BACKGROUND: Treating pregnant HIV+ women with antiretroviral therapy (ART) has dramatically reduced maternal to child HIV transmission. However, long-term cardiotoxicity following in utero exposure to ART is a concern.

METHODS: To determine the cardiovascular effects of ART exposure on HIV- infants born to HIV+ mothers, echocardiograms at birth, 6 mo and 12 mo on infants enrolled in CHAART were compared to serial echos of HIV- infants in the P2C2 study, in which few received ART. All CHAART infants (N=91) were exposed to ART and 89% were exposed to highly active ART (HAART). No P2C2 infants (N=216) were exposed to ART or HAART. LV mass and septal wall thickness were normalized to BSA.

RESULTS: Mean LV mass ranged from 0.37 to 1.53 sd below normal in both cohorts, but the CHAART measurements for females progressively declined from the P2C2 measurements; at birth there was a 0.38 sd difference (p=0.03), and the difference increased to 0.98 sd and 0.85 sd at 6 mo and 12 mo respectively (p<0.001). The CHAART measurements for males were 0.49 sd and 0.35 sd lower than P2C2 measurements at 6 mo (p=0.01) and 12 mo (p=0.04). Septal wall thickness was slightly elevated in the P2C2 group but CHAART measurements were constantly lower than the P2C2 measurements by 1.2 sd at all ages (p<.001). LV afterload decreased slightly over time in the P2C2 group. The CHAART LV afterload measurements were 0.51 sd lower than the P2C2 measurements at birth (p=0.03) but moved in a positive direction until they were 0.48 sd higher than the P2C2 measurements by 12 mo (p=0.02).

CONCLUSION: ART exposure during fetal life is associated with progressive reductions in LV mass and septal wall thickness, and increases in LV afterload. We speculate that ART exposure results in reduced myocardial growth, increasing risk for higher LV afterload and impaired LV function. Long-term cardiac outcome studies are needed.

OBJECTIVES: The purpose of this study is to determine the nature and rate of recovery of neurocognitive deficits resulting from mild traumatic brain injury (MTBI) in children.

DESIGN/METHODS: Prospective, longitudinal, observational study using a convenience sample from a tertiary care pediatric emergency department (ED) of a Level 1 Trauma Center. Period: November 2004-February 2006. Subjects: Children ages 10-17 years treated in the ED and discharged. MTBI group: patients with blunt head trauma, GCS 13-15, no intracranial abnormalities, and any combination of: loss of consciousness <30 minutes, post-traumatic amnesia <24 hours, altered mental status, or focal neurological deficits. Control group: patients with isolated extremity injuries. Measures: Symbol Digit Modalities Test (SDMT), a measure of cognitive processing speed; and a 12 item Post Concussion Symptom Questionnaire. Assessments were completed in person at baseline and at 1 and 4-5 weeks post injury. Analysis: Fisher’s exact tests and t-tests, repeated measures mixed models with random intercept, and Wilcoxon rank sum tests, with Bonferroni adjustment for multiple comparisons.

RESULTS: This analysis includes 29 MTBI patients and 45 controls. There were no differences between groups with regard to prior head injury or prior loss of consciousness; ADHD was more prevalent in the control group (p=0.0128). The recovery trajectory for the SDMT was not different between groups (p=0.6078), but there was a statistically significant difference within groups over time (p<0.0001). In both groups, a significant difference exists between time 0 and 1; scores peaked at 1 week and leveled off. Patients with MTBI had more post-concussive symptoms than injured controls at all time points (p<0.009); they returned to pre-injury status within 4-5 weeks.

CONCLUSIONS: Adolescents with MTBI experience significant neurocognitive changes that, on average, resolve within 5 weeks of injury. However, patients with extremity injuries also demonstrate neurocognitive deficits that recover over time. This suggests that some deficits observed after MTBI may not be due, exclusively, to brain injury and may occur following other types of trauma.

BACKGROUND: There is increasing recognition that local community involvement and accountability are important factors in improving outcomes for young children. The Australian Early Development Index (AEDI) aims to measure and compare the health and development of populations of children across Australia to help communities assess how well they are doing in supporting young children and their families.

