Showing papers by "Flinders University published in 2016"

Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)

Abstract: In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. For example, a key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process versus those that measure flux through the autophagy pathway (i.e., the complete process including the amount and rate of cargo sequestered and degraded). In particular, a block in macroautophagy that results in autophagosome accumulation must be differentiated from stimuli that increase autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. It is worth emphasizing here that lysosomal digestion is a stage of autophagy and evaluating its competence is a crucial part of the evaluation of autophagic flux, or complete autophagy. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. Along these lines, because of the potential for pleiotropic effects due to blocking autophagy through genetic manipulation, it is imperative to target by gene knockout or RNA interference more than one autophagy-related protein. In addition, some individual Atg proteins, or groups of proteins, are involved in other cellular pathways implying that not all Atg proteins can be used as a specific marker for an autophagic process. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular assays, we hope to encourage technical innovation in the field.

Gut microbiome remodeling induces depressive-like behaviors through a pathway mediated by the host's metabolism

Abstract: Major depressive disorder (MDD) is the result of complex gene-environment interactions. According to the World Health Organization, MDD is the leading cause of disability worldwide, and it is a major contributor to the overall global burden of disease. However, the definitive environmental mechanisms underlying the pathophysiology of MDD remain elusive. The gut microbiome is an increasingly recognized environmental factor that can shape the brain through the microbiota-gut-brain axis. We show here that the absence of gut microbiota in germ-free (GF) mice resulted in decreased immobility time in the forced swimming test relative to conventionally raised healthy control mice. Moreover, from clinical sampling, the gut microbiotic compositions of MDD patients and healthy controls were significantly different with MDD patients characterized by significant changes in the relative abundance of Firmicutes, Actinobacteria and Bacteroidetes. Fecal microbiota transplantation of GF mice with 'depression microbiota' derived from MDD patients resulted in depression-like behaviors compared with colonization with 'healthy microbiota' derived from healthy control individuals. Mice harboring 'depression microbiota' primarily exhibited disturbances of microbial genes and host metabolites involved in carbohydrate and amino acid metabolism. This study demonstrates that dysbiosis of the gut microbiome may have a causal role in the development of depressive-like behaviors, in a pathway that is mediated through the host's metabolism.

A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants

Abstract: Advanced age-related macular degeneration (AMD) is the leading cause of blindness in the elderly, with limited therapeutic options. Here we report on a study of >12 million variants, including 163,714 directly genotyped, mostly rare, protein-altering variants. Analyzing 16,144 patients and 17,832 controls, we identify 52 independently associated common and rare variants (P < 5 × 10(-8)) distributed across 34 loci. Although wet and dry AMD subtypes exhibit predominantly shared genetics, we identify the first genetic association signal specific to wet AMD, near MMP9 (difference P value = 4.1 × 10(-10)). Very rare coding variants (frequency <0.1%) in CFH, CFI and TIMP3 suggest causal roles for these genes, as does a splice variant in SLC16A8. Our results support the hypothesis that rare coding variants can pinpoint causal genes within known genetic loci and illustrate that applying the approach systematically to detect new loci requires extremely large sample sizes.

