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Background: Initial oral antibiotics may be as effective as intravenous (IV) antibiotics for children hospitalized with community-acquired pneumonia (CAP), but further data are needed., Objective: We evaluated for associations of initial antibiotic route (IV vs. oral) with length of stay (LOS) and secondary outcomes for children hospitalized with CAP., Methods: This multicenter, retrospective cohort study included children with CAP who were hospitalized for >48 h, had chest radiographs, and received antibiotics at four children's hospitals between 2014 and 2020. Data were obtained from the Pediatric Health Information System and manual chart review. The exposure was initial antibiotic route (i.e., first antibiotic given intravenously or orally). We performed multivariable regression modeling using inverse probability treatment weights from propensity scores. Outcomes included LOS, oxygen duration, cost, care escalation, and readmission or emergency department revisit., Results: Of 1147 included children, 37% received initial oral antibiotics. Within the propensity balanced sample, LOS was 73.5 h (IQR 61.0, 99.5) and 78.7 (61.0, 118.0) for patients with initial oral and IV antibiotics, respectively. Children receiving initial oral antibiotics had an 8% reduction in LOS (OR 0.92 [95% CI: 0.87, 0.94]) and 14% reduction in cost (OR 0.86 [95% CI 0.79, 0.94]) versus those receiving initial IV antibiotics. There were no differences in other outcomes., Conclusions: Children with CAP receiving initial oral antibiotics had reduced LOS and hospital cost without differences in escalated care or return visits. Starting hospitalized children on oral antibiotics is likely a safe and effective alternative to IV treatment., (© 2024 Society of Hospital Medicine.)

Background: Hospitalization rates for childhood pneumonia vary widely. Risk-based clinical decision support (CDS) interventions may reduce unwarranted variation., Methods: We conducted a pragmatic randomized trial in two US pediatric emergency departments (EDs) comparing electronic health record (EHR)-integrated prognostic CDS versus usual care for promoting appropriate ED disposition in children (<18 years) with pneumonia. Encounters were randomized 1:1 to usual care versus custom CDS featuring a validated pneumonia severity score predicting risk for severe in-hospital outcomes. Clinicians retained full decision-making authority. The primary outcome was inappropriate ED disposition, defined as early transition to lower- or higher-level care. Safety and implementation outcomes were also evaluated., Results: The study enrolled 536 encounters (269 usual care and 267 CDS). Baseline characteristics were similar across arms. Inappropriate disposition occurred in 3% of usual care encounters and 2% of CDS encounters (adjusted odds ratio: 0.99, 95% confidence interval: [0.32, 2.95]). Length of stay was also similar and adverse safety outcomes were uncommon in both arms. The tool's custom user interface and content were viewed as strengths by surveyed clinicians (>70% satisfied). Implementation barriers include intrinsic (e.g., reaching the right person at the right time) and extrinsic factors (i.e., global pandemic)., Conclusions: EHR-based prognostic CDS did not improve ED disposition decisions for children with pneumonia. Although the intervention's content was favorably received, low subject accrual and workflow integration problems likely limited effectiveness. Clinical Trials Registration: NCT06033079., (© 2024 Society of Hospital Medicine.)

Background: Children with high-intensity neurologic impairment (HINI) have an increased risk of urinary tract infection (UTI) and prolonged intravenous (IV) antibiotic exposure., Objective: To determine the association between short (≤3 days) and long (>3 days) IV antibiotic courses and UTI treatment failure in hospitalized children with HINI., Methods: We performed a retrospective cohort study examining UTI hospitalizations at 49 hospitals in the Pediatric Health Information System from 2016 to 2021 for children (1-18 years) with HINI. The primary outcome was UTI readmission within 30 days. Our secondary outcome was the association of hospital-level variation in short IV antibiotic course use with readmission. Readmission rates were compared between short and long courses using multivariable regression., Results: Of 5612 hospitalizations, 3840 (68.4%) had short IV antibiotic courses. In our adjusted model, children with short IV courses were less likely than with long courses to have a 30-day UTI readmission (4.0%, 95% CI [3.6%, 4.5%] vs. 6.3%, 95% CI [5.1%, 7.8%]). Despite marked hospital-level variation in short IV course use (50.0%-87.5% of hospitalizations), there was no correlation with readmissions., Conclusions: Children with HINI hospitalized with UTI had low UTI readmission rates, but those who received long IV antibiotic courses were more likely to experience UTI readmission versus those receiving short courses. While residual confounding may influence our results, we did not find that short IV courses impacted readmission at the hospital level despite variation in use across institutions. Long IV antibiotic courses are associated with risks and may not confer benefit in this population., (© 2024 Society of Hospital Medicine.)

We examined associations between a validated, multidimensional measure of social determinants of health and population-based hospitalization rates among children <18 years across 18 states from the 2017 Healthcare Cost and Utilization Project State Inpatient Databases and the US Census. The exposure was ZIP code-level Child Opportunity Index (COI), a composite measure of neighborhood resources and conditions that matter for children's health. The cohort included 614,823 hospitalizations among a population of 29,244,065 children (21.02 hospitalizations per 1000). Adjusted hospitalization rates decreased significantly and in a stepwise fashion as COI increased (p < .001 for each), from 26.56 per 1000 (95% confidence interval [CI] 26.41-26.71) in very low COI areas to 14.76 per 1000 (95% CI 14.66-14.87) in very high COI areas (incidence rate ratio 1.8; 95% CI 1.78-1.81). Decreasing neighborhood opportunity was associated with increasing hospitalization rates among children in 18 US states. These data underscore the importance of social context and community-engaged solutions for health systems aiming to eliminate care inequities., (© 2023 Society of Hospital Medicine.)

Background: Electronic health record-based clinical decision support (CDS) is a promising antibiotic stewardship strategy. Few studies have evaluated the effectiveness of antibiotic CDS in the pediatric emergency department (ED)., Objective: To compare the effectiveness of antibiotic CDS vs. usual care for promoting guideline-concordant antibiotic prescribing for pneumonia in the pediatric ED., Design: Pragmatic randomized clinical trial., Setting and Participants: Encounters for children (6 months-18 years) with pneumonia presenting to two tertiary care children s hospital EDs in the United States., Intervention: CDS or usual care was randomly assigned during 4-week periods within each site. The CDS intervention provided antibiotic recommendations tailored to each encounter and in accordance with national guidelines., Main Outcome and Measures: The primary outcome was exclusive guideline-concordant antibiotic prescribing within the first 24 h of care. Safety outcomes included time to first antibiotic order, encounter length of stay, delayed intensive care, and 3- and 7-day revisits., Results: 1027 encounters were included, encompassing 478 randomized to usual care and 549 to CDS. Exclusive guideline-concordant prescribing did not differ at 24 h (CDS, 51.7% vs. usual care, 53.3%; odds ratio [OR] 0.94 [95% confidence interval [CI]: 0.73, 1.20]). In pre-specified stratified analyses, CDS was associated with guideline-concordant prescribing among encounters discharged from the ED (74.9% vs. 66.0%; OR 1.53 [95% CI: 1.01, 2.33]), but not among hospitalized encounters. Mean time to first antibiotic was shorter in the CDS group (3.0 vs 3.4 h; p = .024). There were no differences in safety outcomes., Conclusions: Effectiveness of ED-based antibiotic CDS was greatest among those discharged from the ED. Longitudinal interventions designed to target both ED and inpatient clinicians and to address common implementation challenges may enhance the effectiveness of CDS as a stewardship tool., (© 2023 Society of Hospital Medicine.)

