Causal mediation analysis decomposition of between-hospital variance

Causal variance decompositions for a given disease-specific quality indicator can be used to quantify differences in performance between hospitals or health care providers. While variance decompositions can demonstrate variation in quality of care, causal mediation analysis can be used to study care pathways leading to the differences in performance between the institutions. This raises the question of whether the two approaches can be combined to decompose between-hospital variation in an outcome type indicator to that mediated through a given process (indirect effect) and remaining variation due to all other pathways (direct effect). For this purpose, we derive a causal mediation analysis decomposition of between-hospital variance, discuss its interpretation, and propose an estimation approach based on generalized linear mixed models for the outcome and the mediator. We study the performance of the estimators in a simulation study and demonstrate its use in administrative data on kidney cancer care in Ontario.Comment: Health Serv Outcomes Res Method (2021

Interleukin-1 beta converting enzyme is necessary for development of depression-like behavior following intracerebroventricular administration of lipopolysaccharide to mice

BACKGROUND: Interleukin-1 beta converting enzyme (ICE, caspase 1) is a cysteine protease that processes immature pro-IL-1β into active mature IL-1β. IL-1β is a pro-inflammatory cytokine that mediates many of the physiological and behavioral responses to inflammation. Genetic deletion of ICE has previously been shown to prevent some negative physiologic responses to lipopolysaccharide (LPS)-induced inflammation. METHODS: Here we used a preclinical murine model to test the hypothesis that ICE is necessary for development of depression-like behaviors following intracerebroventricular (ICV) treatment with LPS. Adult male ICE knockout (ICE KO) and congenic wild-type C57BL/6 J (WT) mice were administered LPS either ICV at 100 ng/mouse or intraperitoneally (IP) at 830 μg/kg body weight or an equal volume of saline as controls. Mice were monitored up to 48 h after treatment for both sickness and depression-like behaviors. RESULTS: LPS given ICV induced a loss of body weight in both WT and ICE KO mice. This sickness response was similar between WT and ICE KO mice. As expected, LPS administered ICV increased immobility in the forced swim test (FST) and decreased sucrose preference in WT mice but no change in either of these two depression-like behaviors was observed in ICE KO mice. Expression of TNF-α and CD11b in brain was lower in ICE-KO mice at 24 h following ICV administration of LPS compared to WT mice. In contrast, when LPS was given systemically, sickness response, depression-like behaviors, and expression of these genes were similar between the two strains of mice. CONCLUSIONS: These findings indicate that ICE plays a specific role in depression-like behavior induced by a central inflammatory stimuli even though it is not required when LPS is administered systemically

A robust and reliable method for detecting signals of interest in multiexponential decays

The concept of rejecting the null hypothesis for definitively detecting a signal was extended to relaxation spectrum space for multiexponential reconstruction. The novel test was applied to the problem of detecting the myelin signal, which is believed to have a time constant below 40ms, in T2 decays from MRI's of the human brain. It was demonstrated that the test allowed the detection of a signal in a relaxation spectrum using only the information in the data, thus avoiding any potentially unreliable prior information. The test was implemented both explicitly and implicitly for simulated T2 measurements. For the explicit implementation, the null hypothesis was that a relaxation spectrum existed that had no signal below 40ms and that was consistent with the T2 decay. The confidence level by which the null hypothesis could be rejected gave the confidence level that there was signal below the 40ms time constant. The explicit implementation assessed the test's performance with and without prior information where the prior information was the nonnegative relaxation spectrum assumption. The test was also implemented implicitly with a data conserving multiexponential reconstruction algorithm that used left invertible matrices and that has been published previously. The implicit and explicit implementations demonstrated similar characteristics in detecting the myelin signal in both the simulated and experimental T2 decays, providing additional evidence to support the close link between the two tests. [Full abstract in paper]Comment: 23 pages with 8 figure

Does mode of administration affect health-related quality-of-life outcomes after stroke?

Telephone interviews and postal surveys may be a resource-efficient way of assessing health-related quality-of-life post-stroke, if they produce data equivalent to face-to-face interviews. This study explored whether telephone interviews and postal surveys of the Stroke and Aphasia Quality of Life Scale (SAQOL-39g) yielded similar results to face-to-face interviews. Participants included people with aphasia and comprised two groups: group one (n =22) were 3-6 months post-stroke; group two (n =26) were ≥1 year post-stroke. They completed either a face-to-face and a telephone interview or a face-to-face interview and a postal survey of the SAQOL-39g. Response rates were higher for group two (87%) than for group one (72-77%). There were no significant differences between respondents and non-respondents on demographics, co-morbidities, stroke severity, or communication impairment. Concordance between face-to-face and telephone administrations (.90-.98) was excellent; and very good-excellent between face-to-face and postal administrations (.84-.96), although scores in postal administrations were lower (significant for psychosocial domain and overall SAQOL-39g in group two). These findings suggest that the SAQOL-39g yields similar results in different modes of administration. Researchers and clinicians may employ alternative modes, particularly in the longer term post-stroke, in order to reduce costs or facilitate clients with access difficulties

