PURPOSE Neuroendocrine tumors (NETs) are considered rare tumors and can produce a variety of hormones. In this study, we examined the epidemiology of and prognostic factors for NETs, because a thorough examination of neither had previously been performed. METHODS The Surveillance, Epidemiology, and End Results (SEER) Program registries were searched to identify NET cases from 1973 to 2004. Associated population data were used for incidence and prevalence analyses. Results We identified 35,618 patients with NETs. We observed a significant increase in the reported annual age-adjusted incidence of NETs from 1973 (1.09/100,000) to 2004 (5.25/100,000). Using the SEER 9 registry data, we estimated the 29-year limited-duration prevalence of NETs on January 1, 2004, to be 9,263. Also, the estimated 29-year limited-duration prevalence in the United States on that date was 103,312 cases (35/100,000). The most common primary tumor site varied by race, with the lung being the most common in white patients, and the rectum being the most common in Asian/Pacific Islander, American Indian/Alaskan Native, and African American patients. Additionally, survival duration varied by histologic grade. In multivariate analysis of patients with well-differentiated to moderately differentiated NETs, disease stage, primary tumor site, histologic grade, sex, race, age, and year of diagnosis were predictors of outcome (P < .001). CONCLUSION We observed increased reported incidence of NETs and increased survival durations over time, suggesting that NETs are more prevalent than previously reported. Clinicians need to be become familiar with the natural history and patterns of disease progression, which are characteristic of these tumors.

The transtheoretical model posits that health behavior change involves progress through six stages of change: precontemplation, contemplation, preparation, action, maintenance, and termination. Ten processes of change have been identified for producing progress along with decisional balance, self-efficacy, and temptations. Basic research has generated a rule of thumb for at-risk populations: 40% in precontemplation, 40% in contemplation, and 20% in preparation. Across 12 health behaviors, consistent patterns have been found between the pros and cons of changing and the stages of change. Applied research has demonstrated dramatic improvements in recruitment, retention, and progress using stage-matched interventions and proactive recruitment procedures. The most promising outcomes to data have been found with computer-based individualized and interactive interventions. The most promising enhancement to the computer-based programs are personalized counselors. One of the most striking results to date for stage-matched programs is the similarity between participants reactively recruited who reached us for help and those proactively recruited who we reached out to help. If results with stage-matched interventions continue to be replicated, health promotion programs will be able to produce unprecedented impacts on entire at-risk populations.

BACKGROUND

Nivolumab, a programmed death 1 (PD-1) checkpoint inhibitor, was associated with encouraging overall survival in uncontrolled studies involving previously treated patients with advanced renal-cell carcinoma. This randomized, open-label, phase 3 study compared nivolumab with everolimus in patients with renal-cell carcinoma who had received previous treatment.

METHODS

A total of 821 patients with advanced clear-cell renal-cell carcinoma for which they had received previous treatment with one or two regimens of antiangiogenic therapy were randomly assigned (in a 1:1 ratio) to receive 3 mg of nivolumab per kilogram of body weight intravenously every 2 weeks or a 10-mg everolimus tablet orally once daily. The primary end point was overall survival. The secondary end points included the objective response rate and safety.

RESULTS

The median overall survival was 25.0 months (95% confidence interval [CI], 21.8 to not estimable) with nivolumab and 19.6 months (95% CI, 17.6 to 23.1) with everolimus. The hazard ratio for death with nivolumab versus everolimus was 0.73 (98.5% CI, 0.57 to 0.93; P=0.002), which met the prespecified criterion for superiority (P≤0.0148). The objective response rate was greater with nivolumab than with everolimus (25% vs. 5%; odds ratio, 5.98 [95% CI, 3.68 to 9.72]; P<0.001). The median progression-free survival was 4.6 months (95% CI, 3.7 to 5.4) with nivolumab and 4.4 months (95% CI, 3.7 to 5.5) with everolimus (hazard ratio, 0.88; 95% CI, 0.75 to 1.03; P=0.11). Grade 3 or 4 treatment-related adverse events occurred in 19% of the patients receiving nivolumab and in 37% of the patients receiving everolimus; the most common event with nivolumab was fatigue (in 2% of the patients), and the most common event with everolimus was anemia (in 8%).

CONCLUSIONS

Among patients with previously treated advanced renal-cell carcinoma, overall survival was longer and fewer grade 3 or 4 adverse events occurred with nivolumab than with everolimus. (Funded by Bristol-Myers Squibb; CheckMate 025 ClinicalTrials.gov number, NCT01668784.).

