Showing papers by "Maastricht University published in 2013"

Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration

Abstract: Cerebral small vessel disease (SVD) is a common accompaniment of ageing. Features seen on neuroimaging include recent small subcortical infarcts, lacunes, white matter hyperintensities, perivascular spaces, microbleeds, and brain atrophy. SVD can present as a stroke or cognitive decline, or can have few or no symptoms. SVD frequently coexists with neurodegenerative disease, and can exacerbate cognitive deficits, physical disabilities, and other symptoms of neurodegeneration. Terminology and definitions for imaging the features of SVD vary widely, which is also true for protocols for image acquisition and image analysis. This lack of consistency hampers progress in identifying the contribution of SVD to the pathophysiology and clinical features of common neurodegenerative diseases. We are an international working group from the Centres of Excellence in Neurodegeneration. We completed a structured process to develop definitions and imaging standards for markers and consequences of SVD. We aimed to achieve the following: first, to provide a common advisory about terms and definitions for features visible on MRI; second, to suggest minimum standards for image acquisition and analysis; third, to agree on standards for scientific reporting of changes related to SVD on neuroimaging; and fourth, to review emerging imaging methods for detection and quantification of preclinical manifestations of SVD. Our findings and recommendations apply to research studies, and can be used in the clinical setting to standardise image interpretation, acquisition, and reporting. This Position Paper summarises the main outcomes of this international effort to provide the STandards for ReportIng Vascular changes on nEuroimaging (STRIVE).

Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs

Abstract: Most psychiatric disorders are moderately to highly heritable. The degree to which genetic variation is unique to individual disorders or shared across disorders is unclear. To examine shared genetic etiology, we use genome-wide genotype data from the Psychiatric Genomics Consortium (PGC) for cases and controls in schizophrenia, bipolar disorder, major depressive disorder, autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD). We apply univariate and bivariate methods for the estimation of genetic variation within and covariation between disorders. SNPs explained 17-29% of the variance in liability. The genetic correlation calculated using common SNPs was high between schizophrenia and bipolar disorder (0.68 ± 0.04 s.e.), moderate between schizophrenia and major depressive disorder (0.43 ± 0.06 s.e.), bipolar disorder and major depressive disorder (0.47 ± 0.06 s.e.), and ADHD and major depressive disorder (0.32 ± 0.07 s.e.), low between schizophrenia and ASD (0.16 ± 0.06 s.e.) and non-significant for other pairs of disorders as well as between psychiatric disorders and the negative control of Crohn's disease. This empirical evidence of shared genetic etiology for psychiatric disorders can inform nosology and encourages the investigation of common pathophysiologies for related disorders.

Benefits of mindfulness at work: the role of mindfulness in emotion regulation, emotional exhaustion, and job satisfaction

Abstract: Mindfulness describes a state of consciousness in which individuals attend to ongoing events and experiences in a receptive and non-judgmental way. The present research investigated the idea that mindfulness reduces emotional exhaustion and improves job satisfaction. The authors further suggest that these associations are mediated by the emotion regulation strategy of surface acting. Study 1 was a 5-day diary study with 219 employees and revealed that mindfulness negatively related to emotional exhaustion and positively related to job satisfaction at both the within- and the between-person levels. Both relationships were mediated by surface acting at both levels of analysis. Study 2 was an experimental field study, in which participants (N = 64) were randomly assigned to a self-training mindfulness intervention group or a control group. Results revealed that participants in the mindfulness intervention group experienced significantly less emotional exhaustion and more job satisfaction than participants in the control group. The causal effect of mindfulness self-training on emotional exhaustion was mediated by surface acting. Implications for using mindfulness and mindfulness training interventions in organizational research and practice are discussed in conclusion.

