacterial overgrowth. There are many cases in the literature of children who have been treated for recurrent pneumonia or lung abscess for many months before the correct diagnosis of airway foreign body was entertained. Therefore, it is important to consider the diagnosis of foreign body aspiration in all children who have unexplainable pulmonary pathology, such as persistent lung infections, bronchiectasis,or new-onset asthmatic symptoms. In these instances, the use of flexible bronchoscopy may aid in the diagnosis. Acute expansion of a lung caused by a ball-valve foreign body may lead to respiratory symptoms or pneumothorax. Less common complications of chronic aspiration of a foreign body include perforation of the bronchial tree and fistula formation. In a recent multicenter study, Reilly and colleagues (see Suggested Reading)retrospectively reviewed the charts of 507 children evaluated for foreign body aspiration. The most common complications among children in whom the diagnosis was delayed were croup, pneumonia, pneumothorax,atelectasis, stricture, and perforation.In an attempt to reduce these preventable complications associated with delayed diagnosis, many advocate the aggressive use of bronchoscopy in children in whom foreign body aspiration is suspected. Mantor and colleagues (see Suggested Reading)retrospectively evaluated the diagnosis and treatment of 76 patients in whom foreign body aspiration was suspected during the 1980s. Nine of the 76 patients had a delay in diagnosis prior to arrival at the institution and required longer hospital stays due to complications resulting from the retained foreign body. No foreign body was found in 9% of the 73 patients who underwent rigid bronchoscopy. There was no morbidity or mortality associated with the procedure. These authors concluded that a negative bronchoscopy rate of 10% to 15% appears to be acceptable to prevent the morbidity associated with the missed diagnosis of foreign body aspiration.As long as children have mouths and their world contains objects that fit into those mouths, foreign body aspiration will occur. The only way to reduce the number of associated deaths is through public education and legislation. As discussed previously,many of the objects commonly aspirated are foods, such as peanuts. Therefore, parents and care-takers should be educated by clinicians to withhold such foods until the child is old enough to chew them adequately. Additionally, they should be reminded to keep small objects such as pins and tacks out of their child’s reach.Further attempts to prevent aspiration injuries during childhood have been stimulated by federal regulations,led by the Consumer Products Safety Commission. The Small Parts Test Fixture, a federally mandated test to screen toy parts for potential ingestion by children younger than 3 years of age, is an example of recent legislation attempting to reduce aspiration injuries. This law defines specific dimensions of objects that pose potential aspiration risks. It requires that toy manufacturers clearly label their products when they contain small parts that may be aspirated. Only through such legislation and public education can aspiration injuries and deaths be prevented.Foreign body aspiration accounts for a significant number of preventable childhood deaths each year in the United States. Fortunately, the number of deaths has declined over the past decade, but morbidity remains significant. This decrease has been attributed to better education of the public and stricter guidelines for toy manufacturers. Primary care physicians must help to educate parents of small children about the potential for foreign body aspiration and ways to prevent it.

OBJECTIVE: We previously demonstrated that parents whose children die in a pediatric intensive care unit (PICU) have a high level of complicated grief symptoms 6 months after the death. In this study, we investigate the change in the extent of complicated grief symptoms among these parents between 6 and 18 months postdeath and identify factors predicting improvement. METHODS: One hundred thirty-eight parents of 106 children completed surveys at 6 and 18 months. Surveys included the Inventory of Complicated Grief (ICG), measures of grief avoidance, attachment, caregiving and social support, and demographics. Multivariable analysis was performed using generalized estimating equations to identify characteristics independently associated with improvement in ICG score. RESULTS: ICG scores were 33.4 ± 13.6 at 6 months and 28.0 ± 13.5 at 18 months, representing an improvement in ICG score of 5.4 + 8.0 (95% confidence interval [CI] 4.1-6.8, p < 0.001). Variables independently associated with greater improvement in ICG score included traumatic death and greater grief avoidance. Variables independently associated with less improvement included being the biological parent and having more responsive caregiving. Parents with one or two surviving children had more improvement in ICG score than those with no surviving children whereas parents with three or more surviving children had less improvement. CONCLUSION: Complicated grief symptoms decrease among parents between 6 and 18 months after their child's death in the PICU; however, high symptom levels persists for some. Better understanding of the trajectory of complicated grief will allow parents at risk for persistent distress to receive professional support.

