A Primary Care-Based Quality Improvement Project to Reduce Asthma Emergency Department Visits.

BACKGROUND AND OBJECTIVES: Asthma exacerbation is a common and often preventable cause of Emergency Department (ED) utilization. Children eligible for Medicaid are at increased risk of poor asthma control and subsequent ED visits. In 2010, we implemented a multicomponent longitudinal quality improvement project to improve pediatric asthma care for our primary care population, which was 90% Medicaid-eligible. Our goal was to reduce asthma-related ED visits by patients ages 2 to 18 years by 3% annually. METHODS: The setting was a multisite large urban high-risk primary care network affiliated with a children's hospital. We implemented 5 sequential interventions within our network of pediatric primary care centers to increase: use of asthma action plans by clinicians, primary care-based Asthma Specialty Clinic visits (extended asthma visits in the main primary care site), use of a standard asthma note at all visits, documentation of the Asthma Control Test, and step-up therapy for children with poorly controlled asthma. RESULTS: At baseline in 2010, there were 21.7 asthma-related ED visits per 1000 patients per year. By 2019, asthma-related ED visits decreased to 14.5 per 1000 patients per year, a 33% decrease, with 2 center line shifts over time. We achieved and sustained our goal metrics for 4 of 5 key interventions. CONCLUSIONS: We reduced ED utilization for asthma in a large, high-risk pediatric population. The interventions implemented and used over time in this project demonstrate that sustainable outcomes can be achieved in a large network of primary care clinics.

Increasing Exclusive Nursery Care of Late Preterm and Low Birth Weight Infants.

BACKGROUND AND OBJECTIVE: Late preterm (LPT) and low birth weight (LBW) infants are populations at increased risk for NICU admission, partly due to feeding-related conditions. This study was aimed to increase the percentage of LPT and LBW infants receiving exclusive nursery care using quality improvement methodologies. METHODS: A multidisciplinary team implemented interventions at a single academic center. Included infants were 35 to 36 weeks gestational age and term infants with birth weights <2500 g admitted from the delivery room to the nursery. Drivers of change included feeding protocol, knowledge, and care standardization. We used statistical process control charts to track data over time. The primary outcome was the percentage of infants receiving exclusive nursery care. Secondary outcomes included rates of hypoglycemia, phototherapy, and average weight loss. Balancing measures were exclusive breast milk feeding rates and length of stay. RESULTS: Included infants totaled 1336. The percentage of LPT and LBW infants receiving exclusive nursery care increased from 83.9% to 88.8% with special cause variation starting 1 month into the postintervention period. Reduction in neonatal hypoglycemia, 51.7% to 45.1%, coincided. Among infants receiving exclusive nursery care, phototherapy, weight loss, exclusive breast milk feeding, and length of stay had no special cause variation. CONCLUSIONS: Interventions involving a nursery feeding protocol, knowledge, and standardization of care for LPT and LBW infants were associated with increased exclusive nursery care (4.9%) and reduced rates of neonatal hypoglycemia (6.6%) without adverse effects. This quality initiative allowed for the preservation of the mother-infant dyad using high-value care.

The Autonomy Toolbox: A Multicenter Collaborative to Promote Resident Autonomy.

OBJECTIVES: Autonomy is necessary for resident professional development and well-being. A recent focus on patient safety has increased supervision and decreased trainee autonomy. Few validated interventions exist to improve resident autonomy. We aimed to use quality improvement methods to increase our autonomy metric, the Resident Autonomy Score (RAS), by 25% within 1 year and sustain for 6 months. METHODS: We developed a bundled-intervention approach to improve senior resident (SR) perception of autonomy on Pediatric Hospital Medicine (PHM) services at 5 academic children's hospitals. We surveyed SR and PHM faculty perceptions of autonomy and targeted interventions toward areas with the highest discordance. Interventions included SR and faculty development, expectation-setting huddles, and SR independent rounding. We developed a Resident Autonomy Score (RAS) index to track SR perceptions over time. RESULTS: Forty-six percent of SRs and 59% of PHM faculty completed the needs assessment survey querying how often SRs were afforded opportunities to provide autonomous medical care. Faculty and SR ratings were discordant in these domains: SR input in medical decisions, SR autonomous decision-making in straightforward cases, follow-through on SR plans, faculty feedback, SR as team leader, and level of attending oversight. The RAS increased by 19% (3.67 to 4.36) 1 month after SR and faculty professional development and before expectation-setting and independent rounding. This increase was sustained throughout the 18-month study period. CONCLUSIONS: SRs and faculty perceive discordant levels of SR autonomy. We created an adaptable autonomy toolbox that led to sustained improvement in perception of SR autonomy.

