Ann Arbor Center for Independent Living

The 1000 Genomes Project set out to provide a comprehensive description of common human genetic variation by applying whole-genome sequencing to a diverse set of individuals from multiple populations. Here we report completion of the project, having reconstructed the genomes of 2,504 individuals from 26 populations using a combination of low-coverage whole-genome sequencing, deep exome sequencing, and dense microarray genotyping. We characterized a broad spectrum of genetic variation, in total over 88 million variants (84.7 million single nucleotide polymorphisms (SNPs), 3.6 million short insertions/deletions (indels), and 60,000 structural variants), all phased onto high-quality haplotypes. This resource includes >99% of SNP variants with a frequency of >1% for a variety of ancestries. We describe the distribution of genetic variation across the global sample, and discuss the implications for common disease studies. Results for the final phase of the 1000 Genomes Project are presented including whole-genome sequencing, targeted exome sequencing, and genotyping on high-density SNP arrays for 2,504 individuals across 26 populations, providing a global reference data set to support biomedical genetics. The 1000 Genomes Project has sought to comprehensively catalogue human genetic variation across populations, providing a valuable public genomic resource. The data obtained so far have found applications ranging from association studies and fine mapping studies to the filtering of likely neutral variants in rare-disease cohorts. The authors now report on the final phase of the project, phase 3, which covers previously uncharacterized areas of human genetic diversity in terms of the populations sampled and categories of characterized variation. The sample now includes more than 2,500 individuals from 26 global populations, with low coverage whole-genome and deep exome sequencing, as well as dense microarray genotyping. They find that while most common variants are shared across populations, rarer variants are often restricted to closely related populations. The authors also demonstrate the use of the phase 3 dataset as a reference panel for imputation to improve the resolution in genetic association studies.

Studies of the human microbiome have revealed that even healthy individuals differ remarkably in the microbes that occupy habitats such as the gut, skin and vagina. Much of this diversity remains unexplained, although diet, environment, host genetics and early microbial exposure have all been implicated. Accordingly, to characterize the ecology of human-associated microbial communities, the Human Microbiome Project has analysed the largest cohort and set of distinct, clinically relevant body habitats so far. We found the diversity and abundance of each habitat’s signature microbes to vary widely even among healthy subjects, with strong niche specialization both within and among individuals. The project encountered an estimated 81–99% of the genera, enzyme families and community configurations occupied by the healthy Western microbiome. Metagenomic carriage of metabolic pathways was stable among individuals despite variation in community structure, and ethnic/racial background proved to be one of the strongest associations of both pathways and microbes with clinical metadata. These results thus delineate the range of structural and functional configurations normal in the microbial communities of a healthy population, enabling future characterization of the epidemiology, ecology and translational applications of the human microbiome. The Human Microbiome Project Consortium reports the first results of their analysis of microbial communities from distinct, clinically relevant body habitats in a human cohort; the insights into the microbial communities of a healthy population lay foundations for future exploration of the epidemiology, ecology and translational applications of the human microbiome. The Human Microbiome Project (HMP), supported by the National Institutes of Health Common Fund, has the goal of characterizing the microbial communities that inhabit and interact with the human body in sickness and in health. In two Articles in this issue of Nature, the HMP Consortium presents the first population-scale details of the organismal and functional composition of the microbiota across five areas of the body. An associated News & Views discusses the initial results — which, along with those of a series of co-publications, already constitute the most extensive catalogue of organisms and genes related to the human microbiome yet published — and highlights some of the major questions that the project will tackle in the next few years.

