IL-17 can be protective or deleterious in murine pneumococcal pneumonia

Streptococcus pneumoniae is the major bacterial cause of community-acquired pneumonia, and the leading agent of childhood pneumonia deaths worldwide. Nasal colonization is an essential step prior to infection. The cytokine IL-17 protects against such colonization and vaccines that enhance IL-17 responses to pneumococcal colonization are being developed. The role of IL-17 in host defence against pneumonia is not known. To address this issue, we have utilized a murine model of pneumococcal pneumonia in which the gene for the IL-17 cytokine family receptor, Il17ra, has been inactivated. Using this model, we show that IL-17 produced predominantly from γδ T cells protects mice against death from the invasive TIGR4 strain (serotype 4) which expresses a relatively thin capsule. However, in pneumonia produced by two heavily encapsulated strains with low invasive potential (serotypes 3 and 6B), IL-17 significantly enhanced mortality. Neutrophil uptake and killing of the serotype 3 strain was significantly impaired compared to the serotype 4 strain and depletion of neutrophils with antibody enhanced survival of mice infected with the highly encapsulated SRL1 strain. These data strongly suggest that IL-17 mediated neutrophil recruitment to the lungs clears infection from the invasive TIGR4 strain but that lung neutrophils exacerbate disease caused by the highly encapsulated pneumococcal strains. Thus, whilst augmenting IL-17 immune responses against pneumococci may decrease nasal colonization, this may worsen outcome during pneumonia caused by some strains

Hurry up and decide: Empirical tests of the choice overload effect using cognitive process models

The choice overload effect emerged as a rebuttal to the notion that having more options from which to choose is always preferable. Jessup, Veinott, Todd, and Busemeyer (2009) used a modified version of decision field theory, a cognitive process model of choice, to generate multiple mechanisms based on psychological principles for the choice overload effect as it pertains to choice probability. Here we experimentally tested 2 of these mechanisms—time out and preference change—in a virtual hiring task to see whether participants hired more applicants when choosing from small relative to large sets of applicants. We further wanted to observe how the distribution of options affected choice. The choice overload effect replicated. More importantly, we observed that the time out mechanism did indeed account for choice overload effects, whereas the conflict-based preference change mechanism did not. Model fitting via simulation provided converging support because the time-out model provided a superior fit relative to the preference change model. This further demonstrates the value of utilizing models that incorporate underlying cognitive processes when exploring behaviors of interest to psychology, marketing, economics, and other related disciplines

Chapter 48 In Vivo Bioluminescence Imaging to Assess Compound Efficacy Against Trypanosoma brucei

Traditional animal models for human African trypanosomiasis rely on detecting Trypanosoma brucei brucei parasitemia in the blood. Testing the efficacy of new compounds in these models is cumbersome because it may take several months after treatment before surviving parasites become detectable in the blood. To expedite compound screening, we have used a Trypanosoma brucei brucei GVR35 strain expressing red-shifted firefly luciferase to monitor parasite distribution in infected mice through noninvasive wholebody bioluminescence imaging. This protocol describes the infection and in vivo bioluminescence imaging of mice to assess compound efficacy against T. brucei during the two characteristic stages of disease, the hemolymphatic phase (stage 1) and the encephalitic or central nervous system phase (stage 2)

Health care professionals' preferences for extending mammographic breast screening to the over 70s

Background Breast screening improves survival in women aged 50–70. The relative benefits of screening in women over 70 are reduced but women up to age 80 may still benefit. In the UK the National Health Service provides screening by self referral to women >70. This research has investigated health care professionals' (HCPs') preferences for extending screening to older women and factors they consider when advising about screening. Materials and methods UK HCPs for breast or elderly care were recruited. A questionnaire relating to screening in the >70s was administered. A sample of respondents were also interviewed to give added insight. Results Questionnaires were distributed to 488 HCPs and 139 replies received, (29%). A total of 26 professionals were also interviewed. Most felt the current system of self referral was under-utilized due to poor user awareness. Predicted life expectancy, co-morbidity and patient preference were viewed as important factors influencing screening recommendation. Chronological age was thought less important. The present system was thought flawed, but there was little enthusiasm for extending screening due to perceived risks and reduced cost efficacy. Some form of selectivity for fitter women was advocated. Conclusions There was acceptance that fitter older women may benefit from screening whilst the less fit may be harmed suggesting that some form of selective invitation would be preferable to the present system but would be practically difficult and costly to administer. The present system of self referral was felt to be inadequate due to low levels of awareness and uptake

Empirical array quality weights in the analysis of microarray data

BACKGROUND: Assessment of array quality is an essential step in the analysis of data from microarray experiments. Once detected, less reliable arrays are typically excluded or "filtered" from further analysis to avoid misleading results. RESULTS: In this article, a graduated approach to array quality is considered based on empirical reproducibility of the gene expression measures from replicate arrays. Weights are assigned to each microarray by fitting a heteroscedastic linear model with shared array variance terms. A novel gene-by-gene update algorithm is used to efficiently estimate the array variances. The inverse variances are used as weights in the linear model analysis to identify differentially expressed genes. The method successfully assigns lower weights to less reproducible arrays from different experiments. Down-weighting the observations from suspect arrays increases the power to detect differential expression. In smaller experiments, this approach outperforms the usual method of filtering the data. The method is available in the limma software package which is implemented in the R software environment. CONCLUSION: This method complements existing normalisation and spot quality procedures, and allows poorer quality arrays, which would otherwise be discarded, to be included in an analysis. It is applicable to microarray data from experiments with some level of replication