An updated and conservative systematic review and meta-analysis of epidemiological evidence on psychotic experiences in children and adults: on the pathway from proneness to persistence to dimensional expression across mental disorders

Abstract: Background The psychosis-proneness–persistence–impairment model of psychotic disorder incorporates notions of both phenomenological and temporal continuity (persistence) of psychotic experiences (PE), but not structural continuity. Specific testable propositions of phenomenological continuity and persistence are identified. Method Propositions are tested by systematic reviews of the epidemiology of PE, persistence of PE and disorder outcomes, and meta-analyses (including Monte Carlo permutation sampling, MCPS) of reported rates and odds ratios (ORs). Results Estimates of the incidence and prevalence of PE obtained from 61 cohorts revealed a median annual incidence of 2.5% and a prevalence of 7.2%. Meta-analysis of risk factors identified age, minority or migrant status, income, education, employment, marital status, alcohol use, cannabis use, stress, urbanicity and family history of mental illness as important predictors of PE. The mode of assessment accounted for significant variance in the observed rates. Across cohorts, the probability of persistence was very strongly related to the rate of PE at baseline. Of those who report PE, ∼20% go on to experience persistent PE whereas for ∼80%, PE remit over time. Of those with baseline PE, 7.4% develop a psychotic disorder outcome. Conclusions Compelling support is found for the phenomenological and temporal continuity between PE and psychotic disorder and for the fundamental proposition that this relationship is probabilistic. However, imprecision in epidemiological research design, measurement limitations and the epiphenomenological nature of PE invite further robust scrutiny of the continuity theory.

Management of severe perioperative bleeding Guidelines from the European Society of Anaesthesiology

Abstract: The aims of severe perioperative bleeding management are three-fold. First, preoperative identification by anamesis and laboratory testing of those patients for whom the perioperative bleeding risk may be increased. Second, implementation of strategies for correcting preoperative anaemia and stabilisation of the macro- and microcirculations in order to optimise the patient’s tolerance to bleeding. Third, targeted procoagulant interventions to reduce the amount of bleeding, morbidity, mortality and costs. The purpose of these guidelines is to provide an overview of current knowledge on the subject with an assessment of the quality of the evidence in order to allow anaesthetists throughout Europe to integrate this knowledge into daily patient care wherever possible. The Guidelines Committee of the European Society of Anaesthesiology (ESA) formed a task force with members of scientific subcommittees and individual expert members of the ESA. Electronic databases were searched without language restrictions from the year 2000 until 2012. These searches produced 20 664 abstracts. Relevant systematic reviews with meta-analyses, randomised controlled trials, cohort studies, case-control studies and cross-sectional surveys were selected. At the suggestion of the ESA Guideline Committee, the Scottish Intercollegiate Guidelines Network (SIGN) grading system was initially used to assess the level of evidence and to grade recommendations. During the process of guideline development, the official position of the ESA changed to favour the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. This report includes general recommendations as well as specific recommendations in various fields of surgical interventions. The final draft guideline was posted on the ESA website for four weeks and the link was sent to all ESA members. Comments were collated and the guidelines amended as appropriate. When the final draft was complete, the Guidelines Committee and ESA Board ratified the guidelines.

Dose-Dense Temozolomide for Newly Diagnosed Glioblastoma: A Randomized Phase III Clinical Trial

Abstract: Purpose Radiotherapy with concomitant and adjuvant temozolomide is the standard of care for newly diagnosed glioblastoma (GBM) O 6 -methylguanine-DNA methyltransferase (MGMT) methylation status may be an important determinant of treatment response Dose-dense (DD) temozolomide results in prolonged depletion of MGMT in blood mononuclear cells and possibly in tumor This trial tested whether DD temozolomide improves overall survival (OS) or progression-free survival (PFS) in patients with newly diagnosed GBM Patients and Methods This phase III trial enrolled patients older than age 18 years with a Karnofsky performance score of 60 with adequate tissue Stratification included clinical factors and tumor MGMT methylation status Patients were randomly assigned to standard temozolomide (arm 1) or DD temozolomide (arm 2) for 6 to 12 cycles The primary end point was OS Secondary analyses evaluated the impact of MGMT status

Cold acclimation recruits human brown fat and increases nonshivering thermogenesis

Abstract: In recent years, it has been shown that humans have active brown adipose tissue (BAT) depots, raising the question of whether activation and recruitment of BAT can be a target to counterbalance the current obesity pandemic. Here, we show that a 10-day cold acclimation protocol in humans increases BAT activity in parallel with an increase in nonshivering thermogenesis (NST). No sex differences in BAT presence and activity were found either before or after cold acclimation. Respiration measurements in permeabilized fibers and isolated mitochondria revealed no significant contribution of skeletal muscle mitochondrial uncoupling to the increased NST. Based on cell-specific markers and on uncoupling protein-1 (characteristic of both BAT and beige/brite cells), this study did not show “browning” of abdominal subcutaneous white adipose tissue upon cold acclimation. The observed physiological acclimation is in line with the subjective changes in temperature sensation; upon cold acclimation, the subjects judged the environment warmer, felt more comfortable in the cold, and reported less shivering. The combined results suggest that a variable indoor environment with frequent cold exposures might be an acceptable and economic manner to increase energy expenditure and may contribute to counteracting the current obesity epidemic.