DESIGN/METHODS: The AEDI, originally developed in Canada and modified slightly for use in Australia, is a population measure of development based on a checklist completed by children’s teachers during the first year of formal schooling. It consists of over 100 questions measuring five developmental domains: language and cognitive skills; emotional maturity; physical health and well-being; communication skills and general knowledge; and, social competence. Data on children in their first year of school are aggregated, analysed and reported for each suburb or postcode across each domain.

RESULTS: In 2004 and 2005 the AEDI was completed by 1,037 teachers for 18,619 children in 28 communities across Australia. The average age of the children was 6 years (SD 0.46). In the overall national sample there were 22.7% of children with one or more developmental vulnerabilities and 10.9% with two or more. Demographic markers such as socio-economic status, ethnic background and indigenous status were all powerful predictors of developmental vulnerability across each of the AEDI domains. However, these markers do not fully explain the observed variability between and within the participating communities. The proportion of children identified as developmentally vulnerable across each of the AEDI domains was observed to vary significantly between communities and was also evident within communities (i.e. between localities and suburbs within communities).

CONCLUSIONS: This is the largest single database of children’s development in Australia. In this population significant proportions of children are developmentally at risk; however within communities the developmental variability suggests local risk and protective factors play an important role in making a difference to outcomes for children.

BACKGROUND: Teaching in the continuity setting requires teaching curriculum content efficiently and directly observing resident performance. Nationally, family-centered care to strengthen the physician-family trust has become a priority. Moving the teaching encounter to the bedside and away from the conference area is one method which may accomplish these educational goals and preserve family-centered care. In the adult literature, bedside presentations have been shown to be favored by patients and to positively impact teaching and learning.

OBJECTIVE: To compare family, preceptor (PRE), and resident (RES) perceptions, and length of visit, for bedside presentations (BP) versus conference area presentations (CAP) in an outpatient pediatric primary care setting.

DESIGN/METHODS: An 8-wk crossover study design was used in which PRE and first-year pediatric RES alternated weekly the location of patient presentations between the exam room and the conference area. After the visit, a research assistant surveyed parents and recorded the time elapsed since arrival at the clinic. At the end of the study, RES and PRE were surveyed on their experiences with both BP and CAP. Differences in ratings based on location of presentation were calculated. Data were analyzed using Chi square, signed-ranks, and t-tests as appropriate.

RESULTS: 348 RES encounters were studied (151 BP v. 189 CAP) involving 15 first yr RES and 15 PRE. Visit length was comparable (BP mean 1.6 hrs. v. CAP 1.58, P=0.53). Parent satisfaction was high in both locations. PRE favored BP for adding opportunities to evaluate RES competencies (P=0.008), provide legitimate feedback (P=0.03), and role-model (P=0.008). PRE felt that BP decreased RES comfort level when discussing sensitive topics (P=0.02). RES were less comfortable with BP for discussing sensitive topics (P=0.03), and felt more embarrassed when they didn’t know the answer to a PRE question (P=0.03). RES reported that BP presentations permitted preceptors to demonstrate more physical exam skills (P=0.03) and to observe interactions more to provide feedback (P=0.008).

CONCLUSIONS: BP require the same amount of time and result in equally high parent satisfaction as CAP. Although RES are less comfortable with BP, PRE are better able to observe, evaluate, and give feedback on resident skills and to role model and teach using a hands-on approach.

The stabilization phase of this study is being reported elsewhere in this meeting (two additional subjects were included after this initial report). Participating subjects in this 6-month Phase are 24 adolescents (12M; 12F) and 5 young adults (2M; 3F) referred to us in various degrees of metabolic control as reflected by altered baseline measurements of glucose 236.6 (116.6) mg/dL; fructosamine 472.6 (126.6) umol/L; and glycosylated hemoglobin (HbA1c) 9.8 (2.3) g/dL. Baseline demographics of the 24 adolescents are: Age 14.7y (2.1); Bone age 14.1 (2.2); CA/BA 1.0 (0.1); Height 153.8cm (9.4); Weight 51.0kg (10.2); BMI 21.7 (3.2); Duration of DM 6.7 (2.8). Baseline demographics of the 5 young adults are: Age 20.6y (2.2); Bone age (BA) 18.8 (0.4); CA/BA 1.1 (0.1); Height 161.1cm (12.8); Weight 62.5kg (9.3); BMI 23.0 (1.8); Duration of DM 7.0 (1.7). Mean age for the entire group is 15.7y (3.0); BA 14.9 (2.7); CA/BA 1.1 (0.1); Duration of the DM is 6.8 (2.6).