Background: Children in mental health crises are increasingly admitted to children's hospitals awaiting inpatient psychiatric placement. During hospitalization, patients may exhibit acute agitation prompting pharmacologic restraint use., Objective: To determine hospital-level incidence and variation of pharmacologic restraint use among children admitted for mental health conditions in children's hospitals., Design, Setting, and Participants: We examined data for children (5 to ≤18 years) admitted to children's hospitals with a primary mental health condition from 2018 to 2020 using the Pediatric Health Information System database. Hospital rates of parenteral pharmacologic restraint use per 1000 mental health bed days were determined and compared after adjusting for patient-level and demographic factors. Cluster analysis (k-means) was used to group hospitals based on overall restraint use (rate quartiles) and drug class. Hospital-level factors for pharmacologic restraint use were compared., Results: Of 29,834 included encounters, 3747 (12.6%) had pharmacologic restraint use. Adjusted hospital rates ranged from 35 to 389 pharmacologic restraint use days per 1000 mental health bed days with a mean of 175 (standard deviation: 72). Cluster analysis revealed three hospitals were high utilizers of all drug classes. No significant differences in pharmacologic restraint use were found in the hospital-level analysis., Conclusions: Children's hospitals demonstrate wide variation in pharmacologic restraint rates for mental health hospitalizations, with a 10-fold difference in adjusted rates between highest and lowest utilizers, and high overall utilizers order medications across all drug classes., (© 2022 Society of Hospital Medicine.)

Background: Underlying comorbidities are common in children with pneumonia., Objective: To determine associations between comorbidity-related functional limitations and risk for severe pneumonia outcomes., Design, Setting, and Participants: We prospectively enrolled children <18 years with and without comorbidities presenting to the emergency department with clinical and radiographic pneumonia at two institutions. Comorbidities included chronic conditions requiring daily medications, frequent healthcare visits, or which limited age-appropriate activities. Among children with comorbidities, functional limitations were defined as none or mild, moderate, and severe., Main Outcomes and Measures: Outcomes included an ordinal severity outcome, categorized as very severe (mechanical ventilation, shock, or death), severe (intensive care without very severe features), moderate (hospitalization without severe features), or mild (discharged home), and length of stay (LOS). Multivariable ordinal logistic regression was used to examine associations between comorbidity-related functional limitations and outcomes, while accounting for relevant covariates., Results: A cohort of 1116 children, including 452 (40.5%) with comorbidities; 200 (44.2%) had none or mild functional limitations, 93 (20.6%) moderate, and 159 (35.2%) had severe limitations. In multivariable analysis, comorbidity-related functional limitations were associated with the ordinal severity outcome and LOS (p < .001 for both). Children with severe functional limitations had tripling of the odds of a more severe ordinal (adjusted odds ratio [aOR]: 3.01, 95% confidence interval [2.05, 4.43]) and quadrupling of the odds for longer LOS (aOR: 4.72 [3.33, 6.70]) as compared to children without comorbidities., Conclusion: Comorbidity-related functional limitations are important predictors of disease outcomes in children with pneumonia. Consideration of functional limitations, rather than the presence of comorbidity alone, is critical when assessing risk of severe outcomes., (© 2022 Society of Hospital Medicine.)

Background: Disproportionately high acute care utilization among children with medical complexity (CMC) is influenced by patient-level social complexity., Objective: The objective of this study was to determine associations between ZIP code-level opportunity and acute care utilization among CMC., Design, Setting, and Participants: This cross-sectional, multicenter study used the Pediatric Health Information Systems database, identifying encounters between 2016-2019. CMC aged 28 days to <16 years with an initial emergency department (ED) encounter or inpatient/observation admission in 2016 were included in primary analyses., Main Outcome and Measures: We assessed associations between the nationally-normed, multi-dimensional, ZIP code-level Child Opportunity Index 2.0 (COI) (high COI = greater opportunity), and total utilization days (hospital bed-days + ED discharge encounters). Analyses were conducted using negative binomial generalized estimating equations, adjusting for age and distance from hospital and clustered by hospital. Secondary outcomes included intensive care unit (ICU) days and cost of care., Results: A total of 23,197 CMC were included in primary analyses. In unadjusted analyses, utilization days decreased in a stepwise fashion from 47.1 (95% confidence interval: 45.5, 48.7) days in the lowest COI quintile to 38.6 (36.9, 40.4) days in the highest quintile (p < .001). The same trend was present across all outcome measures, though was not significant for ICU days. In adjusted analyses, patients from the lowest COI quintile utilized care at 1.22-times the rate of those from the highest COI quintile (1.17, 1.27)., Conclusions: CMC from low opportunity ZIP codes utilize more acute care. They may benefit from hospital and community-based interventions aimed at equitably improving child health outcomes., (© 2022 Society of Hospital Medicine.)

Background: Little is known about the clinical factors associated with COVID-19 disease severity in children and adolescents., Methods: We conducted a retrospective cohort study across 45 US children's hospitals between April 2020 to September 2020 of pediatric patients discharged with a primary diagnosis of COVID-19. We assessed factors associated with hospitalization and factors associated with clinical severity (eg, admission to inpatient floor, admission to intensive care unit [ICU], admission to ICU with mechanical ventilation, shock, death) among those hospitalized., Results: Among 19,976 COVID-19 encounters, 15,913 (79.7%) patients were discharged from the emergency department (ED) and 4063 (20.3%) were hospitalized. The clinical severity distribution among those hospitalized was moderate (3222, 79.3%), severe (431, 11.3%), and very severe (380, 9.4%). Factors associated with hospitalization vs discharge from the ED included private payor insurance (adjusted odds ratio [aOR],1.16; 95% CI, 1.1-1.3), obesity/type 2 diabetes mellitus (type 2 DM) (aOR, 10.4; 95% CI, 8.9-13.3), asthma (aOR, 1.4; 95% CI, 1.3-1.6), cardiovascular disease, (aOR, 5.0; 95% CI, 4.3- 5.8), immunocompromised condition (aOR, 5.9; 95% CI, 5.0-6.7), pulmonary disease (aOR, 5.3; 95% CI, 3.4-8.2), and neurologic disease (aOR, 3.2; 95% CI, 2.7-5.8). Among children and adolescents hospitalized with COVID-19, greater disease severity was associated with Black or other non-White race; age greater than 4 years; and obesity/type 2 DM, cardiovascular, neuromuscular, and pulmonary conditions., Conclusions: Among children and adolescents presenting to US children's hospital EDs with COVID-19, 20% were hospitalized; of these, 21% received care in the ICU. Older children and adolescents had a lower risk for hospitalization but more severe illness when hospitalized. There were differences in disease severity by race and ethnicity and the presence of selected comorbidities. These factors should be taken into consideration when prioritizing mitigation and vaccination strategies.

The impact of COVID-19 public health interventions on pediatric illnesses nationwide is unknown. We performed a multicenter, cross-sectional study of encounters at 44 children's hospitals in the United States to assess changes in healthcare utilization during the pandemic. The COVID-19 pandemic was associated with substantial reductions in encounters for respiratory diseases; these large reductions were consistent across illness subgroups. Although encounters for nonrespiratory diseases decreased as well, reductions were more modest and varied by age. Encounters for respiratory diseases among adolescents declined to a lesser degree and returned to previous levels faster compared with those of younger children. Further study is needed to determine the contributions of decreased illness and changes in care-seeking behavior to this observed reduction.