Measuring health literacy in populations: illuminating the design and development process of the European Health Literacy Survey Questionnaire (HLS-EU-Q)

Abstract: Several measurement tools have been developed to measure health literacy. The tools vary in their approach and design, but few have focused on comprehensive health literacy in populations. This paper describes the design and development of the European Health Literacy Survey Questionnaire (HLS-EU-Q), an innovative, comprehensive tool to measure health literacy in populations. Based on a conceptual model and definition, the process involved item development, pre-testing, field-testing, external consultation, plain language check, and translation from English to Bulgarian, Dutch, German, Greek, Polish, and Spanish. The development process resulted in the HLS-EU-Q, which entailed two sections, a core health literacy section and a section on determinants and outcomes associated to health literacy. The health literacy section included 47 items addressing self-reported difficulties in accessing, understanding, appraising and applying information in tasks concerning decisions making in healthcare, disease prevention, and health promotion. The second section included items related to, health behaviour, health status, health service use, community participation, socio-demographic and socio-economic factors. By illuminating the detailed steps in the design and development process of the HLS-EU-Q, it is the aim to provide a deeper understanding of its purpose, its capability and its limitations for others using the tool. By stimulating a wide application it is the vision that HLS-EU-Q will be validated in more countries to enhance the understanding of health literacy in different populations.

Surviving in a Marine Desert: The Sponge Loop Retains Resources Within Coral Reefs

Abstract: Ever since Darwin’s early descriptions of coral reefs, scientists have debated how one of the world’s most productive and diverse ecosystems can thrive in the marine equivalent of a desert. It is an enigma how the flux of dissolved organic matter (DOM), the largest resource produced on reefs, is transferred to higher trophic levels. Here we show that sponges make DOM available to fauna by rapidly expelling filter cells as detritus that is subsequently consumed by reef fauna. This “sponge loop” was confirmed in aquarium and in situ food web experiments, using 13C- and 15N-enriched DOM. The DOM-sponge-fauna pathway explains why biological hot spots such as coral reefs persist in oligotrophic seas—the reef’s paradox—and has implications for reef ecosystem functioning and conservation strategies.

Type I and II Endometrial Cancers: Have They Different Risk Factors?

Abstract: Purpose Endometrial cancers have long been divided into estrogen-dependent type I and the less common clinically aggressive estrogen-independent type II. Little is known about risk factors for type II tumors because most studies lack sufficient cases to study these much less common tumors separately. We examined whether so-called classical endometrial cancer risk factors also influence the risk of type II tumors. Patients and Methods Individual-level data from 10 cohort and 14 case-control studies from the Epidemiology of Endometrial Cancer Consortium were pooled. A total of 14,069 endometrial cancer cases and 35,312 controls were included. We classified endometrioid (n = 7,246), adenocarcinoma not otherwise specified (n = 4,830), and adenocarcinoma with squamous differentiation (n = 777) as type I tumors and serous (n = 508) and mixed cell (n = 346) as type II tumors. Results Parity, oral contraceptive use, cigarette smoking, age at menarche, and diabetes were associated with type I and type II tumors to...

Development of an instrument for measuring different types of cognitive load

Abstract: According to cognitive load theory, instructions can impose three types of cognitive load on the learner: intrinsic load, extraneous load, and germane load. Proper measurement of the different types of cognitive load can help us understand why the effectiveness and efficiency of learning environments may differ as a function of instructional formats and learner characteristics. In this article, we present a ten-item instrument for the measurement of the three types of cognitive load. Principal component analysis on data from a lecture in statistics for PhD students (n = 56) in psychology and health sciences revealed a three-component solution, consistent with the types of load that the different items were intended to measure. This solution was confirmed by a confirmatory factor analysis of data from three lectures in statistics for different cohorts of bachelor students in the social and health sciences (ns = 171, 136, and 148), and received further support from a randomized experiment with university freshmen in the health sciences (n = 58).

