Astrocytes are endogenous regulators of basal transmission at central synapses.

Basal synaptic transmission involves the release of neurotransmitters at individual synapses in response to a single action potential. Recent discoveries show that astrocytes modulate the activity of neuronal networks upon sustained and intense synaptic activity. However, their ability to regulate basal synaptic transmission remains ill defined and controversial. Here, we show that astrocytes in the hippocampal CA1 region detect synaptic activity induced by single-synaptic stimulation. Astrocyte activation occurs at functional compartments found along astrocytic processes and involves metabotropic glutamate subtype 5 receptors. In response, astrocytes increase basal synaptic transmission, as revealed by the blockade of their activity with a Ca(2+) chelator. Astrocytic modulation of basal synaptic transmission is mediated by the release of purines and the activation of presynaptic A(2A) receptors by adenosine. Our work uncovers an essential role for astrocytes in the regulation of elementary synaptic communication and provides insight into fundamental aspects of brain function.

Determination of [N-13]-ammonia extraction fraction in patients with coronary artery disease by calibration to invasive coronary and fractional flow reserve.

BACKGROUND: This study presents a new extraction fraction (EF) model based on physiological measures of invasive coronary flow reserve (CFR) and fractional flow reserve (FFR) in patients with suspected coronary artery disease (CAD) and normal index microcirculatory resistance (IMR). To ascertain the clinical relevance of the new EFs, flow measurements using the newly patient-determined EFs were compared to flow measurements using traditional animal-determined EFs. METHODS: 39 patients were retrospectively selected that included a total of 91 vascular territories with invasive coronary angiography physiological measures. [N-13]-ammonia dynamic rest/adenosine-stress PET imaging was conducted in all patients and absolute myocardial flow was estimated using four published compartmental models. The extraction fraction during hyperemic flow was iteratively estimated by maximizing the agreement between invasive CFR and FFR with the non-invasive analogs myocardial flow reserve (MFR) and relative flow reserve (RFR) at similar physiological states, respectively. RESULTS: Using the new patient-determined EFs, agreement between CFR vs MFR for Model 1 and 2 was moderate and poor for Model 3 and 4. All models showed moderate agreement for FFR vs RFR. When using published models of animal-determined EFs, agreement between CFR vs MFR remained moderate for Model 1 and 2, and poor for Model 3 and 4. Similarly, all models showed moderate agreement for FFR vs RFR using animal-determined EF values. None of the observed differences were statistically significant. CONCLUSIONS: Flow measurements using extraction fraction correction for [N-13]-ammonia based on calibration to invasive intracoronary angiography physiological measures in patients with CAD were not discordant from those reported in the literature. Either patient-determined or traditional animal-determined EF correction, when used with the appropriate flow model, yields moderate agreement with invasive measurements of coronary flow reserve and fractional flow reserve.

Postvaccination Serum Antirotavirus Immunoglobulin A as a Correlate of Protection Against Rotavirus Gastroenteritis Across Settings.

BACKGROUND: A correlate of protection for rotavirus gastroenteritis would facilitate rapid assessment of vaccination strategies and the next generation of rotavirus vaccines. We aimed to quantify a threshold of postvaccine serum antirotavirus immunoglobulin A (IgA) as an individual-level immune correlate of protection against rotavirus gastroenteritis. METHODS: Individual-level data on 5074 infants in 9 GlaxoSmithKline Rotarix Phase 2/3 clinical trials from 16 countries were pooled. Cox proportional hazard models were fit to estimate hazard ratios (HRs) describing the relationship between IgA thresholds and occurrence of rotavirus gastroenteritis. RESULTS: Seroconversion (IgA ≥ 20 U/mL) conferred substantial protection against any and severe rotavirus gastroenteritis to age 1 year. In low child mortality settings, seroconversion provided near perfect protection against severe rotavirus gastroenteritis (HR, 0.04; 95% confidence interval [CI], .01-.31). In high child mortality settings, seroconversion dramatically reduced the risk of severe rotavirus gastroenteritis (HR, 0.46; 95% CI, .25-.86). As IgA threshold increased, risk of rotavirus gastroenteritis generally decreased. A given IgA threshold provided better protection in low compared to high child mortality settings. DISCUSSION: Postvaccination antirotavirus IgA is a valuable correlate of protection against rotavirus gastroenteritis to age 1 year. Seroconversion provides an informative threshold for assessing rotavirus vaccine performance.

