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Transcranial-focused ultrasound (tFUS) procedures such as neuromodulation and blood-brain barrier (BBB) opening require precise focus placement within the brain. MRI is currently the most reliable tool for focus localization but can be prohibitive for procedures requiring recurrent therapies. We designed, fabricated, and characterized a patient-specific, 3-D-printed, stereotactic frame for repeated tFUS therapy. The frame is compact, with minimal footprint, can be removed and re-secured between treatments while maintaining sub-mm accuracy, and will allow for precise and repeatable transcranial FUS treatment without the need for MR-guidance following the initial calibration scan. Focus localization and repeatability were assessed via MR-thermometry and MR-acoustic radiation force imaging (ARFI) on an ex vivo skull phantom and in vivo nonhuman primates (NHPs), respectively. Focal localization, registration, steering, and re-steering were accomplished during the initial MRI calibration scan session. Keeping steering coordinates fixed in subsequent therapy and imaging sessions, we found good agreement between steered foci and the intended target, with target registration error (TRE) of 1.2 ± 0.3 ( n = 4 , ex vivo) and 1.0 ± 0.5 ( n = 3 , in vivo) mm. Focus position (steered and non-steered) was consistent, with sub-mm variation in each dimension between studies. Our 3-D-printed, patient-specific stereotactic frame can reliably position and orient the ultrasound transducer for repeated targeting of brain regions using a single MR-based calibration. The compact frame allows for high-precision tFUS to be carried out outside the magnet and could help reduce the cost of tFUS treatments where repeated application of an ultrasound focus is required with high precision.

Objective: Deep brain stimulation (DBS) is an effective treatment to improve motor symptoms in Parkinson's disease (PD). The Globus Pallidus (GPi) and the Subthalamic Nucleus (STN) are the most targeted brain regions for stimulation and produce similar improvements in PD motor symptoms. However, our understanding of stimulation effects across targets on inhibitory action control processes is limited. We compared the effects of STN (n = 20) and GPi (n = 13) DBS on inhibitory control in PD patients., Methods: We recruited PD patients undergoing DBS at the Vanderbilt Movement Disorders Clinic and measured their performance on an inhibitory action control task (Simon task) before surgery (optimally treated medication state) and after surgery in their optimally treated state (medication plus their DBS device turned on)., Results: DBS to both STN and GPi targets induced an increase in fast impulsive errors while simultaneously producing more proficient reactive suppression of interference from action impulses., Conclusions: Stimulation in GPi produced similar effects as STN DBS, indicating that stimulation to either target increases the initial susceptibility to act on strong action impulses while concomitantly improving the ability to suppress ongoing interference from activated impulses., Significance: Action impulse control processes are similarly impacted by stimulating dissociable nodes in frontal-basal ganglia circuitry., (Copyright © 2022 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Objective: Deep brain stimulation (DBS) improves motor symptoms in Parkinson's disease (PD), but it can also disrupt verbal fluency with significant costs to quality of life. The current study investigated how variability of bilateral active electrode coordinates along the superior/inferior, anterior/posterior, and lateral/medial axes in the subthalamic nucleus (STN) or the globus pallidus interna (GPi) contribute to changes in verbal fluency. We predicted that electrode location in the left hemisphere would be linked to changes in fluency, especially in the STN., Methods: Forty PD participants treated with bilateral DBS targeting STN (n = 23) or GPi (n = 17) completed verbal fluency testing in their optimally treated state before and after DBS therapy. Normalized atlas coordinates from left and right active electrode positions along superior/inferior, anterior/posterior, and lateral/medial axes were used to predict changes in fluency postoperatively, separately for patients with STN and GPi targets., Results: Consistent with prior studies, fluency significantly declined pre- to postsurgery (in both DBS targets). In STN-DBS patients, electrode position along the inferior to superior axis in the left STN was a significant predictor of fluency changes; relatively more superior left active electrode was associated with the largest fluency declines in STN. Electrode coordinates in right STN or GPi (left or right) did not predict fluency changes., Interpretation: We discuss these findings in light of putative mechanisms and potential clinical impact., (© 2021 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background: Stereotactic electroencephalography (SEEG) is a minimally invasive neurosurgical method to localize epileptogenic brain regions in epilepsy but requires days in the hospital with interventions to trigger several seizures., Objective: To make initial progress in the development of network analysis methods to identify epileptogenic brain regions using brief, resting-state SEEG data segments, without requiring seizure recordings., Methods: In a cohort of 15 adult focal epilepsy patients undergoing SEEG, we evaluated functional connectivity (alpha-band imaginary coherence) across sampled regions using brief (2 min) resting-state data segments. Bootstrapped logistic regression was used to generate a model to predict epileptogenicity of individual regions., Results: Compared to nonepileptogenic structures, we found increased functional connectivity within epileptogenic regions (P < .05) and between epileptogenic areas and other structures (P < .01, paired t-tests, corrected). Epileptogenic areas also demonstrated higher clustering coefficient (P < .01) and betweenness centrality (P < .01), and greater decay of functional connectivity with distance (P < .05, paired t-tests, corrected). Our functional connectivity model to predict epileptogenicity of individual regions demonstrated an area under the curve of 0.78 and accuracy of 80.4%., Conclusion: Our study represents a preliminary step towards defining resting-state SEEG functional connectivity patterns to help localize epileptogenic brain regions ahead of neurosurgical treatment without requiring seizure recordings., (Copyright © 2019 by the Congress of Neurological Surgeons.)

