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Background: An earlier cluster randomized controlled trial (RCT) of Hutterite colonies had shown that if more than 80% of children and adolescents were immunized with influenza vaccine there was a statistically significant reduction in laboratory-confirmed influenza among all unimmunized community members. We assessed the impact of this intervention for two additional influenza seasonal periods., Methods: Follow-up data for two influenza seasonal periods of a cluster randomized trial involving 1053 Canadian children and adolescents aged 36 months to 15 years in Season 2 and 1014 in Season 3 who received the study vaccine, and 2805 community members in Season 2 and 2840 in Season 3 who did not receive the study vaccine. Follow-up for Season 2 began November 18, 2009 and ended April 25, 2010 while Season 3 extended from December 6, 2010 and ended May 27, 2011. Children were randomly assigned in a blinded manner according to community membership to receive either inactivated trivalent influenza vaccine or hepatitis A. The primary outcome was confirmed influenza A and B infection using RT-PCR assay. Due to the outbreak of 2009 H1N1 pandemic, data in Season 2 were excluded for analysis., Results: For an analysis of the combined Season 1 and Season 3 data, among non-recipients (i.e., participants who did not receive study vaccines), 66 of the 2794 (2.4%) participants in the influenza vaccine colonies and 121 of the 2301 (5.3%) participants in the hepatitis A colonies had influenza confirmed by RT-PCR, for a protective effectiveness of 60% (95% CI, 6% to 83%; P = 0.04); among all study participants (i.e., including both those who received study vaccine and those who did not), 125 of the 3806 (3.3%) in the influenza vaccine colonies and 239 of the 3243 (7.4%) in the hepatitis A colonies had influenza confirmed by RT-PCR, for a protective effectiveness of 63% (95% CI, 5% to 85%; P = 0.04)., Conclusion: Immunizing children and adolescents with inactivated influenza vaccine can offer a protective effect among unimmunized community members for influenza A and B together when considered over multiple years of seasonal influenza., Trial Registration: Clinicaltrials.gov NCT00877396., Competing Interests: The authors have declared that no competing interests exist.

This study looked at a classical truth logic of multi-propositions that is new in some ways: [1] Alethic modalities were mixed with logical consistency and incompatibility in a single plate form, i.e., necessary consistency (NC), possible consistency (PC)/ possible incompatibility (PI) and impossible incompatibility (IPI); [2] multi-propositions were judged by individuals as either NC, PC/PI, or IPI; [3] Four quantifiers; All (∀), No (∼∀), Some (∃), and Some Not (∼∃) of four propositional modes and three shapes (, ▱ and) are used to evaluate predictions; and [4] it inspired by multi-propositional of dual-process theories (DPTs) of deduction and modal syllogistic of multi-propositions, from which logicians have derived general hypotheses. HP 1- Individuals will more likely to endorse inferences as PC/PI rather than NC. HP 2: It's easier to calculate that inference has PC/ PI if it has also NC. Generally, logicians predict more endorsing PC for NC than for PI proposition. HP 3: It's easier to calculate that inference is not NC if it is also not PC. Generally, logicians predict more PI than IPI proposition endorses as NC. A modal syllogistic as a classical truth logic is presented by multi-propositions (two premises and one inference), each one from four modes has quantifiers such as universal quantifiers and existential quantifier; ∀, ∼∀, ∃, and ∼ ∃. They were evaluated by a single-mental model (Experiment I) and a multi-mental model (Experiment II). Logicians applied the immediate inference task (IIT), evaluation task (ET), and production task (PT) to evaluate three experiments. The results of the experiments suggested that students mostly endorsed PC/PI inferences over NC inferences. Even when logicians divided PC/PI separately as PC and PI, individuals endorsed PC most likely as compared to NC, and PI than IPI. Logicians also highlighted fallacies that were continuously resisted and endorsed when students were asked to judge multi-propositions that had NC. The purpose of this experimental study is to present a glimpse of students' endorsement of multi-propositions and explain that each individual has a different working memory and intelligence. [ABSTRACT FROM AUTHOR]

Background: Induced abortion is one of the most common gynecological procedures in the world, with as many as three in every ten pregnancies ending in abortion. It, however, remains controversial. The objective of this scoping review was to explore and map existing literature on the experiences of those who provide abortion care. Methods and findings: This exploratory review followed the Levac et al. guidelines and was reported in accordance with the PRISMA-ScR checklist. CINAHL, Cochrane, EMBASE, PsycInfo, PubMed, and Web of Science were used to identify peer-reviewed, original research articles published on providers' experience of abortion. We identified 106 relevant studies, which include a total sample of 4,250 providers from 28 countries and six continents. Most of the studies were qualitative (n = 83), though quantitative (n = 15) and mixed methods (n = 8) studies were also included. We identified two overarching themes: (1) Providers' experiences with abortion stigma and (2) Providers' reflections on their abortion work. Our findings suggest that providers from around the world experience challenges within society and their communities and workplaces which reinforce the stigmatization and marginalization of abortion and pose questions about the morality of this work. Most, however, are proud of their work, believe abortion care to be socially important and necessary, and remain committed to the provision of care. Conclusions: The findings of this review provide a comprehensive overview on the known experiences of providing abortion care. It is a key point of reference for international providers, researchers, and advocates to further this area of research or discussion in their own territories. The findings of this review will inform future work on how to support providers against stigmatization and will offer providers the chance to reflect on their own experiences. [ABSTRACT FROM AUTHOR]

Recent work on transformer-based neural networks has led to impressive advances on multiple-choice natural language processing (NLP) problems, such as Question Answering (QA) and abductive reasoning. Despite these advances, there is limited work still on systematically evaluating such models in ambiguous situations where (for example) no correct answer exists for a given prompt among the provided set of choices. Such ambiguous situations are not infrequent in real world applications. We design and conduct an experimental study of this phenomenon using three probes that aim to 'confuse' the model by perturbing QA instances in a consistent and well-defined manner. Using a detailed set of results based on an established transformer-based multiple-choice QA system on two established benchmark datasets, we show that the model's confidence in its results is very different from that of an expected model that is 'agnostic' to all choices that are incorrect. Our results suggest that high performance on idealized QA instances should not be used to infer or extrapolate similarly high performance on more ambiguous instances. Auxiliary results suggest that the model may not be able to distinguish between these two situations with sufficient certainty. Stronger testing protocols and benchmarking may hence be necessary before such models are deployed in front-facing systems or ambiguous decision making with significant human impact. [ABSTRACT FROM AUTHOR]

Moss, was frequently found growing in litchi orchards. However, less known about whether it can be used as a visual bio-indicator for evaluating soil fertility and health. Therefore, soil chemical and biological properties, microbial community structures and the metabolic functions of microbes in soils between moss- and non-moss-growth areas were analyzed using traditional and high-throughput sequencing technologies. The results showed that pH and the contents of and available phosphorus (AP) in moss growth areas were significantly lower than those of non-moss growth areas, but the contents of alkali-hydrolyzable nitrogen (AN) and available potassium (AK) were significantly increased. In comparison with the soil of the non-moss-growth area, the abundances of hypotrophic microorganisms, such as Chloroflexi, Cyanobacteria and WPS-2 enriched in the soil of the moss-grown area. Moreover, the proportions of eutrophic microorganisms, such as Proteobacteria and Firmicutes also declined in the soils of the moss-growth area. Furthermore, the metabolic pathways of soil bacteria and fungi were also degraded in the moss-growth area. All above results indicated that not only lower soil fertility, but also soil microbial diversity also declined in moss growth area which compared to those of non-moss growth area. In one word, moss can be considered using as a visual bio-indicator for representing soil degradation in litchi orchards. [ABSTRACT FROM AUTHOR]

