National Performance Benchmarks for Modern Screening Digital Mammography: Update from the Breast Cancer Surveillance Consortium

Purpose To establish performance benchmarks for modern screening digital mammography and assess performance trends over time in U.S. community practice. Materials and Methods This HIPAA-compliant, institutional review board-approved study measured the performance of digital screening mammography interpreted by 359 radiologists across 95 facilities in six Breast Cancer Surveillance Consortium (BCSC) registries. The study included 1 682 504 digital screening mammograms performed between 2007 and 2013 in 792 808 women. Performance measures were calculated according to the American College of Radiology Breast Imaging Reporting and Data System, 5th edition, and were compared with published benchmarks by the BCSC, the National Mammography Database, and performance recommendations by expert opinion. Benchmarks were derived from the distribution of performance metrics across radiologists and were presented as 50th (median), 10th, 25th, 75th, and 90th percentiles, with graphic presentations using smoothed curves. Results Mean screening performance measures were as follows: abnormal interpretation rate (AIR), 11.6 (95% confidence interval [CI]: 11.5, 11.6); cancers detected per 1000 screens, or cancer detection rate (CDR), 5.1 (95% CI: 5.0, 5.2); sensitivity, 86.9% (95% CI: 86.3%, 87.6%); specificity, 88.9% (95% CI: 88.8%, 88.9%); false-negative rate per 1000 screens, 0.8 (95% CI: 0.7, 0.8); positive predictive value (PPV) 1, 4.4% (95% CI: 4.3%, 4.5%); PPV2, 25.6% (95% CI: 25.1%, 26.1%); PPV3, 28.6% (95% CI: 28.0%, 29.3%); cancers stage 0 or 1, 76.9%; minimal cancers, 57.7%; and node-negative invasive cancers, 79.4%. Recommended CDRs were achieved by 92.1% of radiologists in community practice, and 97.1% achieved recommended ranges for sensitivity. Only 59.0% of radiologists achieved recommended AIRs, and only 63.0% achieved recommended levels of specificity. Conclusion The majority of radiologists in the BCSC surpass cancer detection recommendations for screening mammography; however, AIRs continue to be higher than the recommended rate for almost half of radiologists interpreting screening mammograms. © RSNA, 2016 Online supplemental material is available for this article

HSV Usurps Eukaryotic Initiation Factor 3 Subunit M for Viral Protein Translation: Novel Prevention Target

Prevention of genital herpes is a global health priority. B5, a recently identified ubiquitous human protein, was proposed as a candidate HSV entry receptor. The current studies explored its role in HSV infection. Viral plaque formation was reduced by ∼90% in human cells transfected with small interfering RNA targeting B5 or nectin-1, an established entry receptor. However, the mechanisms were distinct. Silencing of nectin-1 prevented intracellular delivery of viral capsids, nuclear transport of a viral tegument protein, and release of calcium stores required for entry. In contrast, B5 silencing had no effect on these markers of entry, but inhibited viral protein translation. Specifically, viral immediate early genes, ICP0 and ICP4, were transcribed, polyadenylated and transported from the nucleus to the cytoplasm, but the viral transcripts did not associate with ribosomes or polysomes in B5-silenced cells. In contrast, immediate early gene viral transcripts were detected in polysome fractions isolated from control cells. These findings are consistent with sequencing studies demonstrating that B5 is eukaryotic initiation factor 3 subunit m (eIF3m). Although B5 silencing altered the polysome profile of cells, silencing had little effect on cellular RNA or protein expression and was not cytotoxic, suggesting that this subunit is not essential for host cellular protein synthesis. Together these results demonstrate that B5 plays a major role in the initiation of HSV protein translation and could provide a novel target for strategies to prevent primary and recurrent herpetic disease

Childhood socioeconomic position and objectively measured physical capability levels in adulthood: a systematic review and meta-analysis