Patients with Parkinson's disease (PD) often experience reductions in the proficiency to inhibit actions. The motor symptoms of PD can be effectively treated with deep brain stimulation (DBS) of the subthalamic nucleus (STN), a key structure in the frontal-striatal network that may be directly involved in regulating inhibitory control. However, the precise role of the STN in stopping control is unclear. The STN consists of functional subterritories linked to dissociable cortical networks, although the boundaries of the subregions are still under debate. We investigated whether stimulating the dorsal and ventral subregions of the STN would show dissociable effects on ability to stop. We studied 12 PD patients with STN DBS. Patients with two adjacent contacts positioned within the bounds of the dorsal and ventral STN completed two testing sessions (OFF medication) with low amplitude stimulation (0.4 mA) at either the dorsal or ventral contacts bilaterally, while performing the stop task. Ventral, but not dorsal, DBS improved stopping latencies. Go reactions were similar between dorsal and ventral DBS STN. Stimulation in the ventral, but not dorsal, subregion of the STN improved stopping speed, confirming the involvement of the STN in stopping control and supporting the STN functional subregions., (© The Author(s) 2020. Published by Oxford University Press.)

Background: Besides vaccines and otitis media medicines, most products prescribed for children have not been studied in the pediatric population. To remedy this, Congress enacted legislation in 1997, known as pediatric exclusivity (PE), which provides 6 months of additional market protection to drug sponsors in exchange for studying their products in children., Methods: We reviewed requests for pediatric studies and subsequent labeling for drugs granted PE from 1998 through 2012. Regression analysis estimates the probability of demonstrating efficacy in PE trials. Variables include therapeutic group, year of exclusivity, product sales, initiation process, and small disease population., Results: From 1998 through 2012, the US Food and Drug Administration issued 401 pediatric study requests. For 189 drugs, studies were completed and granted exclusivity. A total of 173 drugs (92%) received new pediatric labeling, with 108 (57%) receiving a new or expanded pediatric indication. Three drugs had non-efficacy trials. Efficacy was not established for 78 drugs. Oncology, cardiovascular, and endocrine drugs were less likely to demonstrate efficacy (P < .01) compared with gastrointestinal and pain/anesthesia drugs. Drugs studied later in the program were less likely to demonstrate efficacy (P < .05). Sales, initiation process, and small disease population were not significant predictors., Conclusions: Most drugs (173; 92%) granted exclusivity added pediatric information to their labeling as a result of PE, with 108 (57%) receiving a new or expanded pediatric indication. Therapeutic area and year of exclusivity influenced the likelihood of obtaining a pediatric indication. Positive and negative outcomes continue to inform the construct of future pediatric trials., (Copyright © 2014 by the American Academy of Pediatrics.)

Objectives: Presently, there is no consensus on endpoint measures to assess clinical outcomes for pediatric ulcerative colitis (UC). This study reviewed the endpoints used in the registration trials of approved drugs for pediatric UC., Methods: The primary efficacy endpoints of all registration trials completed from 1950 to 2008 that led to Food and Drug Administration approval for indications in pediatric and adult UC were reviewed., Results: Colazal and Remicade have been approved for pediatric UC indication, and clinical response was used as a primary endpoint in these registration trials. The clinical response in the adult Colazal trials was defined as a reduction of rectal bleeding and improvement in at least one of the other assessed symptoms (stool frequency, patient functional assessment, abdominal pain, sigmoidoscopic grade, and physician's global assessment) assessed by the Sutherland UC Activity Index. The pediatric Colazal trial defined clinical response using the Modified Sutherland UC Activity Index, which excluded abdominal pain and functional assessment. Both adult and pediatric Remicade trials used clinical response defined by the Mayo score as the primary endpoint. The Pediatric Ulcerative Colitis Activity Index was used to measure various secondary endpoints in the pediatric Remicade trial., Conclusions: Pediatric-specific endpoints were used, but outcome measures and definition of clinical response were not consistent in pediatric UC trials. Consensus on the definition of successful treatment outcome (clinical response and/or remission) and collaboration in the development of well-defined and reliable measures of signs and symptoms for use in conjunction with endoscopic parameters of mucosal healing will facilitate pediatric drug development.

There is a high prevalence of hypovitaminosis D in patients with back pain regardless of whether or not they require surgical intervention. Furthermore, the risk of hypovitaminosis D is not limited to individuals with traditional clinical risk factors. Vitamin D plays an essential role in bone formation, maintenance, and remodeling, as well as muscle function. Published data indicate that hypovitaminosis D could adversely affect bone formation and muscle function in multiple ways. The literature contains numerous reports of myopathy and/or musculoskeletal pain associated with hypovitaminosis D. In terms of spinal fusion outcomes, a patient may have a significant decrease in pain and the presence of de novo bone on an X-ray, yet their functional ability may remain severely limited. Hypovitaminosis D may be a contributing factor to the persistent postoperative pain experienced by these patients. Indeed, hypovitaminosis D is not asymptomatic, and symptoms can manifest themselves independent of the musculoskeletal pathological changes associated with conditions like osteomalacia. It appears that vitamin D status is routinely overlooked, and there is a need to raise awareness about its importance among all healthcare practitioners who treat spine patients.

