Diagnostic imaging and biopsy pathways following abnormal screen-film and digital screening mammography

The transition from screen-film to digital mammography may have altered diagnostic evaluation of women following a positive screening examination. This study compared use and timeliness of diagnostic imaging and biopsy for women screened with screen-film or digital mammography

Chronic cisplatin treatment promotes enhanced damage repair and tumor progression in a mouse model of lung cancer

Chemotherapy resistance is a major obstacle in cancer treatment, yet the mechanisms of response to specific therapies have been largely unexplored in vivo. Employing genetic, genomic, and imaging approaches, we examined the dynamics of response to a mainstay chemotherapeutic, cisplatin, in multiple mouse models of human non-small-cell lung cancer (NSCLC). We show that lung tumors initially respond to cisplatin by sensing DNA damage, undergoing cell cycle arrest, and inducing apoptosis—leading to a significant reduction in tumor burden. Importantly, we demonstrate that this response does not depend on the tumor suppressor p53 or its transcriptional target, p21. Prolonged cisplatin treatment promotes the emergence of resistant tumors with enhanced repair capacity that are cross-resistant to platinum analogs, exhibit advanced histopathology, and possess an increased frequency of genomic alterations. Cisplatin-resistant tumors express elevated levels of multiple DNA damage repair and cell cycle arrest-related genes, including p53-inducible protein with a death domain (Pidd). We demonstrate a novel role for PIDD as a regulator of chemotherapy response in human lung tumor cells.National Institutes of Health (U.S.) (grant 5-UO1-CA84306)National Cancer Institute (U.S.) (CA034992

Financial considerations in the conduct of multi-centre randomised controlled trials: evidence from a qualitative study.

National Coordinating Centre for Research Methodology; Medical Research Council, UK Department of Health; Chief Scientist OfficeNot peer reviewedPublisher PD

Common, low-frequency, rare, and ultra-rare coding variants contribute to COVID-19 severity

The combined impact of common and rare exonic variants in COVID-19 host genetics is currently insufficiently understood. Here, common and rare variants from whole-exome sequencing data of about 4000 SARS-CoV-2-positive individuals were used to define an interpretable machine-learning model for predicting COVID-19 severity. First, variants were converted into separate sets of Boolean features, depending on the absence or the presence of variants in each gene. An ensemble of LASSO logistic regression models was used to identify the most informative Boolean features with respect to the genetic bases of severity. The Boolean features selected by these logistic models were combined into an Integrated PolyGenic Score that offers a synthetic and interpretable index for describing the contribution of host genetics in COVID-19 severity, as demonstrated through testing in several independent cohorts. Selected features belong to ultra-rare, rare, low-frequency, and common variants, including those in linkage disequilibrium with known GWAS loci. Noteworthily, around one quarter of the selected genes are sex-specific. Pathway analysis of the selected genes associated with COVID-19 severity reflected the multi-organ nature of the disease. The proposed model might provide useful information for developing diagnostics and therapeutics, while also being able to guide bedside disease management. © 2021, The Author(s)

An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers

Introduction: Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. In the present study, we tested the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers. Methods: We genotyped 22,214 (11,421 affected, 10,793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched in affected or unaffected individuals. Results: We discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers compared with the rest of clade T (hazard ratio (HR) = 0.55; 95% confidence interval (CI), 0.34 to 0.88; P = 0.01). Compared with the most frequent haplogroup in the general population (that is, H and T clades), the T1a1 haplogroup has a HR of 0.62 (95% CI, 0.40 to 0.95; P = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk. Conclusions: This study illustrates how original approaches such as the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effects.Peer reviewe

The Art of Winning Hearts and Minds: Explaining Divergent Outcomes of Confucius Institutes in the U.S.

After the first Confucius Institute opened in 2004, the Chinese government-funded program grew quickly. Today, there are over 500 in the world and over 100 institutes in the United States. Despite this apparent success, this dissertation explains why some institutions establish Confucius Institutes, while others close or fail to establish Confucius Institutes. Using qualitative research methods, this project analyzes the experience of seventeen U.S. institutions through interviews and publicly available data and records. Theoretically, this project acknowledges the work of public diplomacy scholars but grounds the research in literature that helps explain the institutions’ decisions from the organizational level. It focuses specifically on the role of internal institutional need, policy entrepreneurs and sponsorship, internal opposition, and the reputation and perception of the transnational Confucius Institute network. Data suggest that an institution’s need and its perception of the larger network are the main drivers of the partnership outcome. The majority of institutions indicated that a desire to start or grow Chinese language programs on campus was a major impetus to the establishment of the Confucius Institute. Similarly, an institution’s perception of the larger transnational Confucius Institute network played an important role in determining partnership outcomes. A number of the closed and failed-to-establish cases, however, had negative experiences with aspects of the network