Qualitative research methods: when to use them and how to judge them

Abstract: In March 2015, an impressive set of guidelines for best practice on how to incorporate psychosocial care in routine infertility care was published by the ESHRE Psychology and Counselling Guideline Development Group (ESHRE Psychology and Counselling Guideline Development Group, 2015). The authors report that the guidelines are based on a comprehensive review of the literature and we congratulate them on their meticulous compilation of evidence into a clinically useful document. However, when we read the methodology section, we were baffled and disappointed to find that evidence from research using qualitative methods was not included in the formulation of the guidelines. Despite stating that ‘qualitative research has significant value to assess the lived experience of infertility and fertility treatment’, the group excluded this body of evidence because qualitative research is ‘not generally hypothesis-driven and not objective/neutral, as the researcher puts him/herself in the position of the participant to understand how the world is from the person’s perspective’. Qualitative and quantitative research methods are often juxtaposed as representing two different world views. In quantitative circles, qualitative research is commonly viewed with suspicion and considered lightweight because it involves small samples which may not be representative of the broader population, it is seen as not objective, and the results are assessed as biased by the researchers’ own experiences or opinions. In qualitative circles, quantitative research can be dismissed as oversimplifying individual experience in the cause of generalisation, failing to acknowledge researcher biases and expectations in research design, and requiring guesswork to understand the human meaning of aggregate data. As social scientists who investigate psychosocial aspects of human reproduction, we use qualitative and quantitative methods, separately or together, depending on the research question. The crucial part is to know when to use what method. The peer-review process is a pillar of scientific publishing. One of the important roles of reviewers is to assess the scientific rigour of the studies from which authors draw their conclusions. If rigour is lacking, the paper should not be published. As with research using quantitative methods, research using qualitative methods is home to the good, the bad and the ugly. It is essential that reviewers know the difference. Rejection letters are hard to take but more often than not they are based on legitimate critique. However, from time to time it is obvious that the reviewer has little grasp of what constitutes rigour or quality in qualitative research. The first author (K.H.) recently submitted a paper that reported findings from a qualitative study about fertility-related knowledge and information-seeking behaviour among people of reproductive age. In the rejection letter one of the reviewers (not from Human Reproduction) lamented, ‘Even for a qualitative study, I would expect that some form of confidence interval and paired t-tables analysis, etc. be used to analyse the significance of results’. This comment reveals the reviewer’s inappropriate application to qualitative research of criteria relevant only to quantitative research. In this commentary, we give illustrative examples of questions most appropriately answered using qualitative methods and provide general advice about how to appraise the scientific rigour of qualitative studies. We hope this will help the journal’s reviewers and readers appreciate the legitimate place of qualitative research and ensure we do not throw the baby out with the bath water by excluding or rejecting papers simply because they report the results of qualitative studies.

From gut dysbiosis to altered brain function and mental illness: mechanisms and pathways

Abstract: The human body hosts an enormous abundance and diversity of microbes, which perform a range of essential and beneficial functions. Our appreciation of the importance of these microbial communities to many aspects of human physiology has grown dramatically in recent years. We know, for example, that animals raised in a germ-free environment exhibit substantially altered immune and metabolic function, while the disruption of commensal microbiota in humans is associated with the development of a growing number of diseases. Evidence is now emerging that, through interactions with the gut–brain axis, the bidirectional communication system between the central nervous system and the gastrointestinal tract, the gut microbiome can also influence neural development, cognition and behaviour, with recent evidence that changes in behaviour alter gut microbiota composition, while modifications of the microbiome can induce depressive-like behaviours. Although an association between enteropathy and certain psychiatric conditions has long been recognized, it now appears that gut microbes represent direct mediators of psychopathology. Here, we examine roles of gut microbiome in shaping brain development and neurological function, and the mechanisms by which it can contribute to mental illness. Further, we discuss how the insight provided by this new and exciting field of research can inform care and provide a basis for the design of novel, microbiota-targeted, therapies.

Board Composition and Corporate Social Responsibility: The Role of Diversity, Gender, Strategy and Decision Making

Abstract: This paper aims to critically review the existing literature on the relationship between corporate governance, in particular board diversity, and both corporate social responsibility (CSR) and corporate social responsibility reporting (CSRR) and to suggest some important avenues for future research in this field. Assuming that both CSR and CSRR are outcomes of boards’ decisions, this paper proposes that examining boards’ decision making processes with regard to CSR would provide more insight into the link between board diversity and CSR. Particularly, the paper stresses the importance of studies linking gender diversity and CSR decision making processes, which is quite rare in the existing literature. It also highlights the importance of more qualitative methods and longitudinal studies for the development of understanding of the diversity–CSR relationship.

