Health promotion in an Australian Aboriginal community: the Growing Strong Brains® toolkit

Aim: The aim of this paper is to describe the implementation and evaluation of the Growing Strong Brains® (GSB) toolkit in a remote Aboriginal community in Western Australia (WA) over a 2-year period, 2018–2019. Background: Ngala, a community service organisation in WA, developed the GSB toolkit in 2014, a culturally appropriate and interactive resource to build knowledge of early childhood development within Aboriginal communities. This was in response to evidence that a higher percentage of children in Aboriginal communities were developmentally vulnerable compared to the rest of the population. The GSB toolkit promotes awareness and understanding of early brain development pre-birth and in the early years of a child’s life. Methods: The project was underpinned by participatory action research (PAR). Reflective PAR review cycles (n = 5) monitored local community engagement, navigated challenges and utilised community strengths. Fifty-nine local service providers attended a 2-day formal training. Data were collected by using various methods throughout the project, including feedback following training, focus groups, surveys, one-on-one interviews using yarning techniques and reflective feedback from the Project Lead. Findings: Establishing local Aboriginal project staff was pivotal to the success of the project. When delivering services for and with Aboriginal people, it is essential that cultural competence, safety and decision-making is carried through from planning to implementation and evaluation, and involves genuine, respectful and authentic relationships. Sufficient time allocation directed towards building relationships with other service providers and local community members needs to be considered and built into future projects. The Growing Strong Brains® project is embedded within the local community, and anticipated implementation outcomes were achieved. The support of the local people and service providers was beyond expectation, enabling the building of local capacity, and the development of a common understanding of the key messages from the GSB toolkit to allow integration throughout all levels of the community. This project has been important to build on the strategies necessary to introduce, implement and evaluate the GSB toolkit in other remote Aboriginal communities

An assertion language for constraint logic programs

In an advanced program development environment, such as that discussed in the introduction of this book, several tools may coexist which handle both the program and information on the program in different ways. Also, these tools may interact among themselves and with the user. Thus, the different tools and the user need some way to communicate. It is our design principie that such communication be performed in terms of assertions. Assertions are syntactic objects which allow expressing properties of programs. Several assertion languages have been used in the past in different contexts, mainly related to program debugging. In this chapter we propose a general language of assertions which is used in different tools for validation and debugging of constraint logic programs in the context of the DiSCiPl project. The assertion language proposed is parametric w.r.t. the particular constraint domain and properties of interest being used in each different tool. The language proposed is quite general in that it poses few restrictions on the kind of properties which may be expressed. We believe the assertion language we propose is of practical relevance and appropriate for the different uses required in the tools considered

On the Reliability of Cross Correlation Function Lag Determinations in Active Galactic Nuclei

Many AGN exhibit a highly variable luminosity. Some AGN also show a pronounced time delay between variations seen in their optical continuum and in their emission lines. In effect, the emission lines are light echoes of the continuum. This light travel-time delay provides a characteristic radius of the region producing the emission lines. The cross correlation function (CCF) is the standard tool used to measure the time lag between the continuum and line variations. For the few well-sampled AGN, the lag ranges from 1-100 days, depending upon which line is used and the luminosity of the AGN. In the best sampled AGN, NGC 5548, the H_beta lag shows year-to-year changes, ranging from about 8.7 days to about 22.9 days over a span of 8 years. In this paper it is demonstrated that, in the context of AGN variability studies, the lag estimate using the CCF is biased too low and subject to a large variance. Thus the year-to-year changes of the measured lag in NGC 5548 do not necessarily imply changes in the AGN structure. The bias and large variance are consequences of finite duration sampling and the dominance of long timescale trends in the light curves, not due to noise or irregular sampling. Lag estimates can be substantially improved by removing low frequency power from the light curves prior to computing the CCF.Comment: To appear in the PASP, vol 111, 1999 Nov; 37 pages; 10 figure

A cardinal role for cathepsin D in co-ordinating the host-mediated apoptosis of macrophages and killing of pneumococci

The bactericidal function of macrophages against pneumococci is enhanced by their apoptotic demise, which is controlled by the anti-apoptotic protein Mcl-1. Here, we show that lysosomal membrane permeabilization (LMP) and cytosolic translocation of activated cathepsin D occur prior to activation of a mitochondrial pathway of macrophage apoptosis. Pharmacological inhibition or knockout of cathepsin D during pneumococcal infection blocked macrophage apoptosis. As a result of cathepsin D activation, Mcl-1 interacted with its ubiquitin ligase Mule and expression declined. Inhibition of cathepsin D had no effect on early bacterial killing but inhibited the late phase of apoptosis-associated killing of pneumococci in vitro. Mice bearing a cathepsin D-/- hematopoietic system demonstrated reduced macrophage apoptosis in vivo, with decreased clearance of pneumococci and enhanced recruitment of neutrophils to control pulmonary infection. These findings establish an unexpected role for a cathepsin D-mediated lysosomal pathway of apoptosis in pulmonary host defense and underscore the importance of apoptosis-associated microbial killing to macrophage function