CD4 T cells play critical roles in mediating adaptive immunity to a variety of pathogens. They are also involved in autoimmunity, asthma, and allergic responses as well as in tumor immunity. During TCR activation in a particular cytokine milieu, naive CD4 T cells may differentiate into one of several lineages of T helper (Th) cells, including Th1, Th2, Th17, and iTreg, as defined by their pattern of cytokine production and function. In this review, we summarize the discovery, functions, and relationships among Th cells; the cytokine and signaling requirements for their development; the networks of transcription factors involved in their differentiation; the epigenetic regulation of their key cytokines and transcription factors; and human diseases involving defective CD4 T cell differentiation.

BACKGROUND

The current practice of removing adenomatous polyps of the colon and rectum is based on the belief that this will prevent colorectal cancer. To address the hypothesis that colonoscopic polypectomy reduces the incidence of colorectal cancer, we analyzed the results of the National Polyp Study with reference to other published results.

METHODS

The study cohort consisted of 1418 patients who had a complete colonoscopy during which one or more adenomas of the colon or rectum were removed. The patients subsequently underwent periodic colonoscopy during an average follow-up of 5.9 years, and the incidence of colorectal cancer was ascertained. The incidence rate of colorectal cancer was compared with that in three reference groups, including two cohorts in which colonic polyps were not removed and one general-population registry, after adjustment for sex, age, and polyp size.

RESULTS

Ninety-seven percent of the patients were followed clinically for a total of 8401 person-years, and 80 percent returned for one or more of their scheduled colonoscopies. Five asymptomatic early-stage colorectal cancers (malignant polyps) were detected by colonoscopy (three at three years, one at six years, and one at seven years). No symptomatic cancers were detected. The numbers of colorectal cancers expected on the basis of the rates in the three reference groups were 48.3, 43.4, and 20.7, for reductions in the incidence of colorectal cancer of 90, 88, and 76 percent, respectively (P < 0.001).

CONCLUSIONS

Colonoscopic polypectomy resulted in a lower-than-expected incidence of colorectal cancer. These results support the view that colorectal adenomas progress to adenocarcinomas, as well as the current practice of searching for and removing adenomatous polyps to prevent colorectal cancer.

OBJECTIVE

To describe the psychometric properties of the Strengths and Difficulties Questionnaire (SDQ), a brief measure of the prosocial behavior and psychopathology of 3-16-year-olds that can be completed by parents, teachers, or youths.

METHODS

A nationwide epidemiological sample of 10,438 British 5-15-year-olds obtained SDQs from 96% of parents, 70% of teachers, and 91% of 11-15-year-olds. Blind to the SDQ findings, all subjects were also assigned DSM-IVdiagnoses based on a clinical review of detailed interview measures.

RESULTS

The predicted five-factor structure (emotional, conduct, hyperactivity-inattention, peer, prosocial) was confirmed. Internalizing and externalizing scales were relatively "uncontaminated" by one another. Reliability was generally satisfactory, whether judged by internal consistency (mean Cronbach a: .73), cross-informant correlation (mean: 0.34), or retest stability after 4 to 6 months (mean: 0.62). SDQ scores above the 90th percentile predicted a substantially raised probability of independently diagnosed psychiatric disorders (mean odds ratio: 15.7 for parent scales, 15.2 for teacher scales, 6.2 for youth scales).

CONCLUSIONS

The reliability and validity of the SDQ make it a useful brief measure of the adjustment and psychopathology of children and adolescents.

5 sets of criteria for diagnosis of Behçet's disease are in use--a problem which has hindered interpretation of different studies and collaborative research. An international study group, which included at least one proponent of 4 of the sets, was formed to derive new, internationally agreed diagnostic criteria for Behçet's disease. Data on 914 patients with Behçet's disease, from 12 centres in 7 countries, were compared with controls from the same centres. The new set of diagnostic criteria--which requires the presence of oral ulceration plus any two of genital ulceration, typical defined eye lesions, typical defined skin lesions, or a positive pathergy test--was simpler to use and had an improved discriminatory performance than its predecessors.