<p><b>Background:</b> Grip strength, walking speed, chair rising and standing balance time are objective measures of physical capability that characterise current health and predict survival in older populations. Socioeconomic position (SEP) in childhood may influence the peak level of physical capability achieved in early adulthood, thereby affecting levels in later adulthood. We have undertaken a systematic review with meta-analyses to test the hypothesis that adverse childhood SEP is associated with lower levels of objectively measured physical capability in adulthood.</p> <p><b>Methods and Findings:</b> Relevant studies published by May 2010 were identified through literature searches using EMBASE and MEDLINE. Unpublished results were obtained from study investigators. Results were provided by all study investigators in a standard format and pooled using random-effects meta-analyses. 19 studies were included in the review. Total sample sizes in meta-analyses ranged from N = 17,215 for chair rise time to N = 1,061,855 for grip strength. Although heterogeneity was detected, there was consistent evidence in age adjusted models that lower childhood SEP was associated with modest reductions in physical capability levels in adulthood: comparing the lowest with the highest childhood SEP there was a reduction in grip strength of 0.13 standard deviations (95% CI: 0.06, 0.21), a reduction in mean walking speed of 0.07 m/s (0.05, 0.10), an increase in mean chair rise time of 6% (4%, 8%) and an odds ratio of an inability to balance for 5s of 1.26 (1.02, 1.55). Adjustment for the potential mediating factors, adult SEP and body size attenuated associations greatly. However, despite this attenuation, for walking speed and chair rise time, there was still evidence of moderate associations.</p> <p><b>Conclusions:</b> Policies targeting socioeconomic inequalities in childhood may have additional benefits in promoting the maintenance of independence in later life.</p&gt

Genome-wide association and epidemiological analyses reveal common genetic origins between uterine leiomyomata and endometriosis

Abstract: Uterine leiomyomata (UL) are the most common neoplasms of the female reproductive tract and primary cause for hysterectomy, leading to considerable morbidity and high economic burden. Here we conduct a GWAS meta-analysis in 35,474 cases and 267,505 female controls of European ancestry, identifying eight novel genome-wide significant (P < 5 × 10−8) loci, in addition to confirming 21 previously reported loci, including multiple independent signals at 10 loci. Phenotypic stratification of UL by heavy menstrual bleeding in 3409 cases and 199,171 female controls reveals genome-wide significant associations at three of the 29 UL loci: 5p15.33 (TERT), 5q35.2 (FGFR4) and 11q22.3 (ATM). Four loci identified in the meta-analysis are also associated with endometriosis risk; an epidemiological meta-analysis across 402,868 women suggests at least a doubling of risk for UL diagnosis among those with a history of endometriosis. These findings increase our understanding of genetic contribution and biology underlying UL development, and suggest overlapping genetic origins with endometriosis

A population study comparing screening performance of prototypes for depression and anxiety with standard scales

<p>Abstract</p> <p>Background</p> <p>Screening instruments for mental disorders need to be short, engaging, and valid. Current screening instruments are usually questionnaire-based and may be opaque to the user. A prototype approach where individuals identify with a description of an individual with typical symptoms of depression, anxiety, social phobia or panic may be a shorter, faster and more acceptable method for screening. The aim of the study was to evaluate the accuracy of four new prototype screeners for predicting depression and anxiety disorders and to compare their performance with existing scales.</p> <p>Methods</p> <p>Short and ultra-short prototypes were developed for Major Depressive Disorder (MDD), Generalised Anxiety Disorder (GAD), Panic Disorder (PD) and Social Phobia (SP). Prototypes were compared to typical short and ultra-short self-report screening scales, such as the Centre for Epidemiology Scale, CES-D and the GAD-7, and their short forms. The Mini International Neuropsychiatric Interview (MINI) version 6 <abbrgrp><abbr bid="B1">1</abbr></abbrgrp> was used as the gold standard for obtaining clinical criteria through a telephone interview. From a population sample, 225 individuals who endorsed a prototype and 101 who did not were administered the MINI. Receiver operating characteristic (ROC) curves were plotted for the short and ultra short prototypes and for the short and ultra short screening scales.</p> <p>Results</p> <p>The study found that the rates of endorsement of the prototypes were commensurate with prevalence estimates. The short-form and ultra short scales outperformed the short and ultra short prototypes for every disorder except GAD, where the GAD prototype outperformed the GAD 7.</p> <p>Conclusions</p> <p>The findings suggest that people may be able to self-identify generalised anxiety more accurately than depression based on a description of a prototypical case. However, levels of identification were lower than expected. Considerable benefits from this method of screening may ensue if our prototypes can be improved for Major Depressive Disorder, Social Phobia and Panic Disorder.</p

