Search

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., (© 2021. American Society of Nuclear Cardiology.)

Introduction: Vaccination has significantly reduced morbidity and mortality resulting from rotavirus infection worldwide. However, rotavirus vaccine efficacy (VE) appears to wane over the first 2 years since vaccination, particularly in developing countries. Statistical methods for detecting VE waning and estimating its rate have been used in a few studies, but comparisons of methods for evaluating VE waning have not yet been performed. In this work we present and compare three methods - Durham's method, Tian's method, and time-dependent covariate (TDC) method - based on generalizations of the Cox proportional hazard model., Methods: We developed a new stochastic agent-based simulation model to generate data from a hypothetical rotavirus vaccine trial where the protective efficacy of the vaccine may vary over time. Input parameters to the simulation model were obtained from studies on rotavirus infections in four developing countries. We applied each of the methods to four simulated datasets and compared the type-1 error probabilities and the powers of the resulting statistical tests. We also compared estimated and true values of VE over time., Results: Durham's method had the highest power of detecting true VE waning of the three methods. This method also provided quite accurate estimates of VE in each period and of the per-period drop in VE., Conclusions: Durham's method is somewhat more powerful than the other two Cox proportional hazards model-based methods for detecting VE waning and provides more information about the temporal behavior of VE.

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., (Published by Oxford University Press for the Infectious Diseases Society of America 2020.)

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 [β] = 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 (β = 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., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: BAL has received personal fees from Takeda Pharmaceuticals, personal fees from CDC Foundation, and personal fees from Hall Booth Smith, P.C., outside the submitted work. All other authors declare no competing interests.

Introduction : Influenza vaccination is regarded as the most effective way to prevent influenza infection. Due to the rapid genetic changes that influenza viruses undergo, seasonal influenza vaccines must be reformulated and re-administered annually necessitating the evaluation of influenza vaccine effectiveness (VE) each year. The estimation of influenza VE presents numerous challenges. Areas Covered : This review aims to identify, discuss, and, where possible, offer suggestions for dealing with the following challenges in estimating influenza VE: different outcomes of interest against which VE is estimated, study designs used to assess VE, sources of bias and confounding, repeat vaccination, waning immunity, population level effects of vaccination, and VE in at-risk populations. Expert Opinion : The estimation of influenza VE has improved with surveillance networks, better understanding of sources of bias and confounding, and the implementation of advanced statistical methods. Future research should focus on better estimates of the indirect effects of vaccination, the biological effects of vaccination, and how vaccines interact with the immune system. Specifically, little is known about how influenza vaccination impacts an individual's infectiousness, how vaccines wane over time, and the impact of repeated vaccination.

Background: Rotavirus is the leading cause of severe diarrhea among children worldwide, and vaccines can reduce morbidity and mortality by 50-98%. The test-negative control (TNC) study design is increasingly used for evaluating the effectiveness of vaccines against rotavirus and other vaccine-preventable diseases. In this study design, symptomatic patients who seek medical care are tested for the pathogen of interest. Those who test positive (negative) are classified as cases (controls)., Methods: We use a probability model to evaluate the bias of estimates of rotavirus vaccine effectiveness (VE) against rotavirus diarrhea resulting in hospitalization in the presence of possible confounding and selection biases due to differences in the propensity of seeking medical care (PSMC) between vaccinated and unvaccinated children., Results: The TNC-based VE estimate corrects for confounding bias when the confounder's effects on the probabilities of rotavirus and non-rotavirus related hospitalizations are equal. If this condition is not met, then the estimated VE may be substantially biased. The bias is more severe in low-income countries, where VE is known to be lower. Under our model, differences in PSMC between vaccinated and unvaccinated children do not result in selection bias when the TNC study design is used., Conclusions: In practice, one can expect the association of PSMC (or other potential confounders) with the probabilities of rotavirus and non-rotavirus related hospitalization to be similar, in which case the confounding effects will only result in small bias in the VE estimate from TNC studies. The results of this work, along with those of our previous paper, confirm the TNC design can be expected to provide reliable estimates of rotavirus VE in both high- and low-income countries., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Test-negative (TN) studies have become the most widely used study design for the estimation of influenza vaccine effectiveness (VE) and are easily incorporated into existing influenza surveillance networks. We seek to determine the bias of TN-based VE estimates during a pandemic using a dynamic probability model. The model is used to evaluate and compare the bias of VE estimates under various sources of bias when vaccination occurs after the beginning of an outbreak, such as during a pandemic. The model includes two covariates (health status and health awareness), which may affect the probabilities of vaccination, developing influenza and non-influenza acute respiratory illness (ARI), and seeking medical care. Specifically, we evaluate the bias of VE estimates when (1) vaccination affects the probability of developing a non-influenza ARI; (2) vaccination affects the probability of seeking medical care; (3) a covariate (e.g. health status) is related to both the probabilities of vaccination and developing an ARI; and (4) a covariate (e.g. health awareness) is related to both the probabilities of vaccination and of seeking medical care. We considered two outcomes against which the vaccine is supposed to protect: symptomatic influenza and medically-attended influenza. When vaccination begins during an outbreak, we found that the effect of delayed onset of vaccination is unpredictable. VE estimates from TN studies were biased regardless of the source of bias present. However, if the core assumption of the TN design is satisfied, that is, if vaccination does not affect the probability of non-influenza ARI, then TN-based VE estimates against medically-attended influenza will only suffer from small (<0.05) to moderate bias (≥0.05 and <0.10). These results suggest that if sources of bias listed above are ruled out, TN studies are a valid study design for the estimation of VE during a pandemic., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

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., (© The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

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.

