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Herein we present the evaluation of 11C-labeled-maleimides as radiotracers for positron emission tomography imaging of GSK-3 associated with Alzheimer′s disease (AD). 3-Acetyl-4-(1-[11C]-methyl-1H-indol-3-yl)[1H]pyrrole-2,5-dione ([11C]-2) was obtained by direct methylation using [11C]-CH3I and Cs2CO3in DMF with a 31 ± 4% radiochemical yield and a radiochemical purity of 97.7 ± 0.8%. [11C]-2was stable both in its final formulation and in human plasma for 120 min and had a plasma protein binding of 70 ± 1% and a LogD7.4value of 1.84 ± 0.04. [11C]-2ex vivobiodistributions in healthy animals demonstrated significant brain uptake and retention, showing its ability to penetrate the intact blood–brain barrier. In vivoPET imaging in mice bearing AD showed, with respect to normal animals, significant differences in uptake in the hypothalamus, the striatum, and the amygdala and a significant increase in amygdala uptake in later stages of the pathology. These results are very promising, and further studies are being performed for a complete validation of this compound as novel tracer for AD.

Omicron subvariants continuingly challenge current vaccination strategies. Here, we demonstrate nearly complete escape of the XBB.1.5, CH.1.1, and CA.3.1 variants from neutralizing antibodies stimulated by three doses of mRNA vaccine or by BA.4/5 wave infection, but neutralization is rescued by a BA.5-containing bivalent booster. CH.1.1 and CA.3.1 show strong immune escape from monoclonal antibody S309. Additionally, XBB.1.5, CH.1.1, and CA.3.1 spike proteins exhibit increased fusogenicity and enhanced processing compared with BA.2. Homology modeling reveals the key roles of G252V and F486P in the neutralization resistance of XBB.1.5, with F486P also enhancing receptor binding. Further, K444T/M and L452R in CH.1.1 and CA.3.1 likely drive escape from class II neutralizing antibodies, whereas R346T and G339H mutations could confer the strong neutralization resistance of these two subvariants to S309-like antibodies. Overall, our results support the need for administration of the bivalent mRNA vaccine and continued surveillance of Omicron subvariants.

BackgroundAlthough non-fire-related carbon monoxide (CO) poisoning is almost entirely preventable, over 400 people die and 20 000 people are injured each year in the USA from unintentional CO poisoning. Thus, there is a critical need for evidence-based interventions for preventing CO poisoning and increasing the proper use and installation of CO detectors.MethodsA randomised, controlled trial (Project CODE, a Carbon Monoxide Detector Education intervention) with 2-week and 6-month follow-up home observations was conducted in 299 parents of children aged ≤18 years recruited in the emergency department of a level 1 paediatric trauma centre. The intervention group received an educational tool, a spiral-bound, laminated booklet that resembled a CO detector containing theory-based safety messages based on the precaution adoption process model, a plug-in CO detector and 9 V battery. The control group received a one page flyer on CO poisoning prevention.ResultsAlthough the difference was not statistically significant, mean CO knowledge score increased at a greater rate for the intervention group than the control group. Intervention group parents were more likely to exhibit ‘safe’ CO detector use than control group parents at the 2-week follow-up (RR: 2.75; 95% CI 2.06 to 3.69) and 6-month follow-up (RR: 2.78; 95% CI 2.06 to 3.76), after adjusting for self-reported CO detector use behaviour at enrolment and annual per capita income.ConclusionsAn emergency department-delivered intervention containing a theory-based educational tool paired with a CO detector can be an effective method for increasing knowledge about CO poisoning, for prevention and for appropriate use of a CO detector.Trial registration numberNCT00959478.

New Omicron subvariants continue to emerge throughout the world. In particular, the XBB subvariant, which is a recombinant virus between BA.2.10.1.1 and BA.2.75.3.1.1.1, as well as the BA.2.3.20 and BR.2 subvariants that contain mutations distinct from BA.2 and BA.2.75, are currently increasing in proportion of variants sequenced. Here we show that antibodies induced by 3-dose mRNA booster vaccination as well as BA.1- and BA.4/5-wave infection effectively neutralize BA.2, BR.2, and BA.2.3.20 but have significantly reduced efficiency against XBB. In addition, the BA.2.3.20 subvariant exhibits enhanced infectivity in the lung-derived CaLu-3 cells and in 293T-ACE2 cells. Overall, our results demonstrate that the XBB subvariant is highly neutralization resistant, which highlights the need for continued monitoring of the immune escape and tissue tropism of emerging Omicron subvariants.