In-Office Amoxicillin to Increase Graded-Dose Challenges at Initial Evaluation for Penicillin Allergy.

BACKGROUND: More than 90% of pediatric patients labeled with a penicillin allergy can tolerate subsequent treatment courses without reaction. Graded-dose challenges (GDCs) are an important tool to clarify reported penicillin allergy. OBJECTIVE: To increase the use of same-day amoxicillin GDCs among patients with a low-risk penicillin allergy history who presented for outpatient allergy office evaluation from 2% to 15% and sustain for 6 months. METHODS: New patients evaluated in an academic pediatric allergy clinic with a documented penicillin allergy were included, regardless of reason for referral. The percentage of these patients who were administered a GDC to amoxicillin at the initial evaluation was assessed over time. Multiple interventions were implemented to increase same-day GDC: amoxicillin, previously only available from pharmacy, was made available in clinic, and penicillin-allergic patients were scheduled earlier in the clinic session. RESULTS: The baseline rate of new patients with penicillin allergy who received a GDC increased from 2% to 18% after amoxicillin was stocked in the allergy clinic. GDCs further increased to 34% after penicillin-allergic patients were scheduled at a time conducive to challenge. CONCLUSIONS: Amoxicillin availability in the clinic setting increased the percentage of eligible patients who completed same-day GDCs. Scheduling adjustments further increased the ability to conduct GDCs. Proactive penicillin allergy delabeling efforts can be assisted through practical approaches in the outpatient setting.

Coagulation factor-XII induces interleukin-6 by primary lung fibroblasts: a role in idiopathic pulmonary fibrosis?

The mechanisms driving idiopathic pulmonary fibrosis (IPF) remain undefined, however it is postulated that coagulation imbalances may play a role. The impact of blood-derived clotting factors, including factor XII (FXII) has not been investigated in the context of IPF. Plasma levels of FXII were measured by ELISA in patients with IPF and in age-matched healthy donors. Expression of FXII in human lung tissue was quantified using multiplex immunohistochemistry and Western blotting. Mechanistic investigation of FXII activity was assessed in vitro on primary lung fibroblasts using qPCR and specific receptor/FXII inhibition. The functional outcome of FXII on fibroblast migration was examined by high-content image analysis. Compared with 35 healthy donors, plasma levels of FXII were not higher in patients with IPF (n = 27, P > 0.05). Tissue FXII was elevated in IPF (n = 11) and increased numbers of FXII+ cells were found in IPF (n = 8) lung tissue compared with nondiseased controls (n = 6, P < 0.0001). Activated FXII induced IL6 mRNA and IL-6 protein in fibroblasts that was blocked by anti-FXII antibody, CSL312. FXII induced IL-6 production via PAR-1 and NF-κB. FXII induced migration of fibroblasts in a concentration-dependent manner. FXII is normally confined to the circulation but it leaks from damaged vessels into the lung interstitium in IPF where it 1) induces IL-6 production and 2) enhances migration of resident fibroblasts, critical events that drive chronic inflammation and therefore, contribute to fibrotic disease progression. Targeting FXII-induced fibroblastic processes in IPF may ameliorate pulmonary fibrosis.

Effect of Context on the Contribution of Individual Harmonics to Residue Pitch.

