Antimicrobial peptide LL-37 and recombinant human mannose-binding lectin express distinct age- and pathogen-specific antimicrobial activity in human newborn cord blood in vitro

Background: There is a need to prevent and treat infection in newborns. One approach is administration of antimicrobial proteins and peptides (APPs) such as LL-37, a membrane-active cathelicidin antimicrobial peptide, and mannose-binding lectin (MBL), a pattern-recognition protein that binds to microbial surface polysaccharides resulting in opsonization and complement activation. Low plasma/serum levels of LL-37 and of MBL have been correlated with infection and exogenous administration of these agents may enhance host defense. Methods: The antimicrobial activity of LL-37 (15 µg/ml) or rMBL (0.5, 2 and 10 µg/ml) was tested in hirudin-anticoagulated preterm and term human cord blood (N = 12-14) against Staphylococcus aureus (SA) USA 300 (2x10 4 CFU/ml), Staphylococcus epidermis (SE) 1457 (2x10 4 CFU/ml) and Candida albicans (CA) SC5314 (1x10 4 CFU/ml). After incubation (1, 45, or 180 min), CFUs were enumerated by plating blood onto agar plates. Supernatants were collected for measurement of MBL via ELISA. Results: Preterm cord blood demonstrated impaired endogenous killing capacity against SA and SE compared to term blood. Addition of LL-37 strongly enhanced antimicrobial/antifungal activity vs SA, SE and CA in term blood and SE and CA in preterm blood. By contrast, rMBL showed modest fungistatic activity vs CA in a sub-analysis of term newborns with high basal MBL levels. Baseline MBL levels varied within preterm and term cohorts with no correlation to gestational age. In summary, exogenous LL-37 demonstrated significant antimicrobial activity against SA, SE and CA in term and SE and CA in preterm human blood tested in vitro. rMBL demonstrated modest antifungal activity in term cord blood of individuals with high baseline MBL levels. Conclusions: To the extent that our in vitro results predict the effects of APPs in vivo, development of APPs for prevention and treatment of infection should take into account host age as well as the target pathogen

Cluster detection methods applied to the Upper Cape Cod cancer data

BACKGROUND: A variety of statistical methods have been suggested to assess the degree and/or the location of spatial clustering of disease cases. However, there is relatively little in the literature devoted to comparison and critique of different methods. Most of the available comparative studies rely on simulated data rather than real data sets. METHODS: We have chosen three methods currently used for examining spatial disease patterns: the M-statistic of Bonetti and Pagano; the Generalized Additive Model (GAM) method as applied by Webster; and Kulldorff's spatial scan statistic. We apply these statistics to analyze breast cancer data from the Upper Cape Cancer Incidence Study using three different latency assumptions. RESULTS: The three different latency assumptions produced three different spatial patterns of cases and controls. For 20 year latency, all three methods generally concur. However, for 15 year latency and no latency assumptions, the methods produce different results when testing for global clustering. CONCLUSION: The comparative analyses of real data sets by different statistical methods provides insight into directions for further research. We suggest a research program designed around examining real data sets to guide focused investigation of relevant features using simulated data, for the purpose of understanding how to interpret statistical methods applied to epidemiological data with a spatial component

A power comparison of generalized additive models and the spatial scan statistic in a case-control setting

<p>Abstract</p> <p>Background</p> <p>A common, important problem in spatial epidemiology is measuring and identifying variation in disease risk across a study region. In application of statistical methods, the problem has two parts. First, spatial variation in risk must be detected across the study region and, second, areas of increased or decreased risk must be correctly identified. The location of such areas may give clues to environmental sources of exposure and disease etiology. One statistical method applicable in spatial epidemiologic settings is a generalized additive model (GAM) which can be applied with a bivariate LOESS smoother to account for geographic location as a possible predictor of disease status. A natural hypothesis when applying this method is whether residential location of subjects is associated with the outcome, i.e. is the smoothing term necessary? Permutation tests are a reasonable hypothesis testing method and provide adequate power under a simple alternative hypothesis. These tests have yet to be compared to other spatial statistics.</p> <p>Results</p> <p>This research uses simulated point data generated under three alternative hypotheses to evaluate the properties of the permutation methods and compare them to the popular spatial scan statistic in a case-control setting. Case 1 was a single circular cluster centered in a circular study region. The spatial scan statistic had the highest power though the GAM method estimates did not fall far behind. Case 2 was a single point source located at the center of a circular cluster and Case 3 was a line source at the center of the horizontal axis of a square study region. Each had linearly decreasing logodds with distance from the point. The GAM methods outperformed the scan statistic in Cases 2 and 3. Comparing sensitivity, measured as the proportion of the exposure source correctly identified as high or low risk, the GAM methods outperformed the scan statistic in all three Cases.</p> <p>Conclusions</p> <p>The GAM permutation testing methods provide a regression-based alternative to the spatial scan statistic. Across all hypotheses examined in this research, the GAM methods had competing or greater power estimates and sensitivities exceeding that of the spatial scan statistic.</p