Introduction:Obesity, chronic inflammation, and elevated levels of atherogenic lipids have been associated with increased risk of ASCVD events. Current AHA/ACC guidelines identify existing risk enhancers for ASCVD including persistently elevated LDL-C or triglycerides, chronic kidney disease, chronic inflammatory conditions, and elevated inflammatory markers.Hypothesis:We hypothesized that in a population-level study of adults with diabetes mellitus (DM) without a history of prior ASCVD events, the average body mass index (BMI), hepatic fibrosis score (FIB-4), and neutrophil to lymphocyte ratio (NLR) are higher in the cohort of patients with other, AHA-identified ASCVD risk enhancers.Methods:We performed a hypothesis-driven secondary analysis using a cross-sectional dataset of EHR data from 7 health systems participating in PaTH, a Partner Network in PCORnet. Adults over 40 with DM and without ASCVD were included if they had LDL-c assessed in the most recent year of available data and had >6 months of pre-index data available. We describe cohort-level averages and standard deviations of the most recent lab values and clinical measurements for cohorts with and without AHA/ACC defined ASCVD risk enhancers.Results:We identified 50,749 patients in our baseline risk cohort and 67,593 patients in our enhanced risk cohort across the 7 sites. The enhanced risk cohort had a higher mean (SE) BMI 34.1 (0.28) vs 33.7 (0.29) kg/m2, FIB-4 score 1.5 (0.01) vs 1.4 (0.01) and NLR 62.5 (0.24) vs 61.2 (0.23) compared to the baseline risk cohort. NLR and FIB-4 demonstrated consistently higher averages in the enhanced-risk cohorts across sites.Conclusions:FIB-4 score and NLR both have higher population averages in cohorts with other markers of enhanced ASCVD risk in an adult diabetic patient population. The role of these markers in independently predicting ASCVD risk should be further explored with adjusted analyses in longitudinal datasets.

Introduction:Patients with ASCVD are at increased risk for CV events. The 2018 AHA/ACC lipid guidelines recommend treating these patients with high intensity or maximally tolerated statin therapy. The objective of this study was to describe lipid lowering treatment (LLT) patterns and lipid values across 7 regional health systems.Methods:We conducted a cross-sectional analysis of electronic health records transformed into the PCORnet common data model (CDM) from 7 sites in the PaTH Clinical Research Network. Adults were eligible for inclusion if an LDL-C value was measured within the past year and > 6 months of pre-index data were available prior to the first LDL-C value in the study period. We defined computable phenotypes for adults meeting AHA/ACC criteria for ASCVD at very high risk (VHR) and not at very high risk (NVHR). Medication use was assessed during the study period using the CDM prescribing table. Descriptive statistics were used to summarize LLT and lipid values within these groups and across sites.Results:NVHR patients (n=69,854) had mean (SD) LDL-C, TG and non-HDL-C of 92.1 (37), 138 (104) and 114.4 (43) mg/dl, respectively; 71% had LDL-C > 70 mg/dL, 30% had TGs 150-500 mg/dL, and 61% had non-HDL-C ≥ 100 mg/dL. VHR patients (n=117, 689) had mean (SD) LDL-C, TG and non-HDL-C of 82.9 (43), 138.5 (99), and 106 (43) mg/dl, respectively; 58.6% had LDL-C > 70 mg/dL, 30.5% had TGs 150-500 mg/dL, and 49.8% had non-HDL-C ≥ 100 mg/dL. Documented LLT in NVHR and VHR patients was 58% and 69% for statin therapy, 25% and 36% for high intensity statin therapy, 12% and 16% for statin therapy + another LLT, while 37% and 27% had no documented LLT.Conclusions:In this cross-sectional study of NVHR and VHR ASCVD patients, although most had documented statin therapy, only 25% and 36%, respectively were on high intensity statins while more than a quarter of patients had no documented LLT. Recorded LDL, TG and non-HDL-C lab values suggest there may be unaddressed risk in these populations.

Introduction:Per AHA guidelines, adults between 40-75 with borderline (5-7.5%) 10-year ASCVD risk (approximately 2.5% of this population in prior studies) should have the decision to start statin therapy personalized. Per AHA guidelines, elevated apolipoprotein B-100 (apoB) and elevated lipoprotein(a) (Lp(a)) are risk enhancing factors that may be considered in this decision.Hypothesis:We hypothesize that <10% of the estimated borderline 10-year ASCVD risk population between 40-75 years of age are tested for apo(B) or Lp(a).Methods:We performed a hypothesis-driven secondary analysis of a cross-sectional dataset of adults with LDL-c assessed in the most recent year of available data from 7 health systems participating in PaTH, a Partner Network in PCORnet. Participating sites reported summaries of demographics, diagnoses and lab testing for their health system populations as well as sub-cohorts of patients with prior ASCVD events, diabetes (DM), and a history of LDL > 190mg/dl. We evaluated the lifetime testing for apo(B) and Lp(a) in the whole population and subtracted out the testing in the high-risk cohorts.Results:From a population of 784,406 adults, we identified a cohort of 301,235 aged 40-75 without prior ASCVD event, DM, or LDL > 190. We estimated that 2.5% of this population (7,531) had borderline 10-year ASCVD risk. A total of 730 individuals were tested for apoB and 892 for Lp(a) across the entire non-high-risk cohort (0.2% and 0.3%). Assuming only the borderline risk group was tested, this represents testing rates of 9.7% for apoB and 11.8% for Lp(a), ranging across healthcare systems from 0-27% for apoB and 0-42% for Lp(a).Conclusions:Within the constraints of our population-based cross-sectional study, we found it plausible that >10% of the borderline-risk population utilized either apoB or Lp(a) testing for further risk stratification. Future work should be done to directly evaluate the use of these parameters in the borderline-risk population.