Impaired Mitochondrial Microbicidal Responses in Chronic Obstructive Pulmonary Disease Macrophages

RATIONALE: Chronic obstructive pulmonary disease (COPD) is characterized by impaired clearance of pulmonary bacteria. OBJECTIVES: The effect of COPD on alveolar macrophage (AM) microbicidal responses was investigated. METHODS: Alveolar macrophages (AMs) were obtained from bronchoalveolar lavage from healthy donors or COPD patients and challenged with opsonized serotype 14 Streptococcus pneumoniae. Cells were assessed for apoptosis, bactericidal activity and mitochondrial reactive oxygen species (mROS) production. A transgenic mouse line, in which the CD68 promoter ensures macrophage specific expression of human Mcl-1 (CD68.hMcl-1), was used to model the molecular aspects of COPD. MEASUREMENTS AND MAIN RESULTS: COPD AM had elevated levels of Mcl-1, an anti-apoptotic Bcl-2 family member, with selective reduction of delayed intracellular bacterial killing. CD68.hMcl-1 AM phenocopied the microbicidal defect since transgenic mice demonstrated impaired clearance of pulmonary bacteria and increased neutrophilic inflammation. Murine bone marrow-derived macrophages (BMDM) and human monocyte-derived macrophages (MDM) generated mitochondrial reactive oxygen species (mROS) in response to pneumococci, which co-localized with bacteria and phagolysosomes to enhance bacterial killing. The Mcl-1 transgene increased oxygen consumption rates and mROS expression in mock-infected BMDM but reduced caspase-dependent mROS production after pneumococcal challenge. COPD AM also increased basal mROS expression, but failed to increase production after pneumococcal challenge, in keeping with reduced intracellular bacterial killing. The defect in COPD AM intracellular killing was associated with a reduced ratio of mROS /superoxide dismutase 2. CONCLUSIONS: Upregulation of Mcl-1 and chronic adaption to oxidative stress alters mitochondrial metabolism and microbicidal function, reducing the delayed phase of intracellular bacterial clearance in COPD

Optimization of Fluconazole Dosing for the Prevention and Treatment of Invasive Candidiasis Based on the Pharmacokinetics of Fluconazole in Critically Ill Patients

The efficacy of fluconazole is related to the area under the plasma concentration-time curve (AUC) over the MIC of the microorganism. Physiological changes in critically ill patients may affect the exposure of fluconazole, and therefore dosing adjustments might be needed. The aim of this study was to evaluate variability in fluconazole drug concentration in intensive care unit (ICU) patients and to develop a pharmacokinetic model to support personalized fluconazole dosing. A prospective observational pharmacokinetic study was performed in critically ill patients receiving fluconazole either as prophylaxis or as treatment. The association between fluconazole exposure and patient variables was studied. Pharmacokinetic modeling was performed with a nonparametric adaptive grid (NPAG) algorithm using R package Pmetrics. Data from 33 patients were available for pharmacokinetic analysis. Patients on dialysis and solid organ transplant patients had a significantly lower exposure to fluconazole. The population was best described with a one-compartment model, where the mean volume of distribution was 51.52 liters (standard deviation [SD], 19.81) and the mean clearance was 0.767 liters/h (SD, 0.46). Creatinine clearance was tested as a potential covariate in the model, but was not included in the final population model. A significant positive correlation was found between the fluconazole exposure (AUC) and the trough concentration (C-min). Substantial variability in fluconazole plasma concentrations in critically ill adults was observed, where the majority of patients were underexposed. Fluconazole C-min therapeutic drug monitoring (TDM)-guided dosing can be used to optimize therapy in critically ill patients

Peri-Operative Risk Factors Associated with Post-Operative Cognitive Dysfunction (POCD): An Umbrella Review of Meta-Analyses of Observational Studies

This umbrella review aimed to systematically identify the peri-operative risk factors associated with post-operative cognitive dysfunction (POCD) using meta-analyses of observational studies. To date, no review has synthesised nor assessed the strength of the available evidence examining risk factors for POCD. Database searches from journal inception to December 2022 consisted of systematic reviews with meta-analyses that included observational studies examining pre-, intra- and post-operative risk factors for POCD. A total of 330 papers were initially screened. Eleven meta-analyses were included in this umbrella review, which consisted of 73 risk factors in a total population of 67,622 participants. Most pertained to pre-operative risk factors (74%) that were predominantly examined using prospective designs and in cardiac-related surgeries (71%). Overall, 31 of the 73 factors (42%) were associated with a higher risk of POCD. However, there was no convincing (class I) or highly suggestive (class II) evidence for associations between risk factors and POCD, and suggestive evidence (class III) was limited to two risk factors (pre-operative age and pre-operative diabetes). Given that the overall strength of the evidence is limited, further large-scale studies that examine risk factors across various surgery types are recommended

Reply to Van Daele et al., "Fluconazole Underexposure in Critically Ill Patients:a Matter of Using the Right Targets?"

We thank Van Daele et al (1) for their interest in our study investigating the pharmacokinetics in critically ill patients with aim to optimize fluconazole dosing for the prevention and treatment of invasive candida infections (2).…