Background and aims: This qualitative study aimed to explore how the development of tolerance to both the psychoactive and respiratory depressant effects of heroin on re-exposure are experienced by people who use heroin. Methods: Semi-structured one-to-one interviews were conducted with 20 adults who currently or previously used heroin (for at least 6 months), with any type of administration (injected, smoked) and experience of abstinence (at least 2 weeks) and relapse. Topic guides explored the participants understanding of tolerance, their experience of developing tolerance to heroin and of tolerance following relapse. Interviews were audio‐recorded and transcribed. Thematic analysis was used to generate salient themes. Results: The analysis produced three broad themes: lay understanding of tolerance; tolerating tolerance; and rapid tolerance development following relapse. Tolerance was defined as the body adapting to regular drug use, so that the drug no longer produced the same level of effect. Tolerance was experienced as interacting and co-developing with physical dependence and the symptoms of withdrawal. Indeed, several participants did not differentiate between tolerance and dependence. Most participants did not notice tolerance to respiratory depression. Tolerance levels fluctuated—increasing over periods of regular use and reducing when abstinent. Using more drug was the most common response to increasing tolerance to the desired effects. On re-use following abstinence, tolerance was experienced as developing more quickly in the most recent relapse compared to the first. Tolerance was also perceived to return more quickly with each abstinence-relapse cycle. Conclusions: Qualitative accounts of tolerance report that tolerance returns more quickly with each relapse episode. By elucidating the mechanism(s) involved and potentially discovering how they could be switched on prior to relapse occurring we might be able to develop a beneficial harm reduction treatment for people in abstinence that would protect against overdose occurring on subsequent relapse. [ABSTRACT FROM AUTHOR]

More than 2,000 common bottlenose dolphins (Tursiops truncatus) inhabit the Barataria Bay Estuarine System in Louisiana, USA, a highly productive estuary with variable salinity driven by natural and man-made processes. It was unclear whether dolphins that are long-term residents to specific areas within the basin move in response to fluctuations in salinity, which at times can decline to 0 parts per thousand in portions of the basin. In June 2017, we conducted health assessments and deployed satellite telemetry tags on dolphins in the northern portions of the Barataria Bay Estuarine System Stock area (9 females; 4 males). We analyzed their fine-scale movements relative to modeled salinity trends compared to dolphins tagged near the barrier islands (higher salinity environments) from 2011 to 2017 (37 females; 21 males). Even though we observed different movement patterns among individual dolphins, we found no evidence that tagged dolphins moved coincident with changes in salinity. One tagged dolphin spent at least 35 consecutive days, and 75 days in total, in salinity under 5 parts per thousand. Health assessments took place early in a seasonal period of decreased salinity. Nonetheless, we found an increased prevalence of skin lesions, as well as abnormalities in serum biochemical markers and urine:serum osmolality ratios for dolphins sampled in lower salinity areas. This study provides essential information on the likely behavioral responses of dolphins to changes in salinity (e.g., severe storms or from the proposed Mid-Barataria Sediment Diversion project) and on physiological markers to inform the timing and severity of impacts from low salinity exposure. [ABSTRACT FROM AUTHOR]

Anthropogenic activities in catchments used for drinking water production largely contaminates source waters, and this may impact the quality of the final drinking water product. These contaminants may also affect taxonomic and functional profiles of the bacterial communities in the drinking water. Here, we report an integrated insight into the microbiome and water quality of four water treatment plants (NWC, NWE, WCA and NWG) that supply portable water to communities in South Africa. A new scoring system based on combined significant changes of physicochemical parameters and microbial abundance from raw to treated water was used to evaluate the effectiveness of the treatment plants at water purification. Physicochemical parameters which include total soluble solids, turbidity, pH, nitrites and phosphorus among others, were measured in source, treated, and distributed water. There were general statistically significant (P ≤ 0.05) differences between raw and treated water, demonstrating the effectiveness of the purification process. Illumina sequencing of the 16S rRNA gene was used for taxonomic profiling of the microbial communities and this data was used to infer functional attributes of the communities. Structure and composition of the bacterial communities differed significantly (P < 0.05) among the treatment plants, only NWE and NWG showed no significant differences (P > 0.05), this correlated with the predicted functional profile of the microbial communities obtained from Phylogenetic Investigation of Communities by Reconstruction of Observed States (PICRUSt), as well as the likely pollutants of source water. Bacteroidetes, Chlorobi and Fibrobacteres significantly differed (P < 0.05) between raw and distributed water. PICRUSt inferred a number of pathways involved in the degradation of xenobiotics such as Dichlorodiphenyltrichloroethane, atrazine and polycyclic aromatic hydrocarbons. More worryingly, was the presence of pathways involved in beta-lactam resistance, potential pathogenic Escherichia coli infection, Vibrio cholerae infection, and Shigellosis. Also present in drinking and treated water were OTUs associated with a number of opportunistic pathogens. [ABSTRACT FROM AUTHOR]

Predictive models have been developed for influenza but have seldom been validated. Typically they have focused on patients meeting a definition of infection that includes fever. Less is known about how models perform when more symptoms are considered. We, therefore, aimed to create and internally validate predictive scores of acute respiratory infection (ARI) symptoms to diagnose influenza virus infection as confirmed by polymerase chain reaction (PCR) from respiratory specimens. Data from a completed trial to study the indirect effect of influenza immunization in Hutterite communities were randomly split into two independent groups for model derivation and validation. We applied different multivariable modelling techniques and constructed Receiver Operating Characteristics (ROC) curves to determine predictive indexes at different cut-points. From 2008–2011, 3288 first seasonal ARI episodes and 321 (9.8%) influenza positive events occurred in 2202 individuals. In children up to 17 years, the significant predictors of influenza virus infection were fever, chills, and cough along with being of age 6 years and older. In adults, presence of chills and cough but not fever were highly specific for influenza virus infection (sensitivity 30%, specificity 96%). Performance of the models in the validation set was not significantly different. The predictors were consistently found to be significant irrespective of the multivariable technique. Symptomatic predictors of influenza virus infection vary between children and adults. The scores could assist clinicians in their test and treat decisions but the results need to be externally validated prior to application in clinical practice. [ABSTRACT FROM AUTHOR]

For most pathogens, vaccination reduces the spread of the infection and total number of cases; thus, public policy usually advocates maximizing vaccination coverage. We use simple mathematical models to explore how this may be different for pathogens, such as influenza, which exhibit strain variation. Our models predict that the total number of seasonal influenza infections is minimized at an intermediate (rather than maximal) level of vaccination, and, somewhat counter-intuitively, further increasing the level of the vaccination coverage may lead to higher number of influenza infections and be detrimental to the public interest. This arises due to the combined effects of: competition between multiple co-circulating strains; limited breadth of protection afforded by the vaccine; and short-term strain-transcending immunity following natural infection. The study highlights the need for better quantification of the components of vaccine efficacy and longevity of strain-transcending cross-immunity in order to generate nuanced recommendations for influenza vaccine coverage levels. [ABSTRACT FROM AUTHOR]

This study evaluates the effects of toxic metal pollution in the highly contaminated Sarno River (South Italy), by using the aquatic moss Leptodictyum riparium in bags at 3 representative sites of the river. Biological effects were assessed by metal bioaccumulation, ultrastructural changes, oxidative stress, as Reactive Oxygen Species (ROS) production and Glutathione S-transferase (GST) activity, as well as Heat Shock Proteins 70 (HSP70s) induction. The results showed that L. riparium is a valuable bioindicator for toxic metal pollution of water ecosystem, accumulating different amounts of toxic metals from the aquatic environment. Toxic metal pollution caused severe ultrastructural damage, as well as increased ROS production and induction of GST and HSP70s, in the samples exposed at the polluted sites. To assess the role and the effect of toxic metals on L. riparium, were also cultured in vitro with Cd, Cr, Cu, Fe, Ni, Pb, Zn at the same concentrations as measured at the 3 sites. Ultrastructure, ROS, GST, and HSP70s resulted severely affected by toxic metals. Based on our findings, we confirm L. riparium as a model organism in freshwater biomonitoring surveys, and GST and HSP70s as promising biomarkers of metal toxicity. [ABSTRACT FROM AUTHOR]