More Than Words: The Influence of Affective Content and Linguistic Style Matches in Online Reviews on Conversion Rates

Abstract: Customers increasingly rely on other consumers' reviews to make purchase decisions online. New insights into the customer review phenomenon can be derived from studying the semantic content and style properties of verbatim customer reviews to examine their influence on online retail sites' conversion rates. The authors employ text mining to extract changes in affective content and linguistic style properties of customer book reviews on Amazon.com. A dynamic panel data model reveals that the influence of positive affective content on conversion rates is asymmetrical, such that greater increases in positive affective content in customer reviews have a smaller effect on subsequent increases in conversion rate. No such tapering-off effect occurs for changes in negative affective content in reviews. Furthermore, positive changes in affective cues and increasing congruence with the product interest group's typical linguistic style directly and conjointly increase conversion rates. These findings suggest that managers should identify and promote the most influential reviews in a given product category, provide instructions to stimulate reviewers to write powerful reviews, and adapt the style of their own editorial reviews to the relevant product category.

A European Organisation for Research and Treatment of Cancer Phase III Trial of Adjuvant Whole-Brain Radiotherapy Versus Observation in Patients With One to Three Brain Metastases From Solid Tumors After Surgical Resection or Radiosurgery: Quality-of-Life Results

Abstract: Purpose This phase III trial compared adjuvant whole-brain radiotherapy (WBRT) with observation after either surgery or radiosurgery of a limited number of brain metastases in patients with stable solid tumors. Here, we report the health-related quality-of-life (HRQOL) results. Patients and Methods HRQOL was a secondary end point in the trial. HRQOL was assessed at baseline, at 8 weeks, and then every 3 months for 3 years with the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire C30 and Brain Cancer Module. The following six primary HRQOL scales were considered: global health status; physical, cognitive, role, and emotional functioning; and fatigue. Statistical significance required P ≤ .05, and clinical relevance required a ≥ 10-point difference. Results Compliance was 88.3% at baseline and dropped to 45.0% at 1 year; thus, only the first year was analyzed. Overall, patients in the observation only arm reported better HRQOL scores than did patients who rece...

Multiple independent variants at the TERT locus are associated with telomere length and risks of breast and ovarian cancer

Abstract: TERT-locus SNPs and leukocyte telomere measures are reportedly associated with risks of multiple cancers. Using the Illumina custom genotyping array iCOG, we analyzed similar to 480 SNPs at the TERT locus in breast (n = 103,991), ovarian (n = 39,774) and BRCA1 mutation carrier (n = 11,705) cancer cases and controls. Leukocyte telomere measurements were also available for 53,724 participants. Most associations cluster into three independent peaks. The minor allele at the peak 1 SNP rs2736108 associates with longer telomeres (P = 5.8 x 10(-7)), lower risks for estrogen receptor (ER)-negative (P = 1.0 x 10(-8)) and BRCA1 mutation carrier (P = 1.1 x 10(-5)) breast cancers and altered promoter assay signal. The minor allele at the peak 2 SNP rs7705526 associates with longer telomeres (P = 2.3 x 10(-14)), higher risk of low-malignant-potential ovarian cancer (P = 1.3 x 10(-15)) and greater promoter activity. The minor alleles at the peak 3 SNPs rs10069690 and rs2242652 increase ER-negative (P = 1.2 x 10(-12)) and BRCA1 mutation carrier (P = 1.6 x 10-14) breast and invasive ovarian (P = 1.3 x 10(-11)) cancer risks but not via altered telomere length. The cancer risk alleles of rs2242652 and rs10069690, respectively, increase silencing and generate a truncated TERT splice variant.

