Because the human gut microbiota can play a major role in host health, there is currently some interest in the manipulation of the composition of the gut flora towards a potentially more remedial community. Attempts have been made to increase bacterial groups such as Bifidobacterium and Lactobacillus that are perceived as exerting health-promoting properties. Probiotics, defined as microbial food supplements that beneficially affect the host by improving its intestinal microbial balance, have been used to change the composition of colonic microbiota. However, such changes may be transient, and the implantation of exogenous bacteria therefore becomes limited. In contrast, prebiotics are nondigestible food ingredients that beneficially affect the host by selectively stimulating the growth and/or activity of one or a limited number of bacterial species already resident in the colon, and thus attempt to improve host health. Intake of prebiotics can significantly modulate the colonic microbiota by increasing the number of specific bacteria and thus changing the composition of the microbiota. Nondigestible oligosaccharides in general, and fructooligosaccharides in particular, are prebiotics. They have been shown to stimulate the growth of endogenous bifidobacteria, which, after a short feeding period, become predominant in human feces. Moreover, these prebiotics modulate lipid metabolism, most likely via fermentation products. By combining the rationale of pro- and prebiotics, the concept of synbiotics is proposed to characterize some colonic foods with interesting nutritional properties that make these compounds candidates for classification as health-enhancing functional food ingredients.

BACKGROUND

Roughly 3 million people worldwide were receiving antiretroviral therapy (ART) at the end of 2007, but an estimated 6.7 million were still in need of treatment and a further 2.7 million became infected with HIV in 2007. Prevention efforts might reduce HIV incidence but are unlikely to eliminate this disease. We investigated a theoretical strategy of universal voluntary HIV testing and immediate treatment with ART, and examined the conditions under which the HIV epidemic could be driven towards elimination.

METHODS

We used mathematical models to explore the effect on the case reproduction number (stochastic model) and long-term dynamics of the HIV epidemic (deterministic transmission model) of testing all people in our test-case community (aged 15 years and older) for HIV every year and starting people on ART immediately after they are diagnosed HIV positive. We used data from South Africa as the test case for a generalised epidemic, and assumed that all HIV transmission was heterosexual.

RESULTS

The studied strategy could greatly accelerate the transition from the present endemic phase, in which most adults living with HIV are not receiving ART, to an elimination phase, in which most are on ART, within 5 years. It could reduce HIV incidence and mortality to less than one case per 1000 people per year by 2016, or within 10 years of full implementation of the strategy, and reduce the prevalence of HIV to less than 1% within 50 years. We estimate that in 2032, the yearly cost of the present strategy and the theoretical strategy would both be US$1.7 billion; however, after this time, the cost of the present strategy would continue to increase whereas that of the theoretical strategy would decrease.

CONCLUSIONS

Universal voluntary HIV testing and immediate ART, combined with present prevention approaches, could have a major effect on severe generalised HIV/AIDS epidemics. This approach merits further mathematical modelling, research, and broad consultation.

Our ability to have an experience of another's pain is characteristic of empathy. Using functional imaging, we assessed brain activity while volunteers experienced a painful stimulus and compared it to that elicited when they observed a signal indicating that their loved one--present in the same room--was receiving a similar pain stimulus. Bilateral anterior insula (AI), rostral anterior cingulate cortex (ACC), brainstem, and cerebellum were activated when subjects received pain and also by a signal that a loved one experienced pain. AI and ACC activation correlated with individual empathy scores. Activity in the posterior insula/secondary somatosensory cortex, the sensorimotor cortex (SI/MI), and the caudal ACC was specific to receiving pain. Thus, a neural response in AI and rostral ACC, activated in common for "self" and "other" conditions, suggests that the neural substrate for empathic experience does not involve the entire "pain matrix." We conclude that only that part of the pain network associated with its affective qualities, but not its sensory qualities, mediates empathy.

In near-physiological concentrations, glucocorticoid hormones cause the death of several types of normal and neoplastic lymphoid cell, but the mechanisms involved are unknown. One of the earliest structural changes in the dying cell is widespread chromatin condensation, of the type characteristic of apoptosis, the mode of death frequently observed where cell deletion seems to be 'programmed'. It is shown here that this morphological change is closely associated with excision of nucleosome chains from nuclear chromatin, apparently through activation of an intracellular, but non-lysosomal, endonuclease.