There is evidence that the contribution of a given harmonic in a complex tone to residue pitch is influenced by the accuracy with which the frequency of that harmonic is encoded. The present study investigated whether listeners adjust the weights assigned to individual harmonics based on acquired knowledge of the reliability of the frequency estimates of those harmonics. In a two-interval forced-choice task, seven listeners indicated which of two 12-harmonic complex tones had the higher overall pitch. In context trials (60 % of all trials), the fundamental frequency (F0) was 200 Hz in one interval and 200 + ΔF0 Hz in the other. In different (blocked) conditions, either the 3rd or the 4th harmonic (plus the 7th, 9th, and 12th harmonics), were replaced by narrowband noises that were identical in the two intervals. Feedback was provided. In randomly interspersed test trials (40 % of all trials), the fundamental frequency was 200 + ΔF0/2 Hz in both intervals; in the second interval, either the third or the fourth harmonic was shifted slightly up or down in frequency with equal probability. There were no narrowband noises. Feedback was not provided. The results showed that substitution of a harmonic by noise in context trials reduced the contribution of that harmonic to pitch judgements in the test trials by a small but significant amount. This is consistent with the notion that listeners give smaller weight to a harmonic or frequency region when they have learned that this frequency region does not provide reliable information for a given task.

Synthetic Nanoparticles That Promote Tumor Necrosis Factor Receptor 2 Expressing Regulatory T Cells in the Lung and Resistance to Allergic Airways Inflammation.

Synthetic glycine coated 50 nm polystyrene nanoparticles (NP) (PS50G), unlike ambient NP, do not promote pulmonary inflammation, but instead, render lungs resistant to the development of allergic airway inflammation. In this study, we show that PS50G modulate the frequency and phenotype of regulatory T cells (Treg) in the lung, specifically increasing the proportion of tumor necrosis factor 2 (TNFR2) expressing Treg. Mice pre-exposed to PS50G, which were sensitized and then challenged with an allergen a month later, preferentially expanded TNFR2+Foxp3+ Treg, which further expressed enhanced levels of latency associated peptide and cytotoxic T-lymphocyte associated molecule-4. Moreover, PS50G-induced CD103+ dendritic cell activation in the lung was associated with the proliferative expansion of TNFR2+Foxp3+ Treg. These findings provide the first evidence that engineered NP can promote the selective expansion of maximally suppressing TNFR2+Foxp3+ Treg and further suggest a novel mechanism by which NP may promote healthy lung homeostasis.

High Fat Diet Inhibits Dendritic Cell and T Cell Response to Allergens but Does Not Impair Inhalational Respiratory Tolerance.

The incidence of obesity has risen to epidemic proportions in recent decades, most commonly attributed to an increasingly sedentary lifestyle, and a 'western' diet high in fat and low in fibre. Although non-allergic asthma is a well-established co-morbidity of obesity, the influence of obesity on allergic asthma is still under debate. Allergic asthma is thought to result from impaired tolerance to airborne antigens, so-called respiratory tolerance. We sought to investigate whether a diet high in fats affects the development of respiratory tolerance. Mice fed a high fat diet (HFD) for 8 weeks showed weight gain, metabolic disease, and alteration in gut microbiota, metabolites and glucose metabolism compared to age-matched mice fed normal chow diet (ND). Respiratory tolerance was induced by repeated intranasal (i.n.) administration of ovalbumin (OVA), prior to induction of allergic airway inflammation (AAI) by sensitization with OVA in alum i.p. and subsequent i.n. OVA challenge. Surprisingly, respiratory tolerance was induced equally well in HFD and ND mice, as evidenced by decreased lung eosinophilia and serum OVA-specific IgE production. However, in a pilot study, HFD mice showed a tendency for impaired activation of airway dendritic cells and regulatory T cells compared with ND mice after induction of respiratory tolerance. Moreover, the capacity of lymph node cells to produce IL-5 and IL-13 after AAI was drastically diminished in HFD mice compared to ND mice. These results indicate that HFD does not affect the inflammatory or B cell response to an allergen, but inhibits priming of Th2 cells and possibly dendritic cell and regulatory T cell activation.

The activin A antagonist follistatin inhibits cystic fibrosis-like lung inflammation and pathology.