Balancing Inflammation: The Link between Th17 and Regulatory T Cells

CD4+ T cell compartments in mouse and man are composed of multiple distinct subsets each possessing unique phenotypic and functional characteristics. IL-17-producing CD4+ T cells (Th17 cells) represent a distinct subset of the CD4+ T cell lineage. Recent evidence suggests that Th17 cells carry out effector functions similar to cytotoxic CD8+ T cells and play an important role in the clearance of extracellular pathogens and fungi. Th17 cell differentiation and function are closely related to the development and function of regulatory T cells (TREG). The balance between these two cell populations is essential for immune homeostasis and dysregulation of this balance has been implicated in a variety of inflammatory conditions including autoimmunity, allograft rejection, and tumorigenesis. Emerging evidence reports a significant amount of plasticity between the Th17 and regulatory T cell compartments, and the mechanisms by which these cells communicate and influence each other are just beginning to be understood. In this review, we highlight recent findings detailing the mechanisms driving Th17 and TREG plasticity and discuss the biologic consequences of their unique relationship

Advanced optical imaging in living embryos

Developmental biology investigations have evolved from static studies of embryo anatomy and into dynamic studies of the genetic and cellular mechanisms responsible for shaping the embryo anatomy. With the advancement of fluorescent protein fusions, the ability to visualize and comprehend how thousands to millions of cells interact with one another to form tissues and organs in three dimensions (xyz) over time (t) is just beginning to be realized and exploited. In this review, we explore recent advances utilizing confocal and multi-photon time-lapse microscopy to capture gene expression, cell behavior, and embryo development. From choosing the appropriate fluorophore, to labeling strategy, to experimental set-up, and data pipeline handling, this review covers the various aspects related to acquiring and analyzing multi-dimensional data sets. These innovative techniques in multi-dimensional imaging and analysis can be applied across a number of fields in time and space including protein dynamics to cell biology to morphogenesis

Overcoming acculturation: physical education recruits' experiences of an alternative pedagogical approach to games teaching

© 2015 Association for Physical Education Background: Physical education teacher education (PETE) programmes have been identified as a critical platform to encourage the exploration of alternative teaching approaches by pre-service teachers. However, the socio-cultural constraint of acculturation or past physical education and sporting experiences results in the maintenance of the status quo of a teacher-driven, reproductive paradigm. Previous studies have reported successfully overcoming the powerful influence of acculturation, resulting in a change in PETE students' custodial teaching beliefs and receptiveness to alternative teaching approaches. However, to date, limited information has been reported about how PETE students' acculturation shaped their receptiveness to an alternative teaching approach. This is particularly the case for PETE recruits identified in the literature as most resistant to change. Purpose: To explore the features and experiences of an alternative games teaching approach that appealed to PETE recruits identified as most resistant to change, requiring a specific sample of PETE recruits with strong, custodial, traditional physical education teaching beliefs, and whom are high-achieving sporting products of this traditional culture. The alternative teaching approach explored in this study is the constraints-led approach (CLA), which is similar operationally to Teaching Games for Understanding, but distinguished by a neurobiological theoretical framework (nonlinear pedagogy) that informs learning design. Participants and setting: A purposive sample of 10 Australian PETE students was recruited for the study. All participants initially had strong, custodial, traditional physical education teaching beliefs, and were successful sporting products of this teaching approach. After experiencing the CLA as learners during a games unit, participants demonstrated receptiveness to the alternative pedagogy. Data collection and analysis: Semi-structured interviews and written reflections were sources of data collection. Each participant was interviewed separately, once prior to participation in the games unit to explore their positive physical education experiences, and then again after participation to explore the specific games unit learning experiences that influenced their receptiveness to the alternative pedagogy. Participants completed written reflections about their personal experiences after selected practical sessions. Data were qualitatively analysed using grounded theory. Findings: Thorough examination of the data resulted in establishment of two prominent themes related to the appeal of the CLA for the participants: (i) psychomotor (effective in developing skill) and (ii) inclusivity (included students of varying skill level). The efficacy of the CLA in skill development was clearly an important mediator of receptiveness for highly successful products of a traditional culture. This significant finding could be explained by three key factors: the acculturation of the participants, the motor learning theory underpinning the alternative pedagogy and the unit learning design and delivery. The inclusive nature of the CLA provided a solution to the problem of exclusion, which also made the approach attractive to participants. Conclusions: PETE educators could consider these findings when introducing an alternative pedagogy aimed at challenging PETE recruits' custodial, traditional teaching beliefs. To mediate receptiveness, it is important that the learning theory underpinning the alternative approach is operationalised in a research-informed pedagogical learning design that facilitates students' perceptions of the effectiveness of the approach through experiencing and or observing it working

Exploring natural genetic diversity in a bread wheat multi-founder population: Dual imaging of photosynthesis and stomatal kinetics.