Differential Adaptive Stress Testing of Airborne Collision Avoidance Systems

The next-generation Airborne Collision Avoidance System (ACAS X) is currently being developed and tested to replace the Traffic Alert and Collision Avoidance System (TCAS) as the next international standard for collision avoidance. To validate the safety of the system, stress testing in simulation is one of several approaches for analyzing near mid-air collisions (NMACs). Understanding how NMACs can occur is important for characterizing risk and informingdevelopment of the system. Recently, adaptive stress testing (AST) has been proposed as a way to find the most likely path to a failure event. The simulation-based approach accelerates search by formulating stress testing as a sequential decision process then optimizing it using reinforcement learning. The approach has been successfully applied to stress test a prototype of ACAS Xin various simulated aircraft encounters. In some applications, we are not as interestedin the system's absolute performance as its performance relative to another system. Such situations arise, for example, during regression testing or when deciding whether a new system should replace an existing system. In our collision avoidance application, we are interested in finding cases where ACAS X fails but TCAS succeeds in resolving a conflict. Existing approaches do not provide an efficient means to perform this type of analysis. This paper extends the AST approach to differential analysis by searching two simulators simultaneously and maximizing the difference between their outcomes. We call this approach differential adaptive stress testing (DAST). We apply DAST to compare a prototype of ACAS X against TCAS and show examples of encounters found by the algorithm

The Association of Weight loss, Weight status, and Abdominal Obesity with all-cause Mortality in Older Adults

International audienceObjectives: The objectives of this study were to examine whether weight loss, weight status (based on body mass index [BMI] categories), and abdominal obesity (based on waist circumference [WC]) were associated with a 17-year mortality risk in community-dwelling older adults. Methods: Participants were 2,017 community-dwelling adults aged 65 years or above in the longitudinal Enquête de Santé Psychologique-Risques, Incidence et Traitement study. Self-reported weight loss was collected at baseline during face-to-face interviews. Bodyweight (kg), height (m), and WC (cm) were independently measured at the baseline. BMI was categorized as follows: underweight (BMI <18.5 kg/m2), normal weight (18.5–24.9 kg/m2), overweight (25–29.9 kg/m2), and obese (≥30 kg/m2). Abdominal obesity was defined by a WC of ≥102 cm in men and ≥88 cm in women. Adjusted Cox proportional hazards models were used to examine associations of weight loss, weight status, and abdominal obesity with all-cause mortality. Results: Over 17 years of follow-up (median 15.5 years), 812 participants died. Abdominal obesity compared to nonabdominal obesity was associated with a 49% increased mortality risk (95% confidence interval (CI): 1.22–1.83). However, being overweight (but not obese) was associated with a 20% decreased risk (95% CI: 0.66–0.97) compared to a normal BMI. Gender did not affect these associations. In the whole cohort, self-reported weight loss at baseline was not associated with an increased mortality risk after adjusting for health and lifestyle factors. However, in men, a baseline self-reported recent weight loss of >3 kg was associated with a 52% increase in mortality risk (95% CI: 1.05–2.18) in a fully adjusted model. Conclusion: In community-dwelling adults aged ≥65 years, abdominal obesity was strongly associated with increased mortality risk. Being overweight appeared, however, to be protective against mortality. Modest self-reported weight loss was not associated with all-cause mortality in community-dwelling older adults after adjusting for health and lifestyle factors. However, men reporting recent weight loss of more than 3 kg may be at increased risk. The findings of this study support the use of WC, rather than BMI, as a predictor of mortality risk in older adults

Fluctuations in Learners’ Willingness to Communicate During Communicative Task Performance: Conditions and Tendencies

A person’s willingness to communicate (WTC), believed to stem from a combination of proximal and distal variables comprising psychological, linguistic, educational and communicative dimensions of language, appears to be a significant predictor of success in language learning. The ability to communicate is both a means and end of language education, since, on the one hand, being able to express the intended meanings in the target language is generally perceived as the main purpose of any language course and, on the other, linguistic development proceeds in the course of language use. However, MacIntyre (2007, p. 564) observes that some learners, despite extensive study, may never become successful L2 speakers. The inability or unwillingness to sustain contacts with more competent language users may influence the way learners are evaluated in various social contexts. Establishing social networks as a result of frequent communication with target language users is believed to foster linguistic development. WTC, initially considered a stable personality trait and then a result of context-dependent influences, has recently been viewed as a dynamic phenomenon changing its intensity within one communicative event (MacIntyre and Legatto, 2011; MacIntyre et al., 2011). The study whose results are reported here attempts to tap into factors that shape one’s willingness to speak during a communicative task. The measures employed to collect the data - selfratings and surveys - allow looking at the issue from a number of perspectives

Development of a self-report measure of capability wellbeing for adults: the ICECAP-A

Purpose The benefits of health and social care are not confined to patient health alone and therefore broader measures of wellbeing may be useful for economic evaluation.\ud This paper reports the development of a simple measure of capability wellbeing for adults (ICECAP-A).\ud Methods In-depth, informant-led, interviews to identify the attributes of capability wellbeing were conducted with 36 adults in the UK. Eighteen semi-structured, repeat interviews were carried out to develop a capability-based descriptive system for the measure. Informants were purposively selected to ensure variation in socio-economic status, age, sex, ethnicity and health. Data analysis was carried out inductively and iteratively alongside interviews, and findings were used to shape the questions in later interviews.\ud Results Five over-arching attributes of capability wellbeing were identified for the measure: ‘‘stability’’,‘‘attachment’’, ‘‘achievement’’, ‘‘autonomy’’ and ‘‘enjoyment’’. One item, with four response categories, was developed for each attribute for the ICECAP-A descriptive system.\ud Conclusions The ICECAP-A capability measure represents a departure from traditional health economics outcome measures, by treating health status as an influence over broader attributes of capability wellbeing. Further work is required to value and validate the attributes and test the sensitivity of the ICECAP-A to healthcare interventions