Cystic fibrosis (CF) is the most common life-limiting genetically acquired respiratory disorder. Patients with CF have thick mucus obstructing the airways leading to recurrent infections, bronchiectasis and neutrophilic airway inflammation culminating in deteriorating lung function. Current management targets airway infection and mucus clearance, but despite recent advances in care, life expectancy is still only 40 years. We investigated whether activin A is elevated in CF lung disease and whether inhibiting activin A with its natural antagonist follistatin retards lung disease progression. We measured serum activin A levels, lung function and nutritional status in CF patients. We studied the effect of activin A on CF lung pathogenesis by treating newborn CF transgenic mice (ß-ENaC) intranasally with the natural activin A antagonist follistatin. Activin A levels were elevated in the serum of adult CF patients, and correlated inversely with lung function and body mass index. Follistatin treatment of newborn ß-ENaC mice, noted for respiratory pathology mimicking human CF, decreased the airway activin A levels and key features of CF lung disease including mucus hypersecretion, airway neutrophilia and levels of mediators that regulate inflammation and chemotaxis. Follistatin treatment also increased body weight and survival of ß-ENaC mice, with no evidence of local or systemic toxicity. Our findings demonstrate that activin A levels are elevated in CF and provide proof-of-concept for the use of the activin A antagonist, follistatin, as a therapeutic in the long-term management of lung disease in CF patients.

The effects of engineered nanoparticles on pulmonary immune homeostasis.

Engineered nanoparticles (ENP), which could be composed of inorganic metals, metal oxides, metalloids, organic biodegradable and inorganic biocompatible polymers, are being used as carriers for vaccine and drug delivery. There is also increasing interest in their application as delivery agents for the treatment of a variety of lung diseases. Although many studies have shown ENP can be effectively and safely used to enhance the delivery of drugs and vaccines in the periphery, there is concern that some ENP could promote inflammation, with unknown consequences for lung immune homeostasis. In this study, we review research on the effects of ENP on lung immunity, focusing on recent studies using diverse animal models of human lung disease. We summarize how the inflammatory and immune response to ENP is influenced by the diverse biophysical and chemical characteristics of the particles including composition, size and mode of delivery. We further discuss newly described unexpected beneficial properties of ENP administered into the lung, where biocompatible polystyrene or silver nanoparticles can by themselves decrease susceptibility to allergic airways inflammation. Increasing our understanding of the differential effects of diverse types of nanoparticles on pulmonary immune homeostasis, particularly previously underappreciated beneficial outcomes, supports rational ENP translation into novel therapeutics for prevention and/or treatment of inflammatory lung disorders.

Differential uptake of nanoparticles and microparticles by pulmonary APC subsets induces discrete immunological imprints.

There is increasing interest in the use of engineered particles for biomedical applications, although questions exist about their proinflammatory properties and potential adverse health effects. Lung macrophages and dendritic cells (DC) are key regulators of pulmonary immunity, but little is known about their uptake of different sized particles or the nature of the induced immunological imprint. We investigated comparatively the immunological imprints of inert nontoxic polystyrene nanoparticles 50 nm in diameter (PS50G) and 500 nm in diameter (PS500G). Following intratracheal instillation into naive mice, PS50G were preferentially taken up by alveolar and nonalveolar macrophages, B cells, and CD11b(+) and CD103(+) DC in the lung, but exclusively by DC in the draining lymph node (LN). Negligible particle uptake occurred in the draining LN 2 h postinstillation, indicating that particle translocation does not occur via lymphatic drainage. PS50G but not PS500G significantly increased airway levels of mediators that drive DC migration/maturation and DC costimulatory molecule expression. Both particles decreased frequencies of stimulatory CD11b(+)MHC class II(hi) allergen-laden DC in the draining LN, with PS50G having the more pronounced effect. These distinctive particle imprints differentially modulated induction of acute allergic airway inflammation, with PS50G but not PS500G significantly inhibiting adaptive allergen-specific immunity. Our data show that nanoparticles are taken up preferentially by lung APC stimulate cytokine/chemokine production and pulmonary DC maturation and translocate to the lung-draining LN via cell-associated transport. Collectively, these distinctive particle imprints differentially modulate development of subsequent lung immune responses. These findings support the development of lung-specific particulate vaccines, drug delivery systems, and immunomodulators.

The signalling imprints of nanoparticle uptake by bone marrow derived dendritic cells.