Whole-genome association studies present many new statistical and computational challenges due to the large quantity of data obtained. One of these challenges is haplotype inference; methods for haplotype inference designed for small data sets from candidate-gene studies do not scale well to the large number of individuals genotyped in whole-genome association studies. We present a new method and software for inference of haplotype phase and missing data that can accurately phase data from whole-genome association studies, and we present the first comparison of haplotype-inference methods for real and simulated data sets with thousands of genotyped individuals. We find that our method outperforms existing methods in terms of both speed and accuracy for large data sets with thousands of individuals and densely spaced genetic markers, and we use our method to phase a real data set of 3,002 individuals genotyped for 490,032 markers in 3.1 days of computing time, with 99% of masked alleles imputed correctly. Our method is implemented in the Beagle software package, which is freely available.

P2X receptors are membrane ion channels that open in response to the binding of extracellular ATP. Seven genes in vertebrates encode P2X receptor subunits, which are 40-50% identical in amino acid sequence. Each subunit has two transmembrane domains, separated by an extracellular domain (approximately 280 amino acids). Channels form as multimers of several subunits. Homomeric P2X1, P2X2, P2X3, P2X4, P2X5, and P2X7 channels and heteromeric P2X2/3 and P2X1/5 channels have been most fully characterized following heterologous expression. Some agonists (e.g., alphabeta-methylene ATP) and antagonists [e.g., 2',3'-O-(2,4,6-trinitrophenyl)-ATP] are strongly selective for receptors containing P2X1 and P2X3 subunits. All P2X receptors are permeable to small monovalent cations; some have significant calcium or anion permeability. In many cells, activation of homomeric P2X7 receptors induces a permeability increase to larger organic cations including some fluorescent dyes and also signals to the cytoskeleton; these changes probably involve additional interacting proteins. P2X receptors are abundantly distributed, and functional responses are seen in neurons, glia, epithelia, endothelia, bone, muscle, and hemopoietic tissues. The molecular composition of native receptors is becoming understood, and some cells express more than one type of P2X receptor. On smooth muscles, P2X receptors respond to ATP released from sympathetic motor nerves (e.g., in ejaculation). On sensory nerves, they are involved in the initiation of afferent signals in several viscera (e.g., bladder, intestine) and play a key role in sensing tissue-damaging and inflammatory stimuli. Paracrine roles for ATP signaling through P2X receptors are likely in neurohypophysis, ducted glands, airway epithelia, kidney, bone, and hemopoietic tissues. In the last case, P2X7 receptor activation stimulates cytokine release by engaging intracellular signaling pathways.

Oct4 and Nanog are transcription factors required to maintain the pluripotency and self-renewal of embryonic stem (ES) cells. Using the chromatin immunoprecipitation paired-end ditags method, we mapped the binding sites of these factors in the mouse ES cell genome. We identified 1,083 and 3,006 high-confidence binding sites for Oct4 and Nanog, respectively. Comparative location analyses indicated that Oct4 and Nanog overlap substantially in their targets, and they are bound to genes in different configurations. Using de novo motif discovery algorithms, we defined the cis-acting elements mediating their respective binding to genomic sites. By integrating RNA interference-mediated depletion of Oct4 and Nanog with microarray expression profiling, we demonstrated that these factors can activate or suppress transcription. We further showed that common core downstream targets are important to keep ES cells from differentiating. The emerging picture is one in which Oct4 and Nanog control a cascade of pathways that are intricately connected to govern pluripotency, self-renewal, genome surveillance and cell fate determination.

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes.

Human single nucleotide polymorphisms (SNPs) represent the most frequent type of human population DNA variation. One of the main goals of SNP research is to understand the genetics of the human phenotype variation and especially the genetic basis of human complex diseases. Non-synonymous coding SNPs (nsSNPs) comprise a group of SNPs that, together with SNPs in regulatory regions, are believed to have the highest impact on phenotype. Here we present a World Wide Web server to predict the effect of an nsSNP on protein structure and function. The prediction method enabled analysis of the publicly available SNP database HGVbase, which gave rise to a dataset of nsSNPs with predicted functionality. The dataset was further used to compare the effect of various structural and functional characteristics of amino acid substitutions responsible for phenotypic display of nsSNPs. We also studied the dependence of selective pressure on the structural and functional properties of proteins. We found that in our dataset the selection pressure against deleterious SNPs depends on the molecular function of the protein, although it is insensitive to several other protein features considered. The strongest selective pressure was detected for proteins involved in transcription regulation.