Objective: To examine the characteristics of pediatric trials conducted under US legislation and to compare results with data from 2002 to 2007., Methods: We reviewed all pediatric trials provided to the US Food and Drug Administration in submissions that were approved between September 28, 2007 and December 21, 2010. We extracted data for each trial including age range, therapeutic indication, design, duration, and patient and center enrollment by location., Results: Overall 346 studies on 113 drugs and biologicals enrolled 55 819 pediatric patients. The United States participated in 86% of the studies, providing 71% of the centers and 74% of the patients. Corresponding percentages for non-US countries were 43%, 29%, and 26% respectively. Developing or transition countries participated in 22% of the studies, providing 12% of the centers and 10% of the patients; our earlier analysis found corresponding percentages of 38%, 12%, and 23%. The most common therapeutic areas studied in the latter countries were infectious, neurologic, and pulmonary diseases. Seventy-eight vaccine studies enrolled 147 692 patients. The United States participated in 40% of the studies, providing 39% of the centers and 22% of the patients. Corresponding percentages for non-US countries were 74%, 61%, and 78% respectively. Developing or transition countries participated in 27% of the studies, providing 15% of the centers and 52% of the patients., Conclusions: The United States remains an important location for pediatric trials. Developing country involvement in pediatric drug development is not increasing, although these countries participate significantly in vaccine trials.

Objectives: In 1994, the US Food and Drug Administration (FDA) proposed an approach, based on extrapolation of efficacy findings from adults to the pediatric population, to maximize the use of adult data and other data when designing pediatric drug-development programs. We examined the experience of the FDA in using extrapolation to evaluate how and when it was used and any changes in scientific assumptions over time., Methods: We reviewed 370 pediatric studies submitted to the FDA between 1998 and 2008 in response to 159 written requests (166 products) issued under the Pediatric Exclusivity Provision. We identified cases in which efficacy was extrapolated from adult data or other data, we categorized the type of pediatric data required to support extrapolation, and we determined whether the data resulted in new pediatric labeling., Results: Extrapolation of efficacy from adult data occurred for 82.5% of the drug products (137 of 166). Extrapolation was defined as complete for 14.5% of the products (24 of 166) and partial for 68% of them (113 of 166). Approaches to extrapolation changed over time for 19% of the therapeutic indications studied (13 of 67). When extrapolation was used, 61% of the drug products (84 of 137) obtained a new pediatric indication or extension into a new age group; this number decreased to 34% (10 of 29) when there was no extrapolation., Conclusions: Extrapolating efficacy from adult data or other data to the pediatric population can streamline pediatric drug development and help to increase the number of approvals for pediatric use.

We reviewed information about the safety and plasma pharmacokinetic data for amoxicillin, specifically related to its potential use for postexposure inhalational anthrax. Amoxicillin (45 mg/kg/d) given orally in 3 divided doses to pediatric patients <40 kg should yield an adequate time above the MIC for susceptible Bacillus anthracis (< or =0.5 microg/mL) over most of the dosing interval (75-100%). Doses <45 mg/kg/d and dosing intervals longer than 8 hours should not be used for postexposure inhalational anthrax.

Premature infants and those with chronic lung disease or congenital heart disease are at high risk of severe respiratory syncytial virus (RSV) disease. Palivizumab (Synagis), a humanized anti-RSV monoclonal antibody, has been used extensively since 1998 to prevent severe RSV disease in high-risk infants. To monitor for possible palivizumab-resistant mutants, an immunofluorescence binding assay that predicts palivizumab neutralization of RSV was developed. RSV isolates were collected at 8 US sites from 458 infants hospitalized for RSV disease (1998-2002). Palivizumab bound to all 371 RSV isolates able to be evaluated, including 25 from active-palivizumab recipients. The palivizumab epitope appears to be highly conserved, even in infants receiving prophylaxis with palivizumab.

Pediatric studies have resulted in changes in the dose of many medications given to children and an increased awareness of safety issues. An additional 6 months of pediatric exclusivity legislated under the Food and Drug Administration (FDA) Modernization Act of 1997 for pediatric studies undertaken in response to written requests from the FDA have stimulated the conduct of a large number of studies.