Children's hospitals responded to COVID-19 by limiting nonurgent healthcare encounters, conserving personal protective equipment, and restructuring care processes to mitigate viral spread. We assessed year-over-year trends in healthcare encounters and hospital charges across US children's hospitals before and during the COVID-19 pandemic. We performed a retrospective analysis, comparing healthcare encounters and inflation-adjusted charges from 26 tertiary children's hospitals reporting to the PROSPECT database from February 1 to June 30 in 2019 (before the COVID-19 pandemic) and 2020 (during the COVID-19 pandemic). All children's hospitals experienced similar trends in healthcare encounters and charges during the study period. Inpatient bed-days, emergency department visits, and surgeries were lower by a median 36%, 65%, and 77%, respectively, per hospital by the week of April 15 (the nadir) in 2020 compared with 2019. Across the study period in 2020, children's hospitals experienced a median decrease of $276 million in charges.

Background and Objectives: Understanding disparities in child health-related quality of life (HRQoL) may reveal opportunities for targeted improvement. This study examined associations between social disadvantage, access to care, and child physical functioning before and after hospitalization for acute respiratory illness., Methods: From July 1, 2014, to June 30, 2016, children ages 8-16 years and/or caregivers of children 2 weeks to 16 years admitted to five tertiary care children's hospitals for three common respiratory illnesses completed a survey on admission and within 2 to 8 weeks after discharge. Survey items assessed social disadvantage (minority race/ ethnicity, limited English proficiency, low education, and low income), difficulty/delays accessing care, and baseline and follow-up HRQoL physical functioning using the Pediatric Quality of Life Inventory (PedsQL, range 0-100). We examined associations between these three variables at baseline and follow-up using multivariable, mixed-effects linear regression models with multiple imputation sensitivity analyses for missing data., Results: A total of 1,325 patients and/or their caregivers completed both PedsQL assessments. Adjusted mean baseline PedsQL scores were significantly lower for patients with social disadvantage markers, compared with those of patients with none (78.7 for >3 markers versus 85.5 for no markers, difference -6.1 points (95% CI: -8.7, -3.5). The number of social disadvantage markers was not associated with mean follow-up PedsQL scores. Difficulty/delays accessing care were associated with lower PedsQL scores at both time points, but it was not a significant effect modifier between social disadvantage and PedsQL scores., Conclusions: Having social disadvantage markers or difficulty/delays accessing care was associated with lower baseline physical functioning; however, differences were reduced after hospital discharge.

Objective: This study aims to assess whether secondhand smoke (SHS) exposure has an impact on health-related quality of life (HRQOL) in children with acute respiratory illness (ARI)., Methods: This study was nested within a multicenter, prospective cohort study of children (two weeks to 16 years) with ARI (emergency department visits for croup and hospitalizations for croup, asthma, bronchiolitis, and pneumonia) between July 1, 2014 and June 30, 2016. Subjects were surveyed upon enrollment for sociodemographics, healthcare utilization, home SHS exposure (0 or ≥1 smoker in the home), and child HRQOL (Pediatric Quality of Life Physical Functioning Scale) for both baseline health (preceding illness) and acute illness (on admission). Data on insurance status and medical complexity were collected from the Pediatric Hospital Information System database. Multivariable linear mixed regression models examined associations between SHS exposure and HRQOL., Results: Home SHS exposure was reported in 728 (32%) of the 2,309 included children. Compared with nonexposed children, SHS-exposed children had significantly lower HRQOL scores for baseline health (mean difference -3.04 [95% CI -4.34, -1.74]) and acute illness (-2.16 [-4.22, -0.10]). Associations were strongest among children living with two or more smokers. HRQOL scores were lower among SHS-exposed children for all four conditions but only significant at baseline for bronchiolitis (-2.94 [-5.0, -0.89]) and pneumonia (-4.13 [-6.82, -1.44]) and on admission for croup (-5.71 [-10.67, -0.75])., Conclusions: Our study demonstrates an association between regular SHS exposure and decreased HRQOL with a dose-dependent response for children with ARI, providing further evidence of the negative impact of SHS.

Ninety-five adults enrolled in the Etiology of Pneumonia in the Community study with negative admission influenza polymerase chain reaction (PCR) tests received influenza vaccination during hospitalization. Acute and convalescent influenza serology was performed. After vaccination, seropositive (≥1:40) hemagglutination antibody titers (HAI) were achieved in 55% to influenza A(H1N1)pdm09, 58% to influenza A(H3N2), 77% to influenza B (Victoria), and 74% to influenza B (Yamagata) viruses. Sixty-six (69%) patients seroconverted (≥4-fold HAI rise) to ≥1 strain. Failure to seroconvert was associated with diabetes, bacterial detection, baseline seropositive titers for influenza B (Yamagata), and influenza vaccination in the previous season., (© 2018 The Authors. Influenza and Other Respiratory Viruses Published by John Wiley & Sons Ltd.)

Background: Worse outcomes among adults presenting for/receiving care on weekends (ie, "the weekend effect") have been observed for many diseases. However, little is known about the overall impact of the weekend effect in hospitalized children., Objective: o determine the association between weekend admission and length of stay (LOS) and between weekend discharge and 30-day all-cause readmission., Methods: We conducted a retrospective, cross-sectional study of children hospitalized between October 1, 2014 and September 30, 2015 using the Pediatric Health Information System. Birth hospitalizations and planned procedures were excluded. We used generalized linear mixed modeling to assess the independent association between weekend admission and LOS and weekend discharge and readmission risk., Results: Among 390,745 hospitalizations across 43 hospitals, the median LOS was 41 hours (interquartile range [IQR] 24-71) and the 30-day readmission rate was 8.2% (IQR 7.2-9.4). We observed no association between weekend admission and LOS (adjusted LOS [95% CI: weekend 63.70 [61.01-66.52] hours vs weekday 63.40 [60.73-66.19] hours, P = .112). Weekend discharge was associated with slightly increased odds of readmission compared with weekday discharge (adjusted probability of readmission [95% CI]: weekend 0.13 [0.12-0.13] versus weekday 0.11 [0.11-0.12], P < .001) but was variable among individual hospitals. Patient characteristics (ie, number of chronic conditions) were more strongly associated with LOS and readmission risk than weekend admission or discharge., Conclusions: Patient-level factors (ie, clinical and demographic characteristics) are more indicative of longer LOS and readmission risk than weekend admissions or discharges. The overall impact of the weekend effect across children's hospitals was minimal., (© 2018 Society of Hospital Medicine.)

Woodchip bioreactors are widely used to control nitrogen export from agriculture using denitrification. There is abundant evidence that drying-rewetting (DRW) cycles can promote enhanced metabolic rates in soils. A 287-d experiment investigated the effects of weekly DRW cycles on nitrate (NO) removal in woodchip columns in the laboratory receiving constant flow of nitrated water. Columns were exposed to continuous saturation (SAT) or to weekly, 8-h drying-rewetting (8 h of aerobiosis followed by saturation) cycles (DRW). Nitrate concentrations were measured at the column outlets every 2 h using novel multiplexed sampling methods coupled to spectrophotometric analysis. Drying-rewetting columns showed greater export of total and dissolved organic carbon and increased NO removal rates. Nitrate removal rates in DRW columns increased by up to 80%, relative to SAT columns, although DRW removal rates decreased quickly within 3 d after rewetting. Increased NO removal in DRW columns continued even after 39 DRW cycles, with ∼33% higher total NO mass removed over each weekly DRW cycle. Data collected in this experiment provide strong evidence that DRW cycles can dramatically improve NO removal in woodchip bioreactors, with carbon availability being a likely driver of improved efficiency. These results have implications for hydraulic management of woodchip bioreactors and other denitrification practices., (Copyright © by the American Society of Agronomy, Crop Science Society of America, and Soil Science Society of America, Inc.)