Background:Effects of gestational age (GA) and postnatal maturation on upper and lower esophageal sphincter (UES and LES) reflex development remain unclear. We hypothesized very-preterm (VPT) born neonates (< 32?wk GA) have delayed maturation of UES contractile reflex (UESCR) and LES relaxation reflex (LESRR) vs. preterm (PT) born (32–37?wk GA) neonates.Methods:Using provocative manometry, effects of 1,263 graded mid-esophageal stimuli (air, liquid) on sensory-motor characteristics of UESCR and LESRR were investigated in 24 VPT-born and 12 PT-born neonates (37.8?±?0.6 vs. 38.9?±?0.4?wk postmenstrual age respectively, P = 0.14).Results:In response to liquid stimuli (vs. air), VPT-born neonates displayed prolonged UESCR and LESRR response latencies (P < 0.001) and prolonged UESCR and LESRR durations (P < 0.01); unlike PT-born neonates, who exhibit prolonged LESRR response latency (P < 0.01), but similar UESCR and LESRR durations (P = 0.2). Differences were noted in LESRR duration in VPT vs. PT neonates for air stimuli (P = 0.04). With liquid stimuli, increasing GA was associated with decreasing response onset latencies to UESCR and LESRR (P < 0.05), and increasing LESRR duration (P = 0.02).Conclusion:Using GA as categorical or continuous variable, vagus-mediated mechano-sensitive and liquid-sensitive reflex characteristics of UESCR and LESRR are distinct; LESRR differs with varying intrauterine maturation suggesting inhibitory modulation progresses with advancing maturation.

Etanercept blocks tumor necrosis factor (TNF-), a proinflammatory cytokine that plays a role in cancer-related cachexia and tumor growth. A phase III study was conducted to assess the tolerability and efficacy of gemcitabine and etanercept in advanced pancreatic cancer.

In neonatal intensive care unit infants referred for home-tube feeding methods, we evaluated the effect of an innovative diagnostic and management approach on feeding outcomes at discharge and 1 year, by comparing data from historical controls; we hypothesized that clinical and aerodigestive motility characteristics at evaluation were predictive of feeding outcomes at discharge; we assessed the economic impact of feeding outcomes.

In neonatal intensive care unit infants referred for home-tube feeding methods, we evaluated the effect of an innovative diagnostic and management approach on feeding outcomes at discharge and 1 year, by comparing data from historical controls; we hypothesized that clinical and aerodigestive motility characteristics at evaluation were predictive of feeding outcomes at discharge; we assessed the economic impact of feeding outcomes. Patients (N = 100) who were referred for development of long-term feeding management strategy at 46.4 ± 13.1 weeks' postmenstrual age were compared with 50 historical controls that received routine care. The focused approach included swallow-integrated pharyngoesophageal manometry, individualized feeding strategy, and prospective follow-up. Feeding success was defined as ability to achieve oral feedings at discharge and 1 year. Motility characteristics were evaluated in relation to feeding success or failure at discharge. Higher feeding success was achieved in the innovative feeding program (vs historical controls) at discharge (51% vs 10%, P< 0.0001) and at 1 year (84.3% vs 42.9%, P< 0.0001), at a reduced economic burden (P< 0.05). Contributing factors to the innovative program's feeding success (vs feeding failure) were earlier evaluation and discharge (both P< 0.05), greater peristaltic reflex-frequency to provocation (P< 0.05), normal pharyngeal manometry (P< 0.05), oral feeding challenge success (P< 0.05), and suck-swallow-breath-esophageal swallow sequence (P< 0.05). Probability of feeding success demonstrated a prediction rate of 79.6%. Short-term and long-term feeding outcomes in complex neonates can be significantly improved with innovative feeding strategies at a reduced cost. Clinical and aerodigestive motility characteristics were predictive of outcomes.