A simple, objective and accurate way of grouping children undergoing surgery into clinically relevant risk groups is needed. The purpose of this study, is to develop and validate a preoperative risk classification system for postsurgical 30-day mortality for children undergoing a wide variety of operations. The National Surgical Quality Improvement Project-Pediatric participant use file data for calendar years 2012–2014 was analyzed to determine preoperative variables most associated with death within 30 days of operation (D30). Risk groups were created using classification tree analysis based on these preoperative variables. The resulting risk groups were validated using 2015 data, and applied to neonates and higher risk CPT codes to determine validity in high-risk subpopulations. A five-level risk classification was found to be most accurate. The preoperative need for ventilation, oxygen support, inotropic support, sepsis, the need for emergent surgery and a do not resuscitate order defined non-overlapping groups with observed rates of D30 that vary from 0.075% (Very Low Risk) to 38.6% (Very High Risk). When CPT codes where death was never observed are eliminated or when the system is applied to neonates, the groupings remained predictive of death in an ordinal manner. [ABSTRACT FROM AUTHOR]

Introduction: During the 2013–2014 influenza season, Public Health England extended routine influenza vaccination to all 2- and 3-year-old children in England. To estimate the impact of this change in policy on influenza-related morbidity and mortality, we developed a disease transmission and surveillance model informed by real-world data. Methods: We combined real-world and literature data sources to construct a model of influenza transmission and surveillance in England. Data were obtained for four influenza seasons, starting with the 2010–2011 season. Bayesian inference was used to estimate model parameters on a season-by-season basis to assess the impact of targeting 2- and 3-year-old children for influenza vaccination. This provided the basis for the construction of counterfactual scenarios comparing vaccination rates of ~2% and ~35% in the 2- and 3- year-old population to estimate reductions in general practitioner (GP) influenza-like-illness (ILI) consultations, respiratory hospitalizations and deaths in the overall population. Results: Our model was able to replicate the main patterns of influenza across the four seasons as observed through laboratory surveillance data. Targeting 2- and 3-year-old children for influenza vaccination resulted in reductions in the general population of between 6.2–9.9% in influenza-attributable GP ILI consultations, 6.1–10.7% in influenza-attributable respiratory hospitalizations, and 5.7–9.4% in influenza-attributable deaths. The decrease in influenza-attributable ILI consultations represents a reduction of between 4.5% and 7.3% across all ILI consultations. The reduction in influenza-attributable respiratory hospitalizations represents a reduction of between 1.2% and 2.3% across all respiratory hospitalizations. Reductions in influenza-attributable respiratory deaths represent a reduction of between 0.9% and 2.4% in overall respiratory deaths. Conclusion: This study has provided evidence that extending routine influenza vaccination to all healthy children aged 2 and 3 years old leads to benefits in terms of reduced utilization of healthcare resources and fewer respiratory health outcomes and deaths. [ABSTRACT FROM AUTHOR]

Background: Inclusion of vaccine herd-protection effects in cost-effectiveness analyses (CEAs) can impact the CEAs-conclusions. However, empirical epidemiologic data on the size of herd-protection effects from original studies are limited. Methods: We performed a quantitative comparative analysis of the impact of herd-protection effects in CEAs for four childhood vaccinations (pneumococcal, meningococcal, rotavirus and influenza). We considered CEAs reporting incremental-cost-effectiveness-ratios (ICERs) (per quality-adjusted-life-years [QALY] gained; per life-years [LY] gained or per disability-adjusted-life-years [DALY] avoided), both with and without herd protection, while keeping all other model parameters stable. We calculated the size of the ICER-differences without vs with-herd-protection and estimated how often inclusion of herd-protection led to crossing of the cost-effectiveness threshold (of an assumed societal-willingness-to-pay) of $50,000 for more-developed countries or X3GDP/capita (WHO-threshold) for less-developed countries. Results: We identified 35 CEA studies (20 pneumococcal, 4 meningococcal, 8 rotavirus and 3 influenza vaccines) with 99 ICER-analyses (55 per-QALY, 27 per-LY and 17 per-DALY). The median ICER-absolute differences per QALY, LY and DALY (without minus with herd-protection) were $15,620 (IQR: $877 to $48,376); $54,871 (IQR: $787 to $115,026) and $49 (IQR: $15 to $1,636) respectively. When the target-vaccination strategy was not cost-saving without herd-protection, inclusion of herd-protection always resulted in more favorable results. In CEAs that had ICERs above the cost-effectiveness threshold without herd-protection, inclusion of herd-protection led to crossing of that threshold in 45% of the cases. This impacted only CEAs for more developed countries, as all but one CEAs for less developed countries had ICERs below the WHO-cost-effectiveness threshold even without herd-protection. In several analyses, recommendation for the adoption of the target vaccination strategy depended on the inclusion of the herd protection effect. Conclusions: Inclusion of herd-protection effects in CEAs had a substantial impact in the estimated ICERs and made target-vaccination strategies more attractive options in almost half of the cases where ICERs were above the societal-willingness to pay threshold without herd-protection. More empirical epidemiologic data are needed to determine the size of herd-protection effects across diverse settings and also the size of negative vaccine effects, e.g. from serotype substitution. [ABSTRACT FROM AUTHOR]

In this paper we present the development and validation a comprehensive questionnaire to assess college students’ knowledge about modern genetics and genomics, their belief in genetic determinism, and their attitudes towards applications of modern genetics and genomic-based technologies. Written in everyday language with minimal jargon, the Public Understanding and Attitudes towards Genetics and Genomics (PUGGS) questionnaire is intended for use in research on science education and public understanding of science, as a means to investigate relationships between knowledge, determinism and attitudes about modern genetics, which are to date little understood. We developed a set of core ideas and initial items from reviewing the scientific literature on genetics and previous studies on public and student knowledge and attitudes about genetics. Seventeen international experts from different fields (e.g., genetics, education, philosophy of science) reviewed the initial items and their feedback was used to revise the questionnaire. We validated the questionnaire in two pilot tests with samples of university freshmen students. The final questionnaire contains 45 items, including both multiple choice and Likert scale response formats. Cronbach alpha showed good reliability for each section of the questionnaire. In conclusion, the PUGGS questionnaire is a reliable tool for investigating public understanding and attitudes towards modern genetics and genomic-based technologies. [ABSTRACT FROM AUTHOR]

Background: The treatment of differentiated thyroid cancer (DTC) ends in full recovery in 80% of cases. However, in 20% of cases local recurrences or distant metastases are observed, for this reason DTC patients are under life-long follow-up. The most sensitive marker for recurrence is stimulated thyroglobulin (Tg) which, together with neck ultrasound (US), enables correct diagnosis in nearly all cases of the active disease. For many years the only known stimulation was a 4–5 week withdrawal from the L-T4 therapy (THW). For the last couple of years stimulation with the use of recombinant human TSH (rhTSH) has been available. This method of stimulation may have a significant influence in obtaining the Tg level. However, it is important to determine the cut-off level for rhTSH-stimulated Tg (rhTSH/Tg). Materials and Methods: This is a retrospective analysis of consecutive patients from one facility who have qualified over a period of two years for repeated radioiodine therapy (RIA). In our facility the ablation effectiveness evaluation is always carried out with the use of rhTSH, with the repeated therapy following THW. Such a procedure enables two Tg measurements in the same patient after both types of stimulation within 4–5 weeks. The obtained values were compared, cut-off levels in THW conditions were used (2.0 ng/ml for patients in remission and 10.0 ng/ml for patients with an active disease). In order to determine the cut-off level for rhTSH/Tg, regression analysis and ROC curves were used. Results: In 63 patients the Tg measurement of both methods of stimulation were obtained. It was observed that there was a high correlation between rhTSH/Tg and THW/Tg. However, the rhTSH/Tg level was significantly lower than THW/ Tg. The rhTSH/ Tg cut-off levels which corresponded to the 2.0 ng/ml and 10.0 ng/ml limits for THW/Tg were calculated and the values were 0.6 ng/ml and 2.3 ng/ml respectively. Conclusions: The method of stimulation has a significant impact on the obtained Tg concentrations. The assumed THW/Tg cut off levels must not be transferred to rhTSH/Tg. [ABSTRACT FROM AUTHOR]

