Systematic validation of variants of unknown significance in APP, PSEN1 and PSEN2

Alzheimer\u27s disease (AD) is a neurodegenerative disease that is clinically characterized by progressive cognitive decline. More than 200 pathogenic mutations have been identified in amyloid-β precursor protein (APP), presenilin 1 (PSEN1) and presenilin 2 (PSEN2). Additionally, common and rare variants occur within APP, PSEN1, and PSEN2 that may be risk factors, protective factors, or benign, non-pathogenic polymorphisms. Yet, to date, no single study has carefully examined the effect of all of the variants of unknown significance reported in APP, PSEN1 and PSEN2 on Aβ isoform levels in vitro. In this study, we analyzed Aβ isoform levels by ELISA in a cell-based system in which each reported pathogenic and risk variant in APP, PSEN1, and PSEN2 was expressed individually. In order to classify variants for which limited family history data is available, we have implemented an algorithm for determining pathogenicity using available information from multiple domains, including genetic, bioinformatic, and in vitro analyses. We identified 90 variants of unknown significance and classified 19 as likely pathogenic mutations. We also propose that five variants are possibly protective. In defining a subset of these variants as pathogenic, individuals from these families may eligible to enroll in observational studies and clinical trials

An ontology of mechanisms of action in behaviour change interventions

BACKGROUND: Behaviour change interventions influence behaviour through causal processes called “mechanisms of action” (MoAs). Reports of such interventions and their evaluations often use inconsistent or ambiguous terminology, creating problems for searching, evidence synthesis and theory development. This inconsistency includes the reporting of MoAs. An ontology can help address these challenges by serving as a classification system that labels and defines MoAs and their relationships. The aim of this study was to develop an ontology of MoAs of behaviour change interventions. METHODS: To develop the MoA Ontology, we (1) defined the ontology’s scope; (2) identified, labelled and defined the ontology’s entities; (3) refined the ontology by annotating (i.e., coding) MoAs in intervention reports; (4) refined the ontology via stakeholder review of the ontology’s comprehensiveness and clarity; (5) tested whether researchers could reliably apply the ontology to annotate MoAs in intervention evaluation reports; (6) refined the relationships between entities; (7) reviewed the alignment of the MoA Ontology with other relevant ontologies, (8) reviewed the ontology’s alignment with the Theories and Techniques Tool; and (9) published a machine-readable version of the ontology. RESULTS: An MoA was defined as “a process that is causally active in the relationship between a behaviour change intervention scenario and its outcome behaviour”. We created an initial MoA Ontology with 261 entities through Steps 2-5. Inter-rater reliability for annotating study reports using these entities was α=0.68 (“acceptable”) for researchers familiar with the ontology and α=0.47 for researchers unfamiliar with it. As a result of additional revisions (Steps 6-8), 21 further entities were added to the ontology resulting in 282 entities organised in seven hierarchical levels. CONCLUSIONS: The MoA Ontology extensively captures MoAs of behaviour change interventions. The ontology can serve as a controlled vocabulary for MoAs to consistently describe and synthesise evidence about MoAs across diverse sources

Collaboration between local health and local government agencies for health improvement (Review)

Background: In many countries, national, regional and local inter- and intra-agency collaborations have been introduced to improve health outcomes. Evidence is needed on the effectiveness of locally developed partnerships which target changes in health outcomes and behaviours. Objectives: To evaluate the effects of interagency collaboration between local health and local government agencies on health outcomes in any population or age group. Search methods: We searched the Cochrane Public Health Group Specialised Register, AMED, ASSIA, CENTRAL, CINAHL, DoPHER, EMBASE, ERIC, HMIC, IBSS, MEDLINE, MEDLINE In-Process, OpenGrey, PsycINFO, Rehabdata, Social Care Online, Social Services Abstracts, Sociological Abstracts, TRoPHI andWeb of Science from 1966 through to January 2012. ’Snowballing’ methods were used, including expert contact, citation tracking, website searching and reference list follow-up. Selection criteria: Randomized controlled trials (RCTs), controlled clinical trials (CCTs), controlled before-and-after studies (CBAs) and interrupted time series (ITS) where the study reported individual health outcomes arising from interagency collaboration between health and local government agencies compared to standard care. Studies were selected independently in duplicate, with no restriction on population subgroup or disease. Data collection and analysis: Two authors independently conducted data extraction and assessed risk of bias for each study

Is there an association between early weight status and utility based health-related quality of life in young children?