PURPOSE: The treatment of large stone burdens in children is difficult and often requires multiple procedures using a combination of therapies. Recently, laparoscopy has been shown to be effective in the management of larger stone burdens. We report our experience with robot assisted laparoscopic lithotomy in adolescents, and describe our technique. MATERIALS AND METHODS: We retrospectively reviewed our experience with robot assisted laparoscopic pyelolithotomy in 5 patients operated on between 2002 and 2005. Mean patient age at surgery was 16.6 years, and mean followup was 15.4 months. RESULTS: Cystine was the etiology in 4 patients with staghorn stones. The remaining patient had calcium oxalate stones and concurrent ureteropelvic junction obstruction. After pyelotomy stones were removed by a robotic grasper or by a flexible cystoscope introduced through a robotic port. One of the patients had an indwelling ureteral stent placed preoperatively, while 4 had stents placed robotically intraoperatively. Mean operative time was 315.4 minutes (range 165.0 to 462.0), and mean estimated blood loss was 19.0 ml (0.0 to 50.0). Mean hospital stay was 3.8 days (range 2.3 to 5.7), and mean narcotic usage was 2.1 mg/kg morphine (1.5 to 3.5). One patient with a cystine staghorn calculus required conversion to an open procedure because of inability to remove the stone. Of the 4 cases completed robotically 3 were rendered stone-free and 1 had a residual 6 mm lower pole stone. CONCLUSIONS: The early results of robot assisted laparoscopic lithotomy reveal that the procedure is safe and efficacious. Further prospective studies comparing other minimally invasive procedures used for similar stone burdens are needed to determine the benefits of this procedure and its role in stone management.

To investigate the actions of acute and chronic low doses of ethinyl estradiol (EE) on the pulsatile characteristics of GH and gonadotropin release we studied seven girls with Turner's syndrome [mean age, 7.5 +/- 0.75 (+/- SE) yr] on 3 separate study days. At baseline (study I), blood was drawn every 20 min from 2000-0800 h for GH, LH, and FSH determinations. One month after study I the patients were started on 100 ng/kg EE, orally, daily, and an identical study was repeated 1 week (study II) and 5 weeks (study III) from the initiation of low dose EE therapy. A pulse detection algorithm, Cluster, was used to objectively analyze pulsatility profiles. There were consistent and significant increases in all seven patients after 5 weeks of low dose EE therapy in mean GH concentrations (study I, 7.0 +/- 1.1 micrograms/L; study III, 13.4 +/- 1.7; P = 0.008), mean area under the GH pulse (study I, 602 +/- 52 micrograms/L.min; study III, 1350 +/- 261; P = 0.026), and mean GH pulse amplitude (study I, 14.0 +/- 2.2 micrograms/L; study III, 32.8 +/- 6.0; P = 0.018); with no detectable changes in GH pulse frequency (study I, 5.3 +/- 0.6 pulses/12 h; study III, 5.3 +/- 0.4). These findings were not accompanied by any significant changes in plasma somatomedin-C or serum estradiol concentrations or urinary cytological maturation indexes. Conversely, the amount of radioimmunoassayable FSH activity was suppressed after low dose EE therapy, with a decrease in mean FSH concentrations (study I, 23.5 +/- 6.6 IU/L; study III, 5.9 +/- 1.2; P = 0.035) and mean pulse amplitude (study I, 28.6 +/- 8.6 IU/L; study III, 8.2 +/- 1.8; P = 0.038), with no detectable changes in FSH pulse frequency (study I, 7.6 +/- 0.6 pulses/12 h; study III, 7.3 +/- 0.6). Similar qualitative changes in LH pulsatility were observed after low dose estradiol administration. In conclusion, our results demonstrate that low dose EE therapy results in a significant augmentation of pulsatile GH activity, with reciprocal decreases in gonadotropin concentrations in girls with Turner's syndrome. Such observations indicate an exquisite sensitivity of gonadotrope and somatotrope function to low dose estrogen action in this prepubertal hypogonadal model.

AIM: The aim of this systematic review was to inform evidence-based clinical practice guidelines for children with cerebral palsy (CP) and low bone mineral density (BMD). METHOD: A computer-assisted literature search was focused on low BMD in children with CP, and was limited to the following interventions: weight-bearing activities, bisphosphonate use, and vitamin D or calcium supplementation. Articles were classified according to American Academy of Neurology guidelines and recommendation classifications were given based on the evidence for the intervention increasing BMD and decreasing fragility fractures. Studies were included if they were English-language full-text studies, focused on children with CP, and included at least 10 participants receiving the studied interventions. RESULTS: Twenty-one articles underwent full-text review and data abstraction, including seven studies of weight-bearing activities, five studies of vitamin D or calcium supplementation, and nine studies of bisphosphonates administration. Overall, the evidence that bisphosphonates administration increases BMD was assessed as level B (probable) while the evidence that vitamin D or calcium supplementation does so was assessed as level C (possible); there was insufficient evidence to suggest that weight-bearing activities are an effective intervention to improve BMD. The evidence that bisphosphonates help to prevent fragility fractures was assessed as level C (possible); there was inadequate evidence to support the use of weight-bearing activities or vitamin D or calcium supplementation to decrease fragility fractures. INTERPRETATION: Evidence-based clinical practice guidelines were created outlining the suggested role of weight-bearing activities, vitamin D and calcium supplementation, and bisphosphonate use for children with CP with low BMD at risk of fragility fractures.