Ontario, Canada, immunizes against influenza using a trivalent inactivated influenza vaccine (IIV3) under a Universal Influenza Immunization Program (UIIP). The UIIP offers IIV3 free-of-charge to all Ontarians over 6 months of age. A newly approved quadrivalent inactivated influenza vaccine (IIV4) offers wider protection against influenza B disease. We explored the expected cost-utility and budget impact of replacing IIV3 with IIV4, within the context of Ontario’s UIIP, using a probabilistic and static cost-utility model. Wherever possible, epidemiological and cost data were obtained from Ontario sources. Canadian or U.S. sources were used when Ontario data were not available. Vaccine efficacy for IIV3 was obtained from the literature. IIV4 efficacy was derived from meta-analysis of strain-specific vaccine efficacy. Conservatively, herd protection was not considered. In the base case, we used IIV3 and IIV4 prices of $5.5/dose and $7/dose, respectively. We conducted a sensitivity analysis on the price of IIV4, as well as standard univariate and multivariate statistical uncertainty analyses. Over a typical influenza season, relative to IIV3, IIV4 is expected to avert an additional 2,516 influenza cases, 1,683 influenza-associated medical visits, 27 influenza-associated hospitalizations, and 5 influenza-associated deaths. From a societal perspective, IIV4 would generate 76 more Quality Adjusted Life Years (QALYs) and a net societal budget impact of $4,784,112. The incremental cost effectiveness ratio for this comparison was $63,773/QALY. IIV4 remains cost-effective up to a 53% price premium over IIV3. A probabilistic sensitivity analysis showed that IIV4 was cost-effective with a probability of 65% for a threshold of $100,000/QALY gained. IIV4 is expected to achieve reductions in influenza-related morbidity and mortality compared to IIV3. Despite not accounting for herd protection, IIV4 is still expected to be a cost-effective alternative to IIV3 up to a price premium of 53%. Our conclusions were robust in the face of sensitivity analyses. [ABSTRACT FROM AUTHOR]

Although the microneutralization (MN) assay has been shown to be more sensitive than the hemagglutination inhibition (HAI) assay for the measurement of humoral immunity against influenza viruses, further evidence relating MN titres to protective efficacy against infection is needed. Serum antibodies against seasonal H1N1 and H3N2 influenza were measured in children and adolescents (n = 656) by MN and hemagglutination inhibition (HAI) assays. Compared to HAI, the MN assay is more sensitive in detecting serum antibodies and estimates of protective effectiveness against PCR-confirmed infection were higher for both subtypes. Given our findings, the MN assay warrants further consideration as a formal tool for the routine evaluation of vaccine-induced antibody responses. [ABSTRACT FROM AUTHOR]

Background: French Polynesia has one of the highest incidence rates of thyroid cancer worldwide. Relationships with the atmospheric nuclear weapons tests and other environmental, biological, or behavioral factors have already been reported, but genetic susceptibility has yet to be investigated. We assessed the contribution of polymorphisms at the 9q22.33 and 14q13.3 loci identified by GWAS, and within the DNA repair gene ATM, to the risk of differentiated thyroid cancer (DTC) in 177 cases and 275 matched controls from the native population. Principal Findings: For the GWAS SNP rs965513 near FOXE1, an association was found between genotypes G/A and A/A, and risk of DTC. A multiplicative effect of allele A was even noted. An excess risk was also observed in individuals carrying two long alleles of the poly-alanine tract expansion in FOXE1, while no association was observed with rs1867277 falling in the promoter region of the gene. In contrast, the GWAS SNP rs944289 (NKX2-1) did not show any significant association. Although the missense substitution D1853N (rs1801516) in ATM was rare in the population, carriers of the minor allele (A) also showed an excess risk. The relationships between these five polymorphisms and the risk of DTC were not contingent on the body surface area, body mass index, ethnicity or dietary iodine intake. However, an interaction was evidenced between the thyroid radiation dose and rs944289. Significance: A clear link could not be established between the high incidence in French Polynesia and the studied polymorphisms, involved in susceptibility to DTC in other populations. Important variation in allele frequencies was observed in the Polynesian population as compared to the European populations. For FOXE1 rs965513, the direction of association and the effect size was similar to that observed in other populations, whereas for ATM rs1801516, the minor allele was associated to an increased risk in the Polynesian population and with a decreased risk in the European population. [ABSTRACT FROM AUTHOR]

Introduction: Patients with differentiated thyroid cancer (DTC) are treated with (near)-total thyroidectomy followed by remnant ablation. Optimal radioiodine-131 (131I) uptake is achieved by withholding thyroid hormone (THW), pretreatment with recombinant human Thyrotropin Stimulating Hormone (rhTSH) is an alternative. Six randomized trials have been published comparing THW and rhTSH, however comparison is difficult because an uniform definition of ablation success is lacking. Using a strict definition, we performed an observational study aiming to determine the efficacy of rhTSH as preparation for remnant ablation. Patients and Methods: Adult DTC patients with, tumor stage T1b to T3, Nx, N0 and N1, M0 were included in a prospective multicenter observational study with a fully sequential design, using a stopping rule. All patients received remnant ablation with 131I using rhTSH. Ablation success was defined as no visible uptake in the original thyroid bed on a rhTSH stimulated 150 MBq 131I whole body scan (WBS) 9 months after remnant ablation, or no visible uptake in the original thyroid bed on a post therapeutic WBS when a second high dose was necessary. Results: After interim analysis of the first 8 patients, the failure rate was estimated to be 69% (90% confidence interval (CI) 20-86%) and the inclusion of new patients had to be stopped. Final analysis resulted in an ablation success in 11 out of 17 patients (65%, 95% CI 38-86%). Conclusion: According to this study, the efficacy of rhTSH in the preparation of 131I ablation therapy is inferior, when using a strict definition of ablation success. The current lack of agreement as to the definition of successful remnant ablation, makes comparison between different ablation strategies difficult. Our results point to the need for an international consensus on the definition of ablation success, not only in routine patient’s care but also for scientific reasons. Trial Registration: Dutch Trial Registration [ABSTRACT FROM AUTHOR]

The HIV/AIDS pandemic and its impact on women prompt the investigation of prevention strategies to interrupt sexual transmission of HIV. Long-acting drug delivery systems that simultaneously protect womenfrom sexual transmission of HIV and unwanted pregnancy could be important tools in combating the pandemic. We describe the design, in silico, in vitro and in vivo evaluation of a dual-reservoir intravaginal ring that delivers the HIV-1 reverse transcriptase inhibitor tenofovir and the contraceptive levonorgestrel for 90 days. Two polyether urethanes with two different hard segment volume fractions were used to make coaxial extruded reservoir segments with a 100 µm thick rate controlling membrane and a diameter of 5.5 mm that contain 1.3 wt% levonorgestrel. A new mechanistic diffusion model accurately described the levonorgestrel burst release in early time points and pseudo-steady state behavior at later time points. As previously described, tenofovir was formulated as a glycerol paste and filled into a hydrophilic polyurethane, hollow tube reservoir that was melt-sealed by induction welding. These tenofovir-eluting segments and 2 cm long coaxially extruded levonorgestrel eluting segments were joined by induction welding to form rings that released an average of 7.5 mg tenofovir and 21 µg levonorgestrel per day in vitro for 90 days. Levonorgestrel segments placed intravaginally in rabbits resulted in sustained, dose-dependent levels of levonorgestrel in plasma and cervical tissue for 90 days. Polyurethane caps placed between segments successfully prevented diffusion of levonorgestrel into the tenofovir-releasing segment during storage.Hydrated rings endured between 152 N and 354 N tensile load before failure during uniaxial extension testing. In summary, this system represents a significant advance in vaginal drug delivery technology, and is the first in a new class of long-acting multipurpose prevention drug delivery systems. [ABSTRACT FROM AUTHOR]