Nanoparticles (NP) possess remarkable adjuvant and carrier capacity, therefore are used in the development of various vaccine formulations. Our previous studies demonstrated that inert non-toxic 40-50 nm polystyrene NP (PS-NP) can promote strong CD8 T cell and antibody responses to the antigen, in the absence of observable inflammatory responses. Furthermore, instillation of PS-NP inhibited the development of allergic airway inflammation by induction of an immunological imprint via modulation of dendritic cell (DC) function without inducing oxidative stress in the lungs in mice. This is in contrast to many studies which show that a variety of ambient and man-made NP promote lung immunopathology, raising concerns generally about the safe use of NPs in biomedicine. Most NPs are capable of inducing inflammatory pathways in DC largely mediated by signalling via the extracellular signal-regulated kinase 1/2 (ERK). Herein, we investigate whether PS-NPs also activate ERK in DC in vitro. Our data show that PS-NP do not induce ERK activation in two different types of bone marrow derived (BM) DC cultures (expanded with GM-CSF or with GM-CSF together with IL-4). The absence of such signalling was not due to lack of PS-NP uptake by BM-DC as confirmed by confocal microscopy and flow cytometry. The process of NP uptake by DC usually initiates ERK signalling, suggesting an unusual uptake pathway may be engaged by PS-NPs. Indeed, data herein showns that uptake of PS-NP by BM-DC was substantially inhibited by phorbol myristate acetate (PMA) but not cytochalasin D (CCD), suggesting an uptake pathway utilising caveole for PS-NP. Together these data show that BM-DC take up PS-NP via a caveole-dependent pathway which does not trigger ERK signalling which may explain their efficient uptake by DC, without the concomitant activation of conventional inflammatory pathways.

The activin A antagonist follistatin inhibits asthmatic airway remodelling.

BACKGROUND: Current pharmacotherapy is highly effective in the clinical management of the majority of patients with stable asthma, however severe asthma remains inadequately treated. Prevention of airway remodelling is a major unmet clinical need in the management of patients with chronic severe asthma and other inflammatory lung diseases. Accumulating evidence convincingly demonstrates that activin A, a member of the transforming growth factor (TGF)-ß superfamily, is a key driver of airway inflammation, but its role in chronic asthmatic airway remodelling is ill-defined. Follistatin, an endogenously produced protein, binds activin A with high affinity and inhibits its bioactivity. The aim of this study was to test the potential of follistatin as a therapeutic agent to inhibit airway remodelling in an experimental model of chronic allergic airway inflammation. METHODS: BALB/c mice were systemically sensitised with ovalbumin (OVA), and challenged with OVA intranasally three times a week for 10 weeks. Follistatin was instilled intranasally during allergen challenge. RESULTS: Chronic allergen challenge induced mucus hypersecretion and subepithelial collagen deposition which persisted after cessation of challenge. Intranasal follistatin (0.05, 0.5, 5 µg) inhibited the airway remodelling and dose-dependently decreased airway activin A and TGF-ß1, and allergen-specific T helper 2 cytokine production in the lung-draining lymph nodes. Follistatin also impaired the loss of TGF-ß1 and activin RIB immunostaining in airway epithelium which occurred following chronic allergen challenge. CONCLUSIONS: These data demonstrate that follistatin attenuates asthmatic airway remodelling. Our findings point to the potential of follistatin as a therapeutic for prevention of airway remodelling in asthma and other inflammatory lung diseases.

Inert 50-nm polystyrene nanoparticles that modify pulmonary dendritic cell function and inhibit allergic airway inflammation.

Nanoparticles are being developed for diverse biomedical applications, but there is concern about their potential to promote inflammation, particularly in the lung. Although a variety of ambient, anthropogenic and man-made nanoparticles can promote lung inflammation, little is known about the long-term immunomodulatory effects of inert noninflammatory nanoparticles. We previously showed polystyrene 50-nm nanoparticles coated with the neutral amino acid glycine (PS50G nanoparticles) are not inflammatory and are taken up preferentially by dendritic cells (DCs) in the periphery. We tested the effects of such nanoparticles on pulmonary DC function and the development of acute allergic airway inflammation. Surprisingly, exposure to PS50G nanoparticles did not exacerbate but instead inhibited key features of allergic airway inflammation including lung airway and parenchymal inflammation, airway epithelial mucus production, and serum allergen-specific IgE and allergen-specific Th2 cytokines in the lung-draining lymph node (LN) after allergen challenge 1 mo later. PS50G nanoparticles themselves did not induce lung oxidative stress or cardiac or lung inflammation. Mechanistically, PS50G nanoparticles did not impair peripheral allergen sensitization but exerted their effect at the lung allergen challenge phase by inhibiting expansion of CD11c(+)MHCII(hi) DCs in the lung and draining LN and allergen-laden CD11b(hi)MHCII(hi) DCs in the lung after allergen challenge. PS50G nanoparticles further suppressed the ability of CD11b(hi) DCs in the draining LN of allergen-challenged mice to induce proliferation of OVA-specific CD4(+) T cells. The discovery that a defined type of nanoparticle can inhibit, rather than promote, lung inflammation via modulation of DC function opens the door to the discovery of other nanoparticle types with exciting beneficial properties.