Longer-term Direct and Indirect Effects of Infant Rotavirus Vaccination Across All Ages in the United States in 2000-2013: Analysis of a Large Hospital Discharge Data Set.

BACKGROUND: Rotavirus disease rates dramatically declined among children <5 years of age since the rotavirus vaccine was introduced in 2006; population-level impacts remain to be fully elucidated. METHODS: Data from the Healthcare Cost and Utilization Project State Inpatient Databases were used to conduct a time-series analysis of monthly hospital discharges across age groups for acute gastroenteritis and rotavirus from 2000 to 2013. Rate ratios were calculated comparing prevaccine and postvaccine eras. RESULTS: Following vaccine introduction, a decrease in rotavirus hospitalizations occurred with a shift toward biennial patterns across all ages. The 0-4-year age group experienced the largest decrease in rotavirus hospitalizations (rate ratio, 0.14; 95% confidence interval, .09-.23). The 5-19-year and 20-59-year age groups experienced significant declines in rotavirus hospitalization rates overall; the even postvaccine calendar years were characterized by progressively lower rates, and the odd postvaccine years were associated with reductions in rates that diminished over time. Those aged ≥60 years experienced the smallest change in rotavirus hospitalization rates overall, with significant reductions in even postvaccine years compared with prevaccine years (rate ratio, 0.51; 95% confidence interval, .39-.66). CONCLUSIONS: Indirect impacts of infant rotavirus vaccination are apparent in the emergence of biennial patterns in rotavirus hospitalizations that extend to all age groups ineligible for vaccination. These observations are consistent with the notion that young children are of primary importance in disease transmission and that the initial postvaccine period of dramatic population-wide impacts will be followed by more complex incidence patterns across the age range in the long term.

Antirotavirus IgA seroconversion rates in children who receive concomitant oral poliovirus vaccine: A secondary, pooled analysis of Phase II and III trial data from 33 countries.

BACKGROUND: Despite the success of rotavirus vaccines over the last decade, rotavirus remains a leading cause of severe diarrheal disease among young children. Further progress in reducing the burden of disease is inhibited, in part, by vaccine underperformance in certain settings. Early trials suggested that oral poliovirus vaccine (OPV), when administered concomitantly with rotavirus vaccine, reduces rotavirus seroconversion rates after the first rotavirus dose with modest or nonsignificant interference after completion of the full rotavirus vaccine course. Our study aimed to identify a range of individual-level characteristics, including concomitant receipt of OPV, that affect rotavirus vaccine immunogenicity in high- and low-child-mortality settings, controlling for individual- and country-level factors. Our central hypothesis was that OPV administered concomitantly with rotavirus vaccine reduced rotavirus vaccine immunogenicity. METHODS AND FINDINGS: Pooled, individual-level data from GlaxoSmithKline's Phase II and III clinical trials of the monovalent rotavirus vaccine (RV1), Rotarix, were analyzed, including 7,280 vaccinated infants (5-17 weeks of age at first vaccine dose) from 22 trials and 33 countries/territories (5 countries/territories with high, 13 with moderately low, and 15 with very low child mortality). Two standard markers for immune response were examined including antirotavirus immunoglobulin A (IgA) seroconversion (defined as the appearance of serum antirotavirus IgA antibodies in subjects initially seronegative) and serum antirotavirus IgA titer, both collected approximately 4-12 weeks after administration of the last rotavirus vaccine dose. Mixed-effect logistic regression and mixed-effect linear regression of log-transformed data were used to identify individual- and country-level predictors of seroconversion (dichotomous) and antibody titer (continuous), respectively. Infants in high-child-mortality settings had lower odds of seroconverting compared with infants in low-child-mortality settings (odds ratio [OR] = 0.48, 95% confidence interval [CI] 0.43-0.53, p < 0.001). Similarly, among those who seroconverted, infants in high-child-mortality settings had lower IgA titers compared with infants in low-child-mortality settings (mean difference [ß] = 0.83, 95% CI 0.77-0.90, p < 0.001). Infants who received OPV concomitantly with both their first and their second doses of rotavirus vaccine had 0.63 times the odds of seroconverting (OR = 0.63, 95% CI 0.47-0.84, p = 0.002) compared with infants who received OPV but not concomitantly with either dose. In contrast, among infants who seroconverted, OPV concomitantly administered with both the first and second rotavirus vaccine doses was found to be positively associated with antirotavirus IgA titer (ß = 1.28, 95% CI 1.07-1.53, p = 0.009). Our findings may have some limitations in terms of generalizability to routine use of rotavirus vaccine because the analysis was limited to healthy infants receiving RV1 in clinical trial settings. CONCLUSIONS: Our findings suggest that OPV given concomitantly with RV1 was a substantial contributor to reduced antirotavirus IgA seroconversion, and this interference was apparent after the second vaccine dose of RV1, as with the original clinical trials that our reanalysis is based on. However, our findings do suggest that the forthcoming withdrawal of OPV from the infant immunization schedule globally has the potential to improve RV1 performance.