The impact of comorbidity on cancer and its treatment

Abstract: Answer questions and earn CME/CNE Comorbidity is common among cancer patients and, with an aging population, is becoming more so. Comorbidity potentially affects the development, stage at diagnosis, treatment, and outcomes of people with cancer. Despite the intimate relationship between comorbidity and cancer, there is limited consensus on how to record, interpret, or manage comorbidity in the context of cancer, with the result that patients who have comorbidity are less likely to receive treatment with curative intent. Evidence in this area is lacking because of the frequent exclusion of patients with comorbidity from randomized controlled trials. There is evidence that some patients with comorbidity have potentially curative treatment unnecessarily modified, compromising optimal care. Patients with comorbidity have poorer survival, poorer quality of life, and higher health care costs. Strategies to address these issues include improving the evidence base for patients with comorbidity, further development of clinical tools to assist decision making, improved integration and coordination of care, and skill development for clinicians. CA Cancer J Clin 2016;66:337-350. © 2016 American Cancer Society.

Microbes as engines of ecosystem function: When does community structure enhance predictions of ecosystem processes?

Abstract: Microorganisms are vital in mediating the earth's biogeochemical cycles; yet, despite our rapidly increasing ability to explore complex environmental microbial communities, the relationship between microbial community structure and ecosystem processes remains poorly understood. Here, we address a fundamental and unanswered question in microbial ecology: 'When do we need to understand microbial community structure to accurately predict function?' We present a statistical analysis investigating the value of environmental data and microbial community structure independently and in combination for explaining rates of carbon and nitrogen cycling processes within 82 global datasets. Environmental variables were the strongest predictors of process rates but left 44% of variation unexplained on average, suggesting the potential for microbial data to increase model accuracy. Although only 29% of our datasets were significantly improved by adding information on microbial community structure, we observed improvement in models of processes mediated by narrow phylogenetic guilds via functional gene data, and conversely, improvement in models of facultative microbial processes via community diversity metrics. Our results also suggest that microbial diversity can strengthen predictions of respiration rates beyond microbial biomass parameters, as 53% of models were improved by incorporating both sets of predictors compared to 35% by microbial biomass alone. Our analysis represents the first comprehensive analysis of research examining links between microbial community structure and ecosystem function. Taken together, our results indicate that a greater understanding of microbial communities informed by ecological principles may enhance our ability to predict ecosystem process rates relative to assessments based on environmental variables and microbial physiology.

A systematic review of faculty development initiatives designed to enhance teaching effectiveness: A 10-year update: BEME Guide No. 40

Abstract: Background: This review, which focused on faculty development initiatives designed to improve teaching effectiveness, synthesized findings related to intervention types, study characteristics, individual and organizational outcomes, key features, and community building.Methods: This review included 111 studies (between 2002 and 2012) that met the review criteria.Findings: Overall satisfaction with faculty development programs was high. Participants reported increased confidence, enthusiasm, and awareness of effective educational practices. Gains in knowledge and skills, and self-reported changes in teaching behaviors, were frequently noted. Observed behavior changes included enhanced teaching practices, new educational initiatives, new leadership positions, and increased academic output. Organizational changes were infrequently explored. Key features included evidence-informed educational design, relevant content, experiential learning, feedback and reflection, educational projects, intentional co...