The transmission of extracellular signals into their intracellular targets is mediated by a network of interacting proteins that regulate a large number of cellular processes. Cumulative efforts from many laboratories over the past decade have allowed the elucidation of one such signaling mechanism, which involves activations of several membranal signaling molecules followed by a sequential stimulation of several cytoplasmic protein kinases collectively known as mitogen-activated protein kinase (MAPK) signaling cascade. Up to six tiers in this cascade contribute to the amplification and specificity of the transmitted signals that eventually activate several regulatory molecules in the cytoplasm and in the nucleus to initiate cellular processes such as proliferation, differentiation, and development. Moreover, because many oncogenes have been shown to encode proteins that transmit mitogenic signals upstream of this cascade, the MAPK pathway provides a simple unifying explanation for the mechanism of action of most, if not all, nonnuclear oncogenes. The pattern of MAPK cascade is not restricted to growth factor signaling and it is now known that signaling pathways initiated by phorbol esters, ionophors, heat shock, and ligands for seven transmembrane receptors use distinct MAPK cascades with little or no cross-reactivity between them. In this review we emphasize primarily the first MAPK cascade to be discovered that uses the MEK and ERK isoforms and describe their involvement in different cellular processes.

Beneath the complexity and idiopathy of every cancer lies a limited number of 'mission critical' events that have propelled the tumour cell and its progeny into uncontrolled expansion and invasion. One of these is deregulated cell proliferation, which, together with the obligate compensatory suppression of apoptosis needed to support it, provides a minimal 'platform' necessary to support further neoplastic progression. Adroit targeting of these critical events should have potent and specific therapeutic consequences.

METHODS

A reliability study was conducted.

OBJECTIVE

To develop a classification system for lumbar disc degeneration based on routine magnetic resonance imaging, to investigate the applicability of a simple algorithm, and to assess the reliability of this classification system.

BACKGROUND

A standardized nomenclature in the assessment of disc abnormalities is a prerequisite for a comparison of data from different investigations. The reliability of the assessment has a crucial influence on the validity of the data. Grading systems of disc degeneration based on state of the art magnetic resonance imaging and corresponding reproducibility studies currently are sparse.

METHODS

A grading system for lumbar disc degeneration was developed on the basis of the literature. An algorithm to assess the grading was developed and optimized by reviewing lumbar magnetic resonance examinations. The reliability of the algorithm in depicting intervertebral disc alterations was tested on the magnetic resonance images of 300 lumbar intervertebral discs in 60 patients (33 men and 27 women) with a mean age of 40 years (range, 10-83 years). All scans were analyzed independently by three observers. Intra- and interobserver reliabilities were assessed by calculating kappa statistics.

RESULTS

There were 14 Grade I, 82 Grade II, 72 Grade III, 68 Grade IV, and 64 Grade V discs. The kappa coefficients for intra- and interobserver agreement were substantial to excellent: intraobserver (kappa range, 0.84-0.90) and interobserver (kappa range, 0.69-0.81). Complete agreement was obtained, on the average, in 83.8% of all the discs. A difference of one grade occurred in 15.9% and a difference of two or more grades in 1.3% of all the cases.

CONCLUSIONS

Disc degeneration can be graded reliably on routine T2-weighted magnetic resonance images using the grading system and algorithm presented in this investigation.

BACKGROUND

In phase 2 trials, telaprevir, a hepatitis C virus (HCV) genotype 1 protease inhibitor, in combination with peginterferon-ribavirin, as compared with peginterferon-ribavirin alone, has shown improved efficacy, with potential for shortening the duration of treatment in a majority of patients.

METHODS

In this international, phase 3, randomized, double-blind, placebo-controlled trial, we assigned 1088 patients with HCV genotype 1 infection who had not received previous treatment for the infection to one of three groups: a group receiving telaprevir combined with peginterferon alfa-2a and ribavirin for 12 weeks (T12PR group), followed by peginterferon-ribavirin alone for 12 weeks if HCV RNA was undetectable at weeks 4 and 12 or for 36 weeks if HCV RNA was detectable at either time point; a group receiving telaprevir with peginterferon-ribavirin for 8 weeks and placebo with peginterferon-ribavirin for 4 weeks (T8PR group), followed by 12 or 36 weeks of peginterferon-ribavirin on the basis of the same HCV RNA criteria; or a group receiving placebo with peginterferon-ribavirin for 12 weeks, followed by 36 weeks of peginterferon-ribavirin (PR group). The primary end point was the proportion of patients who had undetectable plasma HCV RNA 24 weeks after the last planned dose of study treatment (sustained virologic response).