Purpose: The aims of this study were to examine a national database to assess codeine poisonings before and after the new guidance for pharmacists while also evaluating rates of codeine prescriptions following the introduction of restrictions on supply., Methods: Anonymised enquiry data of reported poisoning cases were reviewed for a period from 2005 to 2016 inclusive. The rate of pharmacy claims for codeine containing products was also examined using the national pharmacy claims database. Segmented regression analysis was used to detect changes in poisonings and claims before and after the new guidance., Results: There were 1851 codeine-related poisonings reported over the study period. An annual decline was evident with a significant 33% reduction from 2010 to 2011 (β2 coefficient for level change, 42.1; 95% CI, -68.1 to -16.0; P = 0.006). Following 2011, the declining rate of codeine poisonings plateaued. Analysis of the national pharmacy claims data revealed no change in the reimbursement rate for co-codamol products restricted by the guidance in 2010 (Incidence rate ratio 1.04, 95% CI, 0.997-1.08; P = 0.07). There was no corresponding increase in the reimbursement of alternative opioid medications., Conclusions: New guidance on codeine supply coincided with an initial reduction in reported codeine poisoning cases. This reduction was in keeping with the previous trend. However, this was without an increase in the prevailing rate of prescription claims for these products or potential substitutes. Policymakers may consider further restriction of codeine products to improve public health outcomes., (© 2019 John Wiley & Sons, Ltd.)

Within a cohort of >2,000 children hospitalized with community-acquired pneumonia, staphylococcal pneumonia was rare (1%) but associated with adverse in-hospital outcomes. Despite this low prevalence, use of antistaphylococcal antibiotics was common (24%). Efforts are needed to minimize overuse of antistaphylococcal antibiotics while also ensuring adequate treatment for pathogen-specific diseases., (© 2018 Society of Hospital Medicine.)

Background: The annual Pediatric Hospital Medicine (PHM) conference serves as a venue for the dissemination of research in this rapidly growing discipline. A measure of research validity is subsequent publication in peer-reviewed journals., Objective: To identify the publication rate of abstracts submitted to the 2014 PHM conference and determine whether presentation format was associated with subsequent journal publication or time to publication., Methods: We identified abstracts submitted to the 2014 PHM conference. Presentation formats included rejected abstracts and poster and oral presentations. Abstracts subsequently published in journals were identified by searching the author and abstract title in PubMed, MedEdPORTAL, and Google Scholar. We used logistic regression and Cox proportional hazards models to determine if presentation format was associated with publication, time to publication, and publishing journal impact factor., Results: Of 226 submitted abstracts, 19.0% were rejected, 68.0% were selected for posters, and 12.8% were selected for oral presentations; 36.3% were subsequently published within 30 months after the conference. Abstracts accepted for oral presentation had more than 7-fold greater odds of publication (adjusted odds ratio 7.8; 95% confidence interval [CI], 2.6-23.5) and a 4-fold greater likelihood of publication at each month (adjusted hazard ratio 4.5; 95% CI, 2.1-9.7) compared with rejected abstracts. Median journal impact factor was significantly higher for oral presentations than other presentation formats (P < 0.01)., Conclusions: Abstract reviewers may be able to identify methodologically sound studies for presentation; however, the low overall publication rate may indicate that presented results are preliminary or signify a need for increased mentorship and resources for research development in PHM.

Microbioreactors play a critical role in process development as they reduce reagent requirements and can facilitate high-throughput screening of process parameters and culture conditions. Here, we have demonstrated and explained in detail, for the first time, the amenability of the automated ambr15 cell culture microbioreactor system for the development of scalable adherent human mesenchymal multipotent stromal/stem cell (hMSC) microcarrier culture processes. This was achieved by first improving suspension and mixing of the microcarriers and then improving cell attachment thereby reducing the initial growth lag phase. The latter was achieved by using only 50% of the final working volume of medium for the first 24 h and using an intermittent agitation strategy. These changes resulted in >150% increase in viable cell density after 24 h compared to the original process (no agitation for 24 h and 100% working volume). Using the same methodology as in the ambr15, similar improvements were obtained with larger scale spinner flask studies. Finally, this improved bioprocess methodology based on a serum-based medium was applied to a serum-free process in the ambr15, resulting in >250% increase in yield compared to the serum-based process. At both scales, the agitation used during culture was the minimum required for microcarrier suspension, N JS . The use of the ambr15, with its improved control compared to the spinner flask, reduced the coefficient of variation on viable cell density in the serum containing medium from 7.65% to 4.08%, and the switch to serum free further reduced these to 1.06-0.54%, respectively. The combination of both serum-free and automated processing improved the reproducibility more than 10-fold compared to the serum-based, manual spinner flask process. The findings of this study demonstrate that the ambr15 microbioreactor is an effective tool for bioprocess development of hMSC microcarrier cultures and that a combination of serum-free medium, control, and automation improves both process yield and consistency. Biotechnol. Bioeng. 2017;114: 2253-2266. © 2017 Wiley Periodicals, Inc., (© 2017 Wiley Periodicals, Inc.)

Background: National guidelines for the management of community-acquired pneumonia (CAP) in children were published in 2011. These guidelines discourage most diagnostic testing for outpatients, as well as repeat testing for hospitalized patients who are improving. We sought to evaluate the temporal trends in diagnostic testing associated with guideline implementation among children with CAP., Methods: Children 1 to 18 years old who were discharged with pneumonia after emergency department (ED) evaluation or hospitalization from January 1, 2008 to June 30, 2014 at any of 32 children's hospitals participating in the Pediatric Health Information System were included. We excluded children with complex chronic conditions and those requiring intensive care or who underwent early pleural drainage. We compared use of diagnostic testing (blood culture, complete blood count [CBC], C-reactive protein [CRP], and chest radiography [CXR]) before and after release of the guidelines, and assessed for temporal trends using interrupted time series analysis. We also calculated the cost impact of these changes on diagnostic utilization and evaluated the variability of the guideline's impact across hospitals., Results: Overall, 220,539 patients were included; 53% were male and the median age was 4 years (interquartile range, 2-7). For patients discharged from the ED with CAP, diagnostic utilization rates for blood culture, CBC, CRP, and CXR were higher after guideline publication compared with expected utilization rates without guidelines. In contrast, initial testing and repeat testing among patients hospitalized with CAP was lower after guideline publication. There were modest reductions in estimated costs associated with these changes. However, wide variability was observed in the impact of the guidelines across hospitals., Conclusions: Publication of national pneumonia guidelines in 2011 was associated with modest changes in diagnostic testing for children with CAP. However, the changes varied across hospitals, and the financial impact was modest. Local implementation efforts are warranted to ensure widespread guideline adherence. Journal of Hospital Medicine 2016;11:317-323. © 2016 Society of Hospital Medicine., Competing Interests: Authors have no conflicts of interest, (© 2015 Society of Hospital Medicine.)