Estimation of the effectiveness of rotavirus vaccines via the test-negative control study design has gained popularity over the past few years. In this study design, children with severe diarrhea who test positive for rotavirus infection are considered as cases, while children who test negative serve as controls. We use a simple probability model to evaluate and compare the test-negative control and the traditional case-control designs with respect to the bias of resulting estimates of rotavirus vaccine effectiveness (VE). Comparisons are performed under two scenarios, corresponding to studies performed in high-income and low-income countries. We consider two potential sources of bias: (a) misclassification bias resulting from imperfect sensitivity and specificity of the test used to diagnose rotavirus infection, and (b) selection bias associated with possible effect of rotavirus vaccination on the probability of contracting severe non-rotavirus diarrhea. Our results suggest that both sources of bias may produce VE estimates with substantial bias. Particularly, lack of perfect specificity is associated with severe negative bias. For example, if the specificity of the diagnostic test is 90% then VE estimates from both types of case-control studies may under-estimate the true VE by more than 20%. If the vaccine protects children against non-rotavirus diarrhea then VE estimates from test-negative control studies may be close to zero even though the true VE is 50%. However, the sensitivity and specificity of the enzyme immunoassay test currently used to diagnose rotavirus infections are both over 99%, and there is no solid evidence that the existing rotavirus vaccines affect the rates of non-rotavirus diarrhea. We therefore conclude that the test-negative control study design is a convenient and reliable alternative for estimation of rotavirus VE., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

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., (Copyright © 2017 John Wiley & Sons, Ltd.)

Estimates of the effectiveness of influenza vaccines are commonly obtained from a test-negative design (TND) study, where cases and controls are patients seeking care for an acute respiratory illness who test positive and negative, respectively, for influenza infection. Vaccine effectiveness (VE) estimates from TND studies are usually interpreted as vaccine effectiveness against medically-attended influenza (MAI). However, it is also important to estimate VE against any influenza illness (symptomatic influenza (SI)) as individuals with SI are still a public health burden even if they do not seek medical care. We present a numerical method to evaluate the bias of TND-based estimates of influenza VE with respect to MAI and SI. We consider two sources of bias: (a) confounding bias due to a (possibly unobserved) covariate that is associated with both vaccination and the probability of the outcome of interest and (b) bias resulting from the effect of vaccination on the probability of seeking care. Our results indicate that (a) VE estimates may suffer from substantial confounding bias when a confounder has a different effect on the probabilities of influenza and non-influenza ARI, and (b) when vaccination reduces the probability of seeking care against influenza ARI, then estimates of VE against MAI may be unbiased while estimates of VE against SI may be have a substantial positive bias., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

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.

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., (Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health 2017. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Background: The test-negative design (TND) to evaluate influenza vaccine effectiveness is based on patients seeking care for acute respiratory infection, with those who test positive for influenza as cases and the test-negatives serving as controls. This design has not been validated for the inpatient setting where selection bias might be different from an outpatient setting., Methods: We derived mathematical expressions for vaccine effectiveness (VE) against laboratory-confirmed influenza hospitalizations and used numerical simulations to verify theoretical results exploring expected biases under various scenarios. We explored meaningful interpretations of VE estimates from inpatient TND studies., Results: VE estimates from inpatient TND studies capture the vaccine-mediated protection of the source population against laboratory-confirmed influenza hospitalizations. If vaccination does not modify disease severity, these estimates are equivalent to VE against influenza virus infection. If chronic cardiopulmonary individuals are enrolled because of non-infectious exacerbation, biased VE estimates (too high) will result. If chronic cardiopulmonary disease status is adjusted for accurately, the VE estimates will be unbiased. If chronic cardiopulmonary illness cannot be adequately be characterized, excluding these individuals may provide unbiased VE estimates., Conclusions: The inpatient TND offers logistic advantages and can provide valid estimates of influenza VE. If highly vaccinated patients with respiratory exacerbation of chronic cardiopulmonary conditions are eligible for study inclusion, biased VE estimates will result unless this group is well characterized and the analysis can adequately adjust for it. Otherwise, such groups of subjects should be excluded from the analysis., (© The Author 2016. Published by Oxford University Press on behalf of the International Epidemiological Association.)

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.

Background: In 2006 and 2008, two new rotavirus vaccines (RotaTeq [RV5] and Rotarix [RV1]) were introduced in the United States. US data on intussusception have been mostly related to RV5, with limited data on RV1., Methods: We assessed intussusception events following RV1 reported to the Vaccine Adverse Event Reporting System (VAERS), a US national passive surveillance system, during February 2008-December 2014. We conducted a self-controlled risk interval analysis using Poisson regression to estimate the daily reporting ratio (DRR) of intussusception after the first 2 doses of RV1 comparing average daily reports 3-6 versus 0-2 days after vaccination. We calculated the excess risk of intussusception per 100,000 vaccinations based on DRRs and background rates of intussusception. Sensitivity analyses were conducted to assess effects of differential reporting completeness and inaccuracy of baseline rates., Results: VAERS received 108 confirmed insusceptible reports after RV1. A significant clustering was observed on days 3-8 after does1 (p=0.001) and days 2-7 after dose 2 (p=0.001). The DRR comparing the 3-6 day and the 0-2 day periods after RV1 dose 1 was 7.5 (95% CI=2.3, 24.6), translating to an excess risk of 1.6 (95% CI=0.3, 5.8) per 100,000 vaccinations. The DRR was elevated but not significant after dose 2 (2.4 [95% CI=0.8,7.5]). The excess risk ranged from 1.2 to 2.8 per 100,000 in sensitivity analysis., Conclusions: We observed a significant increased risk of intussusception 3-6 days after dose 1 of RV1. The estimated small number of intussusception cases attributable to RV1 is outweighed by the benefits of rotavirus vaccination., (Published by Elsevier Ltd.)