After stabilization with basal s.c. glargine insulin and 3 pre-prandial s.c. regular insulin injections, standard therapy continued for 4 weeks for comparison. Immediately thereafter, split doses of Oral-lyn™ immediately before and after lunch replaced lunch-time injection of regular insulin. Patient–collected glucose values, fructosamine and HbA1c were compared weekly (3-4 weeks per each treatment). Values are reported at the end of each phase.

(*Glucose values at baseline were determined by laboratory; other glucose values were determined by glucometer)

After comparison, a 6-month Phase of Oral-lyn™ treatment at lunch time was initiated. Fructosamine and HbA1c results between the 8th and 10th week of treatment demonstrated that fructosamine and HbA1c levels maintain the a trend towards normalization.

In summary, successful replacement of regular s.c insulin for Oral-lyn™ during the initial 10 weeks of this 6-month trial was achieved as demonstrated by patient-collected glucose levels, fructosamine and HbA1c measurements.

BACKGROUND: Acute otitis media (AOM) is one of the most common childhood infections, the leading cause of doctors’ visits, and the most frequent reason children take antibiotics or undergo surgery. The high incidence and high rate of spontaneous recovery from AOM suggest that it is a natural phenomenon, inevitable like a common cold, and part of the gradual maturation of the child’s anatomy and immune system. However, untreated AOM can occasionally lead to suppurative complications. Currently there are no tools to discriminate between children with mild, self-limiting episodes of AOM and those at risk of a prolonged course.

OBJECTIVE: To determine the independent predictors of a prolonged course in children with AOM not initially treated with antibiotics.

METHODS: In an individual patient data meta-analysis with the control groups of 6 randomised controlled trials (n=824 children with acute otitis media, aged 6 months to 12 years), we determined the predictors of poor short term outcome in children with AOM. The primary outcome was a prolonged course of AOM, which was defined as fever and/or pain at 3–7 days.

RESULTS: Of the 824 included children, 303 (37%) had pain and/or fever at 3–7 days. Independent predictors for fever and/or pain at 3-7 days were: age less than 2 years (OR 2.1; 95% CI 1.5–2.9), and bilateral AOM (OR 1.7; 95% CI 1.2–2.4). The prognostic model showed a good fit (goodness-of-fit test p=0.93), and the AUC was 0.63 (95% CI 0.59–0.68). Figure 1 shows the proportion of children experiencing fever and/or pain in the subgroups of the predicting variables during the follow-up period. The absolute risks of pain and/or fever at 3–7 days was highest in children aged less than 2 years with bilateral AOM, i.e. 55% (95% CI 47–63) (20% of all children). The risk in children aged 2 years or older with unilateral AOM was 25% (95% CI 20–30) (47% of all children). The difference regarding the absolute risks of pain and/or fever at 3–7 days was smaller when only age was studied, i.e., 47% (95% CI 43–51) in children aged less than 2 years and 31% (95% CI 25–37) in those aged 2 years or older.

CONCLUSIONS: The risk of a prolonged course was two times higher in children aged less than 2 years with bilateral AOM than in children aged 2 years or older with unilateral AOM. Clinicians can use these features to advise parents and to follow these children more actively.

BACKGROUND: 7VCPnc has been shown to be immunogenic and efficacious when administered in a 4 dose schedule at 2, 4, 6 and 12 months of age. The immunogenicity of 7VCPnc at 2, 3 and 4 months of age has been studied, but not when administered with the other vaccines currently in the UK immunisation schedule, particularly the meningococcal group C conjugate vaccine.