Background: Administrative data can be used to determine optimal management of febrile infants and aid clinical practice guideline development., Objective: Determine the most accurate International Classification of Diseases, Ninth Revision (ICD-9) diagnosis coding strategies for identification of febrile infants., Design: Retrospective cross-sectional study., Setting: Eight emergency departments in the Pediatric Health Information System., Patients: Infants aged <90 days evaluated between July 1, 2012 and June 30, 2013 were randomly selected for medical record review from 1 of 4 ICD-9 diagnosis code groups: (1) discharge diagnosis of fever, (2) admission diagnosis of fever without discharge diagnosis of fever, (3) discharge diagnosis of serious infection without diagnosis of fever, and (4) no diagnosis of fever or serious infection., Exposure: The ICD-9 diagnosis code groups were compared in 4 case-identification algorithms to a reference standard of fever ≥100.4°F documented in the medical record., Measurements: Algorithm predictive accuracy was measured using sensitivity, specificity, and negative and positive predictive values., Results: Among 1790 medical records reviewed, 766 (42.8%) infants had fever. Discharge diagnosis of fever demonstrated high specificity (98.2%, 95% confidence interval [CI]: 97.8-98.6) but low sensitivity (53.2%, 95% CI: 50.0-56.4). A case-identification algorithm of admission or discharge diagnosis of fever exhibited higher sensitivity (71.1%, 95% CI: 68.2-74.0), similar specificity (97.7%, 95% CI: 97.3-98.1), and the highest positive predictive value (86.9%, 95% CI: 84.5-89.3)., Conclusions: A case-identification strategy that includes admission or discharge diagnosis of fever should be considered for febrile infant studies using administrative data, though underclassification of patients is a potential limitation., (© 2015 Society of Hospital Medicine.)

Background: Differences among febrile infant institutional clinical practice guidelines (CPGs) may contribute to practice variation and increased healthcare costs., Objective: Determine the association between pediatric emergency department (ED) CPGs and laboratory testing, hospitalization, ceftriaxone use, and costs in febrile infants., Design: Retrospective cross-sectional study in 2013., Setting: Thirty-three hospitals in the Pediatric Health Information System., Patients: Infants aged ≤56 days with a diagnosis of fever., Exposures: The presence and content of ED-based febrile infant CPGs assessed by electronic survey., Measurements: Using generalized estimating equations, we evaluated the association between CPG recommendations and rates of urine, blood, cerebrospinal fluid (CSF) testing, hospitalization, and ceftriaxone use at ED discharge in 2 age groups: ≤28 days and 29 to 56 days. We also assessed CPG impact on healthcare costs., Results: We included 9377 ED visits; 21 of 33 EDs (63.6%) had a CPG. For neonates ≤28 days, CPG recommendations did not vary and were not associated with differences in testing, hospitalization, or costs. Among infants 29 to 56 days, CPG recommendations for CSF testing and ceftriaxone use varied. CSF testing occurred less often at EDs with CPGs recommending limited testing compared to hospitals without CPGs (adjusted odds ratio: 0.5, 95% confidence interval: 0.3-0.8). Ceftriaxone use at ED discharge varied significantly based on CPG recommendations. Costs were higher for admitted and discharged infants 29 to 56 days old at hospitals with CPGs., Conclusions: CPG recommendations for febrile infants 29 to 56 days old vary across institutions for CSF testing and ceftriaxone use, correlating with observed practice variation. CPGs were not associated with lower healthcare costs., (© 2015 Society of Hospital Medicine.)

Objectives: Six recently published algorithms classify pneumonia patients presenting from the community into high- and low-risk groups for resistant bacteria. Our objective was to compare performance of these algorithms for identifying patients infected with bacteria resistant to traditional community-acquired pneumonia antibiotics., Methods: This was a retrospective study of consecutive adult patients diagnosed with pneumonia in an emergency department and subsequently hospitalized. Each patient was classified as high or low risk for resistant bacteria according to the following algorithms: original health care-associated pneumonia (HCAP) criteria, Summit criteria, Brito and Niederman strategy, Shorr model, Aliberti model, and Shindo model. The reference for comparison was detection of resistant bacteria, defined as methicillin-resistant Staphylococcus aureus or Gram-negative bacteria resistant to ceftriaxone or levofloxacin., Results: A total of 614 patients were studied, including 36 (5.9%) with resistant bacteria. The HCAP criteria classified 304 (49.5%) patients as high risk, with an area under the receiver operating characteristic curve (AUC) of 0.63 (95% confidence interval [CI] = 0.54 to 0.72), sensitivity of 0.69 (95% CI = 0.52 to 0.83), and specificity of 0.52 (95% CI = 0.48 to 0.56). None of the other algorithms improved both sensitivity and specificity or significantly improved the AUC. Compared to the HCAP criteria, the Shorr and Aliberti models classified more patients as high risk, resulting in higher sensitivity and lower specificity. The Shindo model classified fewer patients as high risk, with lower sensitivity and higher specificity., Conclusions: All algorithms for identification of resistant bacteria included in this study had suboptimal performance to guide antibiotic selection. New strategies for selecting empirical antibiotics for community-onset pneumonia are necessary., (© 2015 by the Society for Academic Emergency Medicine.)

We evaluated the performance of time to clinical stability (TCS), a longitudinal outcome measure using 4 physiologic parameters (temperature, heart rate, respiratory rate, and use of supplemental oxygen), among children enrolled in a prospective study of pneumonia hospitalizations. We calculated the time from admission to normalization for each of the 4 parameters individually along with various combinations of these parameters (≥2 parameters). We assessed for agreement between the combined TCS measures and both hospital length of stay and an ordinal severity scale (nonsevere, severe, and very severe). Overall, 323 (96.7%) of 334 included children had ≥1 parameter abnormal on admission; 70 (21%) children had ≥1 parameter abnormal at discharge. For the 4 combined measures, median TCS decreased with increasing age. Increasing TCS was associated with both longer length of stay and increasing disease severity. The simplest combined measure incorporating only respiratory rate and need for supplemental oxygen performed similarly to more complex measures including additional parameters. Our study demonstrates that longitudinal TCS measures may be useful in children with pneumonia, both in clinical settings to assess recovery and readiness for discharge, and as an outcome measure in research and quality assessments. Additional study is needed to further validate our findings., (© 2015 Society of Hospital Medicine.)

Objective: To assess whether radiographic findings predict outcomes among children hospitalized with pneumonia., Methods: This retrospective study included children <18 years of age from 4 children's hospitals admitted in 2010 with clinical and radiographic evidence of pneumonia. Admission radiographs were categorized as single lobar, unilateral or bilateral multilobar, or interstitial. Pleural effusions were classified as absent, small, or moderate/large. Propensity scoring was used to adjust for potential confounders, including need for supplemental oxygen, intensive care, and mechanical ventilation, as well as hospital length of stay and duration of supplemental oxygen., Results: There were 406 children (median age, 3 years). Infiltrate patterns included: single lobar, 61%; multilobar unilateral, 13%; multilobar bilateral, 16%; and interstitial, 10%. Pleural effusion was present in 21%. Overall, 63% required supplemental oxygen (median duration, 31.5 hours), 8% required intensive care, and 3% required mechanical ventilation. Median length of stay was 51.5 hours. Compared with single lobar infiltrate, all other infiltrate patterns were associated with need for intensive care; only bilateral multilobar infiltrate was associated with need for mechanical ventilation (adjusted odds ratio [aOR]: 3.0, 95% confidence interval [CI]: 1.2-7.9). Presence of effusion was associated with increased length of stay and duration of supplemental oxygen; only moderate/large effusion was associated with need for intensive care (aOR: 3.2, 95% CI: 1.1-8.9) and mechanical ventilation (aOR: 14.8, 95% CI: 9.8-22.4)., Conclusions: Admission radiographic findings are associated with important hospital outcomes and care processes and may help predict disease severity., (© 2014 Society of Hospital Medicine.)