BACKGROUND

Despite recent advances in the treatment of advanced non-small-cell lung cancer, there remains a need for effective treatments for progressive disease. We assessed the efficacy of pembrolizumab for patients with previously treated, PD-L1-positive, advanced non-small-cell lung cancer.

METHODS

We did this randomised, open-label, phase 2/3 study at 202 academic medical centres in 24 countries. Patients with previously treated non-small-cell lung cancer with PD-L1 expression on at least 1% of tumour cells were randomly assigned (1:1:1) in blocks of six per stratum with an interactive voice-response system to receive pembrolizumab 2 mg/kg, pembrolizumab 10 mg/kg, or docetaxel 75 mg/m(2) every 3 weeks. The primary endpoints were overall survival and progression-free survival both in the total population and in patients with PD-L1 expression on at least 50% of tumour cells. We used a threshold for significance of p<0.00825 (one-sided) for the analysis of overall survival and a threshold of p<0.001 for progression-free survival. This trial is registered at ClinicalTrials.gov, number NCT01905657.

RESULTS

Between Aug 28, 2013, and Feb 27, 2015, we enrolled 1034 patients: 345 allocated to pembrolizumab 2 mg/kg, 346 allocated to pembrolizumab 10 mg/kg, and 343 allocated to docetaxel. By Sept 30, 2015, 521 patients had died. In the total population, median overall survival was 10.4 months with pembrolizumab 2 mg/kg, 12.7 months with pembrolizumab 10 mg/kg, and 8.5 months with docetaxel. Overall survival was significantly longer for pembrolizumab 2 mg/kg versus docetaxel (hazard ratio [HR] 0.71, 95% CI 0.58-0.88; p=0.0008) and for pembrolizumab 10 mg/kg versus docetaxel (0.61, 0.49-0.75; p<0.0001). Median progression-free survival was 3.9 months with pembrolizumab 2 mg/kg, 4.0 months with pembrolizumab 10 mg/kg, and 4.0 months with docetaxel, with no significant difference for pembrolizumab 2 mg/kg versus docetaxel (0.88, 0.74-1.05; p=0.07) or for pembrolizumab 10 mg/kg versus docetaxel (HR 0.79, 95% CI 0.66-0.94; p=0.004). Among patients with at least 50% of tumour cells expressing PD-L1, overall survival was significantly longer with pembrolizumab 2 mg/kg than with docetaxel (median 14.9 months vs 8.2 months; HR 0.54, 95% CI 0.38-0.77; p=0.0002) and with pembrolizumab 10 mg/kg than with docetaxel (17.3 months vs 8.2 months; 0.50, 0.36-0.70; p<0.0001). Likewise, for this patient population, progression-free survival was significantly longer with pembrolizumab 2 mg/kg than with docetaxel (median 5.0 months vs 4.1 months; HR 0.59, 95% CI 0.44-0.78; p=0.0001) and with pembrolizumab 10 mg/kg than with docetaxel (5.2 months vs 4.1 months; 0.59, 0.45-0.78; p<0.0001). Grade 3-5 treatment-related adverse events were less common with pembrolizumab than with docetaxel (43 [13%] of 339 patients given 2 mg/kg, 55 [16%] of 343 given 10 mg/kg, and 109 [35%] of 309 given docetaxel).

CONCLUSIONS

Pembrolizumab prolongs overall survival and has a favourable benefit-to-risk profile in patients with previously treated, PD-L1-positive, advanced non-small-cell lung cancer. These data establish pembrolizumab as a new treatment option for this population and validate the use of PD-L1 selection.

BACKGROUND

Merck & Co.

A cornerstone of modern biomedical research is the use of mouse models to explore basic pathophysiological mechanisms, evaluate new therapeutic approaches, and make go or no-go decisions to carry new drug candidates forward into clinical trials. Systematic studies evaluating how well murine models mimic human inflammatory diseases are nonexistent. Here, we show that, although acute inflammatory stresses from different etiologies result in highly similar genomic responses in humans, the responses in corresponding mouse models correlate poorly with the human conditions and also, one another. Among genes changed significantly in humans, the murine orthologs are close to random in matching their human counterparts (e.g., R(2) between 0.0 and 0.1). In addition to improvements in the current animal model systems, our study supports higher priority for translational medical research to focus on the more complex human conditions rather than relying on mouse models to study human inflammatory diseases.

