State statutes and regulations related to human papillomavirus vaccination

A cross-sectional analysis of human papillomavirus (HPV) vaccine statutes and regulations from states and the District of Columbia in the United States (U.S.) was conducted from September-November 2018 to advance analyses of policy impact on HPV vaccination uptake. A search was conducted using WestlawNext, a legal research database. Statutes and regulations relevant to the study were analyzed and coded based on their legal attributes into ten broad coding questions and several sub-questions. Of the 212 laws identified by the initial search string, 93 (43.9%) reference HPV vaccination in statute or regulation. An additional three laws were added following subsequent review. There was a total of 52 statutes and 44 regulations from 34 states and the District of Columbia. Most laws were related to developing and distributing HPV vaccination materials for parents, and mechanisms to fund and reimburse for the vaccination. This study can be used by policymakers in jurisdictions that are considering establishing HPV vaccination promotion interventions in state law and highlighting the limited statutory and regulatory efforts that have been implemented to promote HPV vaccination. Importantly, this study can also be used to conduct evaluations of the efficacy of statutory and regulatory strategies in increasing HPV vaccination rates

A 700 year record of Southern Hemisphere extratropical climate variability

Annually dated ice cores from West and East Antarctica provide proxies for past changes in atmospheric circulation over Antarctica and portions of the Southern Ocean, temperature in coastal West and East Antarctica, and the frequency of South Polar penetration of El Niño events. During the period AD 1700–1850, atmospheric circulation over the Antarctic and at least portions of the Southern Hemisphere underwent a mode switch departing from the out-of-phase alternation of multi-decadal long phases of EOF1 and EOF2 modes of the 850 hPa field over the Southern Hemisphere (as defined in the recent record by Thompson and Wallace, 2000; Thompson and Solomon, 2002) that characterizes the remainder of the 700 year long record. From AD 1700 to 1850, lower-tropospheric circulation was replaced by in-phase behavior of the Amundsen Sea Low component of EOF2 and the East Antarctic High component of EOF1. During the first phase of the mode switch, both West and East Antarctic temperatures declined, potentially in response to the increased extent of sea ice surrounding both regions. At the end of the mode switch, West Antarctic coastal temperatures rose and East Antarctic coastal temperatures fell, respectively, to their second highest and lowest of the record. Polar penetration of El Niño events increased during the mode switch. The onset of the AD 1700–1850 mode switch coincides with the extreme state of the Maunder Minimum in solar variability. Late 20th-century West Antarctic coastal temperatures are the highest in the record period, and East Antarctic coastal temperatures close to the lowest. Since AD 1700, extratropical regions of the Southern Hemisphere have experienced significant climate variability coincident with changes in both solar variability and greenhouse gase

High dimensional decision dilemmas in climate models

An important source of uncertainty in climate models is linked to the calibration of model parameters. Interest in systematic and automated parameter optimization procedures stems from the desire to improve the model climatology and to quantify the average sensitivity associated with potential changes in the climate system. Building upon on the smoothness of the response of an atmospheric circulation model (AGCM) to changes of four adjustable parameters, Neelin et al. (2010) used a quadratic metamodel to objectively calibrate the AGCM. The metamodel accurately estimates global spatial averages of common fields of climatic interest, from precipitation, to low and high level winds, from temperature at various levels to sea level pressure and geopotential height, while providing a computationally cheap strategy to explore the influence of parameter settings. Here, guided by the metamodel, the ambiguities or dilemmas related to the decision making process in relation to model sensitivity and optimization are examined. Simulations of current climate are subject to considerable regional-scale biases. Those biases may vary substantially depending on the climate variable considered, and/or on the performance metric adopted. Common dilemmas are associated with model revisions yielding improvement in one field or regional pattern or season, but degradation in another, or improvement in the model climatology but degradation in the interannual variability representation. Challenges are posed to the modeler by the high dimensionality of the model output fields and by the large number of adjustable parameters. The use of the metamodel in the optimization strategy helps visualize trade-offs at a regional level, e.g., how mismatches between sensitivity and error spatial fields yield regional errors under minimization of global objective functions

Liminal Roles as a Source of Creative Agency in Management: The Case of Knowledge-Sharing Communities

Studies suggest that the experience of liminality – of being in an ambiguous, ‘betwixt and between’ position – has creative potential for organizations. We contribute to theory on the link between liminality and creative agency through a study of the coordinators of ‘knowledge-sharing communities’; one of the latest examples of a ‘neo-bureaucratic’ practice that seeks to elicit innovative responses from employees while intensifying control by the organization. Through a role-centred perspective, our study found that both the structural and interpretive aspects of coordinators’ role enactments promoted a degree of creative agency. ‘Front-stage’ and ‘back-stage’ activities were developed to meet the divergent expectations posed by senior management and community members, and the ambiguity of their roles prompted an array of different role interpretations. Our findings contribute to theory by showing how the link between liminality and creative agency is not confined to roles and spaces (consultancy work, professional expertise) that are positioned across organizational boundaries, or free from norms and expectations, but may also apply to roles that are ambiguously situated within organizational contexts and which are subject to divergent expectations. This shows how neo-bureaucratic forms may be both reproduced and renewed through the creative responses of individual managers

Characterizing genomic alterations in cancer by complementary functional associations.

Systematic efforts to sequence the cancer genome have identified large numbers of mutations and copy number alterations in human cancers. However, elucidating the functional consequences of these variants, and their interactions to drive or maintain oncogenic states, remains a challenge in cancer research. We developed REVEALER, a computational method that identifies combinations of mutually exclusive genomic alterations correlated with functional phenotypes, such as the activation or gene dependency of oncogenic pathways or sensitivity to a drug treatment. We used REVEALER to uncover complementary genomic alterations associated with the transcriptional activation of β-catenin and NRF2, MEK-inhibitor sensitivity, and KRAS dependency. REVEALER successfully identified both known and new associations, demonstrating the power of combining functional profiles with extensive characterization of genomic alterations in cancer genomes

An Integrated TCGA Pan-Cancer Clinical Data Resource to Drive High-Quality Survival Outcome Analytics

For a decade, The Cancer Genome Atlas (TCGA) program collected clinicopathologic annotation data along with multi-platform molecular profiles of more than 11,000 human tumors across 33 different cancer types. TCGA clinical data contain key features representing the democratized nature of the data collection process. To ensure proper use of this large clinical dataset associated with genomic features, we developed a standardized dataset named the TCGA Pan-Cancer Clinical Data Resource (TCGA-CDR), which includes four major clinical outcome endpoints. In addition to detailing major challenges and statistical limitations encountered during the effort of integrating the acquired clinical data, we present a summary that includes endpoint usage recommendations for each cancer type. These TCGA-CDR findings appear to be consistent with cancer genomics studies independent of the TCGA effort and provide opportunities for investigating cancer biology using clinical correlates at an unprecedented scale. Analysis of clinicopathologic annotations for over 11,000 cancer patients in the TCGA program leads to the generation of TCGA Clinical Data Resource, which provides recommendations of clinical outcome endpoint usage for 33 cancer types

GISTIC2.0 facilitates sensitive and confident localization of the targets of focal somatic copy-number alteration in human cancers

We describe methods with enhanced power and specificity to identify genes targeted by somatic copy-number alterations (SCNAs) that drive cancer growth. By separating SCNA profiles into underlying arm-level and focal alterations, we improve the estimation of background rates for each category. We additionally describe a probabilistic method for defining the boundaries of selected-for SCNA regions with user-defined confidence. Here we detail this revised computational approach, GISTIC2.0, and validate its performance in real and simulated datasets

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN