Reliability of histopathologic diagnosis of fibrotic interstitial lung disease: an international collaborative standardization project

Malaltia pulmonar intersticial; Fibrosi pulmonar; Pneumònia intersticial habitualEnfermedad pulmonar intersticial; Fibrosis pulmonar; Neumonía intersticial habitualInterstitial lung disease; Pulmonary fibrosis; Usual interstitial pneumoniaBackground Current interstitial lung disease (ILD) diagnostic guidelines assess criteria across clinical, radiologic and pathologic domains. Significant interobserver variation in histopathologic evaluation has previously been shown but the specific source of these discrepancies is poorly documented. We sought to document specific areas of difficulty and develop improved criteria that would reduce overall interobserver variation. Methods Using an internet-based approach, we reviewed selected images of specific diagnostic features of ILD histopathology and whole slide images of fibrotic ILD. After an initial round of review, we confirmed the presence of interobserver variation among our group. We then developed refined criteria and reviewed a second set of cases. Results The initial round reproduced the existing literature on interobserver variation in diagnosis of ILD. Cases which were pre-selected as inconsistent with usual interstitial pneumonia/idiopathic pulmonary fibrosis (UIP/IPF) were confirmed as such by multi-observer review. Cases which were thought to be in the spectrum of chronic fibrotic ILD for which UIP/IPF were in the differential showed marked variation in nearly all aspects of ILD evaluation including extent of inflammation and extent and pattern of fibrosis. A proposed set of more explicit criteria had only modest effects on this outcome. While we were only modestly successful in reducing interobserver variation, we did identify specific reasons that current histopathologic criteria of fibrotic ILD are not well defined in practice. Conclusions Any additional classification scheme must address interobserver variation in histopathologic diagnosis of fibrotic ILD order to remain clinically relevant. Improvements to tissue-based diagnostics may require substantial resources such as larger datasets or novel technologies to improve reproducibility. Benchmarks should be established for expected outcomes among clinically defined subgroups as a quality metric.This research did not receive any specific grant from funding agencies in the public, commercial or not-for-profit sectors

Recent developments in Vorton Theory

This article provides a concise overview of recent theoretical results concerning the theory of vortons, which are defined to be (centrifugally supported) equilibrium configurations of (current carrying) cosmic string loops. Following a presentation of the results of work on the dynamical evolution of small circular string loops, whose minimum energy states are the simplest examples of vortons, recent order of magnitude estimates of the cosmological density of vortons produced in various kinds of theoretical scenario are briefly summarised.Comment: 6 pages Latex. Contribution to 1996 Cosmology Meeting, Peyresq, Franc

Artificial Nightlight Alters the Predator–Prey Dynamics of an Apex Carnivore

Artificial nightlight is increasingly recognized as an important environmental disturbance that influences the habitats and fitness of numerous species. However, its effects on wide‐ranging vertebrates and their interactions remain unclear. Light pollution has the potential to amplify land‐use change, and as such, answering the question of how this sensory stimulant affects behavior and habitat use of species valued for their ecological roles and economic impacts is critical for conservation and land‐use planning. Here, we combined satellite‐derived estimates of light pollution, with GPS‐data from cougars Puma concolor (n = 56), mule deer Odocoileus hemionus (n = 263) and locations of cougar‐killed deer (n = 1562 carcasses), to assess the effects of light exposure on mammal behavior and predator–prey relationships across wildland–urban gradients in the southwestern United States. Our results indicate that deer used the anthropogenic environments to access forage and were more active at night than their wildland conspecifics. Despite higher nightlight levels, cougars killed deer at the wildland–urban interface, but hunted them in the relatively darkest locations. Light had the greatest effect of all covariates on where cougars killed deer at the wildland–urban interface. Both species exhibited functional responses to light pollution at fine scales; individual cougars and deer with less light exposure increasingly avoided illuminated areas when exposed to greater radiance, whereas deer living in the wildland–urban interface selected elevated light levels. We conclude that integrating estimates of light pollution into ecological studies provides crucial insights into how the dynamic human footprint can alter animal behavior and ecosystem function across spatial scales

Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Background Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. Methods We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. Results Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. Conclusions Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.Peer reviewe

Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease

BACKGROUND: Patients with atherosclerotic vascular disease remain at high risk for cardiovascular events despite effective statin-based treatment of low-density lipoprotein (LDL) cholesterol levels. The inhibition of cholesteryl ester transfer protein (CETP) by anacetrapib reduces LDL cholesterol levels and increases high-density lipoprotein (HDL) cholesterol levels. However, trials of other CETP inhibitors have shown neutral or adverse effects on cardiovascular outcomes. METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving 30,449 adults with atherosclerotic vascular disease who were receiving intensive atorvastatin therapy and who had a mean LDL cholesterol level of 61 mg per deciliter (1.58 mmol per liter), a mean non-HDL cholesterol level of 92 mg per deciliter (2.38 mmol per liter), and a mean HDL cholesterol level of 40 mg per deciliter (1.03 mmol per liter). The patients were assigned to receive either 100 mg of anacetrapib once daily (15,225 patients) or matching placebo (15,224 patients). The primary outcome was the first major coronary event, a composite of coronary death, myocardial infarction, or coronary revascularization. RESULTS: During the median follow-up period of 4.1 years, the primary outcome occurred in significantly fewer patients in the anacetrapib group than in the placebo group (1640 of 15,225 patients [10.8%] vs. 1803 of 15,224 patients [11.8%]; rate ratio, 0.91; 95% confidence interval, 0.85 to 0.97; P=0.004). The relative difference in risk was similar across multiple prespecified subgroups. At the trial midpoint, the mean level of HDL cholesterol was higher by 43 mg per deciliter (1.12 mmol per liter) in the anacetrapib group than in the placebo group (a relative difference of 104%), and the mean level of non-HDL cholesterol was lower by 17 mg per deciliter (0.44 mmol per liter), a relative difference of -18%. There were no significant between-group differences in the risk of death, cancer, or other serious adverse events. CONCLUSIONS: Among patients with atherosclerotic vascular disease who were receiving intensive statin therapy, the use of anacetrapib resulted in a lower incidence of major coronary events than the use of placebo. (Funded by Merck and others; Current Controlled Trials number, ISRCTN48678192 ; ClinicalTrials.gov number, NCT01252953 ; and EudraCT number, 2010-023467-18 .)

Ecological Correlates of Land Snails from the Lower Salmon River

Land snails are considered to be excellent ecological indicators for assessing ecosystem health and long term viability. In the last 50 years, the lower Salmon River drainage has undergone extensive human settlement and development which may disturb ecosystem processes and extirpate highly endemic species. As this area contains some of the most diverse land snail assemblages in North America, the relative distribution and abundance of these endemic mollusks may serve as a window to view the influence of anthropogenic effects on the native fauna across the ecosystem. I propose to evaluate the suitability of these land snails as ecological indicator species by examining their underlying ecological correlates (plant associations, water availability, and rock type) as well as their resilience to human settlement based on past and recent surveys conducted within the last 50 years