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This study was conducted to determine the extent of arsenic (As) absorption from soil and house dust impacted by smelter activities near Anaconda, Montana. Female cynomolgus monkeys were given a single oral administration via gelatin capsules of soil (0.62 mg As/kg body wt) or house dust (0.26 mg As/kg body wt), or soluble sodium arsenate by the gavage or intravenous route of administration (0.62 mg As/kg body wt) in a crossover design with a minimum washout period of 14 days. Urine, feces, and cage rinse were collected at 24-hr intervals for 168 hr. Blood was collected at specified time points and area under the curves (AUCs) was determined. Arsenic concentrations for the first 120 hr, representing elimination of greater than 94% of the total administered dose for the three oral treatment groups, were <0.02 1 to 4.68 zg/ml for the urine and <0.24 to 31.1 μg/g for the feces. In general, peak concentrations of As in the urine and feces were obtained during the collection intervals of 0–24 and 24–72 hr, respectively. The main pathway for excretion of As for the intravenous and gavage groups was in the urine, whereas for the soil and dust groups, it was in the feces. Mean absolute percentage bioavailability values based on urinary excretion data were 68, 19, and 14% for the gavage, house dust, and soil treatments, respectively, after normal ization of the intravenous As recovery data to 100%. Correspond ing absolute bioavailability values based on blood were 91, 10, and 11%. The bioavailabiity of soil and house dust As relative to soluble As (by gavage) was between 10 and 30%, depending upon whether urinary or blood values were used. These findings suggest that risks associated with the ingestion of As in soil or dust will be reduced compared to ingestion of comparable quantities of As in drinking water. [ABSTRACT FROM PUBLISHER]

Competing Interests: The authors declare no conflicts of interest.

Background: Cystic fibrosis (CF) is a life-shortening genetic disease, yet life expectancy has recently increased, shifting the focus to disease management and health-related quality of life (HRQoL). Identification of clinical factors, such as weight status and CF-related diabetes (CFRD), that are associated with HRQoL can inform clinicians about the patient's health perception. The goal of this systematic review was two prong: identify the association of pediatric weight status and HRQoL and determine how CFRD status impacts HRQoL., Methods: A systematic review of published research was conducted following the methodology in the Cochrane Handbook on Systematic Reviews for Interventional Studies. Results were reported according to the Preferred Reporting Items for Systematic Review and Meta-Analyses. Risk of bias was assessed using the National Heart Lung & Blood Institute tool. A meta-analysis was not performed due to variability of the inclusion/exclusion criteria, differences in outcome reporting, and insufficient primary outcome data to pool., Results: Nine studies met inclusion criteria (n = 6 explored weight status and n = 3 studied CFRD), for a total of 1585 subjects (CFRD cases = 87). Pediatric weight status was positively associated with HRQoL, most commonly the Body Image and Eating Disturbance domains. CFRD was negatively associated with HRQoL, specifically the Treatment Burden and Weight domains., Conclusions: Based on the limited data available, improved pediatric weight status appears to increase HRQoL while a CFRD diagnosis appears to decrease HRQoL. More research is needed to fully understand the role of these clinical factors on HRQoL, especially with life expectancy increasing among those with CF., (© 2021 Wiley Periodicals LLC.)