Globally, influenza infection is a major cause of morbidity and mortality in the elderly, who are suggested to be the major target group for trivalent influenza vaccine (TIV) vaccination by World Health Organization. In spite of an increasing trend in vaccine coverage rates in many countries, the effect of vaccination among the elderly in reducing hospitalization and mortality remains controversial. In this study, we conducted a historical cohort study to evaluate the temporal pattern of influenza-associated morbidity among persons older than 64 years over a decade. The temporal patterns of influenza-associated morbidity rates among the elderly older than 64 years indicated that Taiwan's elderly P&I outpatient visits have been decreasing since the beginning of the 1999–2000 influenza season; however, hospitalization has been increasing despite significant increases in vaccine coverage. The propensity score logistic regression model was implemented to evaluate the source of bias and it was found that the TIV-receiving group had a higher propensity score than the non-receiving group (P<0.0001). In order to investigate the major factors affecting the temporal pattern of influenza-associated morbidity, we then used the propensity score as a summary confounder in a multivariate Poisson regression model based on the trimmed data. Our final models suggested that the factors affected the temporal pattern of morbidity differently. The variables including co-morbidity, vaccination rate, influenza virus type A and B isolation rate were associated with increased outpatient visits and hospitalization (p<0.05). In contrast, variables including high propensity score, increased 1°C in temperature, matching vaccine strains of type A/H1N1 and type B were associated with decreased outpatient visits and hospitalization (p<0.05). Finally, we assessed the impact of early appearance of antigenic-drifted strains and concluded that an excess influenza-associated morbidity substantial trends toward higher P&I hospitalization, but not outpatient visits, during the influenza season with early appearance of antigenic-drifted strains. [ABSTRACT FROM AUTHOR]

Background: Vaccination is an important strategy in the prevention of influenza, but immunologic response to vaccination can vary widely. Recent studies have shown an association between serum 25-hydroxyvitamin D (25[OH]D) levels and immune function. The purpose of this study was to determine if serum 25(OH)D level correlates with influenza vaccine immunogenicity in children and adolescents. Methods: We conducted a prospective cohort study of children age 3 to 15 years of age vaccinated with trivalent influenza vaccine (A/Brisbane/59/2007[H1N1]-like virus, A/Brisbane/10/2007 [H3N2]-like virus and B/Florida/4/2006-like virus) in Hutterite communities in Alberta, Saskatchewan and Manitoba. Serum 25(OH)D levels were measured at baseline and immunogenicity was assessed using hemagluttination inhibition (HAI) titers done at baseline and 3–5 weeks post vaccination. Logistic regression was used to assess the relationship between serum 25(OH)D level as both a continuous and dichotomous variable and seroprotection, seroconversion, fold increase in geometric mean titer (GMT) and post vaccination titer. Results: A total of 391 children and adolescents were included in the study and 221 (57% had post-vaccination HAI titers. The median serum 25(OH)D level was 61.0 nmol/L (Interquartile range [IQR] 50.0, 71.0). No relationship was found between serum 25(OH)D level and seroprotection (post-vaccination titer ≥40 and ≥320) or seroconversion (post-vaccination titer ≥40 for participants with pre-vaccine titer <10 or four-fold rise in post-vaccination titer for those with a pre-vaccine titer ≥10). Conclusion: Serum 25(OH)D level was not associated with influenza vaccine immunogenicity in otherwise healthy children and adolescents. Other strategies to enhance influenza vaccine response should continue to be evaluated in this population. The role of serum 25(OH)D level in vaccine responsiveness in other populations, especially those hyporesponsive to influenza vaccination, requires further study. [ABSTRACT FROM AUTHOR]

The British Petroleum Deepwater Horizon Oil Spill in the Gulf of Mexico was the biggest oil spill in US history. To assess the impact of the oil spill on the saltmarsh plant community, we examined Advanced Visible Infrared Imaging Spectrometer (AVIRIS) data flown over Barataria Bay, Louisiana in September 2010 and August 2011. Oil contamination was mapped using oil absorption features in pixel spectra and used to examine impact of oil along the oiled shorelines. Results showed that vegetation stress was restricted to the tidal zone extending 14 m inland from the shoreline in September 2010. Four indexes of plant stress and three indexes of canopy water content all consistently showed that stress was highest in pixels next to the shoreline and decreased with increasing distance from the shoreline. Index values along the oiled shoreline were significantly lower than those along the oil-free shoreline. Regression of index values with respect to distance from oil showed that in 2011, index values were no longer correlated with proximity to oil suggesting that the marsh was on its way to recovery. Change detection between the two dates showed that areas denuded of vegetation after the oil impact experienced varying degrees of re-vegetation in the following year. This recovery was poorest in the first three pixels adjacent to the shoreline. This study illustrates the usefulness of high spatial resolution airborne imaging spectroscopy to map actual locations where oil from the spill reached the shore and then to assess its impacts on the plant community. We demonstrate that post-oiling trends in terms of plant health and mortality could be detected and monitored, including recovery of these saltmarsh meadows one year after the oil spill. [ABSTRACT FROM AUTHOR]

Background: The disease burden of children with laboratory-confirmed influenza in China has not been well described. The aim of this study was to understand the epidemiology and socio-economic burden of influenza in children younger than 5 years in outpatient and emergency department settings. Methods: A prospective study of laboratory-confirmed influenza among children presenting to the outpatient settings in Soochow University Affiliated Children's Hospital with symptoms of influenza-like illness (ILI) was performed from March 2011 to February 2012. Throat swabs were collected for detection of influenza virus by reverse transcription polymerase chain reaction assay. Data were collected using a researcher administered questionnaire, concerning demographics, clinical characteristics, direct and indirect costs, day care absence, parental work loss and similar respiratory illness development in the family. Results: Among a total of 6,901 children who sought care at internal outpatient settings, 1,726 (25%) fulfilled the criteria of ILI and 1,537 were enrolled. Influenza was documented in 365 (24%) of enrolled 1,537 ILI cases. Among positive patients, 52 (14%) were type A and 313 (86%) were type B. About 52% of influenza outpatients had over-the-counter medications before physician visit and 41% visited hospitals two or more times. Children who attended daycare missed an average of 1.9 days. For each child with influenza-confirmed disease, the parents missed a mean of 1.8 work days. Similar respiratory symptoms were reported in 43% of family contacts of influenza positive children after onset of the child's illness. The mean direct and indirect costs per episode of influenza were $123.4 for outpatient clinics and $134.6 for emergency departments, and $125.9 for influenza A and $127.5 for influenza B. Conclusions: Influenza is a common cause of influenza-like illness among children and has substantial socio-economic impact on children and their families regarding healthcare seeking and day care/work absence. The direct and indirect costs of childhood influenza impose a heavy financial burden on families. Prevention measures such as influenza vaccine could reduce the occurrence of influenza in children and the economic burden on families. [ABSTRACT FROM AUTHOR]