Background: Urinary tract infections (UTIs) are a common reason for pediatric hospitalizations., Objective: To determine the effect of discordant antibiotic therapy (in vitro nonsusceptibility of the uropathogen to initial antibiotic) on clinical outcomes for children hospitalized for UTI., Design/setting: Multicenter retrospective cohort study in children aged 3 days to 18 years, hospitalized at 5 children's hospitals with a laboratory-confirmed UTI. Data were obtained from medical records and the Pediatric Hospital Information System (PHIS) database., Participants: Patients with laboratory-confirmed UTI., Main Exposure: Discordant antibiotic therapy., Measurements: Length of stay and fever duration. Covariates included age, sex, insurance, race, vesicoureteral reflux, antibiotic prophylaxis, genitourinary abnormality, and chronic care conditions., Results: The median age of the 216 patients was 2.46 years (interquartile range [IQR]: 0.27, 8.89) and 25% were male. The most common causative organisms were E. coli and Klebsiella species. Discordant therapy occurred in 10% of cases and most commonly in cultures positive for Klebsiella species, Enterobacter species, and mixed organisms. In adjusted analyses, discordant therapy was associated with a 1.8 day (95% confidence interval [CI]: 1.5, 2.1) longer length of stay [LOS], but not with fever duration., Conclusions: Discordant antibiotic therapy for UTI is common and associated with longer hospitalizations. Further research is needed to understand the clinical factors contributing to the increased LOS and to inform decisions for empiric antibiotic selection in children with UTIs., (Copyright © 2012 Society of Hospital Medicine.)

A faecal egg count reduction test, using composite samples, was developed in order to assess the efficacy of the flukicide, triclabendazole (TCBZ) on commercial sheep farms in England and Wales. First, a comparison between individual counts and composite counts was conducted using sheep on two farms with different levels of infection. Faecal samples were collected from 50 sheep on each farm at the time of TCBZ treatment and 21&emsp14;days later. The results showed that a composite fluke egg count (CFEC) was as sensitive as using individual samples, and the test was subsequently validated on an additional 18 sheep farms. The pre- and post-treatment CFECs using five composite samples were subjected to bootstrap analysis. The variance in fluke egg counts of composite samples was high, but analyses indicated that 20 individual samples analysed as two composites was as sensitive as using five composites. The two-composite assay was evaluated on another five farms. On seven out of 25 farms sampled, egg counts either did not decrease significantly or increased following treatment, suggesting TCBZ resistance on these farms. This assay represents a practical field test that can be used in the first instance to evaluate the efficacy of TCBZ on sheep farms where resistance is suspected.

Objective: To determine the comparative effectiveness of common pleural drainage procedures for treatment of pneumonia complicated by parapneumonic effusion (ie, complicated pneumonia)., Design: Multicenter retrospective cohort study., Setting: Forty children's hospitals contributing data to the Pediatric Health Information System., Participants: Children with complicated pneumonia requiring pleural drainage., Main Exposures: Initial drainage procedures were categorized as chest tube without fibrinolysis, chest tube with fibrinolysis, video-assisted thoracoscopic surgery (VATS), and thoracotomy., Main Outcome Measures: Length of stay (LOS), additional drainage procedures, readmission within 14 days of discharge, and hospital costs., Results: Initial procedures among 3500 patients included chest tube without fibrinolysis (n = 1762), chest tube with fibrinolysis (n = 623), VATS (n = 408), and thoracotomy (n = 797). Median age was 4.1 years. Overall, 716 (20.5%) patients received an additional drainage procedure (range, 6.8-44.8% across individual hospitals). The median LOS was 10 days (range, 7-14 days across individual hospitals). The median readmission rate was 3.8% (range, 0.8%-33.3%). In multivariable analysis, differences in LOS by initial procedure type were not significant. Patients undergoing initial chest tube placement with or without fibrinolysis were more likely to require additional drainage procedures. However, initial chest tube without fibrinolysis was the least costly strategy., Conclusion: There is variability in the treatment and outcomes of children with complicated pneumonia. Outcomes were similar in patients undergoing initial chest tube placement with or without fibrinolysis. Those undergoing VATS received fewer additional drainage procedures but had no differences in LOS compared with other strategies., (Copyright © 2011 Society of Hospital Medicine.)

The seroprevalence of Fasciola hepatica infection in a population of commercial dairy herds in England and Wales was estimated using an ELISA that detected antibodies to F hepatica in bulk tank milk. A total of 3130 milk samples, obtained as convenience samples from two commercial milk-testing laboratories, were tested during the winter of 2006/07. Herds considered to be seropositive were categorised as low positive, medium positive or high positive. A geospatial map was drawn to show the distribution of infected herds and the seroprevalence of exposure at regional level, using the Nomenclature of Units for Territorial Statistics boundaries, and at a finer spatial level defined by postcode area. Overall, 76 per cent (95 per cent confidence interval [CI] 74 to 77 per cent) of herds carried antibodies to F hepatica; the seroprevalence in England was 72 per cent (95 per cent CI 70 to 74 per cent) and in Wales it was 84 per cent (95 per cent CI 82 to 86 per cent). The highest prevalences of exposure were found in north-west England, where more than 47 per cent of herds were in the high positive exposure category.

In this work a new phenomenological model of growth of cartilage tissue cultured in a rotating bioreactor is developed. It represents an advancement of a previously derived model of deposition of glycosaminoglycan (GAG) in engineered cartilage by (i) introduction of physiological mechanisms of proteoglycan accumulation in the extracellular matrix (ECM) as well as by correlating (ii) local cell densities and (iii) tissue growth to the ECM composition. In particular, previously established predictions and correlations of local oxygen concentrations and GAG synthesis rates are extended to distinguish cell secreted proteoglycan monomers free to diffuse in cell surroundings and outside from the engineered construct, from large aggrecan molecules, which are constrained within the ECM and practically immovable. The model includes kinetics of aggregation, that is, transformation of mobile GAG species into immobile aggregates as well as maintenance of the normal ECM composition after the physiological GAG concentration is reached by incorporation of a product inhibition term. The model also includes mechanisms of the temporal evolution of cell density distributions and tissue growth under in vitro conditions. After a short initial proliferation phase the total cell number in the construct remains constant, but the local cell distribution is leveled out by GAG accumulation and repulsion due to negative molecular charges. Furthermore, strong repulsive forces result in expansion of the local tissue elements observed macroscopically as tissue growth (i.e., construct enlargement). The model is validated by comparison with experimental data of (i) GAG distribution and leakage, (ii) spatial-temporal distributions of cells, and (iii) tissue growth reported in previous works. Validation of the model predictive capability--against a selection of measured data that were not used to construct the model--suggests that the model successfully describes the interplay of several simultaneous processes carried out during in vitro cartilage tissue regeneration and indicates that this approach could also be attractive for application in other tissue engineering systems., ((c) 2009 Wiley Periodicals, Inc.)

Purpose: Prescribing is an effective and economical means of delivering health care. The aim of this study is to assess the quality of prescriptions in an Acute Medical Assessment Unit (AMAU) at Aberdeen Royal Infirmary (ARI)., Methods: Prescription data were collected from all available medication charts of patients admitted to the ward over a 2-week period. Prescription quality indicators were divided into two categories: prescription chart related (e.g. complete patient information and absence of drug-drug interactions (DDIs)) and medication related (e.g. legibility of handwriting, generic prescribing and adherence to hospital's formulary)., Results: Patient identifiers were omitted in 4% (n = 8) of the medication charts included in assessing prescribing quality. Patient allergies were omitted in 36% (n = 76) of charts. At least one DDI was detected in 26% (n = 55) of the charts. The mean number of medications prescribed per patient was seven (95%CI, 6.53-7.65). The median number of medication-related prescribing errors per medication chart was two (interquartile range (IQR), 1-3). The distribution of these errors was significantly higher in charts with five or more medications (p < 0.001)., Conclusion: This study demonstrates a relatively acceptable level of prescription quality compared to the published literature. However, the number of DDIs and level of allergy documentation are of concern emphasising the need for continued education in this field., (Copyright (c) 2009 John Wiley & Sons, Ltd.)