Using highly variable warfarin dosing to identify patients at risk for adverse events

<p>Abstract</p> <p>Background</p> <p>Patients who receive highly variable doses of warfarin may be at risk for poor anticoagulation control and adverse events. However, we lack a system to identify patients with the highest dose variability. Our objectives were to develop a scoring system to identify patients with high dose variability, and to validate this new measure by demonstrating that patients so identified have poor anticoagulation control and higher rates of adverse events (criterion validity).</p> <p>Methods</p> <p>We used a database of over 4, 000 patients who received oral anticoagulation in community practice between 2000-2002. We reviewed the charts of 168 patients with large warfarin dose variation and agreed on 18 risk factor definitions for high dose variability. We identified 109 patients with the highest dose variability (cases), as measured by coefficient of variation (CoV, SD/mean). We matched each case to two controls with low dose variability. Then, we examined all 327 charts, blinded to case/control status, to identify the presence or absence of the 18 risk factors for dose variability. We performed a multivariable analysis to identify independent predictors of high CoV. We also compared anticoagulation control, as measured by percent time in therapeutic range (TTR), and rates of adverse events between groups.</p> <p>Results</p> <p>CoV corresponded with other measures of anticoagulation control. TTR was 53% among cases and 79% among controls (p < 0.001). CoV also predicted adverse events. Six cases experienced a major hemorrhage versus 1 control (p < 0.001) and 3 cases had a thromboembolic event versus 0 control patients (p = 0.04). Independent predictors of high dose variability included hospitalization (OR = 21.3), decreased oral intake (OR = 12.2), use of systemic steroids (OR = 6.1), acetaminophen (OR = 4.0) and antibiotics (OR = 2.7; p < 0.05 for all).</p> <p>Conclusion</p> <p>CoV can be used to identify patients at risk for poor anticoagulation control and adverse events. This new measure has the potential to identify patients at high risk before they suffer adverse events.</p

Overdose rescues by trained and untrained participants and change in opioid use among substance-using participants in overdose education and naloxone distribution programs: a retrospective cohort study

Background: One approach to preventing opioid overdose, a leading cause of premature, preventable mortality, is to provide overdose education and naloxone distribution (OEND). Two outstanding issues for OEND implementation include 1) the dissemination of OEND training from trained to untrained community members; and 2) the concern that OEND provides active substance users with a false sense of security resulting in increased opioid use. Methods: To compare overdose rescue behaviors between trained and untrained rescuers among people reporting naloxone rescue kit use; and determine whether heroin use changed after OEND, we conducted a retrospective cohort study among substance users in the Massachusetts OEND program from 2006 to 2010. We used chi square and t-test statistics to compare the differences in overdose management characteristics among overdoses managed by trained versus untrained participants. We employed Wilcoxon signed rank test to compare median difference among two repeated measures of substance use among participants with drug use information collected more than once. Results: Among 4,926 substance-using participants, 295 trained and 78 untrained participants reported one or more rescues, resulting in 599 rescue reports. We found no statistically significant differences in help-seeking (p = 0.41), rescue breathing (p = 0.54), staying with the victim (p = 0.84) or in the success of naloxone administration (p = 0.69) by trained versus untrained rescuers. We identified 325 OEND participants who had drug use information collected more than once. We found no significant overall change in the number of days using heroin in past 30 days (decreased 38%, increased 35%, did not change 27%, p = 0.52). Conclusion: Among 4926 substance users who participated in OEND, 373(7.6%) reported administering naloxone during an overdose rescue. We found few differences in behavior between trained and untrained overdose rescuers. Prospective studies will be needed to determine the optimal level of training and whether naloxone rescue kits can meet an over-the-counter standard. With no clear evidence of increased heroin use, this concern should not impede expansion of OEND programs or policies that support them

