Penelope Jester

Oral Acyclovir Suppression and Neurodevelopment after Neonatal Herpes

BACKGROUND Poor neurodevelopmental outcomes and recurrences of cutaneous lesions remain unacceptably frequent among survivors of neonatal herpes simplex virus (HSV) disease. METHODS We enrolled neonates with HSV disease in two parallel, identical, double-blind, placebo-controlled studies. Neonates with central nervous system (CNS) involvement were enrolled in one study, and neonates with skin, eye, and mouth involvement only were enrolled in the other. After completing a regimen of 14 to 21 days of parenteral acyclovir, the infants were randomly assigned to immediate acyclovir suppression (300 mg per square meter of body-surface area per dose orally, three times daily for 6 months) or placebo. Cutaneous recurrences were treated with open-label episodic therapy. RESULTS A total of 74 neonates were enrolled--45 with CNS involvement and 29 with skin, eye, and mouth disease. The Mental Development Index of the Bayley Scales of Infant Development (in which scores range from 50 to 150, with a mean of 100 and with higher scores indicating better neurodevelopmental outcomes) was assessed in 28 of the 45 infants with CNS involvement (62%) at 12 months of age. After adjustment for covariates, infants with CNS involvement who had been randomly assigned to acyclovir suppression had significantly higher mean Bayley mental-development scores at 12 months than did infants randomly assigned to placebo (88.24 vs. 68.12, P=0.046). Overall, there was a trend toward more neutropenia in the acyclovir group than in the placebo group (P=0.09). CONCLUSIONS Infants surviving neonatal HSV disease with CNS involvement had improved neurodevelopmental outcomes when they received suppressive therapy with oral acyclovir for 6 months. (Funded by the National Institute of Allergy and Infectious Diseases; CASG 103 and CASG 104 ClinicalTrials.gov numbers, NCT00031460 and NCT00031447, respectively.).

Methods, Results, and Lessons Learned from Process Evaluation of the High 5 School-Based Nutrition Intervention:

This article describes the process evaluation of High 5, a school-based intervention targeting fruit and vegetable consumption among fourth graders and their families. The outcome evaluation involved 28 schools randomized to intervention or control conditions. The intervention included classroom, family, and cafeteria components. Process evaluation was completed on each of these components by using observations, self-report checklists, surveys, and other measures. Results indicated high implementation rates on the classroom activities. Moderate family involvement was attained, perhaps diminishing intervention effects on parent consumption. Cafeterias provided environmental cues, and fruit and vegetable offerings as directed by the program. A lower dose of the intervention was delivered to schools with larger African American enrollments and lower-income families. This article provides insights into the effective elements of a school-based dietary intervention and provides suggestions for process evaluation in similar studies.

Oseltamivir Dosing for Influenza Infection in Premature Neonates

Under the Emergency Use Authorization issued in April 2009, oseltamivir can be used to treat 2009 influenza A (H1N1) virus infection in children aged <1 year. No data exist on the dosing of oseltamivir in premature babies. A hospital health care worker inadvertently exposed 32 neonatal intensive care unit babies to 2009 influenza A (H1N1); a protocol was expeditiously implemented to collect samples for pharmacokinetics and dosage evaluation. Results suggest 1.0 mg/kg/dose twice daily in premature babies produces oseltamivir carboxylate exposures similar to that in older children receiving 3.0 mg/kg/dose twice daily. These results provide initial guidance on dosing oseltamivir in this vulnerable population.

Predictors of sun exposure in adolescents in a southeastern U.S. population

PURPOSE With the increase in melanoma incidence, the sun exposure and protective behaviors of adolescents are of great concern. Limited data are available on the prevalence and predictors of risk behavior in adolescents in the southeastern United States. This study examined the levels of sun exposure and variables predictive of sun exposure among adolescents in two Alabama middle schools. METHODS A total of 509 sixth-graders completed a self-administered survey assessing: (a) their knowledge, attitudes, and beliefs about malignant melanoma; and (b) their sun exposure and sunburns for a specific weekend and for the summer. RESULTS Levels of sun exposure and frequency of sunburn were high. Regression models determined the predictors of weekend and summer sun exposure, and weekend sunburn. Significant predictors varied by outcome and included gender, perceived importance of a suntan, parent and peer modeling, and sunscreen use. CONCLUSION Reducing the risk of melanoma will require a three-pronged intervention strategy with efforts directed at adolescents, their parents, and the broader community.