Asthma remains one of the most important challenges to pediatric public health in the US. A large majority of children with persistent and chronic asthma demonstrate aeroallergen sensitization, which remains a pivotal risk factor associated with the development of persistent, progressive asthma throughout life. In individuals with a tendency toward Type 2 inflammation, sensitization and exposure to high concentrations of offending allergens is associated with increased risk for development of, and impairment from, asthma. The cascade of biological responses to allergens is primarily mediated through IgE antibodies and their production is further stimulated by IgE responses to antigen exposure. In addition, circulating IgE impairs innate anti-viral immune responses. The latter effect could magnify the effects of another early life exposure associated with increased risk of the development of asthma - viral infections. Omalizumab binds to circulating IgE and thus ablates antigen signaling through IgE-related mechanisms. Further, it has been shown restore IFN-α response to rhinovirus and to reduce asthma exacerbations during the viral season. We therefore hypothesized that early blockade of IgE and IgE mediated responses with omalizumab would prevent the development and reduce the severity of asthma in those at high risk for developing asthma. Herein, we describe a double-blind, placebo-controlled trial of omalizumab in 2-3 year old children at high risk for development of asthma to prevent the development and reduce the severity of asthma. We describe the rationale, methods, and lessons learned in implementing this potentially transformative trial aimed at prevention of asthma., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Gastroesophageal reflux (GER) is common among infants, but when symptoms become troublesome, that is defined as gastroesophageal reflux disease (GERD). Making a diagnosis of GERD is difficult because there is no gold standard. GERD can be especially problematic for infants with cystic fibrosis (CF). There are signs and symptoms (ie, malnutrition, recurring aspiration pneumonias, refusal to eat, wheezing, coughing, and asthma) in addition to invasive and noninvasive methods used to determine a diagnosis. The treatments for GERD span from nonpharmacological to surgical, with a laparoscopic Nissen fundoplication being the gold standard of surgical intervention. Although surgical interventions have been demonstrated to reduce symptoms associated with GERD, there is little known about the weight/growth-related outcomes. This case report discusses an infant with CF and GERD requiring multiple interventions and ultimately a laparoscopic Nissen fundoplication and the weight changes from presurgery to postsurgery. The case report is expanded upon with a structured literature review of fundoplication and growth studies. There were 4 available studies that assessed changes in weight/growth before and after fundoplication among children with GERD. Because of the heterogeneity of the nutrition outcomes used, the weight/growth benefits after fundoplication are unclear at this time. Further research in needed to assess the nutrition outcomes among patients with GERD requiring fundoplication., (© 2020 American Society for Parenteral and Enteral Nutrition.)

Meropenem exposures from 15 children (8-17 years old) with cystic fibrosis (CF) acute pulmonary exacerbation were analyzed to define the pharmacodynamic threshold required for a positive response. The primary endpoint was the relative increase in forced expiratory volume in 1 s (↑FEV 1 ) between pre- and posttreatment. Meropenem pharmacodynamic indices (fT > MIC, fAUC/MIC, fC min /MIC) over the first 24 h were estimated for each participant based on their individual parameter estimates and the isolated pathogen with the highest meropenem MIC. Pseudomonas aeruginosa was the most common pathogen (n = 11/15). The mean ± SD ↑FEV 1 was 18.8% ± 11.3% posttreatment. The mean (range) fT > MIC exposure was 63% (0-100%). An E max model determined a significant relationship between fT > MIC and ↑FEV 1 (r 2 = 0.8, P < 0.0004). 65% fT > MIC was a significant predictor of response; the median (25th, 75th %) ↑FEV 1 was 28.5% (22.2%, 31.7%) in those patients who achieved above 65% fT > MIC and 7.8% (1.1%, 12.6%) in those at or below 65% fT > MIC (P = 0.001). This is the first study in CF children to link meropenem exposure with a positive response as measured by ↑FEV 1 . Larger studies are required to confirm this exposure threshold., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objectives: Meropenem is frequently used to treat pulmonary exacerbations in children with cystic fibrosis (CF) in the USA. Prolonged-infusion meropenem improves the time that free drug concentrations remain above the MIC (fT> MIC) in adults, but data in CF children are sparse. We describe the population pharmacokinetics, tolerability and treatment burden of prolonged-infusion meropenem in CF children., Methods: Thirty children aged 6-17 years with a pulmonary exacerbation received 40 mg/kg meropenem every 8 h; each dose was administered as a 3 h infusion. Pharmacokinetics were determined using population methods in Pmetrics. Monte Carlo simulation was employed to compare 0.5 with 3 h infusions to estimate the probability of pharmacodynamic target attainment (PTA) at 40% fT> MIC. NCT#01429259., Results: A two-compartment model fitted the data best with clearance and volume predicted by body weight. Clearance and volume of the central compartment were 0.41 ± 0.23 L/h/kg and 0.30 ± 0.17 L/kg, respectively. Half-life was 1.11 ± 0.38 h. At MICs of 1, 2 and 4 mg/L, PTAs for the 0.5 h infusion were 87.6%, 70.1% and 35.4%, respectively. The prolonged infusion increased PTAs to >99% for these MICs and achieved 82.8% at 8 mg/L. Of the 30 children, 18 (60%) completed treatment with prolonged infusion; 5 did so at home without any reported burden. Nine patients were changed to a 0.5 h infusion when discharged home., Conclusions: In these CF children, meropenem clearance was greater compared with published values from non-CF children. Prolonged infusion provided an exposure benefit against pathogens with MICs ≥1 mg/L, was well tolerated and was feasible to administer in the hospital and home settings, the latter depending on perception and family schedule., (© The Author 2015. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