A catalogue of molecular aberrations that cause ovarian cancer is critical for developing and deploying therapies that will improve patients’ lives. The Cancer Genome Atlas project has analysed messenger RNA expression, microRNA expression, promoter methylation and DNA copy number in 489 high-grade serous ovarian adenocarcinomas and the DNA sequences of exons from coding genes in 316 of these tumours. Here we report that high-grade serous ovarian cancer is characterized by TP53 mutations in almost all tumours (96%); low prevalence but statistically recurrent somatic mutations in nine further genes including NF1, BRCA1, BRCA2, RB1 and CDK12; 113 significant focal DNA copy number aberrations; and promoter methylation events involving 168 genes. Analyses delineated four ovarian cancer transcriptional subtypes, three microRNA subtypes, four promoter methylation subtypes and a transcriptional signature associated with survival duration, and shed new light on the impact that tumours with BRCA1/2 (BRCA1 or BRCA2) and CCNE1 aberrations have on survival. Pathway analyses suggested that homologous recombination is defective in about half of the tumours analysed, and that NOTCH and FOXM1 signalling are involved in serous ovarian cancer pathophysiology. The Cancer Genome Atlas (TCGA) project reports here its analysis of messenger RNA and microRNA expression, promoter methylation, DNA copy number and exome sequences in 489 high-grade serous ovarian adenocarcinomas. The analyses help establish new tumour subtypes. Among other insights is the finding that while the gene encoding p53 tumour suppressor is mutated in almost all tumours, nine other loci including NF1, BRCA1, BRCA2, RB1 and CDK12 carry recurrent albeit low-prevalence mutations. Homologous recombination is defective in about half of the tumours studied, and Notch and FOXM1 signalling are involved in the pathophysiology.

Gastric cancer is a leading cause of cancer deaths, but analysis of its molecular and clinical characteristics has been complicated by histological and aetiological heterogeneity. Here we describe a comprehensive molecular evaluation of 295 primary gastric adenocarcinomas as part of The Cancer Genome Atlas (TCGA) project. We propose a molecular classification dividing gastric cancer into four subtypes: tumours positive for Epstein–Barr virus, which display recurrent PIK3CA mutations, extreme DNA hypermethylation, and amplification of JAK2, CD274 (also known as PD-L1) and PDCD1LG2 (also known as PD-L2); microsatellite unstable tumours, which show elevated mutation rates, including mutations of genes encoding targetable oncogenic signalling proteins; genomically stable tumours, which are enriched for the diffuse histological variant and mutations of RHOA or fusions involving RHO-family GTPase-activating proteins; and tumours with chromosomal instability, which show marked aneuploidy and focal amplification of receptor tyrosine kinases. Identification of these subtypes provides a roadmap for patient stratification and trials of targeted therapies. The Cancer Genome Atlas reports on molecular evaluation of 295 primary gastric adenocarcinomas and proposes a new classification of gastric cancers into 4 subtypes, which should help with clinical assessment and trials of targeted therapies. This contribution from The Cancer Genome Atlas (TCGA) project describes the molecular evaluation of 295 primary gastric adenocarcinomas. Based on the results, the authors propose a novel classification separating gastric cancers into four subtypes according to: Epstein–Barr virus positive status, microsatellite instability, chromosomal instability or genomic stability. Given the histologic and etiologic heterogeneity of gastric cancer identification of these subtypes, using a schema that can readily be applied to patient samples should help with patient stratification and trials of targeted therapies.

The goal of the International HapMap Project is to determine the common patterns of DNA sequence variation in the human genome and to make this information freely available in the public domain. An international consortium is developing a map of these patterns across the genome by determining the genotypes of one million or more sequence variants, their frequencies and the degree of association between them, in DNA samples from populations with ancestry from parts of Africa, Asia and Europe. The HapMap will allow the discovery of sequence variants that affect common disease, will facilitate development of diagnostic tools, and will enhance our ability to choose targets for therapeutic intervention.

incorporating first behaviors (e.g. good at doing sums), then traits (smart), then single abstractions (scientific), then higher order abstrac­ tions (intellectual). Within each of the phases, there is an alternating sequence of first overgeneralizing self-conceptions and then differentiating