Introduction: Recent advances in the diagnosis and treatment of influenza virus infections include: (1) rapid bedside diagnosis methods with simple commercially available tests; and (2) Food and Drug Administration approval of treatment for children 1 year of age and older with neuraminidase inhibitor drugs. For proven benefit antivirals should be used within 2 days of onset of symptoms., Objectives: We conducted a performance improvement exercise comparing the sensitivity and specificity of four rapid tests for influenza viruses: (1) Flu OIA (Biostar); (2) Quickvue Influenza Test (Quidel); (3) Z Stat Flu (ZymeTx); and (4) Directigen Flu A (Becton Dickinson)., Methods: During the 1999 to 2000 epidemic, symptomatic patients seen at the private practice of one of the authors provided specimens collected and processed according to the manufacturer's directions. Throat swabs only were used to collect the specimens for the Z Stat Flu Kit. Directigen was performed immediately, and the others were run in parallel within 12 to 24 h. Specimens were frozen first at -20 degrees C for up to 3 days and shipped in transport medium to the Virology Research Laboratory of the Virginia State Health Department for culture where they were stored at -60 degrees C until cultured. Some of the samples were processed by a commercial laboratory., Results: Specimens from 116 patients were available for influenza culture; for 88 of these culture was performed at the State Health Department Laboratory, and for 28 culture was performed at a local commercial medical laboratory. Influenza virus (A) was detected in 58 of 116 (50%) specimens, 10 (17%) of these only by direct fluorescent antigen samples. Viral culture-direct fluorescent antigen results were used as the standard. Of the 4 tests Biostar and Z Stat Flu required more technician time (by an average of 2-fold). The 4 tests had sensitivities ranging from 72 to 95%. Z Stat differed significantly in sensitivity from the other three (P = 0.001). The specificities of Directigen, Quickvue, Flu OIA and Z Stat Flu were similar (76 to 86%). The positive predictive value of Directigen, Quickvue and FluOIA and Z Stat ranged from 80 to 86%. The negative predictive value of all 4 tests ranged from 75 to 94%. Z Stat Flu had a lower negative predictive value than the other 3 tests (75%; P = 0.001., Conclusion: In this first head-to-head comparison of four rapid diagnostic tests for influenza, Directigen Flu A, Quickvue and Flu OIA appear equivalent in sensitivity, specificity, positive predictive value and negative predictive value. Z Stat Flu was not as sensitive or as efficient as the other three tests.

Traditionally, Streptococcus pneumoniae is identified in the laboratory by demonstrating susceptibility to optochin. Between 1992 and 1998, 4 pneumococcal isolates exhibiting optochin resistance were recovered from patients at Children's National Medical Center. Three of the 4 isolates consisted of mixed populations of optochin-resistant and -susceptible organisms. Both subpopulations had identical antibiograms, serotypes, and restriction fragment profiles. The other isolate was uniformly resistant to optochin. Resistant strains had MICs of optochin 4-30-fold higher than susceptible strains, belonged to different serotypes, and had dissimilar restriction fragment profiles, indicating clonal unrelatedness. Resistance arose from single point mutations in either the a-subunit (W206S) or the c-subunit (G20S, M23I, and A49T) of H(+)-ATPase. There is speculation of a possible association between exposure to antimalarial drugs and evolution of optochin resistance. alpha-Hemolytic streptococci resistant to optochin, particularly invasive isolates, should be tested for bile solubility or with an S. pneumoniae DNA probe before identification as viridans streptococci.

Focal extraintestinal infections from nontyphoid salmonellae have increased in incidence during the past decade. Typically, they are manifested as either osteomyelitis or meningitis as a complication of either bacteremia or enteric fever. Isolated salmonellal soft tissue infections, however, are rare and occur mostly in adults with chronic underlying conditions such as human immunodeficiency virus (HIV) infection, diabetes mellitus, and cell-mediated immunity defects. We report a case of an otherwise healthy adolescent who was exposed to a guinea pig with a skin mass. She subsequently had an isolated soft tissue infection with cartilaginous involvement of the anterior chest wall due to Salmonella enterica serogroup C1 (bioserotype oranienburg).

Management of respiratory syncytial virus lower respiratory tract infection in infants is predominantly supportive and symptomatic. Outpatient management requires close attention to feeding, oral hydration, and monitoring of fever, behavior, and respiratory effort. In the small proportion of patients who need hospitalization, clinicians are concerned primarily with oxygenation and the possibility of oxygen desaturation. Appropriate interventions depend on the level of oxygenation as indicated by pulse oximetry or arterial blood gases. Hydration and symptomatic treatment with alpha- or ss(2 )-adrenergic agonist bronchodilators may lessen the work of breathing. The role of these agents remains controversial, however, and anticholinergic bronchodilators are considered ineffective. Current antiviral therapy is limited to aerosolized ribavirin. Immunotherapy with respiratory syncytial virus immune globulin or a monoclonal antibody has not been rewarding in terms of clinical outcome, although the antiviral effect of these agents has been impressive. There is concern about long-term pulmonary sequelae after respiratory syncytial virus lower respiratory tract infection early in life. Several recent studies, including new data reported here, suggest that ribavirin may have a beneficial effect on some of these sequelae, whereas other studies have failed to demonstrate any benefit. Future studies may help resolve this question.