A Dynamic Model for Evaluation of the Bias of Influenza Vaccine Effectiveness Estimates From Observational Studies.

Given that influenza vaccination is now widely recommended in the United States, observational studies based on patients with acute respiratory illness (ARI) remain as the only option to estimate influenza vaccine effectiveness (VE). We developed a dynamic probability model to evaluate bias of VE estimates from passive surveillance cohort, test-negative, and traditional case-control studies. The model includes 2 covariates (health status and health awareness) that might affect the probabilities of vaccination, developing ARI, and seeking medical care. Our results suggest that test-negative studies produce unbiased estimates of VE against medically attended influenza when: 1) Vaccination does not affect the probability of noninfluenza ARI; and 2) health status has the same effect on the probability of influenza and noninfluenza ARIs. The same estimate might be severely biased (i.e., estimated VE - true VE ≥ 0.20) for estimating VE against symptomatic influenza if the vaccine affects the probability of seeking care against influenza ARI. VE estimates from test-negative studies might also be severely biased for both outcomes of interest when vaccination affects the probability of noninfluenza ARI, but estimates from passive surveillance cohort studies are unbiased in this case. Finally, VE estimates from traditional case-control studies suffer from bias regardless of the source of bias.

Maximum likelihood estimation of influenza vaccine effectiveness against transmission from the household and from the community.

Influenza vaccination is recommended as the best way to protect against influenza infection and illness. Due to seasonal changes in influenza virus types and subtypes, a new vaccine must be produced, and vaccine effectiveness (VE) must be estimated, annually. Since 2010, influenza vaccination has been recommended universally in the United States, making randomized clinical trials unethical. Recent studies have used a monitored household cohort study design to determine separate VE estimates against influenza transmission from the household and community. We developed a probability model and accompanying maximum likelihood procedure to estimate vaccine-related protection against transmission of influenza from the household and the community. Using agent-based stochastic simulations, we validated that we can obtain maximum likelihood estimates of transmission parameters and VE close to their true values. Sensitivity analyses to examine the effect of deviations from our assumptions were conducted. We used our method to estimate transmission parameters and VE from data from a monitored household study in Michigan during the 2012-2013 influenza season and were able to detect a significant protective effect of influenza vaccination against community-acquired transmission.

Estimating Direct and Indirect Protective Effect of Influenza Vaccination in the United States.

With influenza vaccination rates in the United States recently exceeding 45% of the population, it is important to understand the impact that vaccination is having on influenza transmission. In this study, we used a Bayesian modeling approach, combined with a simple dynamical model of influenza transmission, to estimate this impact. The combined framework synthesized evidence from a range of data sources relating to influenza transmission and vaccination in the United States. We found that, for seasonal epidemics, the number of infections averted ranged from 9.6 million in the 2006-2007 season (95% credible interval (CI): 8.7, 10.9) to 37.2 million (95% CI: 34.1, 39.6) in the 2012-2013 season. Expressed in relative terms, the proportion averted ranged from 20.8% (95% CI: 16.8, 24.3) of potential infections in the 2011-2012 season to 47.5% (95% CI: 43.7, 50.8) in the 2008-2009 season. The percentage averted was only 1.04% (95% CI: 0.15, 3.2) for the 2009 H1N1 pandemic, owing to the late timing of the vaccination program in relation to the pandemic in the Northern hemisphere. In the future, further vaccination coverage, as well as improved influenza vaccines (especially those offering better protection in the elderly), could have an even stronger effect on annual influenza epidemics.