Gastroesophageal reflux disease (GERD) is a frequent consideration in intensive care unit neonates. We tested the hypothesis that symptoms in GERD are dependent on the spatiotemporal and physicochemical characteristics of reflux events by evaluating the symptom sensitivity index (SSI) and symptom index (SI) in relation to the refluxate characteristics. Thirty symptomatic neonates (30.7 ± 0.8 wk gestation) were evaluated using manometry and pH-impedance methods. During 704.3 h of recordings, 2063 gastroesophageal reflux (GER) were observed; 54% of the GER were associated with symptoms. Defined by physical characteristics, there were 51.3% liquid, 29.1% gas, and 19.6% mixed GER. Defined by chemical characteristics, there were 48.5% acid and 51.5% nonacid GER. Defined by most proximal extent, 79.2% were supra-UES (upper esophageal sphincter) and 20.8% were infra-UES. Higher SSI was noted with pH-only events (p< 0.0001 versuspH-impedance events). Higher SI was noted with movement symptoms (versussensory, p0.04). In a subset analysis, the frequencies of GER events, acid clearance time, and SSI were all greater in chronic lung disease versusnone (p< 0.001). In conclusion, clinical significance of symptoms as measured by SSI and SI and characterization of spatial-temporal-physical-chemical nature of GER events as defined by pH-impedance methods clarifies the definition of GERD.

Gastroesophageal reflux disease (GERD) is a frequent consideration in intensive care unit neonates. We tested the hypothesis that symptoms in GERD are dependent on the spatiotemporal and physicochemical characteristics of reflux events by evaluating the symptom sensitivity index (SSI) and symptom index (SI) in relation to the refluxate characteristics. Thirty symptomatic neonates (30.7 ± 0.8 wk gestation) were evaluated using manometry and pH-impedance methods. During 704.3 h of recordings, 2063 gastroesophageal reflux (GER) were observed; 54% of the GER were associated with symptoms. Defined by physical characteristics, there were 51.3% liquid, 29.1% gas, and 19.6% mixed GER. Defined by chemical characteristics, there were 48.5% acid and 51.5% nonacid GER. Defined by most proximal extent, 79.2% were supra-UES (upper esophageal sphincter) and 20.8% were infra-UES. Higher SSI was noted with pH-only events (p < 0.0001 versus pH-impedance events). Higher SI was noted with movement symptoms (versus sensory, p = 0.04). In a subset analysis, the frequencies of GER events, acid clearance time, and SSI were all greater in chronic lung disease versus none (p < 0.001). In conclusion, clinical significance of symptoms as measured by SSI and SI and characterization of spatial-temporal-physical-chemical nature of GER events as defined by pH-impedance methods clarifies the definition of GERD.

The impact of timing of appropriate antibiotic initiation for critically ill children with severe bacterial community-acquired pneumonia (CAP) is unknown. We hypothesized that longer time to initiation of correct parenteral antibiotic would be associated with longer durations of mechanical ventilation, intensive care unit length of stay, and hospital length of stay.

The objective was to calculate national estimates of pedestrian-related hospitalizations and associated use of healthcare resources among children ≤19 years of age and to explore the effects of sociodemographic, hospital-related factors, and injury severity on total charges and lengths of stay (LOS) in the United States.

Abnormal swallowing (dysphagia) among neonates is commonly evaluated using the videofluoroscopic swallow study (VSS). Radiological findings considered high risk for administration of oral feeding include nasopharyngeal reflux, laryngeal penetration, aspiration, or pooling. Our aims were to determine pharyngoesophageal motility correlates in neonates with dysphagia and the impact of multidisciplinary feeding strategy. Twenty dysphagic neonates (mean gestation ± standard deviation [SD] = 30.9 ± 4.9 weeks; median 31.1 weeks; range = 23.7–38.6 weeks) with abnormal VSS results were evaluated at 49.9 ± 16.5 weeks (median 41.36 weeks) postmenstrual age. The subjects underwent a swallow-integrated pharyngoesophageal motility assessment of basal and adaptive swallowing reflexes using a micromanometry catheter and pneumohydraulic water perfusion system. Based on observations during the motility study, multidisciplinary feeding strategies were applied and included postural adaptation, sensory modification, hunger manipulation, and operant conditioning methods. To discriminate pharyngoesophageal manometry correlates between oral feeders and tube feeders, data were stratified based on the primary feeding method at discharge, oral feeding versus tube feeding. At discharge, 15 of 20 dysphagic neonates achieved oral feeding success, and the rest required chronic tube feeding. Pharyngoesophageal manometry correlates were significantly different (P< 0.05) between the primary oral feeders versus the chronic tube feeders for swallow frequency, swallow propagation, presence of adaptive peristaltic reflexes, oral feeding challenge test results, and upper esophageal sphincter tone. VSS results or disease characteristics had little effect on the feeding outcomes (P= NS). Swallow-integrated esophageal motility studies permit prolonged evaluation of swallowing reflexes and responses to stimuli under controlled conditions at cribside. The dysfunctional neuromotor mechanisms may be responsible for neonatal dysphagia or its consequences. Manometry may be a better predictor than VSS in identifying patients who are likely to succeed in vigorous intervention programs.

