Assessing harmful effects in systematic reviews.

BACKGROUND: Balanced decisions about health care interventions require reliable evidence on harms as well as benefits. Most systematic reviews focus on efficacy and randomised trials, for which the methodology is well established. Methods to systematically review harmful effects are less well developed and there are few sources of guidance for researchers. We present our own recent experience of conducting systematic reviews of harmful effects and make suggestions for future practice and further research. METHODS: We described and compared the methods used in three systematic reviews. Our evaluation focused on the review question, study designs and quality assessment. RESULTS: One review question focused on providing information on specific harmful effects to furnish an economic model, the other two addressed much broader questions. All three reviews included randomised and observational data, although each defined the inclusion criteria differently. Standard methods were used to assess study quality. Various practical problems were encountered in applying the study design inclusion criteria and assessing quality, mainly because of poor study design, inadequate reporting and the limitations of existing tools. All three reviews generated a large volume of work that did not yield much useful information for health care decision makers. The key areas for improvement we identified were focusing the review question and developing methods for quality assessment of studies of harmful effects. CONCLUSIONS: Systematic reviews of harmful effects are more likely to yield information pertinent to clinical decision-making if they address a focused question. This will enable clear decisions to be made about the type of research to include in the review. The methodology for assessing the quality of harmful effects data in systematic reviews requires further development

Lysosomes in iron metabolism, ageing and apoptosis

The lysosomal compartment is essential for a variety of cellular functions, including the normal turnover of most long-lived proteins and all organelles. The compartment consists of numerous acidic vesicles (pH ∼4 to 5) that constantly fuse and divide. It receives a large number of hydrolases (∼50) from the trans-Golgi network, and substrates from both the cells’ outside (heterophagy) and inside (autophagy). Many macromolecules contain iron that gives rise to an iron-rich environment in lysosomes that recently have degraded such macromolecules. Iron-rich lysosomes are sensitive to oxidative stress, while ‘resting’ lysosomes, which have not recently participated in autophagic events, are not. The magnitude of oxidative stress determines the degree of lysosomal destabilization and, consequently, whether arrested growth, reparative autophagy, apoptosis, or necrosis will follow. Heterophagy is the first step in the process by which immunocompetent cells modify antigens and produce antibodies, while exocytosis of lysosomal enzymes may promote tumor invasion, angiogenesis, and metastasis. Apart from being an essential turnover process, autophagy is also a mechanism by which cells will be able to sustain temporary starvation and rid themselves of intracellular organisms that have invaded, although some pathogens have evolved mechanisms to prevent their destruction. Mutated lysosomal enzymes are the underlying cause of a number of lysosomal storage diseases involving the accumulation of materials that would be the substrate for the corresponding hydrolases, were they not defective. The normal, low-level diffusion of hydrogen peroxide into iron-rich lysosomes causes the slow formation of lipofuscin in long-lived postmitotic cells, where it occupies a substantial part of the lysosomal compartment at the end of the life span. This seems to result in the diversion of newly produced lysosomal enzymes away from autophagosomes, leading to the accumulation of malfunctioning mitochondria and proteins with consequent cellular dysfunction. If autophagy were a perfect turnover process, postmitotic ageing and several age-related neurodegenerative diseases would, perhaps, not take place

Inspired or foolhardy: sensemaking, confidence and entrepreneurs' decision-making.

The purpose of this paper is to investigate the role of confidence in how both new and experienced entrepreneurs interpret and make sense of their business environment to inform decision-making. We illustrate our conceptual arguments with descriptive results from a large-scale (n = 6289) survey on entrepreneurs' perception of business performance and their decisions taken at a time of uncertainty in an economic downturn. Quantitative findings are stratified along experiential lines to explore heterogeneity in entrepreneurial decision-making and directly inform our conceptual arguments, while qualitative data from open questions are used to explain the role of confidence. Newer entrepreneurs are found to be more optimistic in the face of environmental risk, which impacts on their decision-making and innovative capabilities. However, the more experienced entrepreneurs warily maintain margin and restructure to adapt to environmental changes. Instead of looking directly at the confidence of individuals, we show how confidence impacts sensemaking, and ultimately, decision-making. These insights inform research on the behaviour of novice and experienced entrepreneurs in relation to innovative business activities. Specifically, blanket assumptions on the role of confidence may be misplaced as its impact changes with experience to alter how entrepreneurs make sense of their environment