A comparison of the test-negative and the traditional case-control study designs for estimation of influenza vaccine effectiveness under nonrandom vaccination.

BACKGROUND: As annual influenza vaccination is recommended for all U.S. persons aged 6 months or older, it is unethical to conduct randomized clinical trials to estimate influenza vaccine effectiveness (VE). Observational studies are being increasingly used to estimate VE. We developed a probability model for comparing the bias and the precision of VE estimates from two case-control designs: the traditional case-control (TCC) design and the test-negative (TN) design. In both study designs, acute respiratory illness (ARI) patients seeking medical care testing positive for influenza infection are considered cases. In the TN design, ARI patients seeking medical care who test negative serve as controls, while in the TCC design, controls are randomly selected individuals from the community who did not contract an ARI. METHODS: Our model assigns each study participant a covariate corresponding to the person's health status. The probabilities of vaccination and of contracting influenza and non-influenza ARI depend on health status. Hence, our model allows non-random vaccination and confounding. In addition, the probability of seeking care for ARI may depend on vaccination and health status. We consider two outcomes of interest: symptomatic influenza (SI) and medically-attended influenza (MAI). RESULTS: If vaccination does not affect the probability of non-influenza ARI, then VE estimates from TN studies usually have smaller bias than estimates from TCC studies. We also found that if vaccinated influenza ARI patients are less likely to seek medical care than unvaccinated patients because the vaccine reduces symptoms' severity, then estimates of VE from both types of studies may be severely biased when the outcome of interest is SI. The bias is not present when the outcome of interest is MAI. CONCLUSIONS: The TN design produces valid estimates of VE if (a) vaccination does not affect the probabilities of non-influenza ARI and of seeking care against influenza ARI, and (b) the confounding effects resulting from non-random vaccination are similar for influenza and non-influenza ARI. Since the bias of VE estimates depends on the outcome against which the vaccine is supposed to protect, it is important to specify the outcome of interest when evaluating the bias.

The E3 ubiquitin ligase parkin is recruited to the 26 S proteasome via the proteasomal ubiquitin receptor Rpn13.

Mutations in the Park2 gene, encoding the RING-HECT hybrid E3 ubiquitin ligase parkin, are responsible for a common familial form of Parkinson disease. By mono- and polyubiquitinating target proteins, parkin regulates various cellular processes, including degradation of proteins within the 26 S proteasome, a large multimeric degradation machine. In our attempt to further elucidate the function of parkin, we have identified the proteasomal ubiquitin receptor Rpn13/ADRM1 as a parkin-interacting protein. We show that the N-terminal ubiquitin-like (Ubl) domain of parkin binds directly to the pleckstrin-like receptor for ubiquitin (Pru) domain within Rpn13. Using mutational analysis and NMR, we find that Pru binding involves the hydrophobic patch surrounding Ile-44 in the parkin Ubl, a region that is highly conserved between ubiquitin and Ubl domains. However, compared with ubiquitin, the parkin Ubl exhibits greater than 10-fold higher affinity for the Pru domain. Moreover, knockdown of Rpn13 in cells increases parkin levels and abrogates parkin recruitment to the 26 S proteasome, establishing Rpn13 as the major proteasomal receptor for parkin. In contrast, silencing Rpn13 did not impair parkin recruitment to mitochondria or parkin-mediated mitophagy upon carbonyl cyanide m-chlorophenyl hydrazone-induced mitochondrial depolarization. However, it did delay the clearance of mitochondrial proteins (TIM23, TIM44, and TOM20) and enhance parkin autoubiquitination. Taken together, these findings implicate Rpn13 in linking parkin to the 26 S proteasome and regulating the clearance of mitochondrial proteins during mitophagy.

A simulation study of nonparametric total deviation index as a measure of agreement based on quantile regression.