Threatening communication: a critical re-analysis and a revised meta-analytic test of fear appeal theory

Abstract: Despite decades of research, consensus regarding the dynamics of fear appeals remains elusive. A meta-analysis was conducted that was designed to resolve this controversy. Publications that were included in previous meta-analyses were reanalysed, and a number of additional publications were located. The inclusion criteria were full factorial orthogonal manipulations of threat and efficacy, and measurement of behaviour as an outcome. Fixed and random effects models were used to compute mean effect size estimates. Meta-analysis of the six studies that satisfied the inclusion criteria clearly showed a significant interaction between threat and efficacy, such that threat only had an effect under high efficacy (d 0.31), and efficacy only had an effect under high threat (d 0.71). Inconsistency in results regarding the effectiveness of threatening communication can likely be attributed to flawed methodology. Proper tests of fear appeal theory yielded the theoretically hypothesised interaction effect. Threatening communication should exclusively be used when pilot studies indicate that an intervention successfully enhances efficacy.

Local discriminability determines the strength of holistic processing for faces in the fusiform face area.

Abstract: Recent evidence suggests that the Fusiform Face Area (FFA) is not exclusively dedicated to the interactive processing of face features, but also contains neurons sensitive to local features. This suggests the existence of both interactive and local processing modes, consistent with recent behavioral findings that the strength of interactive feature processing (IFP) engages most strongly when similar features need to be disambiguated. Here we address whether the engagement of the FFA into interactive versus featural representational modes is governed by local feature discriminability. We scanned human participants while they matched target features within face pairs, independently of the context of distracter features. IFP was operationalized as the failure to match the target without being distracted by distracter features. Picture-plane inversion was used to disrupt IFP while preserving input properties. We found that FFA activation was comparably strong, irrespective of whether similar target features were embedded in dissimilar contexts(i.e., inducing robust IFP) or dissimilar target features were embedded in the same context (i.e., engaging local processing). Second, inversion decreased FFA activation to faces most robustly when similar target features were embedded in dissimilar contexts, indicating that FFA engages into IFP mainly when features cannot be disambiguated at a local level. Third, by means of Spearman rank correlation tests, we show that the local processing of feature differences in the FFA is supported to a large extent by the Occipital Face Area, the Lateral Occipital Complex, and early visual cortex, suggesting that these regions encode the local aspects of face information. The present findings confirm the co-existence of holistic and featural representations in the FFA. Furthermore, they establish FFA as the main contributor to the featural/holistic representational mode switches determined by local discriminability.

Oral rivaroxaban versus standard therapy for the treatment of symptomatic venous thromboembolism: a pooled analysis of the EINSTEIN-DVT and PE randomized studies

Abstract: Background Standard treatment for venous thromboembolism (VTE) consists of a heparin combined with vitamin K antagonists. Direct oral anticoagulants have been investigated for acute and extended treatment of symptomatic VTE; their use could avoid parenteral treatment and/or laboratory monitoring of anticoagulant effects.

Guidelines for Perioperative Care for Pancreaticoduodenectomy: Enhanced Recovery After Surgery (ERAS®) Society Recommendations

Abstract: Protocols for enhanced recovery provide comprehensive and evidence-based guidelines for best perioperative care. Protocol implementation may reduce complication rates and enhance functional recovery and, as a result of this, also reduce length-of-stay in hospital. There is no comprehensive framework available for pancreaticoduodenectomy. An international working group constructed within the Enhanced Recovery After Surgery (ERAS®) Society constructed a comprehensive and evidence-based framework for best perioperative care for pancreaticoduodenectomy patients. Data were retrieved from standard databases and personal archives. Evidence and recommendations were classified according to the GRADE system and reached through consensus in the group. The quality of evidence was rated “high”, “moderate”, “low” or “very low”. Recommendations were graded as “strong” or “weak”. Comprehensive guidelines are presented. Available evidence is summarised and recommendations given for 27 care items. The quality of evidence varies substantially and further research is needed for many issues to improve the strength of evidence and grade of recommendations. The present evidence-based guidelines provide the necessary platform upon which to base a unified protocol for perioperative care for pancreaticoduodenectomy. A unified protocol allows for comparison between centres and across national borders. It facilitates multi-institutional prospective cohort registries and adequately powered randomised trials.

Interrupting long periods of sitting: good STUFF

Abstract: There is increasing evidence that sedentary behaviour is in itself a health risk, regardless of the daily amount of moderate to vigorous physical activity. Therefore, sedentary behaviour should be targeted as important health behaviour.