Anamorelin in patients with non-small-cell lung cancer and cachexia (ROMANA 1 and ROMANA 2): results from two randomised, double-blind, phase 3 trials

Abstract: Summary Background Patients with advanced cancer frequently experience anorexia and cachexia, which are associated with reduced food intake, altered body composition, and decreased functionality. We assessed anamorelin, a novel ghrelin-receptor agonist, on cachexia in patients with advanced non-small-cell lung cancer and cachexia. Methods ROMANA 1 and ROMANA 2 were randomised, double-blind, placebo-controlled phase 3 trials done at 93 sites in 19 countries. Patients with inoperable stage III or IV non-small-cell lung cancer and cachexia (defined as ≥5% weight loss within 6 months or body-mass index 2 ) were randomly assigned 2:1 to anamorelin 100 mg orally once daily or placebo, with a computer-generated randomisation algorithm stratified by geographical region, cancer treatment status, and weight loss over the previous 6 months. Co-primary efficacy endpoints were the median change in lean body mass and handgrip strength over 12 weeks and were measured in all study participants (intention-to-treat population). Both trials are now completed and are registered with ClinicalTrials.gov, numbers NCT01387269 and NCT01387282. Findings From July 8, 2011, to Jan 28, 2014, 484 patients were enrolled in ROMANA 1 (323 to anamorelin, 161 to placebo), and from July 14, 2011, to Oct 31, 2013, 495 patients were enrolled in ROMANA 2 (330 to anamorelin, 165 to placebo). Over 12 weeks, lean body mass increased in patients assigned to anamorelin compared with those assigned to placebo in ROMANA 1 (median increase 0·99 kg [95% CI 0·61 to 1·36] vs −0·47 kg [–1·00 to 0·21], p vs −0·98 kg [–1·49 to −0·41], p vs −1·58 kg [–2·99 to −1·14], p=0·15) or ROMANA 2 (−1·49 kg [–2·06 to −0·58] vs −0·95 kg [–1·56 to 0·04], p=0·65). There were no differences in grade 3–4 treatment-related adverse events between study groups; the most common grade 3–4 adverse event was hyperglycaemia, occurring in one ( Interpretation Anamorelin significantly increased lean body mass, but not handgrip, strength in patients with advanced non-small-cell lung cancer. Considering the unmet medical need for safe and effective treatments for cachexia, anamorelin might be a treatment option for patients with cancer anorexia and cachexia. Funding Helsinn Therapeutics.

Efficacy and Tolerability of Evolocumab vs Ezetimibe in Patients With Muscle-Related Statin Intolerance: The GAUSS-3 Randomized Clinical Trial

Abstract: Importance Muscle-related statin intolerance is reported by 5% to 20% of patients. Objective To identify patients with muscle symptoms confirmed by statin rechallenge and compare lipid-lowering efficacy for 2 nonstatin therapies, ezetimibe and evolocumab. Design, Setting, and Participants Two-stage randomized clinical trial including 511 adult patients with uncontrolled low-density lipoprotein cholesterol (LDL-C) levels and history of intolerance to 2 or more statins enrolled in 2013 and 2014 globally. Phase A used a 24-week crossover procedure with atorvastatin or placebo to identify patients having symptoms only with atorvastatin but not placebo. In phase B, after a 2-week washout, patients were randomized to ezetimibe or evolocumab for 24 weeks. Interventions Phase A: atorvastatin (20 mg) vs placebo. Phase B: randomization 2:1 to subcutaneous evolocumab (420 mg monthly) or oral ezetimibe (10 mg daily). Main Outcome and Measures Coprimary end points were the mean percent change in LDL-C level from baseline to the mean of weeks 22 and 24 levels and from baseline to week 24 levels. Results Of the 491 patients who entered phase A (mean age, 60.7 [SD, 10.2] years; 246 women [50.1%]; 170 with coronary heart disease [34.6%]; entry mean LDL-C level, 212.3 [SD, 67.9] mg/dL), muscle symptoms occurred in 209 of 491 (42.6%) while taking atorvastatin but not while taking placebo. Of these, 199 entered phase B, along with 19 who proceeded directly to phase B for elevated creatine kinase (N = 218, with 73 randomized to ezetimibe and 145 to evolocumab; entry mean LDL-C level, 219.9 [SD, 72] mg/dL). For the mean of weeks 22 and 24, LDL-C level with ezetimibe was 183.0 mg/dL; mean percent LDL-C change, −16.7% (95% CI, −20.5% to −12.9%), absolute change, −31.0 mg/dL and with evolocumab was 103.6 mg/dL; mean percent change, −54.5% (95% CI, −57.2% to −51.8%); absolute change, −106.8 mg/dL ( P P P = .17). Active study drug was stopped for muscle symptoms in 5 of 73 ezetimibe-treated patients (6.8%) and 1 of 145 evolocumab-treated patients (0.7%). Conclusions and Relevance Among patients with statin intolerance related to muscle-related adverse effects, the use of evolocumab compared with ezetimibe resulted in a significantly greater reduction in LDL-C levels after 24 weeks. Further studies are needed to assess long-term efficacy and safety. Trial Registration clinicaltrials.gov Identifier:NCT01984424