Objectives: To compare the efficacy and safety of meropenem with cefotaxime for the treatment of infants and children with bacterial meningitis., Methods: Infants and children with strongly suspected or documented bacterial meningitis were randomly assigned in a prospective multicenter study to receive either meropenem or cefotaxime. Patients were assessed at the end of therapy and at 5 to 7 weeks and 5 to 7 months after the end of treatment for the presence of neurologic and sensory neural sequelae., Results: A total of 258 children were randomized to either treatment group. A further 8 patients with suspected pneumococcal meningitis were treated with meropenem without randomization. Of the randomized patients 154 were fully evaluable, 79 in the meropenem group and 75 in the cefotaxime group. At the end of treatment there were no significant differences in clinical outcome between the two treatment groups. Clinical cure with or without sequelae was achieved in 97 and 96% of the meropenem- and cefotaxime-treated patients, respectively. At the end of treatment and at 5 to 7 weeks, 46 and 54% of meropenem patients were cured with no sequelae, respectively. Corresponding results for cefotaxime patients were 56 and 58%. All pathogens were eradicated. In total 37 patients had seizures during treatment, 15 (12%) in the meropenem and 22 (17%) in the cefotaxime group. None of the seizures was considered to be drug-related., Conclusions: This trial shows that meropenem is suitable therapy for bacterial meningitis in infants and children and that it offers an efficacy and safety profile similar to that of cefotaxime.

Objective: To determine any long-term differences in adverse effects and pulmonary function between infants with respiratory syncytial virus and lower respiratory tract infection who were treated with ribavirin and a control group., Study Design: Long-term follow-up included enumeration of episodes of respiratory illness, wheezing, and pneumonia and, ultimately, administration of pulmonary function tests (PFTs). Pulse oximetry was done at each visit. During the first 3 years we conducted follow-up in the fall and spring. In years 4 and 5 we conducted 1 visit per year. During years 5 through 7 we conducted PFTs, and starting with year 7 a methacholine chloride challenge was done if forced expiratory volume in 1 second (FEV1) was greater than 70% of predicted value., Results: We prospectively enrolled (December 1983 to February 1985) in a randomized trial of ribavirin vs placebo children who were previously healthy, were premature, or had chronic pulmonary disease. One pulmonologist (R.F.; blinded) scored and interpreted the results of the PFTs. We studied 42 patients aged 1 to 33 months; 2 patients died (1 receiving ribavirin and 1 receiving placebo) and 5 patients receiving placebo were lost to follow-up; 35 patients (24 taking ribavirin and 11 taking placebo) attended 212 visits. Four patients were premature (3 in the ribavirin and 1 in the placebo group), and 3 of these had bronchopulmonary dysplasia (2 in the ribavirin and 1 in the placebo group). From years 1 to 3, there was more reactive airway disease, wheezing, and pneumonia in the placebo than in the ribavirin group (mean score, 22.3 for 12 placebo-treated patients vs. 15.8 for 23 ribavirin-treated patients; P = .07 by Kruskal-Wallis test); for all years, it was 22.0 for 11 placebo-treated patients vs. 16.0 for 22 ribavirin-treated patients (P = .10). After informed consent was given, 19 patients completed PFTs (13 receiving ribavirin and 6 receiving placebo); 7 of 13 ribavirin-treated patients (53%) had normal or mild PFT results vs. 0 of 6 placebo-treated patients (P = .04 by Fisher exact test). On methacholine challenge (7 ribavirin-treated patients and 5 placebo-treated patients), there was more reactivity in the placebo vs. the ribavirin group (exact P = .07). Scoring done by weighting for severity for 19 patients (13 ribavirin-treated patients and 6 placebo-treated patients) (even after correcting for asthma) showed a significant difference in favor of previously ribavirin-treated patients (exact P = .02)., Conclusions: No outward effects were identified from ribavirin exposure. We observed no increase in reactive airway disease, wheezing, and pneumonia in the ribavirin compared with the placebo group. Weighted severity scores suggest long-term beneficial effect of ribavirin therapy; however, larger numbers should be evaluated.

We conducted a multicenter, double-blind, placebo-controlled, randomized trial of a humanized monoclonal antibody against a respiratory syncytial virus (RSV) fusion protein (SB 209763) to evaluate its safety, pharmacokinetics, and fusion inhibition and neutralization titers. Forty-three infants who were either delivered prematurely (

Multidrug-resistant Streptococcus pneumoniae strains have emerged over the past decade at an alarming rate. The molecular mechanism of trimethoprim resistance was investigated in 5 pneumococcal strains isolated in the Washington, DC, area from patients with invasive infections. Cloning and sequencing of the trimethoprim resistance determinant from these pneumococci indicated that an altered chromosome-encoded dihydrofolate reductase (DHFR) was responsible for the observed resistance. Comparison of DHFR sequences from pneumococcal strains with various susceptibilities to trimethoprim, together with site-directed mutagenesis, revealed that substitution of isoleucine-100 with a leucine residue resulted in trimethoprim resistance. Hydrogen bonding between the carbonyl oxygen of isoleucine-100 and the 4-amino group of trimethoprim is proposed to play a critical role in the inhibition of DHFR by trimethoprim. This enzyme-substrate model should facilitate the design of new antibacterial agents with improved activity against S. pneumoniae.