Total deviation index (TDI) captures a prespecified quantile of the absolute deviation of paired observations from raters, observers, methods, assays, instruments, etc. We compare the performance of TDI using nonparametric quantile regression to the TDI assuming normality (Lin, 2000). This simulation study considers three distributions: normal, Poisson, and uniform at quantile levels of 0.8 and 0.9 for cases with and without contamination. Study endpoints include the bias of TDI estimates (compared with their respective theoretical values), standard error of TDI estimates (compared with their true simulated standard errors), and test size (compared with 0.05), and power. Nonparametric TDI using quantile regression, although it slightly underestimates and delivers slightly less power for data without contamination, works satisfactorily under all simulated cases even for moderate (say, ≥40) sample sizes. The performance of the TDI based on a quantile of 0.8 is in general superior to that of 0.9. The performances of nonparametric and parametric TDI methods are compared with a real data example. Nonparametric TDI can be very useful when the underlying distribution on the difference is not normal, especially when it has a heavy tail.

Inactivated influenza vaccines for prevention of community-acquired pneumonia: the limits of using nonspecific outcomes in vaccine effectiveness studies.

BACKGROUND: One to 4 million cases of community-acquired pneumonia (CAP) occur annually in the United States, resulting in 600,000 hospitalizations and 45,000 deaths. Influenza infection facilitates secondary bacterial infections, and influenza vaccination may prevent CAP directly by preventing influenza pneumonia or indirectly by preventing secondary bacterial CAP. METHODS: We investigated how influenza vaccination could affect incidence of CAP using deterministic probability and stochastic simulation models. The models included likely influential factors, including vaccine effectiveness (VE) against influenza, rates of influenza in the unvaccinated, vaccination coverage, and the relative risk (RR) of pneumonia, given influenza infection. To estimate effectiveness of influenza vaccine against CAP, we assumed mean VE against influenza of 55% and vaccine coverage of 38%. RESULTS: Given our baseline parameters, influenza vaccine had a mean effectiveness against CAP of 7% (95% confidence interval = 0-25%). Effectiveness of influenza vaccine against CAP increased as its effectiveness against influenza increased, as RR of pneumonia after influenza infection increased, and as rates of influenza among unvaccinated persons increased. CONCLUSIONS: No matter how effective vaccine may be in preventing influenza infection, it is only modestly effective at preventing CAP. Because of the large annual burden of CAP, a vaccine that is only moderately effective in preventing influenza infection has the potential to prevent a substantial number of CAP cases. This modeling approach may be useful for planning influenza vaccine-probe studies and evaluating the effectiveness of other interventions targeted against infections that manifest in nonspecific outcomes.

A regulated interaction with the UIM protein Eps15 implicates parkin in EGF receptor trafficking and PI(3)K-Akt signalling.

Mutations in the parkin gene are responsible for a common familial form of Parkinson's disease. As parkin encodes an E3 ubiquitin ligase, defects in proteasome-mediated protein degradation are believed to have a central role in the pathogenesis of Parkinson's disease. Here, we report a novel role for parkin in a proteasome-independent ubiquitination pathway. We have identified a regulated interaction between parkin and Eps15, an adaptor protein that is involved in epidermal growth factor (EGF) receptor (EGFR) endocytosis and trafficking. Treatment of cells with EGF stimulates parkin binding to both Eps15 and the EGFR and promotes parkin-mediated ubiquitination of Eps15. Binding of the parkin ubiquitin-like (Ubl) domain to the Eps15 ubiquitin-interacting motifs (UIMs) is required for parkin-mediated Eps15 ubiquitination. Furthermore, EGFR endocytosis and degradation are accelerated in parkin-deficient cells, and EGFR signalling via the phosphoinositide 3-kinase (PI(3)K)-Akt pathway is reduced in parkin knockout mouse brain. We propose that by ubiquitinating Eps15, parkin interferes with the ability of the Eps15 UIMs to bind ubiquitinated EGFR, thereby delaying EGFR internalization and degradation, and promoting PI(3)K-Akt signalling. Considering the role of Akt in neuronal survival, our results have broad new implications for understanding the pathogenesis of Parkinson's disease.

Invasive pneumococcal pneumonia and respiratory virus co-infections.