Herpes Simplex Encephalitis: Lack of Clinical Benefit of Long-term Valacyclovir Therapy

BACKGROUND Despite the proven efficacy of acyclovir (ACV) therapy, herpes simplex encephalitis (HSE) continues to cause substantial morbidity and mortality. Among patients with HSE treated with ACV, the mortality rate is approximately 14%-19%. Among survivors, 45%-60% have neuropsychological sequelae at 1 year. Thus, improving therapeutic approaches to HSE remains a high priority. METHODS Following completion of a standard course of intravenous ACV, 87 adult patients with HSE (confirmed by positive polymerase chain reaction [PCR] for herpes simplex virus DNA in cerebrospinal fluid) were randomized to receive either valacyclovir (VACV) 2 g thrice daily (n = 40) or placebo tablets (n = 47) for 90 days (12 tablets of study medication daily). The primary endpoint was survival with no or mild neuropsychological impairment at 12 months, as measured by the Mattis Dementia Rating Scale (MDRS). Logistic regression was utilized to assess factors related to the primary endpoint. RESULTS The demographic characteristics of the 2 randomization groups were statistically similar with no significant differences in age, sex, or race. At 12 months, there was no significant difference in the MDRS scoring for VACV-treated vs placebo recipients, with 85.7% and 90.2%, respectively, of patients demonstrating no or mild neuropsychological impairment (P = .72). No significant study-related adverse events were encountered in either treatment group. CONCLUSIONS Following standard treatment with intravenous ACV for PCR-confirmed HSE, an additional 3-month course of oral VACV therapy did not provide added benefit as measured by neuropsychological testing 12 months later in a population of relatively high-functioning survivors. CLINICAL TRIALS REGISTRATION NCT00031486.

A Randomized, Double-Blind, Placebo-Controlled Trial of Pleconaril for the Treatment of Neonates With Enterovirus Sepsis

BACKGROUND Neonatal enterovirus sepsis has high mortality. Antiviral therapy is not available. METHODS Neonates with suspected enterovirus sepsis (hepatitis, coagulopathy, and/or myocarditis) with onset at ≤15 days of life were randomized 2:1 to receive oral pleconaril or placebo for 7 days. Serial virologic (oropharynx, rectum, urine, serum), clinical, pharmacokinetic, and safety evaluations were performed. RESULTS Sixty-one subjects were enrolled (43 treatment, 18 placebo), of whom 43 were confirmed enterovirus infected (31 treatment, 12 placebo). There was no difference in day 5 oropharyngeal culture positivity (primary endpoint; 0% in both groups). However, enterovirus-infected subjects in the treatment group became culture negative from all anatomic sites combined faster than placebo group subjects (median 4.0 versus 7.0 days, P = .08), and fewer subjects in the treatment group remained polymerase chain reaction (PCR)-positive from the oropharynx when last sampled (23% versus 58%, P = .02; median, 14.0 days). By intent to treat, 10/43 (23%) subjects in the treatment group and 8/18 (44%) in the placebo group died (P = .02 for 2-month survival difference); among enterovirus-confirmed subjects, 7/31 (23%) in the treatment group died versus 5/12 (42%) in the placebo group (P = .26). All pleconaril recipients attained concentrations greater than the IC90 after the first study day, but 38% were less than the IC90 during the first day of treatment. One subject in the treatment group and three in the placebo group had treatment-related adverse events. CONCLUSIONS Shorter times to culture and PCR negativity and greater survival among pleconaril recipients support potential efficacy and warrant further evaluation.