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., (© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.)

Previous methods for analyzing protein-ligand binding events using the quartz crystal microbalance with dissipation monitoring (QCM-D) fail to account for unintended binding that inevitably occurs during surface measurements and obscure kinetic information. In this article, we present a system of differential equations that accounts for both reversible and irreversible unintended interactions. This model is tested on three protein-ligand systems, each of which has different features, to establish the feasibility of using the QCM-D for protein binding analysis. Based on this analysis, we were able to obtain kinetic information for the intended interaction that is consistent with those obtained in literature via bulk-phase methods. In the appendix, we include a method for decoupling these from the intended binding events and extracting relevant affinity information., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background: In March 2010, 13-valent pneumococcal conjugate vaccine (PCV13) replaced the seven-valent vaccine in the USA. We assessed the effect of PCV13 use on pneumococcus-related admissions to hospital 2 years after the vaccine was introduced, when coverage in children younger than age 5 years had reached 54%., Methods: We used data from a private inpatient discharge record database. We extracted age-specific data for admissions to hospital per month (July 1-June 30) for all-cause pneumonia, invasive pneumococcal disease, non-invasive pneumococcal pneumonia, and empyema (all coded by International Classification of Diseases 9) for 2005-12. We also extracted data for urinary tract infection and hospital admission for any reason as control outcomes. We assessed incidences of hospital admission before and after the introduction of PCV13 and used a negative binomial multiple regression model to estimate how much of the change in hospital admissions could be attributed to the vaccine., Findings: Our model results showed that PCV13 was associated with significant reductions in hospital admissions for all-cause pneumonia for some children (21% [95% CI 14-28] in children aged <2 years, 17% [7-27] in those aged 2-4 years) and for empyema (50% [95% CI 22-68] for children age <2 years, 46% [21-64] for 2-4 years, and 37% [13-54] for 5-17 years). All-cause pneumonia was significantly reduced in adults aged 18-39 years (12% (6-17) but not for other adult age groups. The vaccine also reduced admissions for invasive pneumococcal pneumonia and non-invasive pneumococcal or lobar pneumonia in children and adults, indicating herd protection, although the reduction was only significant in some age groups., Interpretation: Only 2 years into the US programme, PCV13 significantly reduced residual invasive and non-invasive pneumococcal hospital admissions in children younger than 5 years, as well as in some adult age groups. Our study design captured the total prevented hospital burden (directly and indirectly by herd protection) and also showed a reversal of the PCV7 era increase in paediatric empyema related to strain replacement., Funding: Pfizer., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Current oncology guidelines and clinical trials consider giving adjuvant chemotherapy to bladder cancer patients with at least microscopic perivesical tissue invasion (MPVTI) (≥pT3a) on cystectomy. The boundary of muscularis propria (MP) and perivesical tissue is commonly ill defined, and hence, when the tumor involves the interface, interpretation of MPVTI is likely to be subjective. In this study, 20 sets of static images that included 1 nontumoral bladder wall for defining MP-perivesical tissue boundary and 19 bladder cancer cases equivocal for MPVTI with confounding factors were sent to 17 expert genitourinary pathologists for review. The confounding factors were "histoanatomic," as defined by the irregular MP-perivesical tissue boundary, and "tumor related," such as fibrosis, dense inflammation, tumor cells at the edge of the outermost MP muscle bundle, and lymphovascular invasion. These equivocal cases were divided into 3 categories according to the following factors: (1) histoanatomic only (7/19), (2) histoanatomic+tumor related (7/19), and (3) tumor related only (5/19). Participating genitourinary pathologists used different criteria to assess MPVTI: (A) drawing a straight horizontal line using the outermost MP muscle bundle edge as the MP-perivesical tissue boundary reference (3/17); (B) drawing multiple straight lines interconnecting the outermost MP muscle bundle edges (9/17); (C) following the curves of every outermost MP muscle bundle edge (4/17). In category 1 cases, most pathologists who used the A criterion called for absence (6/7), whereas those who used the C criterion called for presence (5/7) of MPVTI, which resulted in disparity in 4/7 cases. There was no circumstance in which criteria A and C agreed on the presence or absence of MPVTI but was opposed by the B criterion in category 1 cases. Median pairwise agreement among all pathologists (regardless of criteria) for all cases (regardless of category) was only "fair" (κ=0.281). However, when only the B criterion was assessed for category 1 cases, median agreement was "substantial" (κ=0.696), and pairwise rater comparisons included 6/36 (17%) "near perfect," 13/36 (36%) "substantial," and 11/36 (31%) "moderate" agreements. When all cases with histoanatomic factors (categories 1 and 2) were combined, median pairwise agreements were: (A) κ=0.588, (B) κ=0.423, and (C) κ=0.512, and the B criterion rater comparisons included 0/36 (0%) "near perfect," 6/36 (17%) "substantial," and 16/36 (44%) "moderate" agreements, which showed the confounding effect of tumor-related factors. For category 3 cases, median pairwise agreement for all pathologists was "fair" (κ=0.286), with consensus agreement in only 2/5 of these equivocal cases. Lymphovascular invasion only at the MP-perivesical tissue boundary was not staged as MPVTI by 87.5% of pathologists. In conclusion, this study showed that interpretation of equivocal cases for MPVTI can be made difficult by factors intrinsic to bladder histoanatomy, defined by an irregular MP-perivesical tissue boundary, and factors related to tumor spread. There are at least 3 different approaches to demarcating an irregular outer MP boundary, and agreement is improved on equivocal cases when a common histoanatomic criterion is used. However, inconsistent agreement of anatomic criteria may cause systematic discrepancy in assessing MPVTI. Tumor-related factors such as dense fibrosis or desmoplasia, obscuring inflammation, tumor cells at the edge of the outermost MP muscle bundle, and admixed lymphovascular invasion can also negatively influence the agreement on interpretation of MPVTI. This study highlights the need to adopt common criteria in defining the outer MP boundary. Future studies may identify the most clinically relevant histoanatomic criteria for MPVTI.