Purpose Few studies focus on the health-related quality of life (HRQoL) of preschool children with overweight or obesity. This is relevant for evaluation of obesity prevention trials using a quality-adjusted life year (QALY) framework. This study examined the association between weight status in the preschool years and HRQoL at age 5 years, using a preference-based instrument. Methods HRQoL [based on parent proxy version of the Health Utilities Index Mark 3 (HUI3)] and weight status were measured in children born in Australia between 2007 and 2009. Children’s health status was scored across eight attributes of the HUI3—vision, hearing, speech, ambulation, dexterity, emotion, cognition and pain, and these were used to calculate a multi-attribute utility score. Ordinary least squares (OLS), Tobit and two-part regressions were used to model the association between weight status and multi-attribute utility. Results Of the 368 children for whom weight status and HUI3 data were available, around 40% had overweight/obesity. After adjusting for child’s sex, maternal education, marital status and household income, no significant association between weight status in the preschool years and multi-attribute utility scores at 5 years was found. Conclusions Alternative approaches for capturing the effects of weight status in the preschool years on preference-based HRQoL outcomes should be tested. The application of the QALY framework to economic evaluations of obesity-related interventions in young children should also consider longitudinal effects over the life-course

Influence of anatomic correction for transposition of the great arteries on myocardial perfusion: Radionuclide imaging with technetium-99m 2-methoxy isobutyl isonitrile

AbstractObjectives. We sought to determine the incidence of late perfusion defects attributable to coronary artery mobilization in patients undergoing anatomic correction for complete transposition of the great arteries.Background. Anatomic correction (arterial switch procedure) is currently the surgical treatment of choice for complete transposition. From its conception, there has been concern about the impact on myocardial perfusion of the coronary artery mobilization and reimplantation involved in the correction. Previous studies have demonstrated myocardial perfusion defects in patients after correction, although a causal relation between coronary mobilization, and perfusion abnormality has not been established.Methods. In a case-comparison study designed to test this hypothesis, 29 children underwent imaging with technetium-99m 2-methoxy isobutyl isonitrile (technetium-99m mibi). Ten had undergone anatomic correction (arterial switch group; interval from operation 6.9 ± 1.42 years [range 4.9 to 9.1]); 9 had required noncoronary open heart surgery for other cardiac lesions (postbypass group; interval from operation 5.6 ± 3.6 years [range 1.0 to 13.25]); and 10 had had no surgical procedure (control group). The latter group comprised children with atrial or ventricular septal defects who required a radionuclide study for shunt calculation. Planar studies were performed in all 29 children, and additional tomographic acquisition was achieved in 25. To assess reversibility of perfusion defects both an exercise and a rest planar study were performed in the arterial switch group.Results. Perfusion abnormalities were observed in seven of the nine children in the postbypass group and in all 10 children in the arterial switch group. The frequency of perfusion defects in these two groups was similar, with at least 25% of the tomographic segments reported being abnormal. The control group had significantly fewer defects than the other two groups (p = 0.02), with only 8% of the tomographic segments judged to be abnormal. In all except one patient in the arterial switch group, the segments reported as abnormal on the planar exercise study were either abnormal or equivocal on the rest study, indicating a fixed abnormality.Conclusions. Although the precise etiology of these perfusion abnormalities cannot be defined from this study, these data suggest that their origin is related more to the insult of open heart surgery itself than to the coronary manipulation involved in the arterial switch procedure. The functional importance requires further study

Out of sight, out of mind – but not out of scope. The need to consider ozone in restoration science, policy and practice

Restoration ecologists have local- to global-scale ambitions in a policy framework of sustainable development goals and reversing biodiversity loss. Emphasis is given to environmental alteration, typically considering land degradation and climate change. Other environmental drivers, such as pollution, receive less attention. Here we emphasize that terrestrial restoration discourse needs to consider tropospheric ozone (O3) pollution. O3’s pervasive influence on plants and other ecosystem components provides for the possibility of consequences at community and ecosystem levels. The precursor chemicals which lead to O3 formation are increasing, precipitously so in rapidly-industrialising regions of the world. Yet, a review of critical restoration guidance and journals suggests that because O3 is out of sight, it remains out of mind. Based on a narrative cross-discipline literature review, we examine: (i) how O3 could affect the achievement of restoration goals; and, (ii) how restoration interventions could feedback on tropospheric O3. Evidence, currently limited, suggests that O3 could impair the achievement of restoration goals to as great an extent as other drivers, but, in general, we lack direct quantification. Restoration interventions (e.g. tree planting) that may be considered successful can actually exacerbate O3 pollution with negative consequences for food security and human health. These wide-ranging effects, across multiple goals, mean that O3 is not out of scope for restoration science, policy and practice. In detailing a strategic ozone-aware restoration agenda, we suggest how restoration science and policy can quantify O3’s influence, while outlining steps practitioners can take to adapt to/mitigate the impacts of O3 pollution

Efficacy of secondary isoniazid preventive therapy among HIVinfected Southern Africans: time to change policy?