I love you ... and heroin: care and collusion among drug-using couples

BACKGROUND: Romantic partnerships between drug-using couples, when they are recognized at all, tend to be viewed as dysfunctional, unstable, utilitarian, and often violent. This study presents a more nuanced portrayal by describing the interpersonal dynamics of 10 heroin and cocaine-using couples from Hartford, Connecticut. RESULTS: These couples cared for each other similarly to the ways that non-drug-using couples care for their intimate partners. However, most also cared by helping each other avoid the symptoms of drug withdrawal. They did this by colluding with each other to procure and use drugs. Care and collusion in procuring and using drugs involved meanings and social practices that were constituted and reproduced by both partners in an interpersonal dynamic that was often overtly gendered. These gendered dynamics could be fluid and changed over time in response to altered circumstances and/or individual agency. They also were shaped by and interacted with long-standing historical, economic and socio-cultural forces including the persistent economic inequality, racism and other forms of structural violence endemic in the inner-city Hartford neighborhoods where these couples resided. As a result, these relationships offered both risk and protection from HIV, HCV and other health threats (e.g. arrest and violence). CONCLUSION: A more complex and nuanced understanding of drug-using couples can be tapped for its potential in shaping prevention and intervention efforts. For example, drug treatment providers need to establish policies which recognize the existence and importance of interpersonal dynamics between drug users, and work with them to coordinate detoxification and treatment for both partners, whenever possible, as well as provide additional couples-oriented services in an integrated and comprehensive drug treatment system

The complex genetics of gait speed:Genome-wide meta-analysis approach

Emerging evidence suggests that the basis for variation in late-life mobility is attributable, in part, to genetic factors, which may become increasingly important with age. Our objective was to systematically assess the contribution of genetic variation to gait speed in older individuals. We conducted a meta-analysis of gait speed GWASs in 31,478 older adults from 17 cohorts of the CHARGE consortium, and validated our results in 2,588 older adults from 4 independent studies. We followed our initial discoveries with network and eQTL analysis of candidate signals in tissues. The meta-analysis resulted in a list of 536 suggestive genome wide significant SNPs in or near 69 genes. Further interrogation with Pathway Analysis placed gait speed as a polygenic complex trait in five major networks. Subsequent eQTL analysis revealed several SNPs significantly associated with the expression of PRSS16, WDSUB1 and PTPRT, which in addition to the meta-analysis and pathway suggested that genetic effects on gait speed may occur through synaptic function and neuronal development pathways. No genome-wide significant signals for gait speed were identified from this moderately large sample of older adults, suggesting that more refined physical function phenotypes will be needed to identify the genetic basis of gait speed in aging

Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice

Psychosocial factors and health as determinants of quality of life in community-dwelling older adults.

PURPOSE: It is important to understand the determinants of differences in quality of life in old age and to include a wide range of possible predictors. The present study investigated the determinants of quality of life in two groups of older adults for whom there was an unusually informative set of possible predictor variables. METHOD: Participants were members of the Lothian Birth Cohorts of 1921 (n = 550) or 1936 (n = 1,091). Four facets of quality of life (QoL) and general QoL were measured using the WHOQOL-BREF. Possible determinants included personality traits, measured with the International Personality Item Pool (IPIP) scales; childhood and old age general cognitive ability, measured with the Moray House Test; minor psychological symptoms, measured with the Hospital Anxiety and Depression Scale (HADS); physical health, assessed by grip strength and cardiovascular disease history; and sociodemographic factors, assessed by interview. RESULTS: Linear regression analyses revealed that HADS depression had the greatest influence on quality of life. Personality traits, most notably Emotional Stability, also predicted quality of life to varying degrees, along with factors reflecting current life circumstances. There were differences between the two cohorts in the variables which predicted quality of life. There were different, conceptually relevant, contributions to the different QoL facets. CONCLUSIONS: Personality traits and minor depressive symptoms have an important influence on self-reported quality of life in old age. Quality of life may be influenced more by current than past circumstances, and this relationship may change with age

A Multisite Preregistered Paradigmatic Test of the Ego-Depletion Effect

We conducted a preregistered multilaboratory project (k = 36; N = 3,531) to assess the size and robustness of ego-depletion effects using a novel replication method, termed the paradigmatic replication approach. Each laboratory implemented one of two procedures that was intended to manipulate self-control and tested performance on a subsequent measure of self-control. Confirmatory tests found a nonsignificant result (d = 0.06). Confirmatory Bayesian meta-analyses using an informed-prior hypothesis (δ = 0.30, SD = 0.15) found that the data were 4 times more likely under the null than the alternative hypothesis. Hence, preregistered analyses did not find evidence for a depletion effect. Exploratory analyses on the full sample (i.e., ignoring exclusion criteria) found a statistically significant effect (d = 0.08); Bayesian analyses showed that the data were about equally likely under the null and informed-prior hypotheses. Exploratory moderator tests suggested that the depletion effect was larger for participants who reported more fatigue but was not moderated by trait self-control, willpower beliefs, or action orientation.</p