The roles of activin A and its binding protein, follistatin, in inflammation and tissue repair.

Activin A, a member of the transforming growth factor-ß superfamily of cytokines, is a critical controller of inflammation, immunity and fibrosis. It is rapidly released into the blood following a lipopolysaccharide challenge in experimental animals, through activation of the Toll-like receptor 4 signalling pathway. Blocking activin action by pre-treatment with its binding protein, follistatin, modifies the inflammatory cytokine cascade, and reduces the severity of the subsequent inflammatory response and mortality. Likewise, high serum levels of activin A are predictive of death in patients with septicaemia. However, activin A has complex immunomodulatory actions. It is produced by inflammatory macrophages, but can regulate either pro- or anti-inflammatory responses in these cells, depending on their prior activation status. Activin A is also produced by Th2 cells, and stimulates antibody production by B cells and the development of regulatory T cells. Production of activin A during inflammatory responses stimulates fibrosis and tissue remodelling, and follistatin inhibits these actions of activin A. The modulation of activin by follistatin may represent an important therapeutic target for the modulation and amelioration of inflammatory and fibrotic disorders.

Interleukin-13 regulates secretion of the tumor growth factor-{beta} superfamily cytokine activin A in allergic airway inflammation.

Activin A is a member of the TGF-beta superfamily and plays a role in allergic inflammation and asthma pathogenesis. Recent evidence suggests that activin A regulates proinflammatory cytokine production and is regulated by inflammatory mediators. In a murine model of acute allergic airway inflammation, we observed previously that increased activin A concentrations in bronchoalveolar lavage (BAL) fluid coincide with Th2 cytokine production in lung-draining lymph nodes and pronounced mucus metaplasia in bronchial epithelium. We therefore hypothesized that IL-13, the key cytokine for mucus production, regulates activin A secretion into BAL fluid in experimental asthma. IL-13 increased BAL fluid activin A concentrations in naive mice and dose dependently induced activin A secretion from cultured human airway epithelium. A key role for IL-13 in the secretion of activin A into the BAL fluid during allergic airway inflammation was confirmed in IL-13-deficient mice. Eosinophils were not involved in this response because there was no difference in BAL fluid activin A concentrations between wild-type and eosinophil-deficient mice. Our data highlight an important role for IL-13 in the regulation of activin A intraepithelially and in BAL fluid in naive mice and during allergic airway inflammation. Given the immunomodulatory and fibrogenic effects of activin A, our findings suggest an important role for IL-13 regulation of activin A in asthma pathogenesis.

Promising particle-based vaccines in cancer therapy.

Immunotherapy and preventative cancer vaccines offer the hope of controlling cancer in humans with few of the undesirable side effects associated with current chemotherapy-based methods. Particulate vaccines are effectively taken up by dendritic cells, inducing both T-cell and antibody responses. Virus-like particles (VLPs) have shown preventive efficacy against cervical cancer. Herein we review a range of leading particle-based vaccine approaches: VLPs, immunostimulating complexes, liposomes, synthetic nanoparticles and microparticles (both biocompatible and biodegradable, such as polylactide-co-glycolides and poly[D,L-lactic-co-glycolic] acid). Immune efficacy, regulatory and safety issues, as well the application of immunotherapeutics to immunosuppressed patients with high levels of Tregs are also discussed. We argue that developmental issues (cost and intellectual property lifespan) and the lack of reliable preclinical animal models, rather than the lack of innovative vaccine approaches, currently present a major obstacle to rapid and effective vaccine development.

Ethnic differences in the prevalence of overweight among young children in Hawaii.