Abnormal swallowing (dysphagia) among neonates is commonly evaluated using the videofluoroscopic swallow study (VSS). Radiological findings considered high risk for administration of oral feeding include nasopharyngeal reflux, laryngeal penetration, aspiration, or pooling. Our aims were to determine pharyngoesophageal motility correlates in neonates with dysphagia and the impact of multidisciplinary feeding strategy.

Feeding problems in neonates with gastroschisis are commonly attributed to foregut dysmotility. However, the dysmotility mechanisms are not well understood. Our aim was to differentiate the pharyngoesophageal motility characteristics in neonates with gastroschisis compared with the controls. Specifically, the characteristics of swallowing, upper esophageal sphincter (UES), esophageal body, and lower esophageal sphincter (LES) were evaluated during basal state and upon provocation. Surgically repaired and recovered study infants with persistent feeding difficulties (n = 8; 36 ± 2 weeks gestational age) and controls (n = 8; 38 ± 2 weeks gestational age) were evaluated at 40 ± 2 weeks and 42 ± 2.5 weeks postmenstrual age, respectively. The basal and adaptive pharyngoesophageal motility characteristics were evaluated using a specially designed esophageal motility catheter with UES and LES sleeves and pneumohydraulic micromanometric water perfusion system at the crib side. Analysis of variance, chi-square, and ttests were applied; data are shown as mean ± standard deviation, and P< 0.05 was considered significant. Birth weight was less in gastroschisis (P< 0.03, vs controls) and length was less at motility study (P< 0.01, vs controls). The study group (vs controls) needed prolonged respiratory support (21 ± 23 vs 1 ± 2 days; P< 0.001) and prolonged gavage feeding (167 ± 100 vs 9 ± 16 days; P< 0.01). Compared with the controls, the gastroschisis group had lower frequency (P< 0.05) and poor propagation of spontaneous swallows (P< 0.001), UES relaxation time was shorter (P< 0.05), rate of relaxation was faster (P< 0.001), and esophageal peristaltic propagation velocity was slower (P< 0.05). Upon esophageal provocation with air and liquids, frequency occurrence of the esophageal reflexes was low (P< 0.05) with respect to primary peristalsis, secondary peristalsis, UES contractile reflex, and LES relaxation reflex. In gastroschisis feeding milestones and respiratory milestones were delayed, basal pharyngoesophageal peristaltic failure was common, adaptive peristaltic reflexes were less frequent and failed to occur, and frequency occurrences of UES and LES responses were impaired. These neuromotor markers may provide clues to define the esophageal motor function abnormalities in infants with an abnormality thought to be limited to the intestine.

Feeding problems in neonates with gastroschisis are commonly attributed to foregut dysmotility. However, the dysmotility mechanisms are not well understood.

Background:The purpose of this study was to characterize bone activity of the alveolar process in C3H/HeJ (C3H) and C57BL/6J (B6) inbred mice. Based on observations in other animal species, we hypothesized that the bone‐formation rate/bone surface (BFR/BS) is greater in the alveolar process compared to the body of the mandible and that the bone anabolic activity is greater in the alveolar process of the mandible than in the maxilla. We also examined the alveolar process of C3H and B6 mice for the presence of secondary osteons. Methods:Jaws from 17‐week‐old C3H and B6 female mice (N = 15/group) were harvested. Histomorphometric parameters were evaluated in sections from the alveolar process, each of which included at least one molar root. Results:In C3H and B6 mice, BFR/BS was not significantly different (P>0.05) between the alveolar process and the body of the mandible. In C3H mice, BFR/BS was significantly greater (P= 0.05) in the mandible compared to the maxilla. BFR/bone volume (BV) was not significantly different (P>0.05) between C3H mandible and maxilla. In the B6 inbred mouse, BFR/BS and BFR/bone volume (BV) were not significantly different (P>0.05) between jaws. After analyzing 165 bone sections, we identified 25 secondary osteons. Conclusions:The surface anabolic activity was not different between the body and the alveolar process of the mandible. The surface activity was greater in the C3H mandible than in the maxilla. Although secondary osteonal bone remodeling existed in the C3H and B6 alveolar bone, this process was not a consistent finding.