Global Estimates on the Number of People Blind or Visually Impaired by Diabetic Retinopathy: A Meta-analysis From 1990 to 2010

Abstract: OBJECTIVE To estimate global and regional trends from 1990 to 2010 of the prevalence and number of persons visually impaired specifically by diabetic retinopathy (DR), as a complication of the precipitous trends in global diabetes, is fundamental for health planning purposes. RESEARCH DESIGN AND METHODS The meta-analysis of published population studies from 1990 to 2012 for the Global Burden of Disease Study 2010 (GBD) yielded estimated global regional trends in DR among other causes of moderate and severe vision impairment (MSVI; presenting visual acuity RESULTS Globally in 2010, out of overall 32.4 million blind and 191 million visually impaired people, 0.8 million were blind and 3.7 million were visually impaired because of DR, with an alarming increase of 27% and 64%, respectively, spanning the two decades from 1990 to 2010. DR accounted for 2.6% of all blindness in 2010 and 1.9% of all MSVI worldwide, increasing from 2.1% and 1.3%, respectively, in 1990. These figures were lower in regions with younger populations ( 4%). CONCLUSIONS The number of persons with visual impairment due to DR worldwide is rising and represents an increasing proportion of all blindness/MSVI causes. Age-standardized prevalence of DR-related blindness/MSVI was higher in sub-Saharan Africa and South Asia. One out of 39 blind people had blindness due to DR, and 1 out of 52 visually impaired people had visual impairment due to DR.

Recent Development of Carbon Nanotube Transparent Conductive Films

Abstract: Transparent conducting films (TCFs) are a critical component in many personal electronic devices. Transparent and conductive doped metal oxides are widely used in industry due to their excellent optoelectronic properties as well as the mature understanding of their production and handling. However, they are not compatible with future flexible electronics developments where large-scale production will likely involve roll-to-roll manufacturing. Recent studies have shown that carbon nanotubes provide unique chemical, physical, and optoelectronic properties, making them an important alternative to doped metal oxides. This Review provides a comprehensive analysis of carbon nanotube transparent conductive films covering detailed fabrication methods including patterning of the films, chemical doping effects, and hybridization with other materials. There is a focus on optoelectronic properties of the films and potential in applications such as photovoltaics, touch panels, liquid crystal displays, and organic light-emitting diodes in conjunction with a critical analysis of both the merits and shortcomings of carbon nanotube transparent conductive films.

Phosphorene and Phosphorene‐Based Materials – Prospects for Future Applications

Abstract: Phosphorene, a single- or few-layered semiconductor material obtained from black phosphorus, has recently been introduced as a new member of the family of two-dimensional (2D) layered materials. Since its discovery, phosphorene has attracted significant attention, and due to its unique properties, is a promising material for many applications including transistors, batteries and photovoltaics (PV). However, based on the current progress in phosphorene production, it is clear that a lot remains to be explored before this material can be used for these applications. After providing a comprehensive overview of recent advancements in phosphorene synthesis, advantages and challenges of the currently available methods for phosphorene production are discussed. An overview of the research progress in the use of phosphorene for a wide range of applications is presented, with a focus on enabling important roles that phosphorene would play in next-generation PV cells. Roadmaps that have the potential to address some of the challenges in phosphorene research are examined because it is clear that the unprecedented chemical, physical and electronic properties of phosphorene and phosphorene-based materials are suitable for various applications, including photovoltaics.