A variety of microbial communities and their genes (the microbiome) exist throughout the human body, with fundamental roles in human health and disease. The National Institutes of Health (NIH)-funded Human Microbiome Project Consortium has established a population-scale framework to develop metagenomic protocols, resulting in a broad range of quality-controlled resources and data including standardized methods for creating, processing and interpreting distinct types of high-throughput metagenomic data available to the scientific community. Here we present resources from a population of 242 healthy adults sampled at 15 or 18 body sites up to three times, which have generated 5,177 microbial taxonomic profiles from 16S ribosomal RNA genes and over 3.5 terabases of metagenomic sequence so far. In parallel, approximately 800 reference strains isolated from the human body have been sequenced. Collectively, these data represent the largest resource describing the abundance and variety of the human microbiome, while providing a framework for current and future studies. The Human Microbiome Project Consortium has established a population-scale framework to study a variety of microbial communities that exist throughout the human body, enabling the generation of a range of quality-controlled data as well as community resources. The Human Microbiome Project (HMP), supported by the National Institutes of Health Common Fund, has the goal of characterizing the microbial communities that inhabit and interact with the human body in sickness and in health. In two Articles in this issue of Nature, the HMP Consortium presents the first population-scale details of the organismal and functional composition of the microbiota across five areas of the body. An associated News & Views discusses the initial results — which, along with those of a series of co-publications, already constitute the most extensive catalogue of organisms and genes related to the human microbiome yet published — and highlights some of the major questions that the project will tackle in the next few years.

The Large Hadron Collider (LHC) at CERN will extend the frontiers of particle physics with its
\nunprecedented high energy and luminosity. Inside the LHC, bunches of up to 1011 protons (p)
\nwill collide 40 million times per second to provide 14 TeV proton-proton collisions at a design
\nluminosity of 1034 cm􀀀2s􀀀1. The LHC will also collide heavy ions (A), in particular lead nuclei, at
\n5.5 TeV per nucleon pair, at a design luminosity of 1027 cm􀀀2s􀀀1.
\nThe high interaction rates, radiation doses, particle multiplicities and energies, as well as the
\nrequirements for precision measurements have set new standards for the design of particle detectors.
\nTwo general purpose detectors, ATLAS (A Toroidal LHC ApparatuS) and CMS (Compact
\nMuon Solenoid) have been built for probing p-p and A-A collisions.
\nThis paper presents a comprehensive overview of the ATLAS detector prior to the first LHC
\ncollisions, written as the installation of the ATLAS detector is nearing completion. This detector
\nrepresents the work of a large collaboration of several thousand physicists, engineers, technicians,
\nand students over a period of fifteen years of dedicated design, development, fabrication, and installation.

The traditional system of company‐centric value creation (that has served us so well over the past 100 years) is becoming obsolete. Leaders now need a new frame of reference for value creation. In the emergent economy, competition will center on personalized co‐creation experiences, resulting in value that is truly unique to each individual. The authors see a new frontier in value creation emerging, replete with fresh opportunities. In this new frontier the role of the consumer has changed from isolated to connected, from unaware to informed, from passive to active. As a result, companies can no longer act autonomously, designing products, developing production processes, crafting marketing messages, and controlling sales channels with little or no interference from consumers. Armed with new tools and dissatisfied with available choices, consumers want to interact with firms and thereby co‐create value. The use of interaction as a basis for co‐creation is at the crux of our emerging reality. The co‐creation experience of the consumer becomes the very basis of value. The authors offer a DART model for managing co‐creation of value processes.