Objective. To determine the efficacy of secondary preventive therapy against tuberculosis (TB) among goldminers working in South Africa. Design. An observational study. Methods. The incidence of recurrent TB was compared between two cohorts of HIV-infected miners: one cohort had received secondary preventive therapy with isoniazid and the other had not. Setting. Health service providing comprehensive care for goldminers. Participants. 338 men received secondary preventive therapy and 221 did not. Main outcome measure. Incidence of recurrent TB. Results. The overall incidence of recurrent TB was reduced by 55% among men who received isoniazid preventive therapy (IPT) compared to those who did not (incidence rates 8.6 and 19.1 per 100 person-years respectively, incidence rate ratio 0.45; 95% CI 0.26 – 0.78). The efficacy of isoniazid preventive therapy was unchanged after controlling for CD4 count and age. The number of person-years of isoniazid preventive therapy required to prevent one case of recurrent TB among individuals with a CD4 count < 200/µl and &#8805;&#61472;200/µl was 5 and 19, respectively. Conclusion. Secondary preventive therapy reduces TB recurrence: the absolute impact appears to be greatest among individuals with low CD4 counts. International TB preventive therapy guidelines for HIV-infected individuals need to be expanded to include recommendations for secondary preventive therapy in settings where TB prevalence is high. Southern African Journal of HIV Medicine Vol. 5(3) 2004: 8-1

Double-outlet right ventricle: Morphologic demonstration using nuclear magnetic resonance imaging

Sixteen patients with double-outlet right ventricle, aged 1 week to 29 years (median 5 months), were studied with a 1.5 tesla nuclear magnetic resonance (NMR) imaging scanner. Two-dimensional echocardiography was performed in all patients. Thirteen patients underwent angiography, including nine who underwent subsequent surgical correction. Three patients underwent postmortem examination.Small children and infants were scanned inside a 32 cm diameter proton head coil. Multiple 5 mm thick sections separated by 0.5 mm and gated to the patient's electrocardiogram were acquired with a spin-echo sequence and an echo time of 30 ms. A combination of standard and oblique imaging planes was used. Imaging times were <90 min. The NMR images were technically unsuitable in one patient because of excessive motion artifact.In the remaining patients, the diagnosis of double outlet right ventricle was confirmed and correlated with surgical and postmortern findings. The NMR images were particularly valuable in demonstrating the interrelations between the great arteries and the anatomy of the outlet septum and the spatial relations between the ventricular septal defect and the great arteries. Although the atrioventricular (AV) valves were not consistently demonstrated, NMR imaging in two patients identified abnormalities of the mitral valve that were not seen with two-dimensional echocardiography. In one patient who had a superoinferior arrangement of the ventricles, NMR imaging was the most useful imaging technique for demonstrating the anatomy.In patients with double-outlet right ventricle, NMR imaging can provide clinically relevant and accurate morphologic information that may contribute to future improvement in patient management

Identification and manipulation of the pleuromutilin gene cluster from Clitopilus passeckerianus for increased rapid antibiotic production

Semi-synthetic derivatives of the tricyclic diterpene antibiotic pleuromutilin from the basidiomycete Clitopilus passeckerianus are important in combatting bacterial infections in human and veterinary medicine. These compounds belong to the only new class of antibiotics for human applications, with novel mode of action and lack of cross-resistance, representing a class with great potential. Basidiomycete fungi, being dikaryotic, are not generally amenable to strain improvement. We report identification of the seven-gene pleuromutilin gene cluster and verify that using various targeted approaches aimed at increasing antibiotic production in C. passeckerianus, no improvement in yield was achieved. The seven-gene pleuromutilin cluster was reconstructed within Aspergillus oryzae giving production of pleuromutilin in an ascomycete, with a significant increase (2106%) in production. This is the first gene cluster from a basidiomycete to be successfully expressed in an ascomycete, and paves the way for the exploitation of a metabolically rich but traditionally overlooked group of fungi

Change in bias in self-reported body mass index in Australia between 1995 and 2008 and the evaluation of correction equations

<p>Abstract</p> <p>Background</p> <p>Many studies have documented the bias in body mass index (BMI) determined from self-reported data on height and weight, but few have examined the change in bias over time.</p> <p>Methods</p> <p>Using data from large, nationally-representative population health surveys, we examined change in bias in height and weight reporting among Australian adults between 1995 and 2008. Our study dataset included 9,635 men and women in 1995 and 9,141 in 2007-2008. We investigated the determinants of the bias and derived correction equations using 2007-2008 data, which can be applied when only self-reported anthropometric data are available.</p> <p>Results</p> <p>In 1995, self-reported BMI (derived from height and weight) was 1.2 units (men) and 1.4 units (women) lower than measured BMI. In 2007-2008, there was still underreporting, but the amount had declined to 0.6 units (men) and 0.7 units (women) below measured BMI. The major determinants of reporting error in 2007-2008 were age, sex, measured BMI, and education of the respondent. Correction equations for height and weight derived from 2007-2008 data and applied to self-reported data were able to adjust for the bias and were accurate across all age and sex strata.</p> <p>Conclusions</p> <p>The diminishing reporting bias in BMI in Australia means that correction equations derived from 2007-2008 data may not be transferable to earlier self-reported data. Second, predictions of future overweight and obesity in Australia based on trends in self-reported information are likely to be inaccurate, as the change in reporting bias will affect the apparent increase in self-reported obesity prevalence.</p