METHODS: 54 healthy term infants were immunised with 7VCPnc (Prevenar, Wyeth) Meningococcus C conjugate vaccine (Meningitec, Wyeth) and combined diphtheria, tetanus, polio, 5-component acellular pertussis, and HiB conjugate vaccine (Pediacel, sanofi Pasteur) in separate limbs. IgG against the 7 pneumococcal serotypes were measured by ELISA at the time of the first immunisation and 4 weeks after the 3rd immunisation. Protection was measured as post immunization levels of specific IgG > 0.35µg/ml and higher than pre-immunisation levels.

RESULTS: Of 38 infants analysed, most produced putative protective IgG levels for serotypes 4 [30/32], 18C [37/38], 19F [26/26], 9V [32/35], 14 [29/35] and 23F[ 29/34], less than half did so with type 6B [16/36]. However, a proportion of these infants failed to demonstrate a 4 fold increase in titres from pre-immunisation levels (type 4 [1/30], type 6B [2/16], type 9V[2/32] type 14[4/29], type 18C[6/37], and type 19F[1/26] and type 23F[3/29]).

Of the 24 infants that were tested against all 7 serotypes only 10 had putatively protective levels to all serotypes with 9 having these levels against 6 serotypes and 4 against 4 serotypes.

CONCLUSIONS: These results suggest that the majority of infants in our cohort are not adequately protected against invasive pneumococcal disease following a primary course of 7VCPnc when administered according to the current UK immunisation schedule. We would therefore reiterate the need for the recommended booster dose.

BACKGROUND: Influenza vaccination is recommended for all children 6–59 months of age. Reported efficacy of TIV is modest in young children. CAIV-T is an investigational live attenuated intranasal influenza vaccine.

OBJECTIVE: To evaluate the efficacy and safety of CAIV-T compared with TIV in preventing culture-confirmed influenza in children 6–59 months of age.

METHODS: Eligible children were randomized (1:1) to receive 1 dose (if previously vaccinated) or 2 doses 35±7 days apart (if previously unvaccinated) of CAIV-T or TIV before the 2004–2005 influenza season.

RESULTS: 7836 children (3893 CAIV-T; 3943 TIV) were included in the per protocol efficacy analysis. The incidence of culture-confirmed influenza illness was 55% lower (P<0.001) in the CAIV-T compared with the TIV group. All H1N1 and about half of B infections were caused by viruses antigenically matched to vaccine; all H3N2 infections were caused by non-vaccine-like strains. CAIV-T was superior to TIV in preventing culture-confirmed H1N1 influenza (89% reduction, P<0.001); in addition, there were 28% fewer cases of culture-confirmed matched influenza B in the CAIV-T group (P=not significant). CAIV-T was superior to TIV in preventing influenza caused by non–vaccine-like H3N2 virus (79% reduction, P<0.001). In children 6–23 months of age, greater relative efficacy for CAIV-T vs TIV was observed against all strains (56% reduction, P<0.001) and all non–vaccine-like strains (64% reduction, P<0.001). The overall incidence of adverse events and serious adverse events was similar in both groups except for a higher incidence of runny nose/nasal congestion in CAIV-T recipients (2.5%–5.6% increase) and a higher incidence of injection site reactions in TIV recipients (3.6%–7.6% increase). There were no significant differences through the whole study period for all reported wheezing or medically significant wheezing (MSW). Previously unvaccinated children 6–23 months had a small but statistically significant increase in MSW at 42 days post dose 1 but not thereafter.

CONCLUSIONS: CAIV-T was significantly more effective than TIV in preventing culture-confirmed influenza illness caused either by strains antigenically similar to those in the vaccine or non-vaccine-like strains in children 6–59 months of age.

Funding Source: This research was supported by MedImmune, Inc.

Off-label Disclaimer: The information concerns a use that has not been approved by the US Food and Drug Administration.