As the name suggests, evidence-based medicine is about finding evidence and using that evidence to make clinical decisions. A cornerstone of evidence-based medicine is the hierarchical system of classifying evidence. This hierarchy is known as the levels of evidence. Physicians are encouraged to find the highest level of evidence to answer clinical questions. Several articles published in plastic surgery journals concerning evidence-based medicine topics have touched on this subject.1–6 Specifically, previous articles have discussed the lack of higher level evidence in Plastic and Reconstructive Surgery and the need to improve the evidence published in the Journal. Before that can be accomplished, it is important to understand the history behind the levels and how they should be interpreted. This article focuses on the origin of levels of evidence, their relevance to the evidence-based medicine movement, and the implications for the field of plastic surgery and the everyday practice of plastic surgery. HISTORY OF LEVELS OF EVIDENCE The levels of evidence were originally described in a report by the Canadian Task Force on the Periodic Health Examination in 1979.7 The report's purpose was to develop recommendations on the periodic health examination and base those recommendations on evidence in the medical literature. The authors developed a system of rating evidence (Table 1) when determining the effectiveness of a particular intervention. The evidence was taken into account when grading recommendations. For example, a grade A recommendation was given if there was good evidence to support a recommendation that a condition be included in the periodic health examination. The levels of evidence were further described and expanded by Sackett8 in an article on levels of evidence for antithrombotic agents in 1989 (Table 2). Both systems place randomized controlled trials at the highest level and case series or expert opinions at the lowest level. The hierarchies rank studies according to the probability of bias. Randomized controlled trials are given the highest level because they are designed to be unbiased and have less risk of systematic errors. For example, by randomly allocating subjects to two or more treatment groups, these types of studies also randomize confounding factors that may bias results. A case series or expert opinion is often biased by the author's experience or opinions, and there is no control of confounding factors.Table 1: Canadian Task Force on the Periodic Health Examination's Levels of EvidenceTable 2: Levels of Evidence from SackettMODIFICATION OF LEVELS Since the introduction of levels of evidence, several other organizations and journals have adopted variations of the classification system. Diverse specialties are often asking different questions, and it was recognized that the type and level of evidence needed to be modified accordingly. Research questions are divided into the following categories: treatment, prognosis, diagnosis, and economic/decision analysis. For example, Table 3 shows the levels of evidence developed by the American Society of Plastic Surgeons for prognosis9 and Table 4 shows the levels developed by the Centre for Evidence-Based Medicine for treatment.10 The two tables highlight the types of studies that are appropriate for the question (prognosis versus treatment) and how quality of data is taken into account when assigning a level. For example, randomized controlled trials are not appropriate when looking at the prognosis of a disease. The question in this instance is, “What will happen if we do nothing at all?” Because a prognosis question does not involve comparing treatments, the highest evidence would come from a cohort study or a systematic review of cohort studies. The levels of evidence also take into account the quality of the data. For example, in the chart from the Centre for Evidence-Based Medicine, a poorly designed randomized controlled trial has the same level of evidence as a cohort study.Table 3: Levels of Evidence for Prognostic StudiesTable 4: Levels of Evidence for Therapeutic StudiesA grading system that provides strength of recommendations based on evidence has also changed over time. Table 5 shows the Grade Practice Recommendations developed by the American Society of Plastic Surgeons. The grading system provides an important component in evidence-based medicine and assists in clinical decision making. For example, a strong recommendation is given when there is level I evidence and consistent evidence from level II, III, and IV studies available. The grading system does not degrade lower level evidence when deciding recommendations if the results are consistent.Table 5: Grade Practice RecommendationsINTERPRETATION OF LEVELS Many journals assign a level to the articles they publish, and authors often assign a level when submitting an abstract to conference proceedings. This allows the reader to know the level of evidence of the research, but the designated level of evidence does always guarantee the quality of the research. It is important that readers not assume that level I evidence is always the best choice or appropriate for the research question. This concept will be very important for all of us to understand as we evolve into the field of evidence-based medicine in plastic surgery. By design, our designated surgical specialty will always have important articles that may have a lower level of evidence because of the level of innovation and technique articles that are needed to move our surgical specialty forward. Although randomized controlled trials are often assigned the highest level of evidence, not all randomized controlled trials are conducted properly, and the results should be scrutinized carefully. Sackett8 stressed the importance of estimating types of errors and the power of studies when interpreting results from randomized controlled trials. For example, a poorly conducted randomized controlled trial may report a negative result because of low power when in fact a real difference exists between treatment groups. Scales such as the Jadad scale have been developed to judge the quality of randomized controlled trials.11 Although physicians may not have the time or inclination to use a scale to assess quality, there are some basic items that should be taken into account. Items used for assessing randomized controlled trials include randomization, blinding, a description of the randomization and blinding process, a description of the number of subjects who withdrew or dropped out of the study, the confidence intervals around study estimates, and a description of the power analysis. For example, Bhandari et al.12 published an article assessing the quality of surgical randomized controlled trials. The authors evaluated the quality of randomized controlled trials reported in the Journal of Bone and Joint Surgery from 1988 to 2000. Articles with a score of greater than 75 percent were deemed high quality, and 60 percent of the articles had a score less than 75 percent. The authors identified 72 randomized controlled trials during this time period, and the mean score was 68 percent. The main reason for the low-quality score was lack of appropriate randomization, blinding, and a description of patient exclusion criteria. Another article found the same quality score of articles in the Journal of Bone and Joint Surgery with a level 1 rating compared with level 2.13 Therefore, one should not assume that level 1 studies are of higher quality than level 2 studies. A resource for surgeons to use when appraising levels of evidence are the users' guides published in the Canadian Journal of Surgery14,15 and the Journal of Bone and Joint Surgery.16 Similar articles that are not specific to surgery have been published in the Journal of the American Medical Association.17,18 PLASTIC SURGERY AND EVIDENCE-BASED MEDICINE The field of plastic surgery has been slow to adopt evidence-based medicine. This was demonstrated in an article examining the level of evidence of articles published in Plastic and Reconstructive Surgery.19 The authors assigned levels of evidence to articles published in Plastic and Reconstructive Surgery over a 20-year period. The majority of studies (93 percent in 1983) were level IV or V, which denotes case series and case reports. Although the results were disappointing, there was some improvement over time. By 2003, there were more level I studies (1.5 percent) and fewer level IV and V studies (87 percent). A recent analysis looked at the number of level I studies in five different plastic surgery journals from 1978 to 2009. The authors defined level I studies as randomized controlled trials and meta-analyses and restricted their search to these studies. The number of level I studies increased from one in 1978 to 32 by 2009.20 From these results, we see that the field of plastic surgery is improving the level of evidence but still has a long way to go, especially in improving the quality of studies published. For example, approximately one-third of the studies involved double blinding, but the majority did not randomize subjects, describe the randomization process, or perform a power analysis. Power analysis is another area of concern in plastic surgery. A review of the plastic surgery literature found that the majority of published studies have inadequate power to detect moderate to large differences between treatment groups.21 Regardless of the level of evidence for a study, if the study is underpowered, the interpretation of results is questionable. Although the goal is to improve the overall level of evidence in plastic surgery, this does not mean that all lower level evidence should be discarded. Case series and case reports are important for hypothesis generation and can lead to more controlled studies. In addition, in the face of overwhelming evidence to support a treatment, such as the use of antibiotics for wound infections, there is no need for a randomized controlled trial. CLINICAL EXAMPLES USING LEVELS OF EVIDENCE To understand how the levels of evidence work and aid the reader in interpreting levels, we provide some examples from the plastic surgery literature. The examples also show the peril of medical decisions based on results from case reports. An association was hypothesized between lymphoma and silicone breast implants based on case reports.22–27 The level of evidence for case reports, depending on the scale used, is IV or V. These case reports were used to generate the hypothesis that a possible association existed. Because of these results, several large retrospective cohort studies from the United States, Canada, Denmark, Sweden, and Finland were conducted.28–32 The level of evidence for a retrospective cohort study is II. All of these studies had many years of follow-up for a large number of patients. Some of the studies found an elevated risk and others found no risk for lymphoma. None of the studies reached statistical significance. Therefore, higher level evidence from cohort studies does not provide evidence of any risk of lymphoma. Finally, a systematic review was performed that combined the evidence from the retrospective cohorts.27 The results found an overall standardized incidence ratio of 0.89 (95 percent confidence interval, 0.67 to 1.18). Because the confidence interval includes 1, the results indicate there is no increased incidence. The level of evidence for the systematic review is I. Based on the best available evidence, there is no association between lymphoma and silicone implants. This example shows how studies with a low level of evidence were used to generate a hypothesis, which then led to higher level evidence that disproved the hypothesis. This example also demonstrates that randomized controlled trials are not feasible for rare events such as cancer and emphasizes the importance of observational studies for a specific study question. A case-control study is a better option and provides higher level evidence for testing the prognosis of the long-term effect of silicone breast implants. Another example is the injection of epinephrine in fingers. Based on case reports before 1950, physicians were advised that epinephrine injection can result in finger ischemia.33 We see in this example that level IV or V evidence was accepted as fact and incorporated into medical textbooks and teaching. However, not all physicians accepted this evidence and were performing injections of epinephrine into the fingers, with no adverse effects on the hand. Obviously, it was time for higher level evidence to resolve this issue. An in-depth review of the literature from 1880 to 2000 by Denkler33 identified 48 cases of digital infarction, of which 21 had been injected with epinephrine. Further analysis found that the addition of procaine to the epinephrine injection was the cause of the ischemia.34 The procaine used in these injections included toxic acidic batches that were recalled in 1948. In addition, several cohort studies found no complications from the use of epinephrine in the fingers and hand.35–37 The results from these cohort studies increased the level of evidence. Based on the best available evidence from these studies, the hypothesis that epinephrine injection will harm fingers was rejected. This example highlights the biases inherent in case reports. It also shows the risk when spurious evidence is handed down and integrated into medical teaching. OBTAINING THE BEST EVIDENCE We have established the need for randomized controlled trials to improve evidence in plastic surgery but have also acknowledged the difficulties, particularly with randomization and blinding. Although randomized controlled trials may not be appropriate for many surgical questions, well-designed and well-conducted cohort or case-control studies could boost the level of evidence. Many of the current studies tend to be descriptive and lack a control group. The way forward seems clear. Plastic surgery researchers need to consider using a cohort or case-control design whenever a randomized controlled trial is not possible. If designed properly, the level of evidence for observational studies can approach or surpass those from a randomized controlled trial. In some instances, observational studies and randomized controlled trials have yielded similar results.38 If enough cohort or case-control studies become available, the prospect of systematic reviews of these studies will increase, which will increase overall evidence levels in plastic surgery. CONCLUSIONS The levels of evidence are an important component of evidence-based medicine. Understanding the levels and why they are assigned to publications and abstracts helps the reader to prioritize information. This is not to say that all level IV evidence should be ignored and all level I evidence accepted as fact. The levels of evidence provide a guide, and the reader needs to be cautious when interpreting these results. ACKNOWLEDGMENTS This work was supported in part by a Midcareer Investigator Award in Patient-Oriented Research (K24 AR053120) from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (to K.C.C.).