Objective: To evaluate the efficacy of high titer respiratory syncytial virus (RSV) immune globulin (RSVIG) in the treatment of previously healthy children hospitalized with proven RSV lower tract infection (LRI)., Method: Infants and young children /=2. 5 were enrolled., Results: One hundred and one previously healthy children hospitalized with RSV LRI received either 1500 mg/kg of RSVIG (RespiGam, MedImmune Inc, Gaithersburg, MD) or albumin placebo in a randomized, double-blind, placebo-controlled trial. Forty-six RSVIG and 52 recipients of placebo met all eligibility criteria. Demographic characteristics of the two groups were similar. More RSVIG recipients (46% vs 29%) had an SaO2 /=3.0) had 1.6 fewer hospital days and 2.7 days less ICU stays., Conclusion: RSVIG infusions seemed safe and generally well tolerated. Although some beneficial effect trends were seen for those with more severe disease who were treated there was no evidence that treatment with RSVIG resulted in reduced hospitalization and reduced ICU stays in all children with RSV disease.

Objectives: To evaluate the efficacy of high-titer intravenous respiratory syncytial virus immune globulin (RSVIG) in the treatment of children at high risk for severe RSV infection who were hospitalized with proven RSV., Methods: Infants and young children younger than 2 years with bronchopulmonary dysplasia, chronic lung disease, congenital heart disease, or prematurity (<32 weeks' gestational age), hospitalized with a history of lower respiratory tract infection (LRI) of less than 4 days, were enrolled in this study. Patients were randomized in a blinded fashion to receive either 1500 mg/kg RSVIG or placebo in equal volumes. They were evaluated daily for safety and respiratory scores and for RSV nasal shedding., Results: One hundred seven high-risk children were randomized--54 in the RSVIG group and 53 in the placebo group. Of these children, 51 in each group were considered evaluable. Children with pulmonary disease, congenital heart disease, or prematurity were equally distributed between the two treatment groups. However, two important differences were found in baseline variables between the two groups: there were more patients in the placebo group who had histories of previous LRI and there was a trend toward more severe disease at study entry in the RSVIG group. This was manifested by a higher entry respiratory score in the RSVIG group than in the placebo group (3.4 +/- 0.2 vs 3.1 +/- .01). A higher proportion of children in the RSVIG group (47%) than in the placebo group (28%) required intensive care at entry and mechanical ventilation at study entry (31% RSVIG-treated vs 18% placebo-treated patients). No significant difference was found between groups in the mean unadjusted duration of hospitalization (RSVIG group, 9.10 +/- 1.18 days; control group, 8.17 +/- 1.08 days). When the mean was adjusted for entry respiratory score, likewise, no difference was observed between each group (8.41 +/- 0.97 vs 8.89 +/- .99 days). The lack of efficacy observed in the study primary endpoint was observed in all diagnostic groups. No differences between the RSVIG and placebo groups were observed in the following secondary endpoints: duration of intensive care unit stay, duration of intensive care unit stay for RSV, mechanical ventilation, or supplemental oxygen. No significant differences in adverse events were reported in the RSVIG group (16 children) when compared with the control group (10 children)., Conclusion: RSVIG treatment was safe but not efficacious in the treatment of children with bronchopulmonary dysplasia, congenital heart disease, or premature gestation who were hospitalized with RSV LRI.

During a 13-month period ending in January, 1995, we obtained 159 samples of middle ear exudate through tympanocentesis (n = 155) or acute spontaneous otorrhea (n = 4) from 151 children enrolled in therapeutic trials of acute otitis media in a pediatric practice in Northern Virginia. Their ages ranged from < 1 to > 6 years of age (mean, 35 months; median, 22 months). Precise diagnostic criteria for acute otitis media always included bulging outward of all or part of the eardrum, opacification of the eardrum regardless of color and impaired mobility to positive and negative pressure via the pneumatic otoscope. Bacterial pathogens were isolated from middle ear fluid in 95% of these children: Streptococcus pneumoniae was recovered from 61 (37%); Haemophilus influenzae from 45 (27%); Moraxella catarrhalis from 41 (25%); Group A streptococcus from 6 (4%); Staphylococcus aureus from 4 (2%); and no growth or microbes of uncertain significance from 8 (5%). Six of the patients had mixed bacterial cultures; 2 of the 6 had at least one ampicillin-resistant bacteria, and a third had 2 ampicillin-resistant bacteria. Eight patients who failed to improve with antimicrobial treatment had a second tympanocentesis performed or developed spontaneous drainage; on that follow-up culture 3 of 8 cultures had different microorganisms; and 5 of the 8 bacterial specimens were resistant to ampicillin or penicillin. Twenty-one percent of the S. pneumoniae strains recovered from the middle ear were resistant to penicillin. Sixty-two percent of the H. influenzae and 98% of the M. catarrhalis isolates were resistant to ampicillin. Overall bacteria resistant to penicillin or ampicillin were recovered in 54% of middle ear fluid from 46 patients who had received a beta-lactam antibiotic in the preceding month as well as in 57% of middle ear fluids from 105 patients who had not. The empiric use of amoxicillin for treatment of acute otitis media should be reexamined in our community particularly in those who appear ill, have a high fever or have severe unremitting otalgia.

Respiratory syncytial virus (RSV) causes serious illness (lower respiratory illness) in preterm infants. RSV antibody-enriched immunoglobulin (RSVIG) that was lyophilized (LYO) protected against RSV lower respiratory illness. The Food and Drug Administration now requires an additional viral inactivation step (VI). We compared LYO, LYO-VI, and a more convenient liquid RSVIG (LIQ-VI) in 30 preterm infants (median age, 7 months; median weight, 5.4 kg). Infants were randomized to receive LYO (n = 10), LYO-VI (n = 10), or LIQ-VI (n = 10) in monthly infusions of 750 mg/kg of body weight per dose (December to March). Children were monitored closely for adverse reactions to RSVIG and for RSV illness.

