A Naturalistic Study of the Acceptability and Effectiveness of Internet-Delivered Cognitive Behavioural Therapy for Psychiatric Disorders in Older Australians

Objectives

The current study investigates the acceptability, effectiveness and uptake of internet-delivered cognitive behavioural therapy (iCBT) amongst older individuals (>60 years) seeking psychiatric treatment in general practice.

Methods

The sample consisted of 2413 (mean age 39.5; range 18–83 years) patients prescribed iCBT through This Way Up clinic by their primary care clinician. The intervention consisted of six fully automated, unassisted online lessons specific to four disorders major depression, generalised anxiety disorder, panic disorder or social phobia. Patients were categorised into five age groups (18–29 years, 30–39 years, 40–49 years, 50–59 years, 60 years and above). 225 (9.3%) patients were aged over 60 years. Analyses were conducted across the four disorders to ensure sufficient sample sizes in the 60 years and older age group. Age differences in adherence to the six lesson courses were assessed to demonstrate acceptability. Age-based reductions in psychological distress (Kessler Psychological Distress Scale; K10) and disability (the World Health Organisation Disability Assessment Schedule; WHODAS-II) were compared to demonstrate effectiveness. To evaluate the uptake of iCBT, the age distribution of those commencing iCBT was compared with the prevalence of these disorders in the 2007 Australian National Survey of Mental Health and Well-Being.

Results

Older adults were more likely to complete all six lessons when compared with their younger counterparts. Marginal model analyses indicated that there were significant reductions in the K10 and WHODAS-II from baseline to post-intervention, regardless of age (p<0.001). The measurement occasion by age interactions were not significant, indicating that individuals showed similar reductions in the K10 and WHODAS-II regardless of age. In general, the age distribution of individuals commencing the iCBT courses matched the age distribution of the four diagnoses in the Australian general population, indicating that iCBT successfully captures older individuals who need treatment.

Conclusion

iCBT is effective and acceptable for use in older populations.     

Unsupervised Clustering of Subcellular Protein Expression Patterns in High-Throughput Microscopy Images Reveals Protein Complexes and Functional Relationships between Proteins

Protein subcellular localization has been systematically characterized in budding yeast using fluorescently tagged proteins. Based on the fluorescence microscopy images, subcellular localization of many proteins can be classified automatically using supervised machine learning approaches that have been trained to recognize predefined image classes based on statistical features. Here, we present an unsupervised analysis of protein expression patterns in a set of high-resolution, high-throughput microscope images. Our analysis is based on 7 biologically interpretable features which are evaluated on automatically identified cells, and whose cell-stage dependency is captured by a continuous model for cell growth. We show that it is possible to identify most previously identified localization patterns in a cluster analysis based on these features and that similarities between the inferred expression patterns contain more information about protein function than can be explained by a previous manual categorization of subcellular localization. Furthermore, the inferred cell-stage associated to each fluorescence measurement allows us to visualize large groups of proteins entering the bud at specific stages of bud growth. These correspond to proteins localized to organelles, revealing that the organelles must be entering the bud in a stereotypical order. We also identify and organize a smaller group of proteins that show subtle differences in the way they move around the bud during growth. Our results suggest that biologically interpretable features based on explicit models of cell morphology will yield unprecedented power for pattern discovery in high-resolution, high-throughput microscopy images.     

The Effectiveness of Internet Cognitive Behavioural Therapy (iCBT) for Depression in Primary Care: A Quality Assurance Study

Background

Depression is a common, recurrent, and debilitating problem and Internet delivered cognitive behaviour therapy (iCBT) could offer one solution. There are at least 25 controlled trials that demonstrate the efficacy of iCBT. The aim of the current paper was to evaluate the effectiveness of an iCBT Program in primary care that had been demonstrated to be efficacious in two randomized controlled trials (RCTs).

Method

Quality assurance data from 359 patients prescribed the Sadness Program in Australia from October 2010 to November 2011 were included.

Results

Intent-to-treat marginal model analyses demonstrated significant reductions in depressive symptoms (PHQ9), distress (K10), and impairment (WHODAS-II) with medium-large effect sizes (Cohen''s d = .51–1.13.), even in severe and/or suicidal patients (Cohen''s d = .50–1.49.) Secondary analyses on patients who completed all 6 lessons showed levels of clinically significant change as indexed by established criteria for remission, recovery, and reliable change.

Conclusions

The Sadness Program is effective when prescribed by primary care practitioners and is consistent with a cost-effective stepped-care framework.     

A Glycolipid Adjuvant, 7DW8-5, Enhances CD8+ T Cell Responses Induced by an Adenovirus-Vectored Malaria Vaccine in Non-Human Primates

A key strategy to a successful vaccine against malaria is to identify and develop new adjuvants that can enhance T-cell responses and improve protective immunity. Upon co-administration with a rodent malaria vaccine in mice, 7DW8-5, a recently identified novel analog of α-galactosylceramide (α-GalCer), enhances the level of malaria-specific protective immune responses more strongly than the parent compound. In this study, we sought to determine whether 7DW8-5 could provide a similar potent adjuvant effect on a candidate human malaria vaccine in the more relevant non-human primate (NHP) model, prior to committing to clinical development. The candidate human malaria vaccine, AdPfCA (NMRC-M3V-Ad-PfCA), consists of two non-replicating recombinant adenoviral (Ad) vectors, one expressing the circumsporozoite protein (CSP) and another expressing the apical membrane antigen-1 (AMA1) of Plasmodium falciparum. In several phase 1 clinical trials, AdPfCA was well tolerated and demonstrated immunogenicity for both humoral and cell-mediated responses. In the study described herein, 25 rhesus macaques received prime and boost intramuscular (IM) immunizations of AdPfCA alone or with an ascending dose of 7DW8-5. Our results indicate that 7DW8-5 is safe and well-tolerated and provides a significant enhancement (up to 9-fold) in malaria-specific CD8+ T-cell responses after both priming and boosting phases, supporting further clinical development.     