Retinal large vessel oxygen saturations correlate with early blood loss and hypoxia in anesthetized swine

BACKGROUND Noninvasive monitoring would likely improve trauma care. Using laser technology, we monitored the oxygen saturation in retinal vessels during exsanguination and hypoxia. METHODS Seven anesthetized swine were bled at 0.4 mL/kg/min for 40 minutes. During exsanguination, retinal venous saturation (SrvO2) was measured using an eye oximeter, and central venous saturation (SvO2) was measured using a fiber-optic catheter. After the shed blood was reinfused, the FiO2 was progressively decreased from 0.97 to 0.07. Femoral artery oxygen saturation (SaO2) and retinal artery oxygen saturation (SraO2) were measured at each increment. RESULTS During exsanguination, SrvO2 correlated with blood loss (r = -0.93) and SvO2 (r = 0.94). SraO2 correlated with SaO2 during incremental hypoxia (R2 = 0.93 +/- 0.15). CONCLUSIONS In this model of exsanguination, retinal venous oxygen saturation correlates with blood volume and with central venous oxygen saturation. The SraO2 correlates with SaO2 during graded hypoxia. Use of an eye oximeter to noninvasively monitor trauma patients appears promising and warrants further study.

Oseltamivir Pharmacokinetics, Dosing, and Resistance Among Children Aged <2 Years With Influenza

BACKGROUND Children <2 years of age are at high risk of influenza-related mortality and morbidity. However, the appropriate dose of oseltamivir for children <2 years of age is unknown. METHODS The National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group evaluated oseltamivir in infants aged <2 years in an age-de-escalation, adaptive design with a targeted systemic exposure. RESULTS From 2006 to 2010, 87 subjects enrolled. An oseltamivir dose of 3.0 mg/kg produced drug exposures within the target range in subjects 0-8 months of age, although there was a greater degree of variability in infants <3 months of age. In subjects 9-11 months of age, a dose of 3.5 mg/kg produced drug exposures within the target range. Six of 10 subjects aged 12-23 months receiving the Food and Drug Administration-approved unit dose for this age group (ie, 30 mg) had oseltamivir carboxylate exposures below the target range. Virus from 3 subjects developed oseltamivir resistance during antiviral treatment. CONCLUSIONS The appropriate twice-daily oral oseltamivir dose for infants ≤8 months of age is 3.0 mg/kg, while the dose for infants 9-11 months old is 3.5 mg/kg.

Oseltamivir pharmacokinetics, dosing, and resistance among children aged

BACKGROUND Children <2 years of age are at high risk of influenza-related mortality and morbidity. However, the appropriate dose of oseltamivir for children <2 years of age is unknown. METHODS The National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group evaluated oseltamivir in infants aged <2 years in an age-de-escalation, adaptive design with a targeted systemic exposure. RESULTS From 2006 to 2010, 87 subjects enrolled. An oseltamivir dose of 3.0 mg/kg produced drug exposures within the target range in subjects 0-8 months of age, although there was a greater degree of variability in infants <3 months of age. In subjects 9-11 months of age, a dose of 3.5 mg/kg produced drug exposures within the target range. Six of 10 subjects aged 12-23 months receiving the Food and Drug Administration-approved unit dose for this age group (ie, 30 mg) had oseltamivir carboxylate exposures below the target range. Virus from 3 subjects developed oseltamivir resistance during antiviral treatment. CONCLUSIONS The appropriate twice-daily oral oseltamivir dose for infants ≤8 months of age is 3.0 mg/kg, while the dose for infants 9-11 months old is 3.5 mg/kg.

Oseltamivir Pharmacokinetics, Dosing, and Resistance in Children From Birth to Two Years of Age with Influenza

BACKGROUND Children <2 years of age are at high risk of influenza-related mortality and morbidity. However, the appropriate dose of oseltamivir for children <2 years of age is unknown. METHODS The National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group evaluated oseltamivir in infants aged <2 years in an age-de-escalation, adaptive design with a targeted systemic exposure. RESULTS From 2006 to 2010, 87 subjects enrolled. An oseltamivir dose of 3.0 mg/kg produced drug exposures within the target range in subjects 0-8 months of age, although there was a greater degree of variability in infants <3 months of age. In subjects 9-11 months of age, a dose of 3.5 mg/kg produced drug exposures within the target range. Six of 10 subjects aged 12-23 months receiving the Food and Drug Administration-approved unit dose for this age group (ie, 30 mg) had oseltamivir carboxylate exposures below the target range. Virus from 3 subjects developed oseltamivir resistance during antiviral treatment. CONCLUSIONS The appropriate twice-daily oral oseltamivir dose for infants ≤8 months of age is 3.0 mg/kg, while the dose for infants 9-11 months old is 3.5 mg/kg.