Complex N-glycans are important for interspecies transmission of H7 influenza A viruses

Influenza A viruses (IAVs) can overcome species barriers by adaptation of the receptor-binding site of the hemagglutinin (HA). To initiate infection, HAs bind to glycan receptors with terminal sialic acids, which are either N-acetylneuraminic acid (NeuAc) or N-glycolylneuraminic acid (NeuGc); the latter is mainly found in horses and pigs but not in birds and humans. We investigated the influence of previously identified equine NeuGc-adapting mutations (S128T, I130V, A135E, T189A, and K193R) in avian H7 IAVs in vitro and in vivo. We observed that these mutations negatively affected viral replication in chicken cells but not in duck cells and positively affected replication in horse cells. In vivo, the mutations reduced virus virulence and mortality in chickens. Ducks excreted high viral loads longer than chickens, although they appeared clinically healthy. To elucidate why these viruses infected chickens and ducks despite the absence of NeuGc, we re-evaluated the receptor binding of H7 HAs using glycan microarray and flow cytometry studies. This re-evaluation demonstrated that mutated avian H7 HAs also bound to α2,3-linked NeuAc and sialyl-LewisX, which have an additional fucose moiety in their terminal epitope, explaining why infection of ducks and chickens was possible. Interestingly, the α2,3-linked NeuAc and sialyl-LewisX epitopes were only bound when presented on tri-antennary N-glycans, emphasizing the importance of investigating the fine receptor specificities of IAVs. In conclusion, the binding of NeuGc-adapted H7 IAV to tri-antennary N-glycans enables viral replication and shedding by chickens and ducks, potentially facilitating interspecies transmission of equine-adapted H7 IAVs

eGirls, eCitizens

eGirls, eCitizens is a landmark work that explores the many forces that shape girls’ and young women’s experiences of privacy, identity, and equality in our digitally networked society. Drawing on the multi-disciplinary expertise of a remarkable team of leading Canadian and international scholars, as well as Canada’s foremost digital literacy organization, MediaSmarts, this collection presents the complex realities of digitized communications for girls and young women as revealed through the findings of The eGirls Project (www.egirlsproject.ca) and other important research initiatives. Aimed at moving dialogues on scholarship and policy around girls and technology away from established binaries of good vs bad, or risk vs opportunity, these seminal contributions explore the interplay of factors that shape online environments characterized by a gendered gaze and too often punctuated by sexualized violence. Perhaps most importantly, this collection offers first-hand perspectives collected from girls and young women themselves, providing a unique window on what it is to be a girl in today’s digitized society

Diagnostic imaging and biopsy pathways following abnormal screen-film and digital screening mammography

OBJECTIVE: The transition from screen-film to digital mammography may have altered diagnostic evaluation of women following a positive screening examination. This study compared use and timeliness of diagnostic imaging and biopsy for women screened with screen-film or digital mammography. MATERIALS AND METHODS: Data were from 35,321 positive screening mammograms on 32,087 women aged 40–89 years, from 22 Breast Cancer Surveillance Consortium facilities in 2005–2008. Diagnostic pathways were classified by their inclusion of diagnostic mammography, ultrasound, magnetic resonance imaging (MRI), and biopsy. We compared time to resolution and frequency of diagnostic pathways by patient characteristics, screening exam modality, and radiology facility. Between-facility differences were evaluated by computing the proportion of mammograms receiving follow-up with a particular pathway for each facility and examining variation in these proportions across facilities. Multinomial logistic regression adjusting for age, calendar year, and facility compared odds of follow-up with each pathway. RESULTS: The median time to resolution of a positive screening mammogram was 10 days. Compared to screen-film mammograms, digital mammograms were more frequently followed by only a single diagnostic mammogram (46% vs. 36%). Pathways following digital screening mammography were also less likely to include biopsy (16% vs. 20%). However, in adjusted analyses most differences were not statistically significant (p = 0.857 for mammography only; p = 0.03 for biopsy). Substantial variability in diagnostic pathway frequency was seen across facilities. For instance, the frequency of evaluation with diagnostic mammography alone ranged from 23% to 55% across facilities. CONCLUSION: Differences in evaluation of positive digital and screen-film screening mammograms were minor, and appeared to be largely attributable to substantial variation between radiology facilities. To guide health systems in their efforts to eliminate practices that do not contribute to effective care, we need further research to identify the causes of this variation and the best evidence-based approach for follow-up