In vitro studies suggest an important role for CEACAM1 (carcinoembryonic antigen-related cell adhesion molecule 1) in infection by multiple gram-negative bacteria. However, in vivo evidence supporting this role is lacking, largely because the bacterial adhesins involved in this host-microbe association do not bind to murine-derived CEACAM1. One of several adhesins expressed by nontypeable Haemophilus influenzae (NTHI), the outer membrane protein P5-homologous adhesin (or P5), is essential for colonization of the chinchilla nasopharynx and infection of the middle ear. Here we reveal that NTHI P5 binds to the chinchilla homologue of CEACAM1 and that rabbit anti-human carcinoembryonic antigen blocks NTHI colonization of the chinchilla nasopharynx, providing the first demonstration of a role for CEACAM receptor binding by any bacterial pathogen in vivo.

ABSTRACTIn vitro studies suggest an important role for CEACAM1 (carcinoembryonic antigen-related cell adhesion molecule 1) in infection by multiple gram-negative bacteria. However, in vivo evidence supporting this role is lacking, largely because the bacterial adhesins involved in this host-microbe association do not bind to murine-derived CEACAM1. One of several adhesins expressed by nontypeable Haemophilus influenzae(NTHI), the outer membrane protein P5-homologous adhesin (or P5), is essential for colonization of the chinchilla nasopharynx and infection of the middle ear. Here we reveal that NTHI P5 binds to the chinchilla homologue of CEACAM1 and that rabbit anti-human carcinoembryonic antigen blocks NTHI colonization of the chinchilla nasopharynx, providing the first demonstration of a role for CEACAM receptor binding by any bacterial pathogen in vivo.

The objective of this study was to describe the epidemiology and financial burden of burn-associated hospitalizations for children younger than 18 years in the United States. Retrospective data analysis of pediatric burn-associated hospitalizations was done using the Healthcare Cost and Utilization Project Kids' Inpatient Database for 2000. An estimated 10,000 children younger than 18 years were hospitalized for burn-associated injuries in the United States in 2000. These children spent an estimated 66,200 days in the hospital with associated hospital charges equal to $211,772,700. Total charges and length of stay for pediatric burn-associated hospitalizations in the United States during 2000 were associated with degree of burn, percentage of total body surface area burned, child's age, region of the United States, hospital location, and hospital type. Children 2 years old or younger were more likely to be nonwhite, be hospitalized for burns, and burn their hands/wrists, compared with children 3 to 17 years of age. Male children in both age groups were more likely to be hospitalized for burns than female children. Children 2 years old or younger were more likely to be burned by hot liquids/vapors and contact with hot substances/objects, while children 3 to 17 years were more likely to be burned by fire/flames. This study is the first national study on healthcare resource utilization for pediatric burn-associated hospitalizations to utilize the KID database. Burns are a major source of pediatric morbidity and are associated with significant national healthcare resource utilization annually. Future burn prevention efforts should emphasize implementing passive injury prevention strategies, especially for young children who are nonwhite and live in low-income communities.

Impairment of the ability to mount an inflammatory response is associated with death from adult critical illness. This phenomenon, characterized by reduced monocyte production of proinflammatory mediators such as tumor necrosis factor (TNF-), is poorly understood in children. We hypothesized that differential expression of inflammation-related genes would be seen in monocytes from children with adverse outcomes from multiple organ dysfunction syndrome (MODS). Ex vivolipopolysaccharide (LPS)-induced TNF- production and plasma cytokines were prospectively measured biweekly in children with dysfunction of two or more organs. Concomitantly, monocyte expression of 28 pro- and anti-inflammatory genes cytokines, Toll-like receptor (TLR)/nuclear factor B (NF-B) signaling pathway members, inflammasome elements was measured. Thirty children (22 survivors, eight nonsurvivors) were evaluated. High mRNA levels for interleukin (IL)-10, IL-1 receptor–associated kinase (IRAK-M), and the putative inflammasome inhibitor pyrin were associated with death (p≤ 0.02). Plasma IL-10 levels were higher and ex vivoTNF- production was lower in nonsurvivors (p< 0.05). Among survivors, high mRNA levels for IL-10, IRAK-M, pyrin, IRAK1, or TLR4 were associated with longer durations of pediatric intensive care unit (PICU) stay and mechanical ventilation (p≤ 0.02). These data suggest that adverse outcomes from pediatric MODS are associated with an anti-inflammatory monocyte mRNA phenotype. Future studies are warranted to explore mechanisms of immunodepression in pediatric critical illness.