RESULTS

Significantly more patients in the T12PR or T8PR group than in the PR group had a sustained virologic response (75% and 69%, respectively, vs. 44%; P<0.001 for the comparison of the T12PR or T8PR group with the PR group). A total of 58% of the patients treated with telaprevir were eligible to receive 24 weeks of total treatment. Anemia, gastrointestinal side effects, and skin rashes occurred at a higher incidence among patients receiving telaprevir than among those receiving peginterferon-ribavirin alone. The overall rate of discontinuation of the treatment regimen owing to adverse events was 10% in the T12PR and T8PR groups and 7% in the PR group.

CONCLUSIONS

Telaprevir with peginterferon-ribavirin, as compared with peginterferon-ribavirin alone, was associated with significantly improved rates of sustained virologic response in patients with HCV genotype 1 infection who had not received previous treatment, with only 24 weeks of therapy administered in the majority of patients. (Funded by Vertex Pharmaceuticals and Tibotec; ADVANCE ClinicalTrials.gov number, NCT00627926.).

BACKGROUND

Data for trends in prevalence of asthma, allergic rhinoconjunctivitis, and eczema over time are scarce. We repeated the International Study of Asthma and Allergies in Childhood (ISAAC) at least 5 years after Phase One, to examine changes in the prevalence of symptoms of these disorders.

METHODS

For the ISAAC Phase Three study, between 2002 and 2003, we did a cross-sectional questionnaire survey of 193,404 children aged 6-7 years from 66 centres in 37 countries, and 304,679 children aged 13-14 years from 106 centres in 56 countries, chosen from a random sample of schools in a defined geographical area.

RESULTS

Phase Three was completed a mean of 7 years after Phase One. Most centres showed a change in prevalence of 1 or more SE for at least one disorder, with increases being twice as common as decreases, and increases being more common in the 6-7 year age-group than in the 13-14 year age-group, and at most levels of mean prevalence. An exception was asthma symptoms in the older age-group, in which decreases were more common at high prevalence. For both age-groups, more centres showed increases in all three disorders more often than showing decreases, but most centres had mixed changes.

CONCLUSIONS

The rise in prevalence of symptoms in many centres is concerning, but the absence of increases in prevalence of asthma symptoms for centres with existing high prevalence in the older age-group is reassuring. The divergent trends in prevalence of symptoms of allergic diseases form the basis for further research into the causes of such disorders.

Non-fatal outcomes of disease and injury increasingly detract from the ability of the world's population to live in full health, a trend largely attributable to an epidemiological transition in many countries from causes affecting children, to non-communicable diseases (NCDs) more common in adults. For the Global Burden of Diseases, Injuries, and Risk Factors Study 2015 (GBD 2015), we estimated the incidence, prevalence, and years lived with disability for diseases and injuries at the global, regional, and national scale over the period of 1990 to 2015.

We estimated incidence and prevalence by age, sex, cause, year, and geography with a wide range of updated and standardised analytical procedures. Improvements from GBD 2013 included the addition of new data sources, updates to literature reviews for 85 causes, and the identification and inclusion of additional studies published up to November, 2015, to expand the database used for estimation of non-fatal outcomes to 60 900 unique data sources. Prevalence and incidence by cause and sequelae were determined with DisMod-MR 2.1, an improved version of the DisMod-MR Bayesian meta-regression tool first developed for GBD 2010 and GBD 2013. For some causes, we used alternative modelling strategies where the complexity of the disease was not suited to DisMod-MR 2.1 or where incidence and prevalence needed to be determined from other data. For GBD 2015 we created a summary indicator that combines measures of income per capita, educational attainment, and fertility (the Socio-demographic Index [SDI]) and used it to compare observed patterns of health loss to the expected pattern for countries or locations with similar SDI scores.