Uncovering the complex genetics of human temperament

Experimental studies of learning suggest that human temperament may depend on the molecular mechanisms for associative conditioning, which are highly conserved in animals. The main genetic pathways for associative conditioning are known in experimental animals, but have not been identified in prior genome-wide association studies (GWAS) of human temperament. We used a data-driven machine learning method for GWAS to uncover the complex genotypic-phenotypic networks and environmental interactions related to human temperament. In a discovery sample of 2149 healthy Finns, we identified sets of single-nucleotide polymorphisms (SNPs) that cluster within particular individuals (i.e., SNP sets) regardless of phenotype. Second, we identified 3 clusters of people with distinct temperament profiles measured by the Temperament and Character Inventory regardless of genotype. Third, we found 51 SNP sets that identified 736 gene loci and were significantly associated with temperament. The identified genes were enriched in pathways activated by associative conditioning in animals, including the ERK, PI3K, and PKC pathways. 74% of the identified genes were unique to a specific temperament profile. Environmental influences measured in childhood and adulthood had small but significant effects. We confirmed the replicability of the 51 Finnish SNP sets in healthy Korean (90%) and German samples (89%), as well as their associations with temperament. The identified SNPs explained nearly all the heritability expected in each sample (37-53%) despite variable cultures and environments. We conclude that human temperament is strongly influenced by more than 700 genes that modulate associative conditioning by molecular processes for synaptic plasticity and long-term memory.Peer reviewe

The disruption of proteostasis in neurodegenerative diseases

Cells count on surveillance systems to monitor and protect the cellular proteome which, besides being highly heterogeneous, is constantly being challenged by intrinsic and environmental factors. In this context, the proteostasis network (PN) is essential to achieve a stable and functional proteome. Disruption of the PN is associated with aging and can lead to and/or potentiate the occurrence of many neurodegenerative diseases (ND). This not only emphasizes the importance of the PN in health span and aging but also how its modulation can be a potential target for intervention and treatment of human diseases.info:eu-repo/semantics/publishedVersio

Internationalization within networks: Exploring the relationship between inward and outward FDI in China’s auto components industry

This is the accepted manuscript. It is currently embargoed pending publication.We explore how the outward FDI strategies of Chinese auto component MNCs are\ud shaped by sub-contracting supply relationships established with developed market MNCs.\ud We argue the strong presence of foreign MNC business networks developed through prior\ud inward FDI constitutes an important home country effect influencing the outward FDI\ud strategies of emerging market MNCs. Using the updated internationalization process model,\ud we show how commitment to business networks is a critical mechanism driving the\ud internationalization trajectories of Chinese auto component MNCs. This includes geographic\ud location choices to psychically distant developed markets, strategic asset seeking orientation,\ud pace of internationalisation and entry mode decisions

Novel roles for GAPDH in cell death and carcinogenesis

Publicado en línea el 25 de septiembre de 2009Growing evidence points to the fact that glucose metabolism has a central role in carcinogenesis. Among the enzymes controlling this energy production pathway, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is of particular interest. Initially identified as a glycolytic enzyme and considered as a housekeeping gene, this enzyme is actually tightly regulated and is involved in numerous cellular functions. Particularly intriguing are recent reports describing GAPDH as a regulator of cell death. However, its role in cell death is unclear; whereas some studies point toward a proapoptotic function, others describe a protective role and suggest its participation in tumor progression. In this study, we highlight recent findings and discuss potential mechanisms through which cells regulate GAPDH to fulfill its diverse functions to influence cell fate.This work was supported in part by l’Association pour la Recherche sur le Cancer, by l’Agence Nationnal de la Recherche, la Fondation de France, Plan Nacional I+D SAF2008-04974 and by grants from The U.S. National Institutes of Health. J-E.R. is a recipient of a contrat d’interface INSERM-CHU de Nice.Peer reviewe