OBJECTIVES: To compare the prevalence of overweight among young children of different ethnic backgrounds and describe the age pattern of overweight in early childhood. METHODS: Cross-sectional study of 21,911 children, 12 to 59 months old, participating in the Hawaii Special Supplemental Nutrition Program for Women, Infants, and Children in 1997-1998. They were grouped in eight ethnic categories. For 1-year-olds we defined overweight as weight-for-age at the 95th percentile or more and underweight as weight-for-age at less than the 10th percentile. For 2- to 4-year-olds overweight was defined as body mass index (BMI) at the 95th percentile or more, underweight as BMI less than 10th percentile, tall stature as height-for-age at the 95th percentile or more, and short stature as height-for-age at less than the 10th percentile. The National Center for Health Statistics 2000 growth charts were the reference values. The analysis included bivariate and multivariate methods. RESULTS: Large differences were found among ethnic groups. Among 1-year-olds, Samoans were the heaviest (17.5% overweight) and Filipinos the lightest (30.2% underweight). Among 2- to 4-year-olds, Samoans were the heaviest (27.0% overweight) and the tallest (16.9% tall), whereas Asians were the lightest (12.2% underweight), and Filipinos the shortest (19.0% short). Hawaiians and Asians also had a high percentage of short children (13.6% and 12.2%, respectively). Prevalence of overweight in all 2- to 4-year-olds was more than the expected 5%, especially for Samoans, Filipinos, Hawaiians, and Asians. At age 2 to 4 years, overweight was almost twice as prevalent as at age 1. Multivariate analysis showed that ethnicity (Samoan) had the strongest independent association with weight-for-age percentile, BMI, and overweight in the two age groups, followed by birth weight. CONCLUSIONS: This is the first study of overweight among children of Asian and Pacific Island backgrounds in Hawaii. It identified important characteristics of growth and will be helpful in the design of appropriate activities to prevent overweight.

Stressors associated with Pacific Islands children diagnosed with cancer and severe blood disorders.

Pediatric cancer patients from the US-associated Pacific Islands have the option of referral to the United States for diagnosis and treatment through historical governmental agreements. These patients and their families travel thousands of miles, relocating for extended periods of time, to complete treatment. The purpose of this study is to describe the characteristics of Pacific Islands children referred for treatment to a pediatric oncology clinic in Hawaii, the support services they utilized, and the difficulties they experienced during their relocation. The medical records of 100 children referred from the Pacific Islands to Kapiolani Women's and Children's Hospital in Honolulu, Hawaii, between 1981 and 2002 were abstracted to gather data on treatment and service utilization. Interviews were conducted with 17 of these families for a more qualitative description of their experiences. The study found that families face considerable financial, emotional, and cultural stressors when relocating from the Pacific Islands to Honolulu for pediatric cancer treatment. The support systems currently in place can only partly address the needs of this population.

T cell reactivity during infectious mononucleosis and persistent gammaherpesvirus infection in mice.

Intranasal infection of mice with murine gammaherpesvirus 68 causes a dramatic increase in numbers of activated CD8(+) T cells in the blood, analogous in many respects to EBV-induced infectious mononucleosis in humans. In the mouse model, this lymphocytosis has two distinct components: an early, conventional virus-specific CD8(+) T cell response, and a later response characterized by a dramatic increase among CD8(+) T cells that bear Vbeta4(+) TCRs. We previously demonstrated that Vbeta4(+)CD8(+) T cells recognize an uncharacterized ligand expressed on latently infected B cells in an MHC-independent manner. The frequency of Vbeta4(+)CD8(+) T cells increases dramatically following the peak of viral latency in the spleen. In the current studies, we show that elevated Vbeta4(+)CD8(+) T cell levels are sustained long-term in persistently infected mice, apparently a consequence of continued ligand expression. In addition, we show that Vbeta4(+)CD8(+) T cells can acquire effector functions, including cytotoxicity and the capacity to secrete IFN-gamma, although they have an atypical activation profile compared with well-characterized CD8(+) T cells specific for conventional viral epitopes. The characteristics of Vbeta4(+)CD8(+) T cells (potential effector function, stimulation by latently infected B cells, and kinetics of expansion) suggested that this dominant T cell response plays a key role in the immune control of latent virus. However, Ab depletion and adoptive transfer studies show that Vbeta4(+)CD8(+) T cells are not essential for this function. This murine model of infection may provide insight into the role of unusual populations of activated T cells associated with persistent viral infections.