We generated 9·3 billion estimates from the various combinations of prevalence, incidence, and YLDs for causes, sequelae, and impairments by age, sex, geography, and year. In 2015, two causes had acute incidences in excess of 1 billion: upper respiratory infections (17·2 billion, 95% uncertainty interval [UI] 15·4-19·2 billion) and diarrhoeal diseases (2·39 billion, 2·30-2·50 billion). Eight causes of chronic disease and injury each affected more than 10% of the world's population in 2015: permanent caries, tension-type headache, iron-deficiency anaemia, age-related and other hearing loss, migraine, genital herpes, refraction and accommodation disorders, and ascariasis. The impairment that affected the greatest number of people in 2015 was anaemia, with 2·36 billion (2·35-2·37 billion) individuals affected. The second and third leading impairments by number of individuals affected were hearing loss and vision loss, respectively. Between 2005 and 2015, there was little change in the leading causes of years lived with disability (YLDs) on a global basis. NCDs accounted for 18 of the leading 20 causes of age-standardised YLDs on a global scale. Where rates were decreasing, the rate of decrease for YLDs was slower than that of years of life lost (YLLs) for nearly every cause included in our analysis. For low SDI geographies, Group 1 causes typically accounted for 20-30% of total disability, largely attributable to nutritional deficiencies, malaria, neglected tropical diseases, HIV/AIDS, and tuberculosis. Lower back and neck pain was the leading global cause of disability in 2015 in most countries. The leading cause was sense organ disorders in 22 countries in Asia and Africa and one in central Latin America; diabetes in four countries in Oceania; HIV/AIDS in three southern sub-Saharan African countries; collective violence and legal intervention in two north African and Middle Eastern countries; iron-deficiency anaemia in Somalia and Venezuela; depression in Uganda; onchoceriasis in Liberia; and other neglected tropical diseases in the Democratic Republic of the Congo.

Ageing of the world's population is increasing the number of people living with sequelae of diseases and injuries. Shifts in the epidemiological profile driven by socioeconomic change also contribute to the continued increase in years lived with disability (YLDs) as well as the rate of increase in YLDs. Despite limitations imposed by gaps in data availability and the variable quality of the data available, the standardised and comprehensive approach of the GBD study provides opportunities to examine broad trends, compare those trends between countries or subnational geographies, benchmark against locations at similar stages of development, and gauge the strength or weakness of the estimates available.

Bill & Melinda Gates Foundation.

One hundred eighteen papillomavirus (PV) types have been completely described, and a yet higher number of presumed new types have been detected by preliminary data such as subgenomic amplicons. The classification of this diverse group of viruses, which include important human pathogens, has been debated for three decades. This article describes the higher-order PV taxonomy following the general criteria established by the International Committee on the Taxonomy of Viruses (ICTV), reviews the literature of the lower order taxa, lists all known "PV types", and interprets their phylogenetic relationship. PVs are a taxonomic family of their own, Papillomaviridae, unrelated to the polyomaviruses. Higher-order phylogenetic assemblages of PV types, such as the "genital human PVs", are considered a genus, the latter group, for example, the genus "Alpha-Papillomavirus". Lower-order assemblages of PV types within each genus are treated as species because they are phylogenetically closely related, but while they have distinct genomic sequences, they have identical or very similar biological or pathological properties. The taxonomic status of PV types, subtypes, and variants remains unchanged and is based on the traditional criteria that the sequence of their L1 genes should be at least 10%, 2-10%, and maximally 2% dissimilar from one another.

Numerous studies demonstrate links between chronic stress and indices of poor health, including risk factors for cardiovascular disease and poorer immune function. Nevertheless, the exact mechanisms of how stress gets "under the skin" remain elusive. We investigated the hypothesis that stress impacts health by modulating the rate of cellular aging. Here we provide evidence that psychological stress--both perceived stress and chronicity of stress--is significantly associated with higher oxidative stress, lower telomerase activity, and shorter telomere length, which are known determinants of cell senescence and longevity, in peripheral blood mononuclear cells from healthy premenopausal women. Women with the highest levels of perceived stress have telomeres shorter on average by the equivalent of at least one decade of additional aging compared to low stress women. These findings have implications for understanding how, at the cellular level, stress may promote earlier onset of age-related diseases.