Impairment of the ability to mount an inflammatory response is associated with death from adult critical illness. This phenomenon, characterized by reduced monocyte production of proinflammatory mediators such as tumor necrosis factor a (TNF-a), is poorly understood in children. We hypothesized that differential expression of inflammation-related genes would be seen in monocytes from children with adverse outcomes from multiple organ dysfunction syndrome (MODS). Ex vivo lipopolysaccharide (LPS)-induced TNF-a production and plasma cytokines were prospectively measured biweekly in children with dysfunction of two or more organs. Concomitantly, monocyte expression of 28 pro- and anti-inflammatory genes [cytokines, Toll-like receptor (TLR)/nuclear factor ?B (NF-?B) signaling pathway members, inflammasome elements] was measured. Thirty children (22 survivors, eight nonsurvivors) were evaluated. High mRNA levels for interleukin (IL)-10, IL-1 receptor–associated kinase (IRAK-M), and the putative inflammasome inhibitor pyrin were associated with death (p = 0.02). Plasma IL-10 levels were higher and ex vivo TNF-a production was lower in nonsurvivors (p < 0.05). Among survivors, high mRNA levels for IL-10, IRAK-M, pyrin, IRAK1, or TLR4 were associated with longer durations of pediatric intensive care unit (PICU) stay and mechanical ventilation (p = 0.02). These data suggest that adverse outcomes from pediatric MODS are associated with an anti-inflammatory monocyte mRNA phenotype. Future studies are warranted to explore mechanisms of immunodepression in pediatric critical illness.

OBJECTIVES To calculate national estimates of motor vehicle crash (MVC)–related hospitalization and associated use of health care resources among patients 20 years and younger and to explore the effects of certain sociodemographic and health care system–related factors and injury severity on use of hospital resources and lengths of stay (LOSs) in the United States. DESIGN Data from the 2003 Healthcare Cost and Utilization Project Kids' Inpatient Database were used. SETTING Pediatric inpatient care in 3438 hospitals in 36 US states. PATIENTS Patients 20 years and younger hospitalized with MVC-related injuries. MAIN OUTCOME MEASURES National estimates of MVC-associated hospitalizations, rates, resource use, Injury Severity Scores, and demographics were calculated. Potentially significant covariate associations were studied using hospital charges and LOS. RESULTS Sixty-two thousand eight hundred eighty MVC-related hospitalizations occurred among patients 20 years and younger in the United States in 2003, resulting in more than $2.0 billion (SD = $1.2 million) in inpatient charges and 304 196 days (SD = 55 113 days) of hospitalization. Mean (SD) hospital charges and LOS were $33 440 ($55 113) and 4.8 (7.7) days, respectively. The mean (SD) Injury Severity Score was 10.3 (11.4). Adolescents aged 18 through 20 years had the highest hospitalization rates (197 cases per 100 000 children). Older age, being male, urban hospital location, mortality during hospitalization, higher injury severity, and longer LOS were significantly associated with higher total charges. Longer LOS was significantly associated with older age, urban hospital location, higher injury severity, and mortality. CONCLUSION Motor vehicle crash–related injuries among children burden health care resources, with nationwide charges exceeding $2 billion annually.--

Bone turnover rates can be altered by metabolic and mechanical demands. Due to the difference in the pattern of loading, we hypothesized that there are differences in bone remodeling rates between the maxillary and mandibular alveolar processes. Furthermore, in a canine model, the alveolar process of teeth that lack contact (e.g., second premolars) would have a different turnover rate than bone supporting teeth with functional contact (e.g., first molars). Six skeletally mature male dogs were given a pair of calcein labels. After sacrifice, specimens representing the anterior and posterior locations of both jaws were prepared for examination by histomorphometric methods to evaluate the bone volume/total volume (BV/TV; %), bone volume (mm2), mineral apposition rate (MAR; µm/day), and bone formation rate (BFR; %/year) in the alveolar process. There were no significant differences (P> 0.05) in the BV/TV within the jaws. The bone volume within the alveolar process of the mandible was 2.8-fold greater than in the maxilla. The MAR was not significantly different between the jaws and anteroposterior locations. However, the BFR was significantly (P< 0.0001) greater in the mandible than in the maxilla. The anterior location had higher (P= 0.002) remodeling than the posterior location in the maxilla but not in the mandible. While there was a greater bone mass and increased remodeling in the mandible, no remodeling gradient in the coronal-apical direction was apparent in the alveolar process. Bone adaptation probably involves a complex interplay of bone turnover, mass, and architecture. Anat Rec Part A, 2006. © 2006 Wiley-Liss, Inc.

