Rational Manual and Automated Scoring Thresholds for the Immunohistochemical Detection of TP53 Missense Mutations in Human Breast Carcinomas

Missense mutations in TP53 are common in human breast cancer, have been associated with worse prognosis, and may predict therapy effect. TP53 missense mutations are associated with aberrant accumulation of p53 protein in tumor cell nuclei. Previous studies have used relatively arbitrary cutoffs to characterize breast tumors as positive for p53 staining by immunohistochemical assays. This study aimed to objectively determine optimal thresholds for p53 positivity by manual and automated scoring methods utilizing whole tissue sections from the Carolina Breast Cancer Study. P53 immunostained slides were available for 564 breast tumors previously assayed for TP53 mutations. Average nuclear p53 staining intensity was manually scored as negative, borderline, weak, moderate, or strong and percentage of positive tumor cells was estimated. Automated p53 signal intensity was measured using the Aperio nuclear v9 algorithm combined with the Genie® histology pattern recognition tool and tuned to achieve optimal nuclear segmentation. ROC curve analysis was performed to determine optimal cutoffs for average staining intensity and percent cells positive to distinguish between tumors with and without a missense mutation. ROC curve analysis demonstrated a threshold of moderate average nuclear staining intensity as a good surrogate for TP53 missense mutations in both manual (AUC=0.87) and automated (AUC=0.84) scoring systems. Both manual and automated immunohistochemical scoring methods predicted missense mutations in breast carcinomas with high accuracy. Validation of the automated intensity scoring threshold suggests a role for such algorithms in detecting TP53 missense mutations in high throughput studies

BRIDGE study warrants critique

David M. Allen, Peter I. Parry, Robert Purssey, Glen I. Spielmans, Jon Jureidini, Nicholas Z. Rosenlicht, David Healy, Irwin Feinber

Dynamics of Immune Reconstitution and Activation Markers in HIV+ Treatment-Naïve Patients Treated with Raltegravir, Tenofovir Disoproxil Fumarate and Emtricitabine

Background: The dynamics of CD4+ T cell reconstitution and changes in immune activation and inflammation in HIV-1 disease following initiation of antiretroviral therapy (ART) are incompletely defined and their underlying mechanisms poorly understood. Methods: Thirty-nine treatment-naïve patients were treated with raltegravir, tenofovir DF and emtricitabine. Immunologic and inflammatory indices were examined in persons with sustained virologic control during 48 weeks of therapy. Results: Initiation of ART increased CD4+ T cell numbers and decreased activation and cell cycle entry among CD4+ and CD8+ T cell subsets, and attenuated markers of coagulation (D-dimer levels) and inflammation (IL-6 and TNFr1). These indices decayed at different rates and almost all remained elevated above levels measured in HIV-seronegatives through 48 weeks of viral control. Greater first and second phase CD4+ T cell restoration was related to lower T cell activation and cell cycling at baseline, to their decay with treatment, and to baseline levels of selected inflammatory indices, but less so to their changes on therapy. Conclusions: ART initiation results in dynamic changes in viral replication, T cell restoration, and indices of immune activation, inflammation, and coagulation. These findings suggest that determinants of T cell activation/cycling and inflammation/coagulation may have distinguishable impact on immune homeostasis. Trial Registration Clinicaltrials.gov NCT0066097

Size as the master trait in modeled copepod fecal pellet carbon flux

Zooplankton fecal pellet flux is a highly variable component of the biological carbon pump. While fecal pellets can comprise 0 to nearly 100% of particulate organic carbon collected in sediment traps, mechanisms for this variability remain poorly understood. Fecal pellet carbon flux is a complex function of several variables. We present a model that incorporates individual-scale metabolic processes to determine fecal pellet production rate, the relationship between body size and fecal pellet size, the relationship between fecal pellet size and sinking rate, and a function representing the breakdown of particles in the water column. When applied to copepod communities sampled by the continuous plankton recorder in the Gulf of Maine over 25 years, a seasonal pattern of fecal pellet carbon flux emerges. The interannual flux time series produced by the model reflects known oceanographic perturbations and shows how organism-scale processes can be scaled up to explain ecosystem level variability. We conclude that fecal pellet carbon flux in the Gulf of Maine is driven by copepod community size structure and copepod abundance, and that the fraction of fecal pellet carbon that reaches depth is a function of copepod size, rather than abundance. Changes in the physical environment which alter the size composition of the copepod community lead to variability in fecal pellet carbon flux. Our results indicate that incorporating size composition into biogeochemical models can more accurately constrain zooplankton-mediated carbon flux.This is the publisher’s final pdf. The article is copyrighted by the Association for the Sciences of Limnology and Oceanography and published by John Wiley & Sons, Inc. It can be found at: http://www.aslo.org/lo/index.htm