Accurate thickness measurement of graphene.

Abstract: Graphene has emerged as a material with a vast variety of applications. The electronic, optical and mechanical properties of graphene are strongly influenced by the number of layers present in a sample. As a result, the dimensional characterization of graphene films is crucial, especially with the continued development of new synthesis methods and applications. A number of techniques exist to determine the thickness of graphene films including optical contrast, Raman scattering and scanning probe microscopy techniques. Atomic force microscopy (AFM), in particular, is used extensively since it provides three-dimensional images that enable the measurement of the lateral dimensions of graphene films as well as the thickness, and by extension the number of layers present. However, in the literature AFM has proven to be inaccurate with a wide range of measured values for single layer graphene thickness reported (between 0.4 and 1.7 nm). This discrepancy has been attributed to tip-surface interactions, image feedback settings and surface chemistry. In this work, we use standard and carbon nanotube modified AFM probes and a relatively new AFM imaging mode known as PeakForce tapping mode to establish a protocol that will allow users to accurately determine the thickness of graphene films. In particular, the error in measuring the first layer is reduced from 0.1-1.3 nm to 0.1-0.3 nm. Furthermore, in the process we establish that the graphene-substrate adsorbate layer and imaging force, in particular the pressure the tip exerts on the surface, are crucial components in the accurate measurement of graphene using AFM. These findings can be applied to other 2D materials.

Assessment of polygenic effects links primary open-angle glaucoma and age-related macular degeneration

Abstract: Primary open-angle glaucoma (POAG) and age-related macular degeneration (AMD) are leading causes of irreversible blindness. Several loci have been mapped using genome-wide association studies. Until very recently, there was no recognized overlap in the genetic contribution to AMD and POAG. At genome-wide significance level, only ABCA1 harbors associations to both diseases. Here, we investigated the genetic architecture of POAG and AMD using genome-wide array data. We estimated the heritability for POAG (h2g = 0.42 ± 0.09) and AMD (h2g = 0.71 ± 0.08). Removing known loci for POAG and AMD decreased the h2g estimates to 0.36 and 0.24, respectively. There was evidence for a positive genetic correlation between POAG and AMD (rg = 0.47 ± 0.25) which remained after removing known loci (rg = 0.64 ± 0.31). We also found that the genetic correlation between sexes for POAG was likely to be less than 1 (rg = 0.33 ± 0.24), suggesting that differences of prevalence among genders may be partly due to heritable factors.

The styrene-maleic acid copolymer: a versatile tool in membrane research

Abstract: A new and promising tool in membrane research is the detergent-free solubilization of membrane proteins by styrene-maleic acid copolymers (SMAs). These amphipathic molecules are able to solubilize lipid bilayers in the form of nanodiscs that are bounded by the polymer. Thus, membrane proteins can be directly extracted from cells in a water-soluble form while conserving a patch of native membrane around them. In this review article, we briefly discuss current methods of membrane protein solubilization and stabilization. We then zoom in on SMAs, describe their physico-chemical properties, and discuss their membrane-solubilizing effect. This is followed by an overview of studies in which SMA has been used to isolate and investigate membrane proteins. Finally, potential future applications of the methodology are discussed for structural and functional studies on membrane proteins in a near-native environment and for characterizing protein-lipid and protein-protein interactions.