Diabetes impairs physiological angiogenesis by molecular mechanisms that are not fully understood. Methylglyoxal (MGO), a metabolite of glycolysis, is increased in patients with diabetes. This study defined the role of MGO in angiogenesis impairment and tested the mechanism in diabetic animals. Endothelial cells and mouse aortas were subjected to Western blot analysis of vascular endothelial growth factor receptor 2 (VEGFR2) protein levels and angiogenesis evaluation by endothelial cell tube formation/migration and aortic ring assays. Incubation with MGO reduced VEGFR2 protein, but not mRNA, levels in a time and dose dependent manner. Genetic knockdown of the receptor for advanced glycation endproducts (RAGE) attenuated the reduction of VEGFR2. Overexpression of Glyoxalase 1, the enzyme that detoxifies MGO, reduced the MGO-protein adducts and prevented VEGFR2 reduction. The VEGFR2 reduction was associated with impaired angiogenesis. Suppression of autophagy either by inhibitors or siRNA, but not of the proteasome and caspase, normalized both the VEGFR2 protein levels and angiogenesis. Conversely, induction of autophagy either by rapamycin or overexpression of LC3 and Beclin-1 reduced VEGFR2 and angiogenesis. MGO increased endothelial LC3B and Beclin-1, markers of autophagy, which were accompanied by an increase of both autophagic flux (LC3 punctae) and co-immunoprecipitation of VEGFR2 with LC3. Pharmacological or genetic suppression of peroxynitrite (ONOO-) generation not only blocked the autophagy but also reversed the reduction of VEGFR2 and angiogenesis. Like MGO-treated aortas from normglycemic C57BL/6J mice, aortas from diabetic db/db and Akita mice presented reductions of angiogenesis or VEGFR2. Administration of either autophagy inhibitor ex vivo or superoxide scavenger in vivo abolished the reductions. Taken together, MGO reduces endothelial angiogenesis through RAGE-mediated, ONOO- dependent and autophagy-induced VEGFR2 degradation, which may represent a new mechanism for diabetic angiogenesis impairment. [ABSTRACT FROM AUTHOR]

VEGFR surface localization plays a critical role in converting extracellular VEGF signaling towards angiogenic outcomes, and the quantitative characterization of these parameters is critical for advancing computational models; however the levels of these receptors on blood vessels is currently unknown. Therefore our aim is to quantitatively determine the VEGFR localization on endothelial cells from mouse hindlimb skeletal muscles. We contextualize this VEGFR quantification through comparison to VEGFR-levels on cells in vitro. Using quantitative fluorescence we measure and compare the levels of VEGFR1 and VEGFR2 on endothelial cells isolated from C57BL/6 and BALB/c gastrocnemius and tibialis anterior hindlimb muscles. Fluorescence measurements are calibrated using beads with known numbers of phycoerythrin molecules. The data show a 2-fold higher VEGFR1 surface localization relative to VEGFR2 with 2,000-3,700 VEGFR1/endothelial cell and 1,300-2,000 VEGFR2/endothelial cell. We determine that endothelial cells from the highly glycolytic muscle, tibialis anterior, contain 30% higher number of VEGFR1 surface receptors than gastrocnemius; BALB/c mice display ~17% higher number of VEGFR1 than C57BL/6. When we compare these results to mouse fibroblasts in vitro, we observe high levels of VEGFR1 (35,800/cell) and very low levels of VEGFR2 (700/cell), while in human endothelial cells in vitro, we observe that the balance of VEGFRs is inverted, with higher levels VEGFR2 (5,800/cell) and lower levels of VEGFR1 (1,800/cell). Our studies also reveal significant cell-to-cell heterogeneity in receptor expression, and the quantification of these dissimilarities ex vivo for the first time provides insight into the balance of anti-angiogenic or modulatory (VEGFR1) and pro-angiogenic (VEGFR2) signaling. [ABSTRACT FROM AUTHOR]

Background: There have been few studies on children hospitalized with influenza published from mainland China. We performed a retrospective review of medical charts to describe the epidemiology, clinical features and direct medical cost of laboratory-proven influenza hospitalized children in Suzhou, China. Methods: Retrospective study on children with documented influenza infection hospitalized at Suzhou Children Hospital during 2005-2009 was conducted using a structured chart review instrument. Results: A total of 480 children were positive by immuno-fluorescent assay for influenza during 2005-2009. The hospitalizations for influenza occurred in 8-12 months of the year, most commonly in the winter with a second late summer peak (August-September). Influenza A accounted for 86.3%, and of these 286 (59.6%) were male, and 87.2% were <5 years of age. The median length of hospital stay was 7 days. Fever was the most common symptom, occurring in 398 (82.9%) children. There were 394 (82.1%) children with pneumonia and 70.2% of these hospitalized children had radiographic evidence of a pulmonary infiltrate. One hundred and twelve children (23.3%) required oxygen treatments and 13 (2.7%) were transferred to the ICU. Multivariable logistic regression showed that compared with the ≤6 months children, those aged >60 months old had shorter hospital stay (OR = 0.45); children with oxygen treatment tended to have longer hospital stays than those without oxygen treatment (OR = 2.14). The mean cost of each influenza-related hospitalization was US$ 624 (US$ 1323 for children referred to ICU and US$ 617 for those cared for on the wards). High risk children had higher total cost than low-risk patients. Conclusion: Compared to other countries, in Suzhou, children hospitalized with influenza have longer hospital stay and higher percentage of pneumonia. The direct medical cost is high relative to family income. Effective strategies of influenza immunization of young children in China may be beneficial in addressing this disease burden. [ABSTRACT FROM AUTHOR]

Knowledge about the diet and ecology of extinct herbivores has important implications for understanding the evolution of plant defence structures, establishing the influences of herbivory on past plant community structure and composition, and identifying pollination and seed dispersal syndromes. The flightless ratite moa (Aves: Dinornithiformes) were New Zealand's largest herbivores prior to their extinction soon after initial human settlement. Here we contribute to the knowledge of moa diet and ecology by reporting the results of a multidisciplinary study of 35 coprolites from a subalpine cave (Euphrates Cave) on the South Island of New Zealand. Ancient DNA analysis and radiocarbon dating revealed the coprolites were deposited by the extinct upland moa (Megalapteryx didinus), and span from at least 6,368±31 until 694±30 14C years BP; the approximate time of their extinction. Using pollen, plant macrofossil, and ancient DNA analyses, we identified at least 67 plant taxa from the coprolites, including the first evidence that moa fed on the nectar-rich flowers of New Zealand flax (Phormium) and tree fuchsia (Fuchsia excorticata). The plant assemblage from the coprolites reflects a highly-generalist feeding ecology for upland moa, including browsing and grazing across the full range of locally available habitats (spanning southern beech (Nothofagus) forest to tussock (Chionochloa) grassland). Intact seeds in the coprolites indicate that upland moa may have been important dispersal agents for several plant taxa. Plant taxa with putative anti-browse adaptations were also identified in the coprolites. Clusters of coprolites (based on pollen assemblages, moa haplotypes, and radiocarbon dates), probably reflect specimens deposited at the same time by individual birds, and reveal the necessity of suitably large sample sizes in coprolite studies to overcome potential biases in diet interpretation. [ABSTRACT FROM AUTHOR]

Background: Interactions of glycoconjugates with endogenous galectins, have been long proposed to participate in several reproductive processes including implantation. In human placenta gal-1, gal-3, gal-8, and gal-13 proteins are known to be present. Each of them has been proposed to play multiple functions, but so far no clear picture has emerged. We hypothesized that gal-1 participates in trophoblast invasion, and conducted Matrigel invasion assay using isolated cytotrophoblast from first trimester placenta and HTR-8/SVneo cell line to test it. Methods and Findings: Function blocking anti-gal-1 antibody was employed to assess participation of endogenous gal-1 in cell adhesion, cell invasion of HTR-8/SVneo cells. When gal-1 was blocked in isolated trophoblast cell invasion was reduced to 75% of control (SEM±6.3, P<0.001) and to 66% of control (SEM±1.7, P<0.001) in HTR-8/SVneo cell line. Increased availability of gal-1, as two molecular forms of recombinant human gal-1 (CS-gal-1 and Ox-gal-1), resulted in increased cell invasion by cytotrophoblast to 151% (SEM±16, P<0.01) with 1 μg/ml of CS-gal-1, and to 192% (SEM±51, P<0.05) with 1 μg/ml of Ox-gal-1. Stimulation was also observed in HTR-8/SVneo cells, to 317% (SEM±58, P<0.001) by CS-gal-1, and to 200% (SEM±24, P<0.001) by Ox-gal-1 at 1 μg/ml. Both sets of results confirmed involvement of gal-1 in trophoblast invasion. Galectin profile of isolated cytotrophoblast and HTR-8/SVneo cells was established using RT-PCR and real-time PCR and found to consist of gal-1, gal-3 and gal-8 for both cell types. Only gal-1 was located at the trophoblast cell membrane, as determined by FACS analysis, which is consistent with the results of the functional tests. Conclusion and Significance: These findings qualify gal-1 as a member of human trophoblast cell invasion machinery. [ABSTRACT FROM AUTHOR]