One of the most popular experimental paradigms for functional neuroimaging studies of working memory has been the n-back task, in which subjects are asked to monitor the identity or location of a series of verbal or nonverbal stimuli and to indicate when the currently presented stimulus is the same as the one presented n trials previously. We conducted a quantitative meta-analysis of 668 sets of activation coordinates in Talairach space reported in 24 primary studies of n-back task variants manipulating process (location vs. identity monitoring) and content (verbal or nonverbal) of working memory. We found the following cortical regions were activated robustly (voxelwise false discovery rate = 1%): lateral premotor cortex; dorsal cingulate and medial premotor cortex; dorsolateral and ventrolateral prefrontal cortex; frontal poles; and medial and lateral posterior parietal cortex. Subsidiary meta-analyses based on appropriate subsets of the primary data demonstrated broadly similar activation patterns for identity monitoring of verbal stimuli and both location and identity monitoring of nonverbal stimuli. There was also some evidence for distinct frontoparietal activation patterns in response to different task variants. The functional specializations of each of the major cortical components in the generic large-scale frontoparietal system are discussed. We conclude that quantitative meta-analysis can be a powerful tool for combining results of multiple primary studies reported in Talairach space. Here, it provides evidence both for broadly consistent activation of frontal and parietal cortical regions by various versions of the n-back working memory paradigm, and for process- and content-specific frontoparietal activation by working memory.

It is controversial whether different cognitive functions can be mapped to discrete regions of the prefrontal cortex (PFC). The localisationist tradition has associated one cognitive function - inhibition - by turns with dorsolateral prefrontal cortex (DLPFC), inferior frontal cortex (IFC), or orbital frontal cortex (OFC). Inhibition is postulated to be a mechanism by which PFC exerts its effects on subcortical and posterior-cortical regions to implement executive control. We review evidence concerning inhibition of responses and task-sets. Whereas neuroimaging implicates diverse PFC foci, advances in human lesion-mapping support the functional localization of such inhibition to right IFC alone. Future research should investigate the generality of this proposed inhibitory function to other task domains, and its interaction within a wider network.

One of the most challenging problems in modern neuroimaging is detailed characterization of neurodegeneration. Quantifying spatial and longitudinal atrophy patterns is an important component of this process. These spatiotemporal signals will aid in discriminating between related diseases, such as frontotemporal dementia (FTD) and Alzheimer's disease (AD), which manifest themselves in the same at-risk population. Here, we develop a novel symmetric image normalization method (SyN) for maximizing the cross-correlation within the space of diffeomorphic maps and provide the Euler-Lagrange equations necessary for this optimization. We then turn to a careful evaluation of our method. Our evaluation uses gold standard, human cortical segmentation to contrast SyN's performance with a related elastic method and with the standard ITK implementation of Thirion's Demons algorithm. The new method compares favorably with both approaches, in particular when the distance between the template brain and the target brain is large. We then report the correlation of volumes gained by algorithmic cortical labelings of FTD and control subjects with those gained by the manual rater. This comparison shows that, of the three methods tested, SyN's volume measurements are the most strongly correlated with volume measurements gained by expert labeling. This study indicates that SyN, with cross-correlation, is a reliable method for normalizing and making anatomical measurements in volumetric MRI of patients and at-risk elderly individuals.

Structural variation (copy number variation [CNV] including deletion and duplication, translocation, inversion) of chromosomes has been identified in some individuals with autism spectrum disorder (ASD), but the full etiologic role is unknown. We performed genome-wide assessment for structural abnormalities in 427 unrelated ASD cases via single-nucleotide polymorphism microarrays and karyotyping. With microarrays, we discovered 277 unbalanced CNVs in 44% of ASD families not present in 500 controls (and re-examined in another 1152 controls). Karyotyping detected additional balanced changes. Although most variants were inherited, we found a total of 27 cases with de novo alterations, and in three (11%) of these individuals, two or more new variants were observed. De novo CNVs were found in approximately 7% and approximately 2% of idiopathic families having one child, or two or more ASD siblings, respectively. We also detected 13 loci with recurrent/overlapping CNV in unrelated cases, and at these sites, deletions and duplications affecting the same gene(s) in different individuals and sometimes in asymptomatic carriers were also found. Notwithstanding complexities, our results further implicate the SHANK3-NLGN4-NRXN1 postsynaptic density genes and also identify novel loci at DPP6-DPP10-PCDH9 (synapse complex), ANKRD11, DPYD, PTCHD1, 15q24, among others, for a role in ASD susceptibility. Our most compelling result discovered CNV at 16p11.2 (p = 0.002) (with characteristics of a genomic disorder) at approximately 1% frequency. Some of the ASD regions were also common to mental retardation loci. Structural variants were found in sufficiently high frequency influencing ASD to suggest that cytogenetic and microarray analyses be considered in routine clinical workup.