In Brief Objective The aim of this article is to summarize the recommended updates to the 2001 Stages of Reproductive Aging Workshop (STRAW) criteria. The 2011 STRAW + 10 reviewed advances in understanding of the critical changes in hypothalamic-pituitary-ovarian function that occur before and after the final menstrual period. Methods Scientists from five countries and multiple disciplines evaluated data from cohort studies of midlife women and in the context of chronic illness and endocrine disorders on change in menstrual, endocrine, and ovarian markers of reproductive aging including antimüllerian hormone, inhibin-B, follicle-stimulating hormone, and antral follicle count. Modifications were adopted by consensus. Results STRAW + 10 simplified bleeding criteria for the early and late menopausal transition, recommended modifications to criteria for the late reproductive stage (Stage −3) and the early postmenopause stage (Stage +1), provided information on the duration of the late transition (Stage −1) and early postmenopause (Stage +1), and recommended application regardless of women’s age, ethnicity, body size, or lifestyle characteristics. Conclusions STRAW + 10 provides a more comprehensive basis for assessing reproductive aging in research and clinical contexts. Application of the STRAW + 10 staging system should improve comparability of studies of midlife women and facilitate clinical decision making. Nonetheless, important knowledge gaps persist, and seven research priorities are identified. STRAW + 10 simplified bleeding criteria for the early and late menopausal transition, recommended modifications to criteria for the late reproductive and the early postmenopause stages, provided information on the duration of the late transition and early postmenopause, and recommended application regardless of women’s age, ethnicity, body size, or lifestyle characteristics.