An internally or externally paced event results not only in the generation of an event-related potential (ERP) but also in a change in the ongoing EEG/MEG in form of an event-related desynchronization (ERD) or event-related synchronization (ERS). The ERP on the one side and the ERD/ERS on the other side are different responses of neuronal structures in the brain. While the former is phase-locked, the latter is not phase-locked to the event. The most important difference between both phenomena is that the ERD/ERS is highly frequency band-specific, whereby either the same or different locations on the scalp can display ERD and ERS simultaneously. Quantification of ERD/ERS in time and space is demonstrated on data from a number of movement experiments.

The epithelia of a number of glands and cavitary organs of the rat and guinea pig have been surveyed, and in all cases investigated, a characteristic tripartite junctional complex has been found between adjacent cells. Although the complex differs in precise arrangement from one organ to another, it has been regularly encountered in the mucosal epithelia of the stomach, intestine, gall bladder, uterus, and oviduct; in the glandular epithelia of the liver, pancreas, parotid, stomach, and thyroid; in the epithelia of pancreatic, hepatic, and salivary ducts; and finally, between the epithelial cells of the nephron (proximal and distal convolution, collecting ducts). The elements of the complex, identified as zonula occludens (tight junction), zonula adhaerens (intermediary junction), and macula adhaerens (desmosome), occupy a juxtaluminal position and succeed each other in the order given in an apical-basal direction. The zonula occludens (tight junction) is characterized by fusion of the adjacent cell membranes resulting in obliteration of the intercellular space over variable distances. Within the obliterated zone, the dense outer leaflets of the adjoining cell membranes converge to form a single intermediate line. A diffuse band of dense cytoplasmic material is often associated with this junction, but its development varies from one epithelium to another. The zonula adhaerens (intermediate junction) is characterized by the presence of an intercellular space ( approximately 200 A) occupied by homogeneous, apparently amorphous material of low density; by strict parallelism of the adjoining cell membranes over distances of 0.2 to 0.5 micro; and by conspicuous bands of dense material located in the subjacent cytoplasmic matrix. The desmosome or macula adhaerens is also characterized by the presence of an intercellular space ( approximately 240 A) which, in this case, contains a central disc of dense material; by discrete cytoplasmic plaques disposed parallel to the inner leaflet of each cell membrane; and by the presence of bundles of cytoplasmic fibrils converging on the plaques. The zonula occludens appears to form a continuous belt-like attachment, whereas the desmosome is a discontinuous, button-like structure. The zomula adhaerens is continuous in most epithelia but discontinuous in some. Observations made during experimental hemoglobinuria in rats showed that the hemoglobin, which undergoes enough concentration in the nephron lumina to act as an electron-opaque mass tracer, does not penetrate the intercellular spaces beyond the zonula occludens. Similar observations were made in pancreatic acini and ducts where discharged zymogen served as a mass tracer. Hence the tight junction is impervious to concentrated protein solutions and appears to function as a diffusion barrier or "seal." The desmosome and probably also the zonula adhaerens may represent intercellular attachment devices.

METHODS

We examined the influence of viral load in relation to other risk factors for the heterosexual transmission of human immunodeficiency virus type 1 (HIV-1). In a community-based study of 15,127 persons in a rural district of Uganda, we identified 415 couples in which one partner was HIV-1-positive and one was initially HIV-1-negative and followed them prospectively for up to 30 months. The incidence of HIV-1 infection per 100 person-years among the initially seronegative partners was examined in relation to behavioral and biologic variables.

RESULTS

The male partner was HIV-1-positive in 228 couples, and the female partner was HIV-1-positive in 187 couples. Ninety of the 415 initially HIV-1-negative partners seroconverted (incidence, 11.8 per 100 person-years). The rate of male-to-female transmission was not significantly different from the rate of female-to-male transmission (12.0 per 100 person-years vs. 11.6 per 100 person-years). The incidence of seroconversion was highest among the partners who were 15 to 19 years of age (15.3 per 100 person-years). The incidence was 16.7 per 100 person-years among 137 uncircumcised male partners, whereas there were no seroconversions among the 50 circumcised male partners (P<0.001). The mean serum HIV-1 RNA level was significantly higher among HIV-1-positive subjects whose partners seroconverted than among those whose partners did not seroconvert (90,254 copies per milliliter vs. 38,029 copies per milliliter, P=0.01). There were no instances of transmission among the 51 subjects with serum HIV-1 RNA levels of less than 1500 copies per milliliter; there was a significant dose-response relation of increased transmission with increasing viral load. In multivariate analyses of log-transformed HIV-1 RNA levels, each log increment in the viral load was associated with a rate ratio of 2.45 for seroconversion (95 percent confidence interval, 1.85 to 3.26).