Do Learners Really Know Best? Urban Legends in Education

Abstract: This article takes a critical look at three pervasive urban legends in education about the nature of learners, learning, and teaching and looks at what educational and psychological research has to say about them. The three legends can be seen as variations on one central theme, namely, that it is the learner who knows best and that she or he should be the controlling force in her or his learning. The first legend is one of learners as digital natives who form a generation of students knowing by nature how to learn from new media, and for whom “old” media and methods used in teaching/learning no longer work. The second legend is the widespread belief that learners have specific learning styles and that education should be individualized to the extent that the pedagogy of teaching/learning is matched to the preferred style of the learner. The final legend is that learners ought to be seen as self-educators who should be given maximum control over what they are learning and their learning trajectory. It con...

Preclinical Alzheimer's disease and its outcome: a longitudinal cohort study

Abstract: Summary Background New research criteria for preclinical Alzheimer's disease have been proposed, which include stages for cognitively normal individuals with abnormal amyloid markers (stage 1), abnormal amyloid and neuronal injury markers (stage 2), or abnormal amyloid and neuronal injury markers and subtle cognitive changes (stage 3). We aimed to investigate the prevalence and long-term outcome of preclinical Alzheimer's disease according to these criteria. Methods Participants were cognitively normal (clinical dementia rating [CDR]=0) community-dwelling volunteers aged at least 65 years who were enrolled between 1998 and 2011 at the Washington University School of Medicine (MO, USA). CSF amyloid-β 1–42 and tau concentrations and a memory composite score were used to classify participants as normal (both markers normal), preclinical Alzheimer's disease stage 1–3, or suspected non-Alzheimer pathophysiology (SNAP, abnormal injury marker without abnormal amyloid marker). The primary outcome was the proportion of participants in each preclinical AD stage. Secondary outcomes included progression to CDR at least 0·5, symptomatic Alzheimer's disease (score of at least 0·5 for memory and at least one other domain and cognitive impairments deemed to be due to Alzheimer's disease), and mortality. We undertook survival analyses using subdistribution and standard Cox hazards models and linear mixed models. Findings Of 311 participants, 129 (41%) were classed as normal, 47 (15%) as stage 1, 36 (12%) as stage 2, 13 (4%) as stage 3, 72 (23%) as SNAP, and 14 (5%) remained unclassified. The 5-year progression rate to CDR at least 0·5, symptomatic Alzheimer's disease was 2% for participants classed as normal, 11% for stage 1, 26% for stage 2, 56% for stage 3, and 5% for SNAP. Compared with individuals classed as normal, participants with preclinical Alzheimer's disease had an increased risk of death after adjusting for covariates (hazard ratio 6·2, 95% CI 1·1–35·0; p=0·040). Interpretation Preclinical Alzheimer's disease is common in cognitively normal elderly people and is associated with future cognitive decline and mortality. Thus, preclinical Alzheimer's disease could be an important target for therapeutic intervention. Funding National Institute of Aging of the National Institutes of Health (P01-AG003991, P50-AG05681, P01-AG02676), Internationale Stichting Alzheimer Onderzoek, the Center for Translational Molecular Medicine project LeARN, the EU/EFPIA Innovative Medicines Initiative Joint Undertaking, and the Charles and Joanne Knight Alzheimer Research Initiative.

A network approach to psychopathology: New insights into clinical longitudinal data

Abstract: In the network approach to psychopathology, disorders are conceptualized as networks of mutually interacting symptoms (e.g., depressed mood) and transdiagnostic factors (e.g., rumination). This suggests that it is necessary to study how symptoms dynamically interact over time in a network architecture. In the present paper, we show how such an architecture can be constructed on the basis of time-series data obtained through Experience Sampling Methodology (ESM). The proposed methodology determines the parameters for the interaction between nodes in the network by estimating a multilevel vector autoregression (VAR) model on the data. The methodology allows combining between-subject and within-subject information in a multilevel framework. The resulting network architecture can subsequently be analyzed through network analysis techniques. In the present study, we apply the method to a set of items that assess mood-related factors. We show that the analysis generates a plausible and replicable network architecture, the structure of which is related to variables such as neuroticism; that is, for subjects who score high on neuroticism, worrying plays a more central role in the network. Implications and extensions of the methodology are discussed.

Innovation and Productivity: An Update

Abstract: This paper reviews the existing evidence regarding the effects of technological and non-technological innovations on the productivity of firms and the existence of possible complementarities between these different forms of innovation.