Multiple myeloma is an incurable malignancy of plasma cells, and its pathogenesis is poorly understood. Here we report the massively parallel sequencing of 38 tumour genomes and their comparison to matched normal DNAs. Several new and unexpected oncogenic mechanisms were suggested by the pattern of somatic mutation across the data set. These include the mutation of genes involved in protein translation (seen in nearly half of the patients), genes involved in histone methylation, and genes involved in blood coagulation. In addition, a broader than anticipated role of NF-κB signalling was indicated by mutations in 11 members of the NF-κB pathway. Of potential immediate clinical relevance, activating mutations of the kinase BRAF were observed in 4% of patients, suggesting the evaluation of BRAF inhibitors in multiple myeloma clinical trials. These results indicate that cancer genome sequencing of large collections of samples will yield new insights into cancer not anticipated by existing knowledge. Multiple myeloma, a malignancy of plasma cells, remains incurable and is poorly understood. Chapman et al. have used next-generation sequencing to compare 38 multiple myeloma genomes with those of normal cells from the same patients. The disease involves mutations of genes with roles in protein translation, histone methylation and blood coagulation. In terms of clinically relevant findings, unexpected activating mutations were found in the kinase BRAF, inhibitors of which have recently shown dramatic clinical activity. This suggests that BRAF inhibitors should be evaluated in patients with BRAF-mutated multiple myeloma. Multiple myeloma, a malignancy of plasma cells, remains incurable and is poorly understood. Using next-generation sequencing of several multiple myeloma genomes reveals that this disease involves mutations of genes involved in protein translation, histone methylation and blood coagulation. The study suggests that BRAF inhibitors should be evaluated in multiple myeloma clinical trials.