To confirm whether respiratory virus infections increase susceptibility to invasive pneumococcal pneumonia, we examined data from 11 influenza seasons (1994-2005) in the United States. Invasive pneumococcal pneumonia was significantly associated with influenza and respiratory syncytial virus activities in 5 seasons. Association strength was higher when strain H3N2 was the predominant influenza A virus strain.

Frequency and determinants of disagreement and error in gleason scores: a population-based study of prostate cancer.

BACKGROUND: To examine factors that affect accuracy and reliability of prostate cancer grade we compared Gleason scores documented in pathology reports and those assigned by urologic pathologists in a population-based study. METHODS: A stratified random sample of 318 prostate cancer cases was selected to ensure representation of whites and African-Americans and to include facilities of various types. The slides borrowed from reporting facilities were scanned and the resulting digital images were re-reviewed by two urologic pathologists. If the two urologic pathologists disagreed, a third urologic pathologist was asked to help arrive at a final "gold standard" result. The agreements between reviewers and between the pathology reports and the "gold standard" were examined by calculating kappa statistics. The determinants of discordance in Gleason scores were evaluated using multivariate models with results expressed as odds ratios (OR) and 95% confidence intervals (CI). RESULTS: The kappa values (95% CI) reflecting agreement between the pathology reports and the "gold standard," were 0.61 (95% CI: 0.54, 0.68) for biopsies, and 0.37 (0.23, 0.51) for prostatectomies. Sixty three percent of discordant biopsies and 72% of discordant prostatectomies showed only minimal differences. Using freestanding laboratories as reference, the likelihood of discordance between pathology reports and expert-assigned biopsy Gleason scores was particularly elevated for small community hospitals (OR = 2.98; 95% CI: 1.73, 5.14). CONCLUSIONS: The level of agreement between pathology reports and expert review depends on the type of diagnosing facility, but may also depend on the level of expertise and specialization of individual pathologists.

A new permutation-based method for assessing agreement between two observers making replicated quantitative readings.

The coefficient of individual equivalence is a permutation-based measure of agreement between two observers making replicated readings on each subject. It compares the observed disagreement between the observers to the expected disagreement under individual equivalence. Individual equivalence of observers requires that for every study subject, the conditional distributions of the readings of the observers given the subject's characteristics are identical. Therefore, under individual equivalence it does not matter which observer is making a particular reading on a given subject. We introduce both nonparametric and parametric methods to estimate the coefficient as well as its standard error. We compare the new coefficient with the coefficient of individual agreement and with the concordance correlation coefficient. We also evaluate the performance of the estimates of the new coefficient via simulations and illustrate this new approach using data from a study comparing two noninvasive techniques for measuring carotid stenosis to an invasive gold standard.

Rural African American parents' knowledge and decisions about human papillomavirus vaccination.

PURPOSE: To identify predictors of human papillomavirus (HPV) vaccination among rural African American families. DESIGN: Cross-sectional descriptive study in schools in three rural counties in southeastern United States. The sample consisted of African American parents or caregivers with children 9 to 13 years of age who attended elementary or middle school in 2010-2011. METHODS: Using an anonymous, 26-item survey, we collected descriptive data during parent-teacher events from African American parents with children in elementary or middle school. The main outcome was measured as a response of "yes" to the statement "I have or will vaccinate my child with the HPV vaccine." In addition, composite scores of knowledge and positive attitudes and beliefs were compared. No interventions were conducted. FINDINGS: We identified predictors of HPV vaccination and found that religious affiliation had a correlation with vaccinating or planning to vaccinate a child. CONCLUSIONS: Results indicate a need for further research on the role of local culture, including religion and faith, in rural African Americans' decisions about giving their children the HPV vaccination. CLINICAL RELEVANCE: This study emphasizes the importance of understanding rural African American parents' knowledge, attitudes, and spiritual beliefs when designing health education programs and public health interventions to increase HPV vaccination uptake among African American boys and girls living in rural areas.

Outpatient antibiotic prescribing and nonsusceptible Streptococcus pneumoniae in the United States, 1996-2003.