Is Decoupling GDP Growth from Environmental Impact Possible

Abstract: The argument that human society can decouple economic growth—defined as growth in Gross Domestic Product (GDP)—from growth in environmental impacts is appealing. If such decoupling is possible, it means that GDP growth is a sustainable societal goal. Here we show that the decoupling concept can be interpreted using an easily understood model of economic growth and environmental impact. The simple model is compared to historical data and modelled projections to demonstrate that growth in GDP ultimately cannot be decoupled from growth in material and energy use. It is therefore misleading to develop growth-oriented policy around the expectation that decoupling is possible. We also note that GDP is increasingly seen as a poor proxy for societal wellbeing. GDP growth is therefore a questionable societal goal. Society can sustainably improve wellbeing, including the wellbeing of its natural assets, but only by discarding GDP growth as the goal in favor of more comprehensive measures of societal wellbeing.

The impact of atrial fibrillation type on the risk of thromboembolism, mortality, and bleeding: a systematic review and meta-analysis

Abstract: Aims Thromboembolic risk stratification schemes and clinical guidelines for atrial fibrillation (AF) regard risk as independent of classification into paroxysmal (PAF) and non-paroxysmal atrial fibrillation (NPAF). The aim of the current study was to conduct a systematic review evaluating the impact of AF type on thromboembolism, bleeding, and mortality. Methods and results PubMed was searched through 27 November 2014 for randomized controlled trials, cohort studies, and case series reporting prospectively collected clinical outcomes stratified by AF type. The incidence of thromboembolism, mortality, and bleeding was extracted. Atrial fibrillation clinical outcome data were extracted from 12 studies containing 99 996 patients. The unadjusted risk ratio (RR) for thromboembolism in NPAF vs. PAF was 1.355 (95% CI: 1.169–1.571, P < 0.001). In the study subset off oral anticoagulation, unadjusted RR was 1.689 (95% CI: 1.151–2.480, P = 0.007). The overall multivariable adjusted hazard ratio (HR) for thromboembolism was 1.384 (95% CI: 1.191–1.608, P < 0.001). The overall unadjusted RR for all-cause mortality was 1.462 (95% CI: 1.255–1.703, P < 0.001). Multivariable adjusted HR for all-cause mortality was 1.217 (95% CI: 1.085–1.365, P < 0.001). Rates of bleeding were similar, with unadjusted RR 1.00 (95% CI: 0.919–1.087, P = 0.994) and adjusted HR 1.025 (95% CI: 0.898–1.170, P = 0.715). Conclusion Non-paroxysmal atrial fibrillation is associated with a highly significant increase in thromboembolism and death. These data suggest the need for new therapies to prevent AF progression and further studies to explore the integration of AF type into models of thromboembolic risk.

Predictors of treatment outcome in individuals with eating disorders: A systematic review and meta‐analysis

Abstract: Objective Understanding the factors that predict a favourable outcome following specialist treatment for an eating disorder may assist in improving treatment efficacy, and in developing novel interventions. This review and meta-analysis examined predictors of treatment outcome and drop-out. Method A literature search was conducted to identify research investigating predictors of outcome in individuals treated for an eating disorder. We organized predictors first by statistical type (simple, meditational, and moderational), and then by category. Average weighted mean effect sizes (r) were calculated for each category of predictor. Results The most robust predictor of outcome at both end of treatment (EoT) and follow-up was the meditational mechanism of greater symptom change early during treatment. Simple baseline predictors associated with better outcomes at both EoT and follow-up included higher BMI, fewer binge/purge behaviors, greater motivation to recover, lower depression, lower shape/weight concern, fewer comorbidities, better interpersonal functioning and fewer familial problems. Drop-out was predicted by more binge/purge behaviors and lower motivation to recover. For most predictors, there was large interstudy variability in effect sizes, and outcomes were operationalized in different ways. There were generally insufficient studies to allow analysis of predictors by eating disorder subtype or treatment type. Discussion To ensure that this area continues to develop with robust and clinically relevant findings, future studies should adopt a consistent definition of outcome and continue to examine complex multivariate predictor models. Growth in this area will allow for stronger conclusions to be drawn about the prediction of outcome for specific diagnoses and treatment types.