Cohen's kappa coefficient, which was introduced in 1960, serves as the most widely employed coefficient to assess inter-observer agreement for categorical outcomes. However, the original kappa can only be applied to cross-sectional binary measurements and, therefore, cannot be applied in the practical situation when the observers evaluate the same subjects at repeated time intervals. This study summarizes six methods of assessing agreement of repeated binary outcomes under different assumptions and discusses under which condition we should use the most appropriate method in practice. These approaches are illustrated using data from the CDC anthrax vaccine adsorbed (AVA) human clinical trial comparing the agreement for two solicited adverse events after AVA between the 1-3 day in-clinic medical record and the patient's diary on the same day. We hope this article can inspire researchers to choose the most appropriate method to assess agreement for their own study with longitudinal binary data.

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.

Background: A modification to the case-control study design has become popular to assess vaccine effectiveness (VE) against viral infections. Subjects with symptomatic illness seeking medical care are tested by a highly specific polymerase chain reaction (PCR) assay for the detection of the infection of interest. Cases are subjects testing positive for the virus; those testing negative represent the comparison group. Influenza and rotavirus VE studies using this design are often termed "test-negative case-control" studies, but this design has not been formally described or evaluated. We explicitly state several assumptions of the design and examine the conditions under which VE estimates derived with it are valid and unbiased., Methods: We derived mathematical expressions for VE estimators obtained using this design and examined their statistical properties. We used simulation methods to test the validity of the estimators and illustrate their performance using an influenza VE study as an example., Results: Because the marginal ratio of cases to non-cases is unknown during enrollment, this design is not a traditional case-control study; we suggest the name "case test-negative" design. Under sets of increasingly general assumptions, we found that the case test-negative design can provide unbiased VE estimates. However, differences in health care-seeking behavior among cases and non-cases by vaccine status, strong viral interference, or modification of the probability of symptomatic illness by vaccine status can bias VE estimates., Conclusions: Vaccine effectiveness estimates derived from case test-negative studies are valid and unbiased under a wide range of assumptions. However, if vaccinated cases are less severely ill and seek care less frequently than unvaccinated cases, then an appropriate adjustment for illness severity is required to avoid bias in effectiveness estimates. Viral interference will lead to a non-trivial bias in the vaccine effectiveness estimate from case test-negative studies only when incidence of influenza is extremely high and duration of transient non-specific immunity is long., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: In 2006 and 2008, 2 new rotavirus vaccines (RotaTeq [RV5] and Rotarix [RV1]) were introduced in the United States., Methods: We assessed intussusception events reported to the Vaccine Adverse Event Reporting System from February 2006 through April 2012 for RV5 and from April 2008 through April 2012 for RV1. For RV5, we conducted a self-controlled risk interval analysis using Poisson regression to estimate the daily reporting ratio (DRR) of intussusception comparing average daily reports 3 to 6 versus 0 to 2 days after vaccination. We calculated reporting rate differences based on DRRs and background rates of intussusception. Sensitivity analyses were conducted to assess effects of differential reporting completeness and inaccuracy of baseline rates. Few reports were submitted after RV1, allowing only a descriptive analysis., Results: The Vaccine Adverse Event Reporting System received 584 confirmed intussusception reports after RV5 and 52 after RV1, with clustering 3 to 6 days after both vaccines. The DRR comparing the 3- to 6-day and the 0- to 2-day periods after RV5 dose 1 was 3.75 (95% confidence interval = 1.90 to 7.39). There was no significant increase in reporting after dose 2 or dose 3. Over all 3 doses, the excess risk of intussusception was 0.79 events (95% confidence interval = -0.04 to 1.62) per 100 000 vaccinations. From the sensitivity analyses, we conclude that under a worst-case scenario, the DRR could be 5.00 and excess risk per 100 000 doses could be 1.36., Conclusions: We observed a persistent clustering of reported intussusception events 3 to 6 days after the first dose of RV5 vaccination. This clustering could translate to a small increased risk of intussusception, which is outweighed by the benefits of rotavirus vaccination.