Occupational therapy for rheumatoid arthritis: A systematic review

Patients with rheumatoid arthritis (RA) show a reduction in physical capacities compared with healthy persons. Symptoms such as pain, fatique, stiffness, and decreased muscle strength cause difficulties with daily activities such as grooming and dressing, cooking a meal, cleaning, shopping, work, and leisure activities. The physical, personal, familial, social, and vocational consequences of RA are extensive. Occupational therapy (OT) is concerned with facililtating people in performing their activities of daily living overcoming barriers by maintaining or improving abilities, or compensating for decreased ability in the performance of occupation (1). The most important interventions in OT are training of skills, counseling, education about joint protection, prescription of assistive devices, and the provision of splints (2). Advice/ instruction in the use of assistive devices, training in self-care activities, and training in productivity activities are the 3 interventions for RA patients chosen most often by occuptional therapists (3). (aut. ref.

On the biomedicalization of alcoholism

The shift in the prevailing view of alcoholism from a moral paradigm towards a biomedical paradigm is often characterized as a form of biomedicalization. We will examine and critique three reasons offered for the claim that viewing alcoholism as a disease is morally problematic. The first is that the new conceptualization of alcoholism as a chronic brain disease will lead to individualization, e.g., a too narrow focus on the individual person, excluding cultural and social dimensions of alcoholism. The second claim is that biomedicalization will lead to stigmatization and discrimination for both alcoholics and people who are at risk of becoming alcoholics. The third claim is that as a result of the biomedical point of view, the autonomy and responsibility of alcoholics and possibly even persons at risk may be unjustly restricted. Our conclusion is that the claims against the biomedical conceptualization of alcoholism as a chronic brain disease are neither specific nor convincing. Not only do some of these concerns also apply to the traditional moral model; above that they are not strong enough to justify the rejection of the new biomedical model altogether. The focus in the scientific and public debate should not be on some massive “biomedicalization objection” but on the various concerns underlying what is framed in terms of the biomedicalization of alcoholism

The self-reported Montgomery-Åsberg depression rating scale is a useful evaluative tool in major depressive disorder

Abstract Background The use of Patient-reported Outcomes (PROs) as secondary endpoints in the development of new antidepressants has grown in recent years. The objective of this study was to assess the psychometric properties of the 9-item, patient-administered version of the Montgomery-Åsberg Depression Rating Scale (MADRS-S). Methods Data from a multicentre, double-blind, 8-week, randomised controlled trial of 278 outpatients diagnosed with Major Depressive Disorder were used to evaluate the validity, reliability and sensitivity to change of the MADRS-S using psychometric methods. A Receiver Operating Characteristic (ROC) curve was plotted to identify the most appropriate threshold to define perceived remission. Results No missing values were found at the item level, indicating good acceptability of the scale. The construct validity was satisfactory: all items contributed to a common underlying concept, as expected. The correlation between MADRS-S and physicians' MADRS was moderate (r = 0.54, p Conclusion Taking account of patient's perceptions of the severity of their own symptoms along with the psychometric properties of the MADRS-S enable its use for evaluative purposes in the development of new antidepressant drugs.</p

Deficits in neurite density underlie white matter structure abnormalities in first-episode psychosis