The activity of ceftolozane/tazobactam was tested against 50 nonduplicate Pseudomonas aeruginosa from 18 cystic fibrosis children collected in 2012-2014. These isolates were multidrug resistant with susceptibility to meropenem, ceftazidime, and piperacillin/tazobactam of 46%, 58%, and 50%, respectively. Ceftolozane/tazobactam was the most active with MIC50, MIC90, and percent susceptibility of 2mg/L, 8 mg/L, and 86%., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Because patients with cystic fibrosis (CF) have pulmonary exacerbations secondary to multi-antibiotic-resistant Gram-negative bacilli, antibiotics, like meropenem, are often utilized. We studied the pharmacokinetics of meropenem (2 g i.v. administered every 8 h in clinically stable CF patients to determine if the recommended maximum doses could sustain adequate concentrations during the dosing interval. These pharmacokinetic data were similar to those obtained in non-CF populations. Using this regimen, concentrations of meropenem exceed the susceptibility breakpoint (4 microg/ml) for 50% of the dosing interval, and therefore provide optimization of the pharmacodynamic profile of the compound., (Copyright 2001 S. Karger AG, Basel)

Respiratory syncytial virus (RSV) is the most important cause of bronchiolitis and pneumonia in young children. The development of an animal model of RSV disease serves to better understanding the pathophysiology of airway disease from RSV infection in infants and children. Groups of six lambs were inoculated intratracheally (IT) or intranasally (IN) with a human strain of RSV (H-RSV). For controls 8 lambs received IT virus-free cell lysate. Tachypnea and fever were observed significantly more often following IT than following IN inoculation of H-RSV or IT placebo (for tachypnea: 20 of 69 days, 5 of 63 days, and 3 of 89 days, respectively, P < 0.001; for fever: 6 of 69 days, 0 of 63 days, and 1 of 89 days, respectively, P < 0.02). Nasal fluid production was significantly more frequent in both IT (14 of 69 days) and IN (15 of 63 days) groups than in the placebo group (2 of 87 days, P < 0.001). Postvaccination geometric mean titers (GMT, arithmetic transformation of log 2) of RSV-specific neutralizing antibody were significantly increased in the IT H-RSV group compared with postplacebo GMTs at 1 week (72 vs. 6.7, P < 0.03). By the second week postinoculation both H-RSV-infected groups had comparable levels of RSV-specific neutralizing antibody titers and had significantly greater GMTs for the second through to the fourth week than the placebo group (144, 128, and 4.8, respectively P < 0.0008). Bacterial isolates of the upper airway were comparable among the three groups. Histopathology at day 28 postinoculation was unremarkable for the three study groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Atmospheres of silicon carbide whiskers (wh) were required for a repeated dose lung deposition study and a subchronic inhalation toxicity study, each involving exposure to three concentrations of whiskers for 6 hr/day, 5 days/week for 1 or 13 weeks. Target concentrations were 0, 500, 1500, and 7500 wh/cc. By using the mean fiber length (10 microns), diameter (0.555 micron), and density (3.2 g/cc) of the bulk material, target mass concentrations were approximately 0, 4, 12, and 60 mg/m3. The Pitt III generator, developed for cotton fiber dispersion at the University of Pittsburgh, was selected. This instrument consists of a vertical 18-in. long cylinder, which is closed at each end with rubber dams and coupled at the base to a loudspeaker. The sonic energy from the loudspeaker fluidizes the test material and the whiskers in the air column are carried out with the exhaust air. The output of the Pitt III generator was altered by changing the sound energy input, the rate of introduction of the test material into the fluidizing cylinder, or the airflow through the cylinder. Separate generation systems were used for each inhalation chamber. Chamber atmospheres were characterized gravimetrically and samples were analyzed by scanning electron microscopy. Mean mass and number concentrations for the subchronic study were 0.09, 3.93, 10.7, and 60.5 mg/m3 and 0, 630, 1746, and 7276 wh/cc, respectively. Weighted mean values for whisker diameters, lengths, and aspect ratios were 0.560 micron, 4.53 microns, and 8.62, respectively. Although whisker lengths were less than half those of the bulk material, nearly 30% of the whiskers were greater than 5 microns long.