Neighborhood Characteristics and Colorectal Cancer Survivors\u27 Quality of Care

Purpose: Quality cancer care entails receipt of a Survivorship Care Plan (SCP). The purpose of this study was to determine differences in SCP delivery by patient-level and neighborhood characteristics. Methods: We obtained California cancer registry data on individuals who were diagnosed with stage I, II, or III colorectal cancer (CRC) between 2012 and 2015 and resided in predetermined geographic areas. We then mailed them a questionnaire, which queried about receipt of a SCP and its content. SCP was defined by content, as summary of cancer treatment, cancer surveillance recommendations, and/or an individualized preventive care. Using logistic regression modeling, each measure of SCP, as well as the summary measure (none vs. any), was evaluated by person-level characteristics. Subsequently, neighborhood-level characteristics were added to the model to explore their additional value. Results: Overall 80% of CRC survivors received a SCP. Receipt of SCPs was associated with person-level characteristics, while neighborhood characteristics did not make an additional contribution. Young, male employed survivors and those with more recent diagnoses or later cancer stages had greater odds of receiving a SCP. Conclusion: When providing SCPs, health care providers prioritize patient groups who they may perceive as vulnerable or likely to benefit from SCPs

Evidence-based Tool for Triggering School Closures during Influenza Outbreaks, Japan

Guidelines available to school administrators to support school closure decisions during influenza outbreaks are usually not evidence-based. Using empirical data on absentee rates of elementary school students in Japan, we developed a simple and practical algorithm for determining the optimal timing of school closures for control of influenza outbreaks

Effect of spatial resolution on cluster detection: a simulation study

BackgroundAggregation of spatial data is intended to protect privacy, but some effects of aggregation on spatial methods have not yet been quantified.MethodsWe generated 3,000 spatial data sets and evaluated power of detection at 12 different levels of aggregation using the spatial scan statistic implemented in SaTScan v6.0.ResultsPower to detect clusters decreased from nearly 100% when using exact locations to roughly 40% at the coarsest level of spatial resolution.ConclusionAggregation has the potential for obfuscation

Antimicrobial peptide LL-37 and recombinant human mannose-binding lectin express distinct age- and pathogen-specific antimicrobial activity in human newborn cord blood in vitro [version 1; referees: 2 approved]

Background: There is a need to prevent and treat infection in newborns. One approach is administration of antimicrobial proteins and peptides (APPs) such as LL-37, a membrane-active cathelicidin antimicrobial peptide, and mannose-binding lectin (MBL), a pattern-recognition protein that binds to microbial surface polysaccharides resulting in opsonization and complement activation. Low plasma/serum levels of LL-37 and of MBL have been correlated with infection and exogenous administration of these agents may enhance host defense. Methods: The antimicrobial activity of LL-37 (15 µg/ml) or rMBL (0.5, 2 and 10 µg/ml) was tested in hirudin-anticoagulated preterm and term human cord blood (N = 12–14) against Staphylococcus aureus (SA) USA 300 (2x104 CFU/ml), Staphylococcus epidermis (SE) 1457 (2x104 CFU/ml) and Candida albicans (CA) SC5314 (1x104 CFU/ml). After incubation (1, 45, or 180 min), CFUs were enumerated by plating blood onto agar plates. Supernatants were collected for measurement of MBL via ELISA. Results: Preterm cord blood demonstrated impaired endogenous killing capacity against SA and SE compared to term blood. Addition of LL-37 strongly enhanced antimicrobial/antifungal activity vs SA, SE and CA in term blood and SE and CA in preterm blood. By contrast, rMBL showed modest fungistatic activity vs CA in a sub-analysis of term newborns with high basal MBL levels. Baseline MBL levels varied within preterm and term cohorts with no correlation to gestational age. In summary, exogenous LL-37 demonstrated significant antimicrobial activity against SA, SE and CA in term and SE and CA in preterm human blood tested in vitro. rMBL demonstrated modest antifungal activity in term cord blood of individuals with high baseline MBL levels. Conclusions: To the extent that our in vitro results predict the effects of APPs in vivo, development of APPs for prevention and treatment of infection should take into account host age as well as the target pathogen

Recognition of Face Identity and Emotion in Expressive Specific Language Impairment

Objective: To study face and emotion recognition in children with mostly expressive specific language impairment (SLI-E). Subjects and Methods: A test movie to study perception and recognition of faces and mimic-gestural expression was applied to 24 children diagnosed as suffering from SLI-E and an age-matched control group of normally developing children. Results: Compared to a normal control group, the SLI-E children scored significantly worse in both the face and expression recognition tasks with a preponderant effect on emotion recognition. The performance of the SLI-E group could not be explained by reduced attention during the test session. Conclusion: We conclude that SLI-E is associated with a deficiency in decoding non-verbal emotional facial and gestural information, which might lead to profound and persistent problems in social interaction and development. Copyright (C) 2012 S. Karger AG, Base