CONCLUSIONS

The viral load is the chief predictor of the risk of heterosexual transmission of HIV-1, and transmission is rare among persons with levels of less than 1500 copies of HIV-1 RNA per milliliter.

Colorectal cancer is the third most common cancer and the third leading cause of cancer death in men and women in the United States. This article provides an overview of colorectal cancer statistics, including the most current data on incidence, survival, and mortality rates and trends. Incidence data were provided by the National Cancer Institute's Surveillance, Epidemiology, and End Results program and the North American Association of Central Cancer Registries. Mortality data were provided by the National Center for Health Statistics. In 2014, an estimated 71,830 men and 65,000 women will be diagnosed with colorectal cancer and 26,270 men and 24,040 women will die of the disease. Greater than one-third of all deaths (29% in men and 43% in women) will occur in individuals aged 80 years and older. There is substantial variation in tumor location by age. For example, 26% of colorectal cancers in women aged younger than 50 years occur in the proximal colon, compared with 56% of cases in women aged 80 years and older. Incidence and death rates are highest in blacks and lowest in Asians/Pacific Islanders; among males during 2006 through 2010, death rates in blacks (29.4 per 100,000 population) were more than double those in Asians/Pacific Islanders (13.1) and 50% higher than those in non-Hispanic whites (19.2). Overall, incidence rates decreased by approximately 3% per year during the past decade (2001-2010). Notably, the largest drops occurred in adults aged 65 and older. For instance, rates for tumors located in the distal colon decreased by more than 5% per year. In contrast, rates increased during this time period among adults younger than 50 years. Colorectal cancer death rates declined by approximately 2% per year during the 1990s and by approximately 3% per year during the past decade. Progress in reducing colorectal cancer death rates can be accelerated by improving access to and use of screening and standard treatment in all populations.

BACKGROUND

A number of studies have computed the minimally important difference (MID) for health-related quality of life instruments.

OBJECTIVE

To determine whether there is consistency in the magnitude of MID estimates from different instruments.

METHODS

We conducted a systematic review of the literature to identify studies that computed an MID and contained sufficient information to compute an effect size (ES). Thirty-eight studies fulfilled the criteria, resulting in 62 ESs.

RESULTS

For all but 6 studies, the MID estimates were close to one half a SD (mean = 0.495, SD = 0.155). There was no consistent relationship with factors such as disease-specific or generic instrument or the number of response options. Negative changes were not associated with larger ESs. Population-based estimation procedures and brief follow-up were associated with smaller ESs, and acute conditions with larger ESs. An explanation for this consistency is that research in psychology has shown that the limit of people's ability to discriminate over a wide range of tasks is approximately 1 part in 7, which is very close to half a SD.

CONCLUSIONS

In most circumstances, the threshold of discrimination for changes in health-related quality of life for chronic diseases appears to be approximately half a SD.

Interobserver agreement for the assessment of handicap in stroke patients was investigated in a group of 10 senior neurologists and 24 residents from two centers. One hundred patients were separately interviewed by two physicians in different combinations. The degree of handicap was recorded by each observer on the modified Rankin scale, which has six grades (0-5). The agreement rates were corrected for chance (kappa statistics). Both physicians agreed on the degree of handicap in 65 patients; they differed by one grade in 32 patients and by two grades in 3 patients. Kappa for all pairwise observations was 0.56; the value for weighted kappa (with quadratic disagreement weights) was 0.91. Our results confirm the value of the modified Rankin scale in the assessment of handicap in stroke patients; nevertheless, further improvements are possible.