Objective: To assess the prevalence and antimicrobial susceptibility of penicillin-resistant pneumococci (PRP) isolated from patients in a pediatric hospital., Methods: All (108) isolates of Streptococcus pneumoniae recovered from usually sterile body sites between June 1, 1992, and May 31, 1993, were screened for susceptibility to penicillin by the E-test method. Minimum inhibitory concentrations of penicillin and other antibiotics were also determined by an agar dilution method for 10 PRP and 22 penicillin-susceptible strains., Results: Fourteen isolates (12.9%) were PRP by the E-test; nine of these (8.3%) were intermediately resistant and five (4.6%) were highly resistant. All strains were sensitive to rifampin and vancomycin. Increased frequency of resistance to oral and parenteral cephalosporins and carbapenems was found among PRP; for most of these antibiotics, resistance exceeded 40% of the PRP. In addition, 20% of the PRP were resistant to macrolides and all penicillin-susceptible and PRP were resistant to a combination of trimethoprim and sulfamethoxazole., Conclusions: The decreased susceptibility to oral and parenteral cephalosporins, macrolides, a combination of trimethoprim and sulfamethoxazole, and carbapenems creates a significant problem in the treatment of pneumococcal infections in both ambulatory and hospitalized patients.

From 1983 to 1992 a total of 64 children were admitted with a diagnosis of malaria to Children's National Medical Center in Washington, DC. Specific etiology is available in 59 of 64. Of these 59 cases 52 (88%) were caused by Plasmodium falciparum. Fifty-one of 52 infections were acquired in Africa, 35 (67%) of these in traveling United States citizens. Eleven (21%) of 52 children were initially admitted to the Intensive Care Unit for i.v. quinidine or quinine therapy. Eight (73%) of these 11 patients compared with 12 (29%) of 41 general ward admissions had been misdiagnosed within 10 days before admission (P = 0.012). Five of 11 Intensive Care Unit patients underwent exchange transfusion. One child died and one was left with severe neurologic deficit. Malaria must be considered in the differential diagnosis for any febrile child who has traveled to or from a malarious area within the previous 12 months. Delayed diagnosis of pediatric Plasmodium falciparum malaria is associated with an increased severity of illness. Because of the frequency of international travel, United States physicians will need to be familiar with the presentation and management of imported P. falciparum malaria.

We randomly assigned children hospitalized with influenza who had been ill < or = 48 hours and who had a temperature > or = 37.8 degrees C to receive either ribavirin or placebo. All patients had evaluations performed for fever reduction, use of acetaminophen for temperature > or = 38.3 degrees C, duration and severity of influenza symptoms, and feeding behavior. Sixty-two patients (35 in the placebo group, 27 in the ribavirin group) had a diagnosis of influenza confirmed by laboratory study. The groups did not differ significantly in age, initial signs and symptoms, or in distribution of influenza A or B infections. The time to reduction of temperature < or = 38.3 degrees C for the ribavirin group was 8.9 hours compared with 22.6 hours for the placebo group (p = 0.04). The mean duration of acetaminophen use was 7.4 hours in the ribavirin group and 16.3 hours in the placebo group (p = 0.14). There were no significant differences between the groups in outcome of respiratory rate, pulse rate, cough, or level of consciousness. Convalescent influenza antibody geometric mean titer for the placebo group was 9.8 compared with 3.6 for the ribavirin group (p = 0.04). Ribavirin was more effective than placebo in accelerating normalization of temperature but there were no other significant differences.

Background: Infants with cardiac disease or prematurity are at risk for severe illness caused by respiratory syncytial virus. Immune globulin with a high titer of antibodies against respiratory syncytial virus may offer infants and young children at risk protection from this serious, common respiratory illness., Methods: We studied 249 infants and young children (mean age, eight months) who had bronchopulmonary dysplasia due to prematurity (n = 102), congenital heart disease (n = 87), or prematurity alone (n = 60). Respiratory syncytial virus immune globulin was given monthly to some of these children in either a high dose (750 mg per kilogram of body weight; n = 81) or low dose (150 mg per kilogram; n = 79); 89 controls received no immune globulin. Group assignments were random. Assessments of respiratory illness and management were conducted without knowledge of the children's group assignments., Results: There were 64 episodes of respiratory syncytial virus infection: 19 in the high-dose group, 16 in the low-dose group, and 29 in the control group. In the high-dose group there were fewer lower respiratory tract infections (7, vs. 20 in the control group; P = 0.01), fewer hospitalizations (6, vs. 18 in the control group; P = 0.02), fewer hospital days (43, vs. 128 in the control group; P = 0.02), fewer days in the intensive care unit (P = 0.05), and less use of ribavirin (P = 0.05). In the low-dose group there was a significant reduction only in the number of days in the intensive care unit (P = 0.03). Adverse events during the 580 infusions were generally mild and included fluid overload (in five children), oxygen desaturation (eight), and fever (six). Six children died: three in the high-dose group, three in the low-dose group, and none in the control group (P = 0.15), but no death was attributed to the use of immune globulin or to illness caused by respiratory syncytial virus., Conclusions: Administration of high doses of respiratory syncytial virus immune globulin is a safe and effective means of preventing lower respiratory tract infection in infants and young children at high risk for this disease.