Background: A well targeted flu vaccine strategy can ensure that vaccines go to those who are at the highest risk of getting infected if unvaccinated. However, prior research has not explicitly examined the association between the risk of flu infection and vaccination rates. Purpose: This study examines the relationship between the risk of flu infection and the probability of getting vaccinated. Methods: Nationally representative data from the US and multivariate regression models were used to estimate what individual characteristics are associated with (1) the risk of flu infection when unvaccinated and (2) flu vaccination rates. These results were used to estimate the correlation between the probability of infection and the probability of getting vaccinated. Separate analyses were performed for the general population and the high priority population that is at increased risk of flu related complications. Results: We find that the high priority population was more likely to get vaccinated compared to the general population. However, within both the high priority and general populations the risk of flu infection when unvaccinated was negatively correlated with vaccination rates (r =20.067, p<0.01). This negative association between the risk of infection when unvaccinated and the probability of vaccination was stronger for the high priority population (r =20.361, p<0.01). Conclusions: There is a poor match between those who get flu vaccines and those who have a high risk of flu infection within both the high priority and general populations. Targeting vaccination to people with low socioeconomic status, people who are engaged in unhealthy behaviors, working people, and families with kids will likely improve effectiveness of flu vaccine policy. [ABSTRACT FROM AUTHOR]

Introduction: The propensity for influenza viruses to mutate and recombine makes them both a familiar threat and a prototype emerging infectious disease. Emerging evidence suggests that the use of MF59-adjuvanted vaccines in older adults and young children enhances protection against influenza infection and reduces adverse influenza-attributable outcomes compared to unadjuvanted vaccines. The health and economic impact of such vaccines in the Canadian population are uncertain. Methods: We constructed an age-structured compartmental model simulating the transmission of influenza in the Canadian population over a ten-year period. We compared projected health outcomes (quality-adjusted life years (QALY) lost), costs, and incremental cost-effectiveness ratios (ICERs) for three strategies: (i) current use of unadjuvanted trivalent influenza vaccine; (ii) use of MF59-adjuvanted influenza vaccine adults $65 in the Canadian population, and (iii) adjuvanted vaccine used in both older adults and children aged < 6. Results: In the base case analysis, use of adjuvanted vaccine in older adults was highly cost-effective (ICER = $2111/QALY gained), but such a program was ''dominated'' by a program that extended the use of adjuvanted vaccine to include young children (ICER = $1612/QALY). Results were similar whether or not a universal influenza immunization program was used in other age groups; projections were robust in the face of wide-ranging sensitivity analyses. Interpretation: Based on the best available data, it is projected that replacement of traditional trivalent influenza vaccines with MF59-adjuvanted vaccines would confer substantial benefits to vaccinated and unvaccinated individuals, and would be economically attractive relative to other widely-used preventive interventions. [ABSTRACT FROM AUTHOR]

The phenotypic state of the cell is commonly thought to be determined by the set of expressed genes. However, given the apparent complexity of genetic networks, it remains open what processes stabilize a particular phenotypic state. Moreover, it is not clear how unique is the mapping between the vector of expressed genes and the cell's phenotypic state. To gain insight on these issues, we study here the expression dynamics of metabolically essential genes in twin cell populations. We show that two yeast cell populations derived from a single steady-state mother population and exhibiting a similar growth phenotype in response to an environmental challenge, displayed diverse expression patterns of essential genes. The observed diversity in the mean expression between populations could not result from stochastic cell-to-cell variability, which would be averaged out in our large cell populations. Remarkably, within a population, sets of expressed genes exhibited coherent dynamics over many generations. Thus, the emerging gene expression patterns resulted from collective population dynamics. It suggests that in a wide range of biological contexts, gene expression reflects a self-organization process coupled to population-environment dynamics [ABSTRACT FROM AUTHOR]

Eps15 Homology Domain-containing 3 (EHD3), a member of the EHD protein family that regulates endocytic recycling, is the first protein reported to be specifically expressed in the glomerular endothelium in the kidney; therefore we generated Ehd3-/- mice and assessed renal development and pathology. Ehd3-/- animals showed no overt defects, and exhibited no proteinuria or glomerular pathology. However, as the expression of EHD4, a related family member, was elevated in the glomerular endothelium of Ehd3-/- mice and suggested functional compensation, we generated and analyzed Ehd3-/-; Ehd4-/- mice. These mice were smaller, possessed smaller and paler kidneys, were proteinuric and died between 3-24 weeks of age. Detailed analyses of Ehd3-/-; Ehd4-/- kidneys demonstrated thrombotic microangiopathy (TMA)-like glomerular lesions including thickening and duplication of glomerular basement membrane, endothelial swelling and loss of fenestrations. Other changes included segmental podocyte foot process effacement, mesangial interposition, and abnormal podocytic and mesangial marker expression. The glomerular lesions observed were strikingly similar to those seen in human pre-eclampsia and mouse models of reduced VEGF expression. As altered glomerular endothelial VEGFR2 expression and localization and increased apoptosis was observed in the absence of EHD3 and EHD4, we propose that EHD-mediated endocytic traffic of key surface receptors such as VEGFR2 is essential for physiological control of glomerular function. Furthermore, Ehd3-/-; Ehd4-/- mice provide a unique model to elucidate mechanisms of glomerular endothelial injury which is observed in a wide variety of human renal and extra-renal diseases. [ABSTRACT FROM AUTHOR]

Background: The presence of lead (Pb) ammunition residues in game meat has been widely documented, yet little information exists regarding the bioaccessibility of this Pb contamination. We study how cooking treatment (recipe) can affect Pb bioaccessibility in meat of animals hunted with Pb ammunition. Methodology/Principal Findings: We used an in vitro gastrointestinal simulation to study bioaccessibility. The simulation was applied to meat from red-legged partridge (Alectoris rufa) hunted with Pb shot pellets and cooked using various traditional Spanish game recipes involving wine or vinegar. Total Pb concentrations in the meat were higher in samples with visible Pb ammunition by X-ray (mean±SE: 3.29±1.12 μg/g w.w.) than in samples without this evidence (1.28±0.61 mg/g). The percentage of Pb that was bioaccessible within the simulated intestine phase was far higher in meat cooked with vinegar (6.75%) and wine (4.51%) than in uncooked meat (0.7%). Risk assessment simulations using our results transformed to bioavailability and the Integrated Exposure Uptake Biokinetic model (IEUBK; US EPA) show that the use of wine instead of vinegar in cooking recipes may reduce the percentage of children that would be expected to have >10 μg/dl of Pb in blood from 2.08% to 0.26% when game meat represents 50% of the meat in diet. Conclusions/Significance: Lead from ammunition in game meat is more bioaccessible after cooking, especially when using highly acidic recipes. These results are important because existing theoretical models regarding Pb uptake and subsequent risk in humans should take such factors into account. [ABSTRACT FROM AUTHOR]