Variations of dopamine (DA) levels induced by drugs of abuse or in the context of Parkinson's disease modulate the number of dendritic spines in medium spiny neurons (MSNs) of the striatum, showing that DA plays a major role in the structural plasticity of MSNs. However, little is presently known regarding early spine development in MSNs occurring before the arrival of cortical inputs and in particular about the role of DA and D1 (D1R) and D2 (D2R) DA receptors. A cell culture model reconstituting early cellular interactions between MSNs, intrinsic cholinergic interneurons and DA neurons was used to study the role of DA in spine formation. After 5 or 10 days in vitro, the presence of DA neurons increased the number of immature spine-like protrusions. In MSN monocultures, chronic activation of D1R or D2R also increased the number of spines and spinophilin expression in MSNs, suggesting a direct role for these receptors. In DA-MSN cocultures, chronic blockade of D1R or D2R reduced the number of dendritic spines. Interestingly, the combined activation or blockade of both D1R and D2R failed to elicit more extensive spine formation, suggesting that both receptors act through a mechanism that is not additive. Finally, we found increased ionotropic glutamate receptor responsiveness and miniature excitatory postsynaptic current (EPSC) frequency in DA-MSN co-cultures, in parallel with a higher number of spines containing PSD-95, suggesting that the newly formed spines present functional post-synaptic machinery preparing the MSNs to receive additional glutamatergic contacts. These results represent a first step in the understanding of how dopamine neurons promote the structural plasticity of MSNs during the development of basal ganglia circuits., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

The transmembrane protein deleted in colorectal cancer (DCC) and its ligand, netrin-1, regulate synaptogenesis during development, but their function in the mature central nervous system is unknown. Given that DCC promotes cell-cell adhesion, is expressed by neurons, and activates proteins that signal at synapses, we hypothesized that DCC expression by neurons regulates synaptic function and plasticity in the adult brain. We report that DCC is enriched in dendritic spines of pyramidal neurons in wild-type mice, and we demonstrate that selective deletion of DCC from neurons in the adult forebrain results in the loss of long-term potentiation (LTP), intact long-term depression, shorter dendritic spines, and impaired spatial and recognition memory. LTP induction requires Src activation of NMDA receptor (NMDAR) function. DCC deletion severely reduced Src activation. We demonstrate that enhancing NMDAR function or activating Src rescues LTP in the absence of DCC. We conclude that DCC activation of Src is required for NMDAR-dependent LTP and certain forms of learning and memory., (Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.)

Treatment of comorbid posttraumatic stress disorder (PTSD) and opioid dependence has been a challenge for many clinicians. There are limited evidence-based guidelines for treatment of this comorbidity. Symptoms of PTSD and opiate dependence may converge, and it is sometimes difficult to differentiate between both conditions. For example, opioid withdrawal symptoms may mimic the hypervigilance and exacerbated startle response of patients with PTSD. A common neurobiologic circuit is suggested for the pathophysiologic mechanism of this comorbidity. There is evidence that opioid substitution therapy may improve treatment outcomes for opioid addiction in patients with comorbid PTSD and opioid dependence. Evidence-based psychotherapeutic intervention is recommended for this population to improve the psychological outcome as well. Combining opioid substitution therapy with evidence-based cognitive behavioral therapy designed for individuals with comorbid PTSD and substance abuse (e.g., Seeking Safety) may improve treatment outcomes in this population. More research is needed to understand the underlying mechanisms for this comorbidity and to improve treatment response.

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., (© 2012 Sigma Theta Tau International.)

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., (Copyright © 2012 Wiley Periodicals, Inc.)

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., (Copyright © 2012 John Wiley & Sons, Ltd.)

Objective: The aim of this study was to evaluate the preparedness for and response of Maine summer camps to the 2009 pandemic influenza H1N1 (pH1N1)., Methods: We conducted a retrospective web-based survey of the Maine Youth Camping Foundation members at the end of the 2009 camping season. The outcome measures were responses to the pandemic including educational efforts, isolation practices and antiviral usages as well as percentage of influenza-like illness (ILI) and laboratory-confirmed influenza outbreaks among Maine residential summer camps., Results: Of 107 residential camps queried, 91 (85%) responded. Although 43 (47%) of 91 camps reported cases of ILI, and 19 (21%) had outbreaks (ie, 3 or more confirmed cases of pH1N1), no respondents reported closing camps or canceling sessions. Most camps reported that they communicated with campers' families about pH1N1 and implemented control measures, including educating campers and staff about symptoms, isolating ill campers and staff, encouraging increased hand washing and hygiene practices and increasing the availability of hand sanitizers. Of the 43 camps with cases of ILI or laboratory-confirmed pH1N1, 25 (58%) used antiviral medication for treatment, and 18 (42%) used antiviral medications for prophylaxis; antiviral practices varied among camps., Conclusions: Summer camps in Maine were in general well prepared for pH1N1. Most camps followed public health guidance and implemented preventive measures. Many camps experienced ILI and outbreaks during the season, but did not report major disruptions. Camps should review their preparedness and disease control plans annually and public health authorities should keep guidance and recommendations simple and consistent.

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.

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.

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., (Copyright © 2011 Elsevier Inc. All rights reserved.)

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., (Copyright © 2010 John Wiley & Sons, Ltd.)