We describe a case of vaccine-derived poliovirus infection in an infant with severe combined immune deficiency (SCID) and an associated community outbreak of infection identified by epidemiologic investigation. The infant, a Minnesota native living in a largely unimmunized Amish community, presented with recurrent infections over the first six months of life, including non-healing ulcers, pneumonia, and gastroenteritis. An immunological evaluation revealed low immunoglobulin levels, significantly low T and absent B cell counts, and low numbers of NK cells, confirming the diagnosis of SCID. Additional workup revealed the diagnosis of Omenn’s syndrome, with a point mutation (K991E) in the RAG-1 gene. Following referral to our institution for bone marrow transplantation (BMT), an evaluation for diarrhea resulted in identification of an enterovirus from a stool culture. This isolate was identified at the Minnesota Department of Health (MDH) as poliovirus type 1 associated with oral poliovirus vaccine. The infant had received no prior immunizations. Sequence analysis of the VP1 gene of the patient’s isolate at the CDC identified the virus as a Sabin type 1 variant, 2.1% divergent from the vaccine strain. The child was not paralyzed. Sequence analysis also suggested that the vaccine-derived virus had originated from another chronically infected, immunodeficient individual (immunodeficiency-associated vaccine-derived polio virus; iVDPV). Sequencing data indicated that the source vaccination was administered approximately 16 months earlier, suggesting that virus had circulated in the community prior to acquisition by the index case. Epidemiological investigation found no source for the virus, and no paralytic disease, in the Amish community in which the child lived. Virological investigation demonstrated that the 3 unvaccinated siblings of the index case were anti-PV1 positive. Four additional healthy children from 2 other Amish families were excreting poliovirus in their stool. The index case remained hospitalized; there were no cases of transmission to health care providers or other patients. Weekly infusions of polio-specific immunoglobulin therapy, as well as oral IgG, had no impact on viral shedding. After 10 weeks of hospitalization, the patient underwent an unrelated-donor BMT. Successful engraftment was noted beginning the week of 2-12-06. Remarkably, bone marrow engraftment resulted in viral clearance. This outbreak demonstrates that iVDPVs can circulate in under-vaccinated communities. It also illustrates the difficulties associated with chronic enterovirus infections in immunocompromised patients, as well as the successful therapeutic utilization of BMT in this setting.

Helper-dependent adenoviral vectors (HDAds) hold tremendous potential for liver-directed gene therapy as they can mediate long-term transgene expression without chronic toxicity. However, due to a nonlinear dose-response, high doses are required to achieve hepatic transduction resulting in dose-dependent acute toxicity. To overcome this important obstacle, we developed a minimally invasive method to preferentially deliver low dose HDAd into the liver of 30 kg baboons to achieve efficient hepatic transduction. Briefly, a single balloon occlusion catheter was percutaneously positioned in the inferior vena cava of baboon 1 to occlude hepatic venous outflow. 1x1011 vp/kg of a HDAd expressing the baboon a-fetoprotein (bAFP) marker was injected directly into the occluded liver via a percutaneously placed hepatic artery (HA) catheter and left to dwell in the liver for 15 min before balloon deflation. As controls, 1x1011 vp/kg was administered to baboon 2 by peripheral intravenous injection and baboon 3 by HA injection without balloon occlusion. All procedures were well tolerated, and all three animals returned to their normal pre-injection states with no clinical manifestations of toxicity. Mild transaminitis was seen in all animals, peaking at 24 to 48 h post-vector but returning towards baseline the next day: For ALT, a 2.3, 1.1, and 1.4-fold increase over baseline were observed for baboons 1, 2 and 3, respectively. For AST, a 4.8, 1.6 and 2.8-fold increase were seen for baboons 1, 2 and 3, respectively. Importantly, serum bAFP levels increased 425-fold over baseline for baboon 1 (from 4.5ng/ml at baseline to 1914ng/ml), while only a modest increase of 12-fold and 5.6-fold were observed for baboon 2 (from 9ng/ml to 109ng/ml) and 3 (from 18ng/ml to 103ng/ml), respectively. To date, bAFP levels have been sustained (>56 days). These results suggest the therapeutic index of HDAd can be significantly improved by delivering the vector preferentially into the liver using a minimally invasive balloon occlusion catheter technique and may be a first step towards clinical application of HDAd for liver-directed gene therapy.