A systematic review of the literature on social support shows that a stress-buffering effect is most consistently found when support is measured as a perception that one's network is ready to provide aid and assistance if needed (Kessler and McLeod, 1985). Two interpretations of this association are considered here: (I) that the perception of support availability indirectly indicates actual network responses to stressful events that more directly promote healthy adjustment; and (2) that the perception of support availability influences adjustment directly by modifying appraisals of the situation. No attempt has been made in the literature to discriminate between these two interpretations. One reason is that a strategy for critically evaluating the competing hypotheses has not yet been developed. A main contribution of our paper is that it exposits such a strategy. A rigorous evaluation of the competing interpretations requires a prospective research design and a data collection effort explicitly aimed at obtaining information about both actual support transactions and perceptions of support availability in hypothetical situations. We know of no data set that meets these dual requirements. As an illustration of the strategy suggested here, however, we analyze cross-sectional data from a large-scale national survey. Although limited, these data provide provisional information about the competing interpretations. Analysis shows that perceived support is, in general, more important than received support in predicting adjustment to stressful life events. We also present evidence that the influence of received support may be mediated by perceived support. These results demonstrate the power of the strategy and argue for a direct evaluation with more appropriate data.

A challenger to the continuing dominance of neorealism and neoliberal institutionalism in the study of international relations in the United States, constructivism is regarded with a great deal of skepticism by mainstream scholars.1 While the reasons for this reception are many, three central ones are the mainstream's miscasting of constructivism as necessarily postmodern and antipositivist; constructivism's own ambivalence about whether it can buy into mainstream social science methods without sacrificing its theoretical distinctiveness; and, related to this ambivalence, constructivism's failure to advance an alternative research program. In this article, I clarify constructivism's claims, outline the differences between conventional and critical constructivism, and suggest a research agenda that both provides alternative understandings of mainstream interna-

Our review has focused centrally on the etiologic significance of social factors in the development of psychopathology. Our implicit assumption has been that social factors in general, and stressors in particular, may play a causal role in the development of psychopathology. Yet the evidence is clear that the vast majority of people who are exposed to stressful life events or to chronic stress situations do not develop significant psychiatric impairments. For this reason, research interest over the past decade has shifted to factors like social support and coping strategies that may ameliorate the impact of stress. We have examined some of the important empirical results from recent studies of stress, support, and coping, and we have discussed ways in which these new understandings have informed long-standing attempts to explain group differences in emotional functioning. In each section of the review we have attempted not only to summarize existing results but also to provide some evaluation of the literature and suggestions for future research. It is important to recognize that the contributors to the work reviewed here do not all share a common research agenda. Some of them are primarily committed to unraveling the psychosocial determinants of a particular clinical disorder. Others are mainly concerned with the effects of a particular stressor. Still others are interested in the processes that link stress to health across a broad array of stress situations and health outcomes. In the face of these diverse interests, it is little wonder that our understanding of social factors in psychopathology is uneven. There is good reason to believe, however that these diverse strands of research are beginning to converge on a common conception of the stress process and on a common research design. The conception at present is only in rough form, but its outlines are nonetheless capable of description. At its center is the notion that stress exposure sets off a process of adaptation. It recognizes that this process unfolds over time, and it acknowledges that this process is modified by structural factors as well as by personal dispositions and vulnerabilities. There is growing recognition that the analysis of this process requires longitudinal methods. Also, it is becoming increasingly clear that experimental interventions are required to unravel the parts of this process that link stress and health. It is too early to know if this nascent convergence will lead to an integrative theory of adaptation, yet it is almost certain to promote methodological and conceptual rigor and facilitate replication and cumulation of findings.(ABSTRACT TRUNCATED AT 400 WORDS)