A seven-valent pneumococcal conjugate vaccine (PCV7) introduced in the United States in 2000 has been shown to reduce invasive pneumococcal disease (IPD) in both vaccinated children and adults through induction of herd immunity. We assessed the impact of infant immunization on pneumococcal pneumonia hospitalizations and mortality in all age groups using Health Care Utilization Project State Inpatient Databases (SID) for 1996 to 2006 from 10 states; SID contain 100% samples of ICD9-coded hospitalization data for the selected states. Compared to a 1996-1997 through 1998-1999 baseline, by the 2005-2006 season, both IPD and pneumococcal pneumonia hospitalizations and deaths had decreased substantially in all age groups, including a 47% (95% confidence interval [CI], 38 to 54%) reduction in nonbacteremic pneumococcal pneumonia (ICD9 code 481 with no codes indicating IPD) in infants <2 years old and a 54% reduction (CI, 53 to 56%) in adults ≥65 years of age. A model developed to calculate the total burden of pneumococcal pneumonia prevented by infant PCV7 vaccination in the United States from 2000 to 2006 estimated a reduction of 788,838 (CI, 695,406 to 875,476) hospitalizations for pneumococcal pneumonia. Ninety percent of the reduction in model-attributed pneumococcal pneumonia hospitalizations occurred through herd immunity among adults 18 years old and older; similar proportions were found in pneumococcal disease mortality prevented by the vaccine. In the first seasons after PCV introduction, when there were substantial state differences in coverage among <5-year-olds, states with greater coverage had significantly fewer influenza-associated pneumonia hospitalizations among children, suggesting that PCV7 use also reduces influenza-attributable pneumonia hospitalizations., (Copyright © 2011 Simonsen et al.)

Background: Using mathematical deterministic models of the epidemiology of hospital-acquired infections and antibiotic resistance, it has been shown that the rates of hospital-acquired bacterial infection and frequency of antibiotic infections can be reduced by (i) restricting the admission of patients colonized with resistant bacteria, (ii) increasing the rate of turnover of patients, (iii) reducing transmission by infection control measures, and (iv) the use of second-line drugs for which there is no resistance. In an effort to explore the generality and robustness of the predictions of these deterministic models to the real world of hospitals, where there is variation in all of the factors contributing to the incidence of infection, we developed and used a stochastic model of the epidemiology of hospital-acquired infections and resistance. In our analysis of the properties of this model we give particular consideration different regimes of using second-line drugs in this process., Methods: We developed a simple model that describes the transmission of drug-sensitive and drug-resistant bacteria in a small hospital. Colonized patients may be treated with a standard drug, for which there is some resistance, and with a second-line drug, for which there is no resistance. We then ran deterministic and stochastic simulation programs, based on this model, to predict the effectiveness of various treatment strategies., Results: The results of the analysis using our stochastic model support the predictions of the deterministic models; not only will the implementation of any of the above listed measures substantially reduce the incidences of hospital-acquired infections and the frequency of resistance, the effects of their implementation should be seen in months rather than the years or decades anticipated to control resistance in open communities. How effectively and how rapidly the application of second-line drugs will contribute to the decline in the frequency of resistance to the first-line drugs depends on how these drugs are administered. The earlier the switch to second-line drugs, the more effective this protocol will be. Switching to second-line drugs at random is more effective than switching after a defined period or only after there is direct evidence that the patient is colonized with bacteria resistant to the first antibiotic., Conclusions: The incidence of hospital-acquired bacterial infections and frequencies of antibiotic resistant bacteria can be markedly and rapidly reduced by different readily implemented procedures. The efficacy using second line drugs to achieve these ends depends on the protocol used for their administration.

We propose a simple method for evaluating agreement between methods of measurement when the measured variable is continuous and the data consists of matched repeated observations made with the same method under different conditions. The conditions may represent different time points, raters, laboratories, treatments, etc. Our approach allows the values of the measured variable and the magnitude of disagreement to vary across the conditions. The coefficient of individual agreement (CIA), which is based on the comparison of the between and within-methods mean squared deviation (MSD) is used to quantify the magnitude of agreement between measurement methods. The new approach is illustrated via two examples from studies designed to compare (a) methods of evaluating carotid stenosis and (b) methods of measuring percent body fat.

Pro-inflammatory chemokines and cytokines play an important role in Wallerian degeneration (WD) after peripheral nerve injury. These pro-inflammatory signals are "turned-off" in a timely manner to ensure that the inflammatory response in the injured nerve is limited. The factors that regulate the turning-off of the pro-inflammatory state are not fully understood. The suppressors of cytokine signaling (SOCS) proteins are potential candidates that could limit the inflammatory response by acting to regulate cytokine signaling at the intracellular level. In this work we show that the expression SOCS1 and SOCS3 proteins differ from each other during WD in the mouse sciatic nerve after cut/ligation and crush injuries. SOCS1 is mainly expressed by macrophages and its expression is inversely correlated with phosphorylation of JAK2 and STAT3 signaling proteins and the expression of pro-inflammatory cytokines IL-1beta and TNFalpha. In addition, treatment of cut/ligated nerves, which express lower levels of SOCS1 as compared to crush injury, with a SOCS1 mimetic peptide leads to a decrease in macrophage numbers at 14 days post-injury and reduces IL-1beta mRNA expression 1 day post-injury. In contrast, SOCS3 expression is restricted mainly to Schwann cells and is negatively correlated with the expression of IL-6 and LIF. These data suggest that SOCS1 and SOCS3 may play different roles in WD and provide a better understanding of some of the potential regulatory mechanisms that may control inflammation and regeneration in the injured peripheral nerve., (Copyright 2009 Elsevier Inc. All rights reserved.)

The coefficients of individual agreement (CIAs), which are based on the ratio of the intra- and inter-observer disagreement, provide a general approach for evaluating agreement between two fixed methods of measurements or human observers. In this paper, programs in both SAS and R are presented for estimation of the CIAs between two observers with quantitative or binary measurements. A detailed illustration of the computations, macro variable definitions, input and output for the SAS and R programs are also included in the text. The programs provide estimations of CIAs, their standard errors as well as confidence intervals, for the cases with or without a reference method. Data from a carotid stenosis screening study is used as an example of quantitative measurements. Data from a study involving the evaluation of mammograms by ten radiologists is used to illustrate a binary data example., (Copyright (c) 2009 Elsevier Ireland Ltd. All rights reserved.)