Ocoee Lake No. 3 is the first reservoir receiving suspended sediments contaminated with trace metals discharged by acid mine effluents from the Ducktown Mining District, Tennessee. Bottom sediments (0-5 cm) from the lake were sampled to assess the potential for future adverse environmental effects if no remediation controls or activities are implemented. The sediments were found to include a major component (173 +/- 19 g kg(-1)) that dissolved in 6 mol L(-1) HCl within 24 h. This acid-soluble and relatively labile fraction contained high concentrations of Fe (460 +/- 40 g kg(-1)), Al (99 +/- 11 g kg(-1)), Mn (10 +/- 8 g kg(-1)), Cu (2000 +/- 700 mg kg(-1)), Zn (1300 +/- 200 mg kg(-1)), and Pb (300 +/- 200 mg kg(-1)). When the pH of water in contact with the sediment was decreased experimentally from 6.4 to 2.6, the concentrations of dissolved trace metals increased by factors of 2200 for Pb, 160 for Cu, 21 for Zn, 9 for Cd, 8 for Ni, and 5 for Co. The order in which metals were released with decreasing pH was the reverse of that reported for pH-dependent sorption of these metals in upstream systems. Substantial release of trace metals from the sediment was observed even by a modest decrease of pH from 6.4 to 5.9. Therefore, the metal-rich sediment of the lake should be considered as potentially hazardous to bottom-dwelling aquatic species and other organisms in the local food chain. In addition, if the reservoir is dredged or if the dam is removed, the accumulated sediment may have to be treated for recovery of sorbed metals.

An elisa with a diagnostic sensitivity of 98 per cent and specificity of 96 per cent was evaluated as a means of assessing the intensity of Fasciola hepatica infection in cattle. A total of 294 blood samples were collected from infected cattle at a local abattoir, and the level of infection in each animal was assessed on the basis of the extent of liver pathology and the presence of flukes; 120 blood samples were also collected from uninfected cattle kept on a farm known to be free of F hepatica. The results indicated that there was a significant correlation (P<0.001) between the elisa values and the intensity of infection. Values between 15 and 28 per cent of a positive control sample indicated a low intensity of infection, values between 28 and 50 per cent indicated a medium intensity of infection and values above 50 per cent indicated a high intensity of infection.

Aerosol delivery of plasmid DNA therapeutic solutions is promising for the treatment of respiratory diseases. However, it poses challenges, most significantly the need to protect the delicate supercoiled (sc) structure of plasmid during aerosolization. Nebulizers for liquid aerosolization using meshes appear a better method for delivery than conventional jet and ultrasonic nebulizers. This paper explores their application to the delivery of plasmid DNA. A computational fluid dynamics model of the dynamics of fluid flow through the nozzle of the MicroAIR mesh nebulizer indicated high strain rates (>10(5) s(-1)) near the nozzle exit capable of causing damage to the shear-sensitive plasmid DNA. Knowledge of the strain rates predicted using CFD and molecule size determined using atomic force microscopy (AFM) enabled estimation of the hydrodynamic force and whether damage of shear-sensitive therapeutics was likely. Plasmids of size 5.7 and 20 kb were aerosolized in the mesh nebulizer. The sc structure of the 5.7-kb plasmid was successfully delivered without damage, while aerosolization of the 20-kb plasmid led to disintegration of the pDNA sc structure as observed in AFM. Subsequent formulation of the sc 20-kb plasmid with PEI resulted in successful aerosol delivery. The maximum hydrodynamic forces computed for the aerosolization of structures of the size of 5.7-kb and PEI formulated 20-kb plasmids were less than the forces reported to damage the structure of double-stranded DNA. A combination of CFD analysis and structure analysis may be used to predict successful aerosol delivery in such a mesh nebulizer.

Background and Purpose: Nicotinic agonists increase sympathetic field-stimulus-evoked contraction of the rodent vas deferens, presumably by increasing evoked neurotransmitter release. This presumption was tested in two species., Experimental Approach: The effect of the nicotinic acetylcholine receptor (nAChR) agonist epibatidine on neurotransmitter release in mouse and guinea pig isolated vas deferens was investigated using contraction studies and conventional intracellular recording techniques., Key Results: In 12 of 14 mouse vasa deferentia, slow bath application of epibatidine (100 nM) had no significant effect on excitatory junction potential (EJP) amplitude and spontaneous EJP (SEJP) frequency. However, rapid application of epibatidine to the mouse vas deferens caused an increase in SEJP frequency (by 530%), with no effect on EJP amplitude. Despite the absence of an effect on EJPs, electrically-evoked contractions of the mouse vas deferens were significantly increased in the presence of epibatidine (by 50%). A transient contraction was reliably induced by a higher epibatidine concentration (1 microM). This contraction was significantly reduced in the presence of prazosin, tetrodotoxin, or alpha,beta-methyleneATP. Epibatidine did not induce a contraction in the presence of a combination of prazosin, alpha,beta-methyleneATP and cyclopentolate. In guinea pig vasa deferentia, bath-applied epibatidine potentiated EJP amplitude in a biphasic pattern, lasting for at least 30 minutes., Conclusion and Implications: The nAChR-mediated augmentation of neurogenic contraction is indeed prejunctional, but in the mouse arises from an increase in spontaneous neurotransmitter release that primes smooth muscle for subsequent contraction, while in the guinea pig there is a direct augmentation of evoked neurotransmitter (ATP) release.

Experimental infection of cattle with Neospora caninum in early gestation causes foetal death, but the foetus survives infection in late gestation. An immunological mechanism of abortion has been suggested; therefore changes in the maternal immune response during pregnancy could account for these differences. We have investigated the peripheral immune responses of pregnant cattle following an intravenous inoculation with 10(7) N. caninum tachyzoites in early and late gestation. Percentages of CD2+ and CD4+ T-cells in peripheral blood mononuclear cells (PBMC) increased 1-2 weeks after infection in both early (day 70) and late (day 210) gestation, and percentages of CD8+ T-cells increased 1-2 weeks after infection at day 70. Interleukin-4 (IL-4) and interferon-gamma (IFN-gamma) mRNA expression in PBMC increased 1-2 weeks after infection at day 210 and IL-4 increased 1-2 weeks after infection at day 70. Immunomagnetic isolation of CD4+ cells from PBMC showed that they were a major source of IL-4 and IFN-gamma, and expression of both cytokines increased in CD4+ cells after infection in early and late gestation. These results suggest that CD4+ cells proliferate and express IL-4 and IFN-gamma in response to N. caninum irrespective of the stage of gestation when infection occurs.

Neospora caninum is an apicomplexan protozoan parasite that is a significant infectious abortifacient agent in cattle. Despite the fact that it is a member of a well described taxonomic group, it is a relatively newly discovered parasite and its biology is not yet fully understood. Cattle become infected either congenitally via transplacental transmission or post-natally by ingesting oocysts derived from the definitive host; dogs and coyotes are the only definitive hosts that have been described to date. It is not known which of these two forms of transmission occurs most frequently and which is the most likely to result in abortion; there are no drugs available to treat infected cattle, so current control strategies rely on prevention of infection by management methods and strict hygiene; an effective vaccine would be a great advantage in its control. Neospora caninum is an economically important veterinary pathogen, but we can also draw analogies between its foetopathic effects and those of human pathogens such as Toxoplasma gondii, Chlamydophila abortus and Plasmodium falciparum. Understanding the immune response and the materno-foetal relationship in N. caninum-infected cattle may help us to design vaccination strategies, not only for neosporosis but also for other foetopathic agents.