BACKGROUND: Streptococcus pneumoniae infections have become increasingly complicated and costly to treat with the spread of antibiotic resistance. We evaluated the relationship between antibiotic prescribing and nonsusceptibility among invasive pneumococcal disease (IPD) isolates. METHODS: Outpatient antibiotic prescription data for penicillins, cephalosporins, macrolides, and trimethoprim-sulfamethoxazole were abstracted from the IMS Health Xponent database to calculate the annual number of prescriptions per capita. We analyzed IPD data from 7 of the Centers for Disease Control and Prevention's Active Bacterial Core surveillance sites (population, 18.6 million) for which data were available for the entire time period under study (1996-2003). Logistic regression models were used to assess whether sites with high antibiotic prescribing rates had a high proportion of nonsusceptible and serotype 19A IPD. RESULTS: Yearly prescribing rates during the period 1996-2003 for children <5 years of age decreased by 37%, from 4.23 to 2.68 prescriptions per capita per year (P < .001), and those for persons ≥5 years of age decreased by 42%, from 0.98 to 0.57 prescriptions per capita per year (P < .001); increases in azithromycin prescribing were noted for both groups. Sites with high rates of antibiotic prescribing had a higher proportion of IPD nonsusceptibility than did low-prescribing sites (P = .003 for penicillin, P < .001 for every other antibiotic class). Cephalosporin and macrolide prescribing were associated with penicillin and multidrug nonsusceptibility and serotype 19A IPD (P < .001). CONCLUSIONS: In sites where antibiotic prescribing is high, the proportion of nonsusceptible IPD is also high, suggesting that local prescribing practices contribute to local resistance patterns. Cephalosporins and macrolides seem to be selecting for penicillin- and multidrug-resistant pneumococci, as well as serotype 19A IPD. Antibiotic use is a major factor contributing to the spread of antibiotic resistance; strategies to reduce antibiotic resistance should continue to include judicious use of antibiotics.

A new permutation-based method for assessing agreement between two observers making replicated binary readings.

A new coefficient for assessing agreement between two observers using a permutation-based method is introduced in this article. When observations are binary, this coefficient compares the observed disagreement (probability of discordance) between the observers with its expected value under the hypothesis of individual equivalence. This hypothesis states that for each subject, the conditional distributions of the readings of the two observers are identical, and therefore from a statistical viewpoint it does not matter which observer makes the reading on this subject. Let K and L denote the numbers of replicated observations that are available from observers X and Y, respectively, on a given subject. Then the expected disagreement under individual equivalence for a subject is based on the (K + L) choosing K possible assignments of X's and Y's to the K + L observations made on this subject. Simple methods for the estimation of the new coefficient and its standard error are derived. The new coefficient is compared with kappa and the coefficient of individual agreement, which is based on comparing the inter and intra observer disagreements. Simulation studies confirm the validity of the estimated coefficient and its standard error. Data from a study involving the evaluation of mammograms by 10 radiologists are used to illustrate this new approach to the evaluation of observer agreement.

Beneficial effects of secretory leukocyte protease inhibitor after spinal cord injury.

Secretory leukocyte protease inhibitor is a serine protease inhibitor produced by various cell types, including neutrophils and activated macrophages, and has anti-inflammatory properties. It has been shown to promote wound healing in the skin and other non-neural tissues, however, its role in central nervous system injury was not known. We now report a beneficial role for secretory leukocyte protease inhibitor after spinal cord injury. After spinal cord contusion injury in mice, secretory leukocyte protease inhibitor is expressed primarily by astrocytes and neutrophils but not macrophages. We show, using transgenic mice over-expressing secretory leukocyte protease inhibitor, that this molecule has an early protective effect after spinal cord contusion injury. Furthermore, wild-type mice treated for the first week after spinal cord contusion injury with recombinant secretory leukocyte protease inhibitor exhibit sustained improvement in locomotor control and reduced secondary tissue damage. Recombinant secretory leukocyte protease inhibitor injected intraperitoneally localizes to the nucleus of circulating leukocytes, is detected in the injured spinal cord, reduces activation of nuclear factor-kappaB and expression of tumour necrosis factor-alpha. Administration of recombinant secretory leukocyte protease inhibitor might therefore be useful for the treatment of acute spinal cord injury.