Mercury distribution, food consumption, body weight, and in vivo protein synthesis were compared as criteria for evaluating the efficacy of D-penicillamine (DPA) in treating experimental methyl mercury (MM) intoxication. Female rats were orally administered MM hydroxide at 40 mg/kg and, after a 7- to 8-d latency period, displayed characteristic neurological signs of MM intoxication. Within 24 h of MM exposure food consumption decreased 75% causing a 12-g drop in body weight, and synthesis of whole blood and kidney protein increased. Protein synthesis in liver was increased 39% by MM after 3 d, and that in cerebellum was decreased 15% after 7 d. Treatment with DPA (1.2 g/kg.d sc on d 2, 3, and 4) prevented the appearance of neurological signs. DPA lowered the Hg content of all tissues; restored food consumption of control levels; increased the onset and amount of body weight gain; returned synthesis of blood, liver, and kidney proteins to control levels; and prevented the decrease in protein synthesis in cerebellum. By itself, DPA produced a transitory decrease in both food consumption and body weight, which could be prevented with vitamin B6. Vitamin B6 antagonized DPA's reversal of MM's action on protein synthesis. Furthermore, DPA and/or vitamin B6 had a variety of effects on protein synthesis in control rats. Thus it was not possible to use protein synthesis to predict the efficacy of the combination of DPA and vitamin B6 as found for the parameters of food consumption, body weight, and Hg distribution. Since changes in body weight and food consumption were the earliest and most pronounced and consistent responses to MM and effective DPA treatment, they were considered the best criteria for evaluating treatment efficacy in experimental MM poisoning in rats.

The effect of methylmercury (MM) on protein synthesis was examined with respect to nutritional deficiency due to decreased food intake, method of amino acid administration, and amino acid uptake. Female rats were administered orally 40 mg MM hydroxide/kg and were compared with both ad libitum and pair-fed control groups. Synthesis of blood, liver, kidney, and cerebellar proteins of pair-fed controls was significantly lower than for ad libitum-fed controls. Relative to ad libitum-fed controls, MM transiently increased synthesis of blood proteins and then decreased it for blood and liver proteins. In contrast, using pair-fed controls, MM increased synthesis of blood and liver proteins. Comparison with either control showed MM to increase protein synthesis in the kidney and decrease it in the cerebellum. Intraperitoneal and intravenous administration of the [14C]amino acids showed similar results. The action of MM on protein synthesis seemed independent of its action on amino acid uptake, since MM did not affect aminoisobutyric acid uptake in the liver and cerebellum and decreased it in the kidney. In summary, we found that the effect of MM on food intake plays a significant role in the action of MM on protein synthesis and must be accounted for with pair-fed controls.

The urinary excretion of 4-aminimidazole-5-carboxamide (AIC) as been reported to be increased in children with acute leukemia and has been correlated with disease status. Using a modification of the method of Skibba et al [5], determinations were made on urine from 26 children with acute leukemia. The urine from ten normal children served as controls. The effect of chemotherapy on urinary AIC was studied comparing patients on vincristine and prednisone (V+P) with those on 6-mercaptopurine, methotrexate, and cyclophosphamide (Triple Rx). Patients in remission on Triple Rx had lower levels of urinary AIC than did patients on Triple Rx in relapse or patients on V+P in either remission or relapse. Twenty patients had sequential measurements. Values for individual patients were not predictive of disease status. One such patient is described. This study demonstrates that chemotherapy, as well as disease status, affects the urinary excretion of AIC in children with acute leukemia.