Human intestinal microbiota composition is associated with local and systemic inflammation in obesity

Abstract: Objective Intestinal microbiota have been suggested to contribute to the development of obesity, but the mechanism remains elusive. The relationship between microbiota composition, intestinal permeability, and inflammation in nonobese and obese subjects was investigated. Design and Methods Fecal microbiota composition of 28 subjects (BMI 18.6-60.3 kg m−2) was analyzed by a phylogenetic profiling microarray. Fecal calprotectin and plasma C-reactive protein levels were determined to evaluate intestinal and systemic inflammation. Furthermore, HbA1c, and plasma levels of transaminases and lipids were analyzed. Gastroduodenal, small intestinal, and colonic permeability were assessed by a multisaccharide test. Results Based on microbiota composition, the study population segregated into two clusters with predominantly obese (15/19) or exclusively nonobese (9/9) subjects. Whereas intestinal permeability did not differ between clusters, the obese cluster showed reduced bacterial diversity, a decreased Bacteroidetes/Firmicutes ratio, and an increased abundance of potential proinflammatory Proteobacteria. Interestingly, fecal calprotectin was only detectable in subjects within the obese microbiota cluster (n = 8/19, P = 0.02). Plasma C-reactive protein was also increased in these subjects (P = 0.0005), and correlated with the Bacteroidetes/Firmicutes ratio (rs = −0.41, P = 0.03). Conclusions Intestinal microbiota alterations in obese subjects are associated with local and systemic inflammation, suggesting that the obesity-related microbiota composition has a proinflammatory effect.

Genome-wide association study in BRCA1 mutation carriers identifies novel loci associated with breast and ovarian cancer risk

Abstract: BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7 x 10(-8), HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4 x 10(-8), HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4 x 10(-8), HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific association. The 17q21.31 locus was also associated with ovarian cancer risk in 8,211 BRCA2 carriers (P = 2 x 10(-4)). These loci may lead to an improved understanding of the etiology of breast and ovarian tumors in BRCA1 carriers. Based on the joint distribution of the known BRCA1 breast cancer risk-modifying loci, we estimated that the breast cancer lifetime risks for the 5% of BRCA1 carriers at lowest risk are 28%-50% compared to 81%-100% for the 5% at highest risk. Similarly, based on the known ovarian cancer risk-modifying loci, the 5% of BRCA1 carriers at lowest risk have an estimated lifetime risk of developing ovarian cancer of 28% or lower, whereas the 5% at highest risk will have a risk of 63% or higher. Such differences in risk may have important implications for risk prediction and clinical management for BRCA1 carriers.

A systematic development process for patient decision aids

Abstract: The original version of the International Patient Decision Aid Standards (IPDAS) recommended that patient decision aids (PtDAs) should be carefully developed, user-tested and open to scrutiny, with a well-documented and systematically applied development process. We carried out a review to check the relevance and scope of this quality dimension and, if necessary, to update it. Our review drew on three sources: a) published papers describing PtDAs evaluated in randomised controlled trials and included in the most recent Cochrane Collaboration review; b) linked papers cited in the trial reports that described how the PtDAs had been developed; and c) papers and web reports outlining the development process used by organisations experienced in developing multiple PtDAs. We then developed an extended model of the development process indicating the various steps on which documentation is required, as well as a checklist to assess the frequency with which each of the elements was publicly reported. Key features common to all patient decision aid (PtDA) development processes include: scoping and design; development of a prototype; ‘alpha’ testing with patients and clinicians in an iterative process; ‘beta’ testing in ‘real life’ conditions (field tests); and production of a final version for use and/or further evaluation. Only about half of the published reports on the development of PtDAs that we reviewed appear to have been field tested with patients, and even fewer had been reviewed or tested by clinicians not involved in the development process. Very few described a distribution strategy, and surprisingly few (17%) described a method for reviewing and synthesizing the clinical evidence. We describe a model development process that includes all the original elements of the original IPDAS criterion, expanded to include consideration of format and distribution plans as well as prototype development. The case for including each of the elements outlined in our model development process is pragmatic rather than evidence-based. Optimal methods for ensuring that each stage of the process is carried out effectively require further development and testing.