Human Protein Reference Database (HPRD) is an object database that integrates a wealth of information relevant to the function of human proteins in health and disease. Data pertaining to thousands of protein-protein interactions, posttranslational modifications, enzyme/substrate relationships, disease associations, tissue expression, and subcellular localization were extracted from the literature for a nonredundant set of 2750 human proteins. Almost all the information was obtained manually by biologists who read and interpreted >300,000 published articles during the annotation process. This database, which has an intuitive query interface allowing easy access to all the features of proteins, was built by using open source technologies and will be freely available at http://www.hprd.org to the academic community. This unified bioinformatics platform will be useful in cataloging and mining the large number of proteomic interactions and alterations that will be discovered in the postgenomic era.

This narrative review provides an overview on the topic of bias as part of a series of articles in Plastic and Reconstructive Surgery on evidence-based medicine. Bias can occur in the planning, data collection, analysis, and publication phases of research. Understanding research bias allows readers to critically and independently review the scientific literature and avoid treatments that are suboptimal or potentially harmful. A thorough understanding of bias and how it affects study results is essential for the practice of evidence-based medicine.

The present paper is concerned with the buffering hypothesis that social support ameliorate. the impact of occupational stress on job-related strain and health. Previous studies of this hypothesis have yielded conflicting results. Our purpose, therefore, is twofold. First, we summarize the literature in this area and review several studies in detail, all of which found main effects of social support on perceived occupational stress and on some health outcome measures. Three of the studies were specifically designed to examine the buffering effects of support. Of the three, two found little or no evidence for buffering (LaRocco and Jones, 1978a; Pinneau, 1975), whereas the third reported buffering effects (House and Wells, 1978). Second, we attempt to reconcile these different conclusions by reanalyzing one data set-first analyzed by Caplan et al. (1975) and then by Pinneau (1975)-using a moderated regression technique identical to that used in the LaRocco and Jones (1978a) and House and Wells (1978) studies. The data usedfor this analysis consist of a randomly stratified sample of men from 23 occupations (N 636). Our review andfindings support the buffering hypothesis for mental and physical health variables (anxiety, depression, irritation, and somatic symptoms), but, as in the previous three studies, fail to support the buffering hypothesis in regard to job-related strains (job dissatisfaction, boredom, dissatisfaction with work load).

Loss of expression of the E-cadherin cell-cell adhesion molecule is important in carcinoma development and progression. Because previous data suggest that loss of E-cadherin expression in breast carcinoma may result from a dominant transcriptional repression pathway acting on the E-cadherin proximal promoter, we pursued studies of cis sequences and transcription factors regulating E-cadherin expression in breast cancer cells. E-box elements in the E-cadherin promoter were found to play a critical negative regulatory role in E-cadherin gene transcription in breast cancer cell lines lacking E-cadherin transcription. The E-box elements had a minimal role in E-cadherin transcription in breast cancer cell lines expressing E-cadherin. Two zinc-finger transcription factors known to bind E-box elements, SLUG and SNAIL, repressed E-cadherin-driven reporter gene constructs containing wild-type promoter sequences but not those with mutations in the E-box elements. Additionally, both SLUG and SNAIL repressed endogenous E-cadherin expression. These findings suggest SLUG and SNAIL are potential repressors of E-cadherin transcription in carcinomas lacking E-cadherin expression. Analysis of the expression patterns of SLUG, SNAIL, and E-cadherin in breast cancer cell lines demonstrated that expression of SLUG was strongly correlated with loss of E-cadherin transcripts. Taken together, the data indicate the E-box elements in the proximal E-cadherin promoter are critical in transcriptional repression of the E-cadherin gene, and SLUG is a likely in vivo repressor of E-cadherin in breast cancer.

A mechanistic analysis of voltage shape changes in lithium metal anodes explains how dead lithium causes capacity fade and failure.