In this paper we introduce the idea of explaining responses, in one cortical area, in terms of an interaction between the influence of another area and some experimental (sensory or task-related) parameter. We refer to these effects as psychophysiological interactions and relate them to interactions based solely on experimental factors (i.e., psychological interactions), in factorial designs, and interactions among neurophysiological measurements (i.e., physiological interactions). We have framed psychophysiological interactions in terms of functional integration by noting that the degree to which the activity in one area can be predicted, on the basis of activity in another, corresponds to the contribution of the second to the first, where this contribution can be related to effective connectivity. A psychophysiological interaction means that the contribution of one area to another changes significantly with the experimental or psychological context. Alternatively these interactions can be thought of as a contribution-dependent change in regional responses to an experimental or psychological factor. In other words the contribution can be thought of as modulating the responses elicited by a particular stimulus or psychological process. The potential importance of this approach lies in (i) conferring a degree of functional specificity on this aspect of effective connectivity and (ii) providing a model of modulation, where the contribution from a distal area can be considered to modulate responses to the psychological or stimulus-specific factor defining the interaction. Although distinct in neurobiological terms, these are equivalent perspectives on the same underlying interaction. We illustrate these points using a functional magnetic resonance imaging study of attention to visual motion and a position emission tomography study of visual priming. We focus on interactions among extrastriate, inferotemporal, and posterior parietal regions during visual processing, under different attentional and perceptual conditions.

BACKGROUND

Everolimus (RAD001) is an orally administered inhibitor of the mammalian target of rapamycin (mTOR), a therapeutic target for metastatic renal cell carcinoma. We did a phase III, randomised, double-blind, placebo-controlled trial of everolimus in patients with metastatic renal cell carcinoma whose disease had progressed on vascular endothelial growth factor-targeted therapy.

METHODS

Patients with metastatic renal cell carcinoma which had progressed on sunitinib, sorafenib, or both, were randomly assigned in a two to one ratio to receive everolimus 10 mg once daily (n=272) or placebo (n=138), in conjunction with best supportive care. Randomisation was done centrally via an interactive voice response system using a validated computer system, and was stratified by Memorial Sloan-Kettering Cancer Center prognostic score and previous anticancer therapy, with a permuted block size of six. The primary endpoint was progression-free survival, assessed via a blinded, independent central review. The study was designed to be terminated after 290 events of progression. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00410124.

RESULTS

All randomised patients were included in efficacy analyses. The results of the second interim analysis indicated a significant difference in efficacy between arms and the trial was thus halted early after 191 progression events had been observed (101 [37%] events in the everolimus group, 90 [65%] in the placebo group; hazard ratio 0.30, 95% CI 0.22-0.40, p<0.0001; median progression-free survival 4.0 [95% CI 3.7-5.5] vs 1.9 [1.8-1.9] months). Stomatitis (107 [40%] patients in the everolimus group vs 11 [8%] in the placebo group), rash (66 [25%] vs six [4%]), and fatigue (53 [20%] vs 22 [16%]) were the most commonly reported adverse events, but were mostly mild or moderate in severity. Pneumonitis (any grade) was detected in 22 (8%) patients in the everolimus group, of whom eight had pneumonitis of grade 3 severity.

CONCLUSIONS

Treatment with everolimus prolongs progression-free survival relative to placebo in patients with metastatic renal cell carcinoma that had progressed on other targeted therapies.

The TRANSFAC database on eukaryotic transcriptional regulation, comprising data on transcription factors, their target genes and regulatory binding sites, has been extended and further developed, both in number of entries and in the scope and structure of the collected data. Structured fields for expression patterns have been introduced for transcription factors from human and mouse, using the CYTOMER database on anatomical structures and developmental stages. The functionality of Match, a tool for matrix-based search of transcription factor binding sites, has been enhanced. For instance, the program now comes along with a number of tissue-(or state-)specific profiles and new profiles can be created and modified with Match Profiler. The GENE table was extended and gained in importance, containing amongst others links to LocusLink, RefSeq and OMIM now. Further, (direct) links between factor and target gene on one hand and between gene and encoded factor on the other hand were introduced. The TRANSFAC public release is available at http://www.gene-regulation.com. For yeast an additional release including the latest data was made available separately as TRANSFAC Saccharomyces Module (TSM) at http://transfac.gbf.de. For CYTOMER free download versions are available at http://www.biobase.de:8080/index.html.

The genome of the yeast Saccharomyces cerevisiae has been completely sequenced through a worldwide collaboration. The sequence of 12,068 kilobases defines 5885 potential protein-encoding genes, approximately 140 genes specifying ribosomal RNA, 40 genes for small nuclear RNA molecules, and 275 transfer RNA genes. In addition, the complete sequence provides information about the higher order organization of yeast's 16 chromosomes and allows some insight into their evolutionary history. The genome shows a considerable amount of apparent genetic redundancy, and one of the major problems to be tackled during the next stage of the yeast genome project is to elucidate the biological functions of all of these genes.