In silico investigation of novel biological pathways: The role of CD200 in regulation of T cell priming in experimental autoimmune encephalomyelitis

The use of simulation to investigate biological domains will inevitably lead to the need to extend existing simulations as new areas of these domains become more fully understood. Such simulation extensions can entail the incorporation of additional cell types, molecules or molecular pathways, all of which can exert a profound influence on the simulation behaviour. Where the biological domain is not well characterised, a structured development methodology must be employed to ensure that the extended simulation is well aligned with its predecessor. We develop and discuss such a methodology, relying on iterative simulation development and sensitivity analysis. The utility of this methodology is demonstrated using a case study simulation of experimental autoimmune encephalomyelitis (EAE), a murine T cell-mediated autoimmune disease model of multiple sclerosis, where it is used to investigate the activity of an additional regulatory pathway. We discuss how application of this methodology guards against creating inappropriate simulation representations of the biology when investigating poorly characterised biological mechanisms.     

Insights into the Mechanism of Ribosomal Incorporation of Mammalian L13a Protein during Ribosome Biogenesis

In contrast to prokaryotes, the precise mechanism of incorporation of ribosomal proteins into ribosomes in eukaryotes is not well understood. For the majority of eukaryotic ribosomal proteins, residues critical for rRNA binding, a key step in the hierarchical assembly of ribosomes, have not been well defined. In this study, we used the mammalian ribosomal protein L13a as a model to investigate the mechanism(s) underlying eukaryotic ribosomal protein incorporation into ribosomes. This work identified the arginine residue at position 68 of L13a as being essential for L13a binding to rRNA and incorporation into ribosomes. We also demonstrated that incorporation of L13a takes place during maturation of the 90S preribosome in the nucleolus, but that translocation of L13a into the nucleolus is not sufficient for its incorporation into ribosomes. Incorporation of L13a into the 90S preribosome was required for rRNA methylation within the 90S complex. However, mutations abolishing ribosomal incorporation of L13a did not affect its ability to be phosphorylated or its extraribosomal function in GAIT element-mediated translational silencing. These results provide new insights into the mechanism of ribosomal incorporation of L13a and will be useful in guiding future studies aimed at fully deciphering mammalian ribosome biogenesis.     

Hemagglutinin Stalk-Based Universal Vaccine Constructs Protect against Group 2 Influenza A Viruses

Current influenza virus vaccines contain H1N1 (phylogenetic group 1 hemagglutinin), H3N2 (phylogenetic group 2 hemagglutinin), and influenza B virus components. These vaccines induce good protection against closely matched strains by predominantly eliciting antibodies against the membrane distal globular head domain of their respective viral hemagglutinins. This domain, however, undergoes rapid antigenic drift, allowing the virus to escape neutralizing antibody responses. The membrane proximal stalk domain of the hemagglutinin is much more conserved compared to the head domain. In recent years, a growing collection of antibodies that neutralize a broad range of influenza virus strains and subtypes by binding to this domain has been isolated. Here, we demonstrate that a vaccination strategy based on the stalk domain of the H3 hemagglutinin (group 2) induces in mice broadly neutralizing anti-stalk antibodies that are highly cross-reactive to heterologous H3, H10, H14, H15, and H7 (derived from the novel Chinese H7N9 virus) hemagglutinins. Furthermore, we demonstrate that these antibodies confer broad protection against influenza viruses expressing various group 2 hemagglutinins, including an H7 subtype. Through passive transfer experiments, we show that the protection is mediated mainly by neutralizing antibodies against the stalk domain. Our data suggest that, in mice, a vaccine strategy based on the hemagglutinin stalk domain can protect against viruses expressing divergent group 2 hemagglutinins.     

Streptomyces bullii sp. nov., isolated from a hyper-arid Atacama Desert soil

A Streptomyces strain isolated from a hyper-arid Atacama Desert soil was characterised using a polyphasic taxonomic approach. The strain, designated C2^T, had chemical and morphological properties typical of the genus Streptomyces. The isolate formed a branch in the Streptomyces 16S rRNA gene tree together with the type strain of Streptomyces chromofuscus and was also loosely related to Streptomyces fragilis NRRL 2424^T. DNA:DNA relatedness values between the isolate and its two phylogenetic neighbours showed that it formed a distinct genomic species. The strain was readily distinguished from these organisms using a combination of morphological and phenotypic data. Based on the genotypic and phenotypic results, isolate C2^T represents a novel species in the genus Streptomyces, for which the name Streptomyces bullii sp. nov. is proposed. The type strain is C2^T (=CGMCC 4.7019^T = KACC 15426^T).     

Functional genomics in the study of yeast cell polarity: moving in the right direction

The budding yeast Saccharomyces cerevisiae has been used extensively for the study of cell polarity, owing to both its experimental tractability and the high conservation of cell polarity and other basic biological processes among eukaryotes. The budding yeast has also served as a pioneer model organism for virtually all genome-scale approaches, including functional genomics, which aims to define gene function and biological pathways systematically through the analysis of high-throughput experimental data. Here, we outline the contributions of functional genomics and high-throughput methodologies to the study of cell polarity in the budding yeast. We integrate data from published genetic screens that use a variety of functional genomics approaches to query different aspects of polarity. Our integrated dataset is enriched for polarity processes, as well as some processes that are not intrinsically linked to cell polarity, and may provide new areas for future study.