Human T-cell leukemia virus type 1 (HTLV-1) is the causative agent of adult T-cell lymphoma/leukemia (ATL). The HTLV-1 envelope gene exhibits limited variability when examined from infected individuals, but has not been tested using infectious clones of the virus in animal models. In vitro assays indicate that HTLV-1 envelope (Env) Ser75Ile, Asn95Asp, and Asn195Asp surface unit (SU) mutants are able to replicate in and immortalize lymphocytes. Herein, we examined the effects of these Env mutants in rabbits inoculated with HTLV-1 immortalized ACH.75, ACH.95, or ACH.195 cell lines (expressing full-length molecular clones with the SU mutations) or the ACH.1 cell line (expressing wild-type SU). All rabbits became infected, and the fidelity of the mutations was maintained throughout the 8-week study. However, SU point mutations resulted in decreased antibody responses to viral group-associated antigen (Gag) and Env antigens. ACH.195 rabbits had a selective decreased antibody response to SU, and one ACH.195 rabbit had an antibody response to both HTLV-1 and HTLV-2 SUs. Some mutant inoculation groups had altered proviral loads. However, peripheral-blood mononuclear cell (PBMC) proviral loads did not correlate with antibody responses. Our data are the first to demonstrate that mutations in critical determinants of HTLV-1 Env SU altered antibody responses and proviral loads, but do not prevent viral replication in vivo.

Human T-cell leukemia virus type 1 (HTLV-1) is the causative agent of adult T-cell lymphoma/leukemia (ATL). The HTLV-1 envelope gene exhibits limited variability when examined from infected individuals, but has not been tested using infectious clones of the virus in animal models. In vitro assays indicate that HTLV-1 envelope (Env) Ser75Ile, Asn95Asp, and Asn195Asp surface unit (SU) mutants are able to replicate in and immortalize lymphocytes. Herein, we examined the effects of these Env mutants in rabbits inoculated with HTLV-1 immortalized ACH.75, ACH.95, or ACH.195 cell lines (expressing full-length molecular clones with the SU mutations) or the ACH.1 cell line (expressing wild-type SU). All rabbits became infected, and the fidelity of the mutations was maintained throughout the 8-week study. However, SU point mutations resulted in decreased antibody responses to viral group-associated antigen (Gag) and Env antigens. ACH.195 rabbits had a selective decreased antibody response to SU, and one ACH.195 rabbit had an antibody response to both HTLV-1 and HTLV-2 SUs. Some mutant inoculation groups had altered proviral loads. However, peripheral-blood mononuclear cell (PBMC) proviral loads did not correlate with antibody responses. Our data are the first to demonstrate that mutations in critical determinants of HTLV-1 Env SU altered antibody responses and proviral loads, but do not prevent viral replication in vivo.

Human T-lymphotropic virus type 1 (HTLV-1) is the etiologic agent of adult T cell leukemia/lymphoma (ATLL), an aggressive CD4+ T lymphocyte malignancy. Activation of T lymphocytes is required for effective retroviral integration into the host cell genome and subsequent viral replication, but the molecular mechanisms involved in HTLV-1-mediated T cell activation remain unclear. HTLV-1 encodes various accessory proteins such as p12I, which has been demonstrated to be critical for HTLV-1 infectivity in vivo in rabbits and in vitro in quiescent primary human T lymphocytes. This hydrophobic protein localizes in the endoplasmic reticulum, increases intracellular calcium, and activates nuclear factor of activated T cell-mediated transcription. To further elucidate the role of p12I in regulation of cellular gene expression, we performed gene array analysis on stable p12I-expressing Jurkat T cells, using Affymetrix U133A arrays. Our data indicate that p12I altered the expression of genes associated with a network of interrelated pathways including T cell signaling, cell proliferation, and apoptosis. Expression of several calcium-regulated genes was found to be altered by p12I, consistent with known properties of the viral protein. Gene array findings were confirmed by semiquantitative RT-PCR in Jurkat T cells and primary CD4+ T lymphocytes. Furthermore, dose-dependent expression of p12I in Jurkat T cells resulted in significant increases in p300 and p300-dependent transcription. This is the first report of a viral protein influencing the transcription of p300, a rate-limiting coadapter critical in HTLV-1-mediated T cell activation. Collectively, our data strongly indicate that HTLV-1 p12I modulates cellular gene expression patterns to hasten the activation of T lymphocytes and thereby promote efficient viral infection.

Quantitative polymerase chain reaction (qPCR), a highly sensitive method of measuring gene expression, is widely used in biomedical research. To produce reliable results, it is essential to use stably expressed reference genes (RGs) for data normalization so that sample-to-sample variation can be controlled. In this study, we examine the effect of different RGs on statistical efficiency by analyzing a qPCR data set that contains 12 target genes and 3 RGs. Our results show that choosing the most stably expressed RG for data normalization does not guarantee reduced variance or improved statistical efficiency. We also provide a formula for determining when data normalization will improve statistical efficiency and hence increase the power of statistical tests in data analysis.

No relevant conflicts of interest to declare.