Recent studies have indicated the existence of tumorigenesis barriers that slow or inhibit the progression of preneoplastic lesions to neoplasia. One such barrier involves DNA replication stress, which leads to activation of the DNA damage checkpoint and thereby to apoptosis or cell cycle arrest, whereas a second barrier is mediated by oncogene-induced senescence. The relationship between these two barriers, if any, has not been elucidated. Here we show that oncogene-induced senescence is associated with signs of DNA replication stress, including prematurely terminated DNA replication forks and DNA double-strand breaks. Inhibiting the DNA double-strand break response kinase ataxia telangiectasia mutated (ATM) suppressed the induction of senescence and in a mouse model led to increased tumour size and invasiveness. Analysis of human precancerous lesions further indicated that DNA damage and senescence markers cosegregate closely. Thus, senescence in human preneoplastic lesions is a manifestation of oncogene-induced DNA replication stress and, together with apoptosis, provides a barrier to malignant progression.

Little is known about the design principles of transcriptional regulation networks that control gene expression in cells. Recent advances in data collection and analysis, however, are generating unprecedented amounts of information about gene regulation networks. To understand these complex wiring diagrams, we sought to break down such networks into basic building blocks. We generalize the notion of motifs, widely used for sequence analysis, to the level of networks. We define 'network motifs' as patterns of interconnections that recur in many different parts of a network at frequencies much higher than those found in randomized networks. We applied new algorithms for systematically detecting network motifs to one of the best-characterized regulation networks, that of direct transcriptional interactions in Escherichia coli. We find that much of the network is composed of repeated appearances of three highly significant motifs. Each network motif has a specific function in determining gene expression, such as generating temporal expression programs and governing the responses to fluctuating external signals. The motif structure also allows an easily interpretable view of the entire known transcriptional network of the organism. This approach may help define the basic computational elements of other biological networks.

A key step toward the discovery of a gene related to a trait is the finding of an association between the trait and one or more haplotypes. Haplotype analyses can also provide critical information regarding the function of a gene; however, when unrelated subjects are sampled, haplotypes are often ambiguous because of unknown linkage phase of the measured sites along a chromosome. A popular method of accounting for this ambiguity in case-control studies uses a likelihood that depends on haplotype frequencies, so that the haplotype frequencies can be compared between the cases and controls; however, this traditional method is limited to a binary trait (case vs. control), and it does not provide a method of testing the statistical significance of specific haplotypes. To address these limitations, we developed new methods of testing the statistical association between haplotypes and a wide variety of traits, including binary, ordinal, and quantitative traits. Our methods allow adjustment for nongenetic covariates, which may be critical when analyzing genetically complex traits. Furthermore, our methods provide several different global tests for association, as well as haplotype-specific tests, which give a meaningful advantage in attempts to understand the roles of many different haplotypes. The statistics can be computed rapidly, making it feasible to evaluate the associations between many haplotypes and a trait. To illustrate the use of our new methods, they are applied to a study of the association of haplotypes (composed of genes from the human-leukocyte-antigen complex) with humoral immune response to measles vaccination. Limited simulations are also presented to demonstrate the validity of our methods, as well as to provide guidelines on how our methods could be used.

An understanding of the basic defect in the inherited disorder cystic fibrosis requires cloning of the cystic fibrosis gene and definition of its protein product. In the absence of direct functional information, chromosomal map position is a guide for locating the gene. Chromosome walking and jumping and complementary DNA hybridization were used to isolate DNA sequences, encompassing more than 500,000 base pairs, from the cystic fibrosis region on the long arm of human chromosome 7. Several transcribed sequences and conserved segments were identified in this cloned region. One of these corresponds to the cystic fibrosis gene and spans approximately 250,000 base pairs of genomic DNA.

OBJECTIVE

To determine the incidence of surgically managed pelvic organ prolapse and urinary incontinence in a population-based cohort, and to describe their clinical characteristics.

METHODS

Our retrospective cohort study included all patients undergoing surgical treatment for prolapse and incontinence during 1995; all were members of Kaiser Permanente Northwest, which included 149,554 women age 20 or older. A standardized data-collection form was used to review all inpatient and outpatient charts of the 395 women identified. Variables examined included age, ethnicity, height, weight, vaginal parity, smoking history, medical history, and surgical history, including the preoperative evaluation, procedure performed, and details of all prior procedures. Analysis included calculation of age-specific and cumulative incidences and determination of the number of primary operations compared with repeat operations performed for prolapse or incontinence.