Objectives: We compared the impact of three household interventions-education, education with alcohol-based hand sanitizer, and education with hand sanitizer and face masks-on incidence and secondary transmission of upper respiratory infections (URIs) and influenza, knowledge of transmission of URIs, and vaccination rates., Methods: A total of 509 primarily Hispanic households participated. Participants reported symptoms twice weekly, and nasal swabs were collected from those with an influenza-like illness (ILI). Households were followed for up to 19 months and home visits were made at least every two months., Results: We recorded 5034 URIs, of which 669 cases reported ILIs and 78 were laboratory-confirmed cases of influenza. Demographic factors significantly associated with infection rates included age, gender, birth location, education, and employment. The Hand Sanitizer group was significantly more likely to report that no household member had symptoms (p < 0.01), but there were no significant differences in rates of infection by intervention group in multivariate analyses. Knowledge improved significantly more in the Hand Sanitizer group (p < 0.0001). The proportion of households that reported > or = 50% of members receiving influenza vaccine increased during the study (p < 0.001). Despite the fact that compliance with mask wearing was poor, mask wearing as well as increased crowding, lower education levels of caretakers, and index cases 0-5 years of age (compared with adults) were associated with significantly lower secondary transmission rates (all p < 0.02)., Conclusions: In this population, there was no detectable additional benefit of hand sanitizer or face masks over targeted education on overall rates of URIs, but mask wearing was associated with reduced secondary transmission and should be encouraged during outbreak situations. During the study period, community concern about methicillin-resistant Staphylococcus aureus was occurring, perhaps contributing to the use of hand sanitizer in the Education control group, and diluting the intervention's measurable impact.

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.

Background: The statistical measure used to quantify the degree of agreement or congruence between two research subjects has been the intraclass or the Pearson correlation coefficient; however, the concordance correlation coefficient (CCC) is another measure of agreement used to examine agreement between two observers or raters., Objectives: The aims of this study were to (a) highlight the differences among three statistical measures used to quantify the degree of agreement or congruence, (b) demonstrate the use of the CCC in examining agreement between heart failure (HF) patients and their family members, and (c) provide nurse researchers another method for evaluating agreement., Methods: Symptom evaluation scores obtained from HF patients and their family members were used in the analysis of this study. To explain the use of the CCC in this analysis, a distinction between Pearson correlation coefficient and intraclass correlation coefficient is discussed. The CCC calculation is then described in detail., Results: The HF patients in this sample were 71 +/- 9.6 years in age, 40% male, and 41.4% African American. Most (75%) family members were female. There were several different categories of family members, but most were spouses. The CCC results indicated that no symptom achieved good agreement, and 8 of 14 symptoms were in moderate agreement (.4

The morphogenesis of oligodendrocytes is essential for central nervous system myelin formation and the rapid propagation of axon potentials through saltatory conduction. However, the discrete cellular events involved in the three-dimensional maturation of oligodendrocytes remain to be fully described. To address this, we followed the developmental stages of oligodendrocytes in mouse organotypic hippocampal slice cultures for 7-60 days using viral-mediated gene delivery of membrane-targeted fluorescent proteins. Using static and time-lapse confocal imaging, we find that postmigratory NG2-expressing cells exhibit slow anatomical reorganization over the course of hours. This is in direct contrast to oligodendrocytes that take on a promyelinating and transitional phenotype, which display a more complex morphology and undergo dramatic actin-dependent structural remodeling over just minutes. More mature myelinating oligodendrocytes, which have pruned most of their processes, still retain some local remodeling behavior at developing internodes, but in general, revert to a relatively stable state. Our findings provide a detailed characterization of cellular events that help shape oligodendrocyte morphology and likely participate in neuron-glial cell interactions and the process of myelination., ((c) 2008 Wiley-Liss, Inc.)

The Rho family of small GTPase proteins are involved in the formation and maintenance of neuronal dendrites. In this study, we show that Daam1, a member of the Diaphanous-related formin protein family and a downstream effector for RhoA, is localized to the dendrites of hippocampal neurons. Immunoblot analysis showed that Daam1 is enriched in the mouse hippocampus and co-fractionates in brain lysates with dendritic and synaptic proteins. Immunohistochemical analysis revealed that Daam1 protein distributes in a punctate pattern throughout the cell body and dendritic shafts of dissociated hippocampal neurons and organotypic hippocampal cultures. Although Daam1 is mostly expressed in the shaft of dendrites, co-stainings with SV2 or PSD95 revealed that Daam1 is also present at some synapses. In addition, viral directed expression of a fluorescently tagged Daam1 fusion protein in hippocampal slices resulted in targeted delivery to the dendrites of pyramidal neurons, leading to a reduction in the density of spines.

We present a general approach to the definition and estimation of coefficients for evaluating agreement between two fixed methods of measurements or human observers. The measured variable is assumed to be continuous with a finite second moment. No other distributional assumptions are made. We introduce the term ;disagreement function' for the function of the observations that is used to quantify the extent of disagreement between the two measurements made on the same subject. The proposed inter-methods agreement coefficients compare the disagreement between measurements made by different methods on the same subject to the corresponding disagreement between replicated measurements made by the same method. Therefore, the new coefficients require data with replications readings. We propose inter-methods agreement coefficients for two practical situations involving two methods that have a measurement error: 1) comparison of a new method to a gold standard (or a reference method), and 2) comparison of two methods where neither method is considered a gold standard. We consider three disagreement functions based on the differences between two measurements: 1) the mean squared difference, 2) the mean absolute difference and 3) the mean relative difference. We then derive non-parametric estimates for the various agreement coefficients. Our approach is illustrated using data from a study comparing systolic blood pressure measurements by a human observer and an automatic monitor. The performance of the new estimates is assessed via stochastic simulations.