Ho:Tm:LuAG has been grown, examined spectroscopically, and lased at 2.1 microm. Ho:Tm:LuAG was selected for this experimental investigation when quantum-mechanical modeling predicted that it would be a good laser material for Ho laser operation on one of the (5)I(7) to (5)I(8) transitions. Lasing was achieved at 2.100 microm, one of the three wavelengths predicted to be most probable for laser action.

The efficacy of cefixime was compared with that of cefaclor in the treatment of 63 patients with acute otitis media. Patients received either a single dose of cefixime (8 mg/kg/day) or 3 divided doses of cefaclor (40 mg/kg/day). On the basis of otoscopic and tympanometric results at 10 to 14 days after the start of treatment, 28 (97%) of 29 cefixime-treated patients and 25 (78%) of 32 cefaclor-treated patients had resolution of acute otitis media. The clinical cure rate associated with all organisms was 94% for cefixime (16 of 17 isolates) and 68% (13 of 19 isolates) for cefaclor. The cure rate for Streptococcus pneumoniae was 12 of 12 (100%) for cefixime and 7 of 7 (100%) for cefaclor; the cure rate for Haemophilus influenzae (which includes 2 patients with mixed infections) was 3 of 4 (75%) for cefixime and 2 of 7 (29%) for cefaclor. One clinical relapse occurred among 29 cefixime-treated patients; however, at 28 days 9 recurrences were observed. Three of 25 (9%) cefaclor-treated patients failed and 4 (13%) relapsed at 10 to 14 days, an additional 2 (10%) experienced recurrence by Day 28. Eight (28%) cefixime-treated patients experienced adverse events (7 gastrointestinal and 1 diarrhea and rash); 8 (25%) cefaclor-treated patients experienced adverse events (all gastrointestinal). Our data suggest that both at end of therapy and for 14 days thereafter, cefixime given once a day for acute otitis media is clinically equivalent to cefaclor given 3 times a day.

Correlation of virulence factors of Escherichia coli with renal inflammation documented by 99mTc-dimercaptosuccinic acid renal scan was undertaken in 59 children with febrile urinary tract infections to identify more accurately the role of bacterial virulence factors in the development of pyelonephritis. P fimbriae were present in 63% of isolates from the positive scan group and 83% of those from the negative scan group (P = 0.126). Multivariate regression analysis showed no significant role for established E. coli virulence factors in the development of pyelonephritis. The pap genome was independently associated with negative scan (P less than 0.007) and with the absence of reflux (P = 0.031). E. coli pyelonephritogenic clone O16:K1:H6 was isolated from negative scan patients and did not produce hemolysin. We conclude that P fimbriae are important in the development of febrile urinary tract infection regardless of the level of infection. Virulent E. coli clones described in prior Scandinavian urinary tract infection studies were not common causes of pyelonephritis in our patient population.

The recent isolation of human herpesvirus 7 (HHV-7) from activated CD4+ T lymphocytes of a healthy individual raises questions regarding the prevalence of this virus in humans and its immunological relationship to previously characterized human herpesviruses. We report that HHV-7 is a ubiquitous virus which is immunologically distinct from the highly prevalent T-lymphotropic HHV-6. Thus, (i) only two of six monoclonal antibodies to HHV-6 cross-reacted with HHV-7-infected cells, (ii) Western immunoblot analyses of viral proteins revealed different patterns for HHV-6- and HHV-7-infected cells, (iii) tests of sequential serum samples from children revealed seroconversion to HHV-6 without concomitant seroconversion to HHV-7, and (iv) in some instances HHV-7 infection occurred in the presence of high titers of HHV-6 antibodies, suggesting the lack of apparent protection of children seropositive for HHV-6 against subsequent infection with HHV-7. On the basis of the analyses of sera from children and adults it can be concluded that HHV-7 is a prevalent human herpesvirus which, like other human herpesviruses, infects during childhood. The age of infection appears to be somewhat later than the very early age documented for HHV-6.

Human herpesvirus 6 (HHV-6) causes exanthem subitum (ES, roseola infantum), a childhood disease characterized by high fever and skin rash. We have analyzed restriction enzyme cleavage patterns of the DNAs of ES virus isolates from Japan and the United States. The patterns of all the ES viral DNAs were highly conserved, except for variable sequences within the terminal repeat sequences. They resembled closely the restriction enzyme patterns of the Z29 strain of HHV-6 but were distinct from those of the U1102 strain. That all ES isolates were closely related whereas the U1102 patterns were very different suggests that the U1102 strain represents a distinct virus. Moreover, the ES isolates all resembled the Z29 strain and not the U1102 strain with respect to reactivity with HHV-6 monoclonal antibodies. These findings provide evidence for the existence of two distinct classes of viruses previously classified as HHV-6. Whereas the Z29-like viruses are involved in ES infections, the association of the U1102-like viruses with human disease has yet to be determined.