RESULTS

The age-specific incidence increased with advancing age. The lifetime risk of undergoing a single operation for prolapse or incontinence by age 80 was 11.1%. Most patients were older, postmenopausal, parous, and overweight. Nearly half were current or former smokers and one-fifth had chronic lung disease. Reoperation was common (29.2% of cases), and the time intervals between repeat procedures decreased with each successive repair.

CONCLUSIONS

Pelvic floor dysfunction is a major health issue for older women, as shown by the 11.1% lifetime risk of undergoing a single operation for pelvic organ prolapse and urinary incontinence, as well as the large proportion of reoperations. Our results warrant further epidemiologic research in order to determine the etiology, natural history, and long-term treatment outcomes of these conditions.

A single protein crystal structure contains information about dynamic properties of the protein as well as providing a static view of one three-dimensional conformation. This additional information is to be found in the distribution of observed electron density about the mean position of each atom. It is general practice to account for this by refining a separate atomic displacement parameter (ADP) for each atomic center. However, these same displacements are often described well by simpler models based on TLS (translation/libration/screw) rigid-body motion of large groups of atoms, for example interdomain hinge motion. A procedure, TLSMD, has been developed that analyzes the distribution of ADPs in a previously refined protein crystal structure in order to generate optimal multi-group TLS descriptions of the constituent protein chains. TLSMD is applicable to crystal structures at any resolution. The models generated by TLSMD analysis can significantly improve the standard crystallographic residuals R and R(free) and can reveal intrinsic dynamic properties of the protein.

A topic that has received attention in both the statistical and medical literature is the estimation of the probability of failure for endpoints that are subject to competing risks. Despite this, it is not uncommon to see the complement of the Kaplan-Meier estimate used in this setting and interpreted as the probability of failure. If one desires an estimate that can be interpreted in this way, however, the cumulative incidence estimate is the appropriate tool to use in such situations. We believe the more commonly seen representations of the Kaplan-Meier estimate and the cumulative incidence estimate do not lend themselves to easy explanation and understanding of this interpretation. We present, therefore, a representation of each estimate in a manner not ordinarily seen, each representation utilizing the concept of censored observations being 'redistributed to the right.' We feel these allow a more intuitive understanding of each estimate and therefore an appreciation of why the Kaplan-Meier method is inappropriate for estimation purposes in the presence of competing risks, while the cumulative incidence estimate is appropriate.

BACKGROUND

Chronic obstructive pulmonary disease (COPD) is characterized by an incompletely reversible limitation in airflow. A physiological variable--the forced expiratory volume in one second (FEV1)--is often used to grade the severity of COPD. However, patients with COPD have systemic manifestations that are not reflected by the FEV1. We hypothesized that a multidimensional grading system that assessed the respiratory and systemic expressions of COPD would better categorize and predict outcome in these patients.

METHODS

We first evaluated 207 patients and found that four factors predicted the risk of death in this cohort: the body-mass index (B), the degree of airflow obstruction (O) and dyspnea (D), and exercise capacity (E), measured by the six-minute-walk test. We used these variables to construct the BODE index, a multidimensional 10-point scale in which higher scores indicate a higher risk of death. We then prospectively validated the index in a cohort of 625 patients, with death from any cause and from respiratory causes as the outcome variables.

RESULTS

There were 25 deaths among the first 207 patients and 162 deaths (26 percent) in the validation cohort. Sixty-one percent of the deaths in the validation cohort were due to respiratory insufficiency, 14 percent to myocardial infarction, 12 percent to lung cancer, and 13 percent to other causes. Patients with higher BODE scores were at higher risk for death; the hazard ratio for death from any cause per one-point increase in the BODE score was 1.34 (95 percent confidence interval, 1.26 to 1.42; P<0.001), and the hazard ratio for death from respiratory causes was 1.62 (95 percent confidence interval, 1.48 to 1.77; P<0.001). The C statistic for the ability of the BODE index to predict the risk of death was larger than that for the FEV1 (0.74 vs. 0.65).

CONCLUSIONS

The BODE index, a simple multidimensional grading system, is better than the FEV1 at predicting the risk of death from any cause and from respiratory causes among patients with COPD.