Liver fluke (Fasciola hepatica) infection caused weight loss, diarrhoea, decreased milk yield and occasionally death in cattle in East Anglia during the winters of 2001 to 2003. The condition had previously been limited mainly to stock imported into this part of Britain from endemically infected areas. In composite faecal samples collected by 16 farm animal veterinary practices in Norfolk, Suffolk and Essex, fluke eggs were found in 15 (28.8 per cent) of 52 previously unaffected suckler herds and 10 (16.7 per cent) of 60 dairy herds. Antibodies to F hepatica were detected by elisa in 32 (53.3 per cent) of the bulk milk samples from these 60 dairy herds, including the 10 in which fluke eggs were found. The emergence of fasciolosis in East Anglia was attributed to recent higher summer rainfall, which favoured the intermediate snail host Lymnaea truncatula and the free-living stages of F hepatica, the increased influx of sheep from endemic fluke areas for seasonal grazing, and the wetter grazing conditions associated with the Environmentally Sensitive Area scheme.

An ELISA developed to diagnose Fasciola hepatica infection in cattle by detecting serum antibodies was adapted and validated for use with samples of bulk-tank milk. The prevalence of the infection in 61 dairy herds was established by using serum antibody levels or faecal egg counts measured in a proportion of the cows in each herd. The correlation between the results of the ELISA and the herd seroprevalence was 0.83. Using a cut-off value of 27 per cent positive, the bulk-tank ELISA identified herds in which more than 25 per cent of the cows were infected with a diagnostic sensitivity of 96 per cent (95 per cent confidence interval 89 to 100 per cent) and a diagnostic specificity of 80 per cent (95 per cent confidence interval 66 to 94 per cent). By applying the ELISA to 623 herds in England and 445 herds in Wales, the prevalence of F hepatica infection in England was estimated to be 48 per cent (95 per cent confidence interval 46 to 54 per cent), and in Wales 86 per cent (95 per cent confidence interval 84 to 90 per cent).

A commercially available serum antibody detection enzyme-linked immunosorbent assay for Neospora caninum in cattle was evaluated against an immunofluorescent antibody test (IFAT) by applying it to 397 sera from normal adult cattle, 352 sera from cattle which had recently aborted, and 422 sera from two herds which had a history of N caninum-associated abortions. It was evaluated in two laboratories and showed high reproducibility, repeatability and almost perfect or substantial agreement with the IFAT.

An enzyme-linked immunosorbent assay (ELISA) to detect antibodies to Neospora species in cattle was developed. Whole formalin-fixed Neospora caninum (NC-Liverpool) tachyzoites were used as antigen and a monoclonal antibody to bovine immunoglobulin light chain and an anti-mouse horseradish peroxidase conjugate were used to reveal bound antibody. A panel of 46 sera, negative by the immunofluorescent antibody test (IFAT), were used in the ELISA at a serum dilution of 1:500 to calculate the negative cut-off value of OD405 = 0.77. There was a 95 per cent agreement between the results of the ELISA and the IFAT with 104 serum samples. The specificity and sensitivity of the ELISA were 96 per cent and 95 per cent, respectively, when compared with the IFAT. No significant cross-reaction was observed with the sera from cattle infected experimentally with Toxoplasma gondii, Cryptosporidium parvum, Babesia divergens, Sarcocystis cruzi, Eimeria alabamensis or E bovis. A significantly modified version of the test is now commercially available.

It has been reported that some breeds of cattle such as the N'Dama mount a more effective antibody response to the variable surface glycoprotein coat of trypanosomes and that this may contribute to their ability to control the infection. Thus we have investigated antibody responses to surface exposed epitopes of the variable surface glycoprotein in Trypanosoma congolense-infected N'Dama (trypanotolerant) and Boran (susceptible) cattle. Similar titres and isotypes were found in both N'Damas and Borans indicating that trypanotolerance is not associated with superior antibody-mediated destruction of trypanosomes. However, significant differences in antibody responses to cryptic VSG epitopes and non-trypanosome antigens were identified. Trypanosusceptible Boran cattle had low IgG1 responses to cryptic epitopes but high IgM responses to non-trypanosome antigens such as beta-galactosidase. In contrast the N'Dama cattle had significantly higher IgG1 responses to cryptic VSG epitopes and negligible responses to beta-galactosidase. These results indicate differences in the induction of anti-trypanosome immune responses between trypanotolerant and susceptible cattle infected with T. congolense.

The high ability of African buffalo, as compared to domestic cattle, to control infections with Trypanosoma brucei brucei ILTat 1.4 organisms did not correlate with the timing or magnitude of parasite surface coat-specific antibody responses and may have resulted from the constitutive presence in buffalo blood of a novel trypanocidal factor. Buffalo plasma and serum contained material that killed bloodstream stage T. b. brucei, T. b. rhodesiense, T. b. gambiense, T. evansi, T. congolense, and T. vivax organisms during four h of incubation at 37 degrees C in vitro. Serum from eland was also trypanocidal whereas serum from oryx, waterbuck, yellow-back duiker, cattle, horse, sheep, goat, mouse, rat, and rabbit was not trypanocidal. The buffalo serum trypanocidal material was not lipoprotein, or IgG, and had the following properties: 1) a density of > 1.24 g/ml determined by flotation ultracentrifugation; 2) insolubility in 50% saturated ammonium sulphate; 3) non-reactivity with anti-bovine IgM, and anti-bovine IgG; 4) non-reactivity with protein G, and protein A; 5) a relative molecular mass of 152 kDa determined by chromatography on Sephacryl S 300, and of 133 kDa determined by chromatography of the 50% SAS cut of IgG-depleted buffalo serum on Superose 12; 6) no associated cholesterol; and 7) inactivation by digestion with proteinase K that was immobilized on agarose.

A cysteine protease of Trypanosoma congolense (congopain) elicited IgG1 antibodies in those cattle which exhibited a degree of resistance to disease during experimental infections (Authié et al. 1992, 1993). The aim of the present study was to investigate further the association between anti-congopain antibodies and resistance to trypanosomiasis, and to provide a lead into the mechanisms responsible for the differential responses to congopain in cattle. Isotype characteristics and kinetics of the antibody response to congopain were studied in three N'Dama (trypanoresistant) and three Boran (susceptible) cattle during primary infection with T. congolense ILNat 3.1. In both groups an IgM response to congopain was elicited, thus demonstrating that congopain is antigenic in both types of cattle. Most of the IgM appeared to be incorporated into immune complexes. IgG was detected as free antibody; IgG1 but not IgG2 was detected. All three N'Dama, but none of the three Boran cattle, mounted a significant IgG response to congopain. Sera from 70 primary-infected cattle belonging to five breeds of differing susceptibility were tested for their reactivity to congopain. High levels of IgG to congopain were observed in the two trypanotolerant breeds, whereas the three susceptible breeds had lower levels of these antibodies. Crosses between N'Dama and Boran cattle, which exhibit an intermediate susceptibility, had intermediate levels of antibodies. Thus, the results from experimental infections confirmed our initial observations. However, under natural tsetse challenge, repeated infections and trypanocidal treatments in Zebu cattle stimulated as high anti-congopain antibody levels as in non-treated trypanotolerant taurine cattle.