Invasive pneumococcal disease in older children and adults declined markedly after introduction in 2000 of the pneumococcal conjugate vaccine for young children. An empirical quantitative model was developed to estimate the herd (indirect) effects on the incidence of invasive disease among persons >or=5 years of age induced by vaccination of young children with 1, 2, or >or=3 doses of the pneumococcal conjugate vaccine, Prevnar (PCV7), containing serotypes 4, 6B, 9V, 14, 18C, 19F and 23F. From 1994 to 2003, cases of invasive pneumococcal disease were prospectively identified in Georgia Health District-3 (eight metropolitan Atlanta counties) by Active Bacterial Core surveillance (ABCs). From 2000 to 2003, vaccine coverage levels of PCV7 for children aged 19-35 months in Fulton and DeKalb counties (of Atlanta) were estimated from the National Immunization Survey (NIS). Based on incidence data and the estimated average number of doses received by 15 months of age, a Poisson regression model was fit, describing the trend in invasive pneumococcal disease in groups not targeted for vaccination (i.e., adults and older children) before and after the introduction of PCV7. Highly significant declines in all the serotypes contained in PCV7 in all unvaccinated populations (5-19, 20-39, 40-64, and >64 years) from 2000 to 2003 were found under the model. No significant change in incidence was seen from 1994 to 1999, indicating rates were stable prior to vaccine introduction. Among unvaccinated persons 5+ years of age, the modeled incidence of disease caused by PCV7 serotypes as a group dropped 38.4%, 62.0%, and 76.6% for 1, 2, and 3 doses, respectively, received on average by the population of children by the time they are 15 months of age. Incidence of serotypes 14 and 23F had consistent significant declines in all unvaccinated age groups. In contrast, the herd immunity effects on vaccine-related serotype 6A incidence were inconsistent. Increasing trends of non-vaccine serotypes, in particular 19A, were noted in most unvaccinated age groups, but these increases were substantially smaller than the concurrent decreases among the vaccine serotypes. Also, the model estimated PCV7 to have a greater (p=0.014) indirect impact on the incidence of invasive pneumococcal disease caused by all vaccine serotypes among African-Americans of all ages than for whites. Thus, conjugate vaccines may be able to induce herd effects even in situations where vaccine coverage is far from complete or with schedules using fewer than 3 or 4 doses. Because the model was based on incidence rates and PCV7 coverage in Atlanta, our findings should be validated in other geographic areas.

Background: Influenza causes substantial morbidity and annual vaccination is the most important prevention strategy. Accurately measuring vaccine effectiveness (VE) is difficult. The clinical syndrome most closely associated with influenza virus infection, influenza-like illness (ILI), is not specific. In addition, laboratory confirmation is infrequently done, and available rapid diagnostic tests are imperfect. The objective of this study was to estimate the joint impact of rapid diagnostic test sensitivity and specificity on VE for three types of study designs: a cohort study, a traditional case-control study, and a case-control study that used as controls individuals with ILI who tested negative for influenza virus infection., Methods: We developed a mathematical model with five input parameters: true VE, attack rates (ARs) of influenza-ILI and non-influenza-ILI and the sensitivity and specificity of the diagnostic test., Results: With imperfect specificity, estimates from all three designs tended to underestimate true VE, but were similar except if fairly extreme inputs were used. Only if test specificity was 95% or more or if influenza attack rates doubled that of background illness did the case-control method slightly overestimate VE. The case-control method usually produced the highest and most accurate estimates, followed by the test-negative design. The bias toward underestimating true VE introduced by low test specificity increased as the AR of influenza- relative to non-influenza-ILI decreases and, to a lesser degree, with lower test sensitivity., Conclusions: Demonstration of a high influenza VE using tests with imperfect sensitivity and specificity should provide reassurance that the program has been effective in reducing influenza illnesses, assuming adequate control of confounding factors.

Specialized postsynaptic structures known as dendritic spines are the primary sites of glutamatergic innervation at synapses of the CNS. Previous studies have shown that spines rapidly remodel their actin cytoskeleton to modify their shape and this has been associated with changes in synaptic physiology. However, the receptors and signaling intermediates that restructure the actin network in spines are only beginning to be identified. We reported previously that the EphA4 receptor tyrosine kinase regulates spine morphology. However, the signaling pathways downstream of EphA4 that induce spine retraction on ephrin ligand binding remain poorly understood. Here, we demonstrate that ephrin stimulation of EphA4 leads to the recruitment and activation of phospholipase Cgamma1 (PLCgamma1) in heterologous cells and in hippocampal slices. This interaction occurs through an Src homology 2 domain of PLCgamma1 and requires the EphA4 juxtamembrane tyrosines. In the brain, PLCgamma1 is found in multiple compartments of synaptosomes and is readily found in postsynaptic density fractions. Consistent with this, PLC activity is required for the maintenance of spine morphology and ephrin-induced spine retraction. Remarkably, EphA4 and PLC activity modulate the association of the actin depolymerizing/severing factor cofilin with the plasma membrane. Because cofilin has been implicated previously in the structural plasticity of spines, this signaling may enable cofilin to depolymerize actin filaments and restructure spines at sites of ephrin-EphA4 contact.