Background: In temperate climates, invasive meningococcal disease (IMD) incidence tends to coincide with or closely follow peak incidence of influenza virus infection; at a seasonal level, increased influenza activity frequently correlates with increased seasonal risk of IMD. Methods: We evaluated 240 cases of IMD reported in central Ontario, Canada, from 2000 to 2006. Associations between environmental and virological (influenza A, influenza B and respiratory syncytial virus (RSV)) exposures and IMD incidence were evaluated using negative binomial regression models controlling for seasonal oscillation. Acute effects of weekly respiratory virus activity on IMD risk were evaluated using a matched-period case-crossover design with random directionality of control selection. Effects were estimated using conditional logistic regression. Results: Multivariable negative binomial regression identified elevated IMD risk with increasing influenza A activity (per 100 case increase, incidence rate ratio = 1.18, 95% confidence interval (CI): 1.06, 1.31). In case-crossover models, increasing weekly influenza A activity was associated with an acute increase in the risk of IMD (per 100 case increase, odds ratio (OR) = 2.03, 95% CI: 1.28 to 3.23). Increasing weekly RSV activity was associated with increased risk of IMD after adjusting for RSV activity in the previous 3 weeks (per 100 case increase, OR = 4.31, 95% CI: 1.14, 16.32). No change in disease risk was seen with increasing influenza B activity. Conclusions: We have identified an acute effect of influenza A and RSV activity on IMD risk. If confirmed, these finding suggest that influenza vaccination may have the indirect benefit of reducing IMD risk. [ABSTRACT FROM AUTHOR]

Background: The optimal vaccination strategy to mitigate the impact of influenza epidemics is unclear. In 2005, a countywide school-based influenza vaccination campaign was launched in Knox County, Tennessee (population 385,899). Approximately 41% and 48% of eligible county children aged 5-17 years were immunized with live attenuated influenza vaccine before the 2005-2006 and 2006-2007 influenza seasons, respectively. We sought to determine the population impact of this campaign. Methods: Laboratory-confirmed influenza data defined influenza seasons. We calculated the incidence of medically attended acute respiratory illness attributable to influenza in Knox and Knox-surrounding counties (concurrent controls) during consecutive seasons (5 precampaign and 2 campaign seasons) using negative binomial regression and rate difference methods. Age-stratified analyses compared the incidence of emergency department (ED) visits and hospitalizations attributable to influenza. Results: During precampaign seasons, estimated ED visit rates attributable to influenza were 12.39 (95% CI: 10.34-14.44) per 1000 Knox children aged 5-17 years and similar in Knox-surrounding counties. During the campaign seasons, annual Knox influenza-associated ED visit rates declined relative to rates in Knox-surrounding counties: rate ratios 0.55 (95% CI: 0.27-0.83) and 0.70 (95% CI: 0.56-0.84) for the first and second campaign seasons, respectively. Overall, there were about 35% or 4.86 per 1000 fewer influenza-associated ED visits among Knox County children aged 5-17 years attributable to the campaign. No significant declines in Knox compared to surrounding counties were detected for influenza associated ED visits in children aged <5 years, all adults combined or selected adult age subgroups, although power for these analyses was limited. Alternate rate-difference analyses yielded consistent results. Conclusion: Vaccination of approximately 45% of Knox school-aged children with influenza vaccine was associated with a 35% annual reduction (4.86 per 1000) in ED visit rates attributable to influenza. Higher vaccination coverage and/or larger studies would be needed to determine whether similar interventions have indirect benefits in other age groups. [ABSTRACT FROM AUTHOR]

Many adult stem cells reside in a special microenvironment known as the niche, where they receive essential signals that specify stem cell identity. Cell-cell adhesion mediated by cadherin and integrin plays a crucial role in maintaining stem cells within the niche. In Drosophila melanogaster, male germline stem cells (GSCs) are attached to niche component cells (i.e., the hub) via adherens junctions. The GSC centrosomes and spindle are oriented toward the hub-GSC junction, where Ecadherin- based adherens junctions are highly concentrated. For this reason, adherens junctions are thought to provide a polarity cue for GSCs to enable proper orientation of centrosomes and spindles, a critical step toward asymmetric stem cell division. However, understanding the role of E-cadherin in GSC polarity has been challenging, since GSCs carrying Ecadherin mutations are not maintained in the niche. Here, we tested whether E-cadherin is required for GSC polarity by expressing a dominant-negative form of E-cadherin. We found that E-cadherin is indeed required for polarizing GSCs toward the hub cells, an effect that may be mediated by Apc2. We also demonstrated that E-cadherin is required for the GSC centrosome orientation checkpoint, which prevents mitosis when centrosomes are not correctly oriented. We propose that E-cadherin orchestrates multiple aspects of stem cell behavior, including polarization of stem cells toward the stem cellniche interface and adhesion of stem cells to the niche supporting cells. [ABSTRACT FROM AUTHOR]

Vascular endothelial growth factor (VEGF), through its activation of cell surface receptor tyrosine kinases including VEGFR1 and VEGFR2, is a vital regulator of stimulatory and inhibitory processes that keep angiogenesis - new capillary growth from existing microvasculature - at a dynamic balance in normal physiology. Soluble VEGF receptor-1 (sVEGFR1) - a naturallyoccurring truncated version of VEGFR1 lacking the transmembrane and intracellular signaling domains - has been postulated to exert inhibitory effects on angiogenic signaling via two mechanisms: direct sequestration of angiogenic ligands such as VEGF; or dominant-negative heterodimerization with surface VEGFRs. In pre-clinical studies, sVEGFR1 gene and protein therapy have demonstrated efficacy in inhibiting tumor angiogenesis; while in clinical studies, sVEGFR1 has shown utility as a diagnostic or prognostic marker in a widening array of angiogenesis-dependent diseases. Here we developed a novel computational multi-tissue model for recapitulating the dynamic systemic distributions of VEGF and sVEGFR1. Model features included: physiologically-based multi-scale compartmentalization of the human body; intercompartmental macromolecular biotransport processes (vascular permeability, lymphatic drainage); and molecularlydetailed binding interactions between the ligand isoforms VEGF121 and VEGF165, signaling receptors VEGFR1 and VEGFR2, non-signaling co-receptor neuropilin-1 (NRP1), as well as sVEGFR1. The model was parameterized to represent a healthy human subject, whereupon we investigated the effects of sVEGFR1 on the distribution and activation of VEGF ligands and receptors. We assessed the healthy baseline stability of circulating VEGF and sVEGFR1 levels in plasma, as well as their reliability in indicating tissue-level angiogenic signaling potential. Unexpectedly, simulated results showed that sVEGFR1 - acting as a diffusible VEGF sink alone, i.e., without sVEGFR1-VEGFR heterodimerization - did not significantly lower interstitial VEGF, nor inhibit signaling potential in tissues. Additionally, the sensitivity of plasma VEGF and sVEGFR1 to physiological fluctuations in transport rates may partially account for the heterogeneity in clinical measurements of these circulating angiogenic markers, potentially hindering their diagnostic reliability for diseases. [ABSTRACT FROM AUTHOR]

VEGF signaling is a key regulator of vessel formation and function. In vascular endothelial cells, this signaling is mediated through its cognate receptor VEGFR2, which is dynamically sorted in response to ligand. Little is known about the underlying mechanism of this intracellular sorting. Here we examined the role of different components of the cytoskeleton in this process. We found that VEGFR2 mainly associates with microtubule fibers and to a lesser extent with intermediate filaments and actin. Microtubule disruption leads to accumulation of VEGFR2 protein in the membrane and cytoplasm leading to defects in VEGF signaling. In contrast, inhibition of actin filaments results in no accumulation of VEGFR2 total protein or apparent changes in microtubule association. Instead, actin inhibition leads to a more global signaling disruption of the ERK1/2 pathway. This is the first report demonstrating that VEGFR2 associates closely with microtubules in modulating the subcellular sorting and signaling of VEGFR2. [ABSTRACT FROM AUTHOR]