Background: Structural abnormalities across multiple white matter tracts are recognised in people with early psychosis, consistent with dysconnectivity as a neuropathological account of symptom expression. We applied advanced neuroimaging techniques to characterise microstructural white matter abnormalities for a deeper understanding of the developmental aetiology of psychosis. Methods: Thirty-five first-episode psychosis patients, and 19 healthy controls, participated in a quantitative neuroimaging study using Neurite Orientation Dispersion and Density Imaging (NODDI), a multi-shell diffusion-weighted MRI technique that distinguishes white matter fibre arrangement and geometry from changes in neurite density. Fractional anisotropy (FA) and mean diffusivity images were also derived. Tract-based spatial statistics compared white matter structure between patients and controls and tested associations with age, symptom severity and medication. Results: Patients with first-episode psychosis had lower regional FA in multiple commissural, corticospinal, and association tracts. These abnormalities predominantly colocalized with regions of reduced neurite density, rather than aberrant fibre bundle arrangement (orientation dispersion index). There was no direct relationship with active symptomatology. FA decreased and orientation dispersion index increased with age in patients, but not controls, suggesting accelerated effects of white matter geometry change. Conclusions: Deficits in neurite density appear fundamental to abnormalities in white matter integrity in early psychosis. In the first application of NODDI in psychosis, we found that processes compromising axonal fibre number, density, and myelination, rather than processes leading to spatial disruption of fibre organisation, are implicated in the aetiology of the disorder. This accords with a neurodevelopmental origin of aberrant brain-wide structural connectivity predisposing individuals to psychosis

DNA Methylation of the First Exon Is Tightly Linked to Transcriptional Silencing

Tissue specific patterns of methylated cytosine residues vary with age, can be altered by environmental factors, and are often abnormal in human disease yet the cellular consequences of DNA methylation are incompletely understood. Although the bodies of highly expressed genes are often extensively methylated in plants, the relationship between intragenic methylation and expression is less clear in mammalian cells. We performed genome-wide analyses of DNA methylation and gene expression to determine how the pattern of intragenic methylation correlates with transcription and to assess the relationship between methylation of exonic and intronic portions of the gene body. We found that dense exonic methylation is far more common than previously recognized or expected statistically, yet first exons are relatively spared compared to more downstream exons and introns. Dense methylation surrounding the transcription start site (TSS) is uncoupled from methylation within more downstream regions suggesting that there are at least two classes of intragenic methylation. Whereas methylation surrounding the TSS is tightly linked to transcriptional silencing, methylation of more downstream regions is unassociated with the magnitude of gene expression. Notably, we found that DNA methylation downstream of the TSS, in the region of the first exon, is much more tightly linked to transcriptional silencing than is methylation in the upstream promoter region. These data provide direct evidence that DNA methylation is interpreted dissimilarly in different regions of the gene body and suggest that first exon methylation blocks transcript initiation, or vice versa. Our data also show that once initiated, downstream methylation is not a significant impediment to polymerase extension. Thus, the consequences of most intragenic DNA methylation must extend beyond the modulation of transcription magnitude

Many Labs 5:Testing pre-data collection peer review as an intervention to increase replicability

Replication studies in psychological science sometimes fail to reproduce prior findings. If these studies use methods that are unfaithful to the original study or ineffective in eliciting the phenomenon of interest, then a failure to replicate may be a failure of the protocol rather than a challenge to the original finding. Formal pre-data-collection peer review by experts may address shortcomings and increase replicability rates. We selected 10 replication studies from the Reproducibility Project: Psychology (RP:P; Open Science Collaboration, 2015) for which the original authors had expressed concerns about the replication designs before data collection; only one of these studies had yielded a statistically significant effect (p < .05). Commenters suggested that lack of adherence to expert review and low-powered tests were the reasons that most of these RP:P studies failed to replicate the original effects. We revised the replication protocols and received formal peer review prior to conducting new replication studies. We administered the RP:P and revised protocols in multiple laboratories (median number of laboratories per original study = 6.5, range = 3?9; median total sample = 1,279.5, range = 276?3,512) for high-powered tests of each original finding with both protocols. Overall, following the preregistered analysis plan, we found that the revised protocols produced effect sizes similar to those of the RP:P protocols (?r = .002 or .014, depending on analytic approach). The median effect size for the revised protocols (r = .05) was similar to that of the RP:P protocols (r = .04) and the original RP:P replications (r = .11), and smaller than that of the original studies (r = .37). Analysis of the cumulative evidence across the original studies and the corresponding three replication attempts provided very precise estimates of the 10 tested effects and indicated that their effect sizes (median r = .07, range = .00?.15) were 78% smaller, on average, than the original effect sizes (median r = .37, range = .19?.50)