A better understanding of crop phenotype under dynamic environmental conditions will help inform the development of new cultivars with superior adaptation to constantly changing field conditions. Recent research has shown that optimising photosynthetic and stomatal conductance traits holds promise for improved crop performance. However, standard phenotyping tools such as gas-exchange systems are limited by their throughput. In this work, a novel approach based on a bespoke gas-exchange chamber allowing combined measurement of the quantum yield of photosystem II (PSII) with an estimation of stomatal conductance via thermal imaging, was used to phenotype a range of bread wheat (Triticum aestivum L.) genotypes, that were a sub-set of a multi-founder experimental population. Datasets were further supplemented by measurement of photosynthetic capacity and stomatal density. First, we showed that measurement of stomatal traits using our dual imaging system compared to standard IRGA methods showed good agreement between the two methods (R2=0.86) for the rapidity of stomatal opening (Ki), with the dual-imager method resulting in less intra-genotype variation. Using the dual-imaging methods, and traditional approaches we found broad and significant variation in key traits, including photosynthetic CO2 uptake at saturating light and ambient CO2 concentration (Asat), photosynthetic CO2 uptake at saturating light and elevated CO2 concentration (Amax), the maximum velocity of Rubisco for carboxylation (Vcmax), time for stomatal opening (Ki), and leaf evaporative cooling. Anatomical analysis revealed significant variation in flag leaf adaxial stomatal density. Associations between traits highlighted significant relationships between leaf evaporative cooling, leaf stomatal conductance under low (gsmin) and high (gsmax) light intensity, and the operating efficiency of PSII (Fq'/Fm'), highlighting the importance of stomatal conductance and stomatal rapidity in maintaining optimal leaf temperature for photosynthesis in wheat. Additionally, gsmin and gsmax were positively associated, indicating that potential combination of preferable traits (i.e. inherently high gsmax, low Ki and maintained leaf evaporative cooling) are present in wheat. This work highlights for the first time the effectiveness of thermal imaging in screening dynamic stomatal conductance in a large panel of wheat genotypes. The wide phenotypic variation observed suggested the presence of exploitable genetic variability in bread wheat for dynamic stomatal conductance traits and photosynthetic capacity for targeted optimisation within future breeding programs

Measurement of the scintillation time spectra and pulse-shape discrimination of low-energy beta and nuclear recoils in liquid argon with DEAP-1

The DEAP-1 low-background liquid argon detector was used to measure scintillation pulse shapes of electron and nuclear recoil events and to demonstrate the feasibility of pulse-shape discrimination (PSD) down to an electron-equivalent energy of 20 keV. In the surface dataset using a triple-coincidence tag we found the fraction of beta events that are misidentified as nuclear recoils to be $<1.4\times 10^{-7}$ (90% C.L.) for energies between 43-86 keVee and for a nuclear recoil acceptance of at least 90%, with 4% systematic uncertainty on the absolute energy scale. The discrimination measurement on surface was limited by nuclear recoils induced by cosmic-ray generated neutrons. This was improved by moving the detector to the SNOLAB underground laboratory, where the reduced background rate allowed the same measurement with only a double-coincidence tag. The combined data set contains $1.23\times10^8$ events. One of those, in the underground data set, is in the nuclear-recoil region of interest. Taking into account the expected background of 0.48 events coming from random pileup, the resulting upper limit on the electronic recoil contamination is $<2.7\times10^{-8}$ (90% C.L.) between 44-89 keVee and for a nuclear recoil acceptance of at least 90%, with 6% systematic uncertainty on the absolute energy scale. We developed a general mathematical framework to describe PSD parameter distributions and used it to build an analytical model of the distributions observed in DEAP-1. Using this model, we project a misidentification fraction of approx. $10^{-10}$ for an electron-equivalent energy threshold of 15 keV for a detector with 8 PE/keVee light yield. This reduction enables a search for spin-independent scattering of WIMPs from 1000 kg of liquid argon with a WIMP-nucleon cross-section sensitivity of $10^{-46}$ cm$^2$, assuming negligible contribution from nuclear recoil backgrounds.Comment: Accepted for publication in Astroparticle Physic