Ten Years of Screening and Testing for Acute HIV Infection in North Carolina

Objective: To describe demographic and behavioral characteristics of persons with acute HIV infection (AHI) over time. Methods: We conducted a retrospective assessment of AHI identified through the Screening and Tracing Active Transmission (STAT) program from 2003 to 2012 in North Carolina (NC). AHI was identified using pooled nucleic acid amplification for antibody negative samples and individual HIV-1 RNA for antibody indeterminate samples. The STAT program provides rapid notification and evaluation. We compared STAT-collected demographic and risk characteristics with all persons requesting tests and all non-AHI diagnoses from the NC State Laboratory of Public Health. Results: The STAT Program identified 236 AHI cases representing 3.4% (95% confidence interval: 3.0% to 3.9%) of all HIV diagnoses. AHI cases were similar to those diagnosed during established HIV. On pretest risk-assessments, AHI cases were predominately black (69.1%), male (80.1%), young (46.8% < 25 years), and men who have sex with men (MSM) (51.7%). Per postdiagnosis interviews, the median age decreased from 35 (interquartile range 25-42) to 27 (interquartile range 22-37) years, and the proportion <25 years increased from 23.8% to 45.2% (trend P 0.04) between 2003 and 2012. AHI men were more likely to report MSM risk post-diagnosis than on pretest risk-assessments (64%-82.9%; P < 0.0001). Post-diagnosis report of MSM risk in men with AHI increased from 71.4% to 96.2%. Conclusions: In NC, 3.4% of individuals diagnosed with HIV infection have AHI. AHI screening provides a real-time source of incidence trends, improves the diagnostic yield of HIV testing, and offers an opportunity to limit onward transmission

Learning through 'prosuming': Insights from media literacy programmes in Asia

10.1177/097172180801300205Science, Technology and Society132259-27

The PHENIX Experiment at RHIC

The physics emphases of the PHENIX collaboration and the design and current status of the PHENIX detector are discussed. The plan of the collaboration for making the most effective use of the available luminosity in the first years of RHIC operation is also presented.Comment: 5 pages, 1 figure. Further details of the PHENIX physics program available at http://www.rhic.bnl.gov/phenix

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

Age at symptom onset and death and disease duration in genetic frontotemporal dementia : an international retrospective cohort study

Background: Frontotemporal dementia is a heterogenous neurodegenerative disorder, with about a third of cases being genetic. Most of this genetic component is accounted for by mutations in GRN, MAPT, and C9orf72. In this study, we aimed to complement previous phenotypic studies by doing an international study of age at symptom onset, age at death, and disease duration in individuals with mutations in GRN, MAPT, and C9orf72. Methods: In this international, retrospective cohort study, we collected data on age at symptom onset, age at death, and disease duration for patients with pathogenic mutations in the GRN and MAPT genes and pathological expansions in the C9orf72 gene through the Frontotemporal Dementia Prevention Initiative and from published papers. We used mixed effects models to explore differences in age at onset, age at death, and disease duration between genetic groups and individual mutations. We also assessed correlations between the age at onset and at death of each individual and the age at onset and at death of their parents and the mean age at onset and at death of their family members. Lastly, we used mixed effects models to investigate the extent to which variability in age at onset and at death could be accounted for by family membership and the specific mutation carried. Findings: Data were available from 3403 individuals from 1492 families: 1433 with C9orf72 expansions (755 families), 1179 with GRN mutations (483 families, 130 different mutations), and 791 with MAPT mutations (254 families, 67 different mutations). Mean age at symptom onset and at death was 49\ub75 years (SD 10\ub70; onset) and 58\ub75 years (11\ub73; death) in the MAPT group, 58\ub72 years (9\ub78; onset) and 65\ub73 years (10\ub79; death) in the C9orf72 group, and 61\ub73 years (8\ub78; onset) and 68\ub78 years (9\ub77; death) in the GRN group. Mean disease duration was 6\ub74 years (SD 4\ub79) in the C9orf72 group, 7\ub71 years (3\ub79) in the GRN group, and 9\ub73 years (6\ub74) in the MAPT group. Individual age at onset and at death was significantly correlated with both parental age at onset and at death and with mean family age at onset and at death in all three groups, with a stronger correlation observed in the MAPT group (r=0\ub745 between individual and parental age at onset, r=0\ub763 between individual and mean family age at onset, r=0\ub758 between individual and parental age at death, and r=0\ub769 between individual and mean family age at death) than in either the C9orf72 group (r=0\ub732 individual and parental age at onset, r=0\ub736 individual and mean family age at onset, r=0\ub738 individual and parental age at death, and r=0\ub740 individual and mean family age at death) or the GRN group (r=0\ub722 individual and parental age at onset, r=0\ub718 individual and mean family age at onset, r=0\ub722 individual and parental age at death, and r=0\ub732 individual and mean family age at death). Modelling showed that the variability in age at onset and at death in the MAPT group was explained partly by the specific mutation (48%, 95% CI 35\u201362, for age at onset; 61%, 47\u201373, for age at death), and even more by family membership (66%, 56\u201375, for age at onset; 74%, 65\u201382, for age at death). In the GRN group, only 2% (0\u201310) of the variability of age at onset and 9% (3\u201321) of that of age of death was explained by the specific mutation, whereas 14% (9\u201322) of the variability of age at onset and 20% (12\u201330) of that of age at death was explained by family membership. In the C9orf72 group, family membership explained 17% (11\u201326) of the variability of age at onset and 19% (12\u201329) of that of age at death. Interpretation: Our study showed that age at symptom onset and at death of people with genetic frontotemporal dementia is influenced by genetic group and, particularly for MAPT mutations, by the specific mutation carried and by family membership. Although estimation of age at onset will be an important factor in future pre-symptomatic therapeutic trials for all three genetic groups, our study suggests that data from other members of the family will be particularly helpful only for individuals with MAPT mutations. Further work in identifying both genetic and environmental factors that modify phenotype in all groups will be important to improve such estimates. Funding: UK Medical Research Council, National Institute for Health Research, and Alzheimer's Society

Driver Fusions and Their Implications in the Development and Treatment of Human Cancers.

Gene fusions represent an important class of somatic alterations in cancer. We systematically investigated fusions in 9,624 tumors across 33 cancer types using multiple fusion calling tools. We identified a total of 25,664 fusions, with a 63% validation rate. Integration of gene expression, copy number, and fusion annotation data revealed that fusions involving oncogenes tend to exhibit increased expression, whereas fusions involving tumor suppressors have the opposite effect. For fusions involving kinases, we found 1,275 with an intact kinase domain, the proportion of which varied significantly across cancer types. Our study suggests that fusions drive the development of 16.5% of cancer cases and function as the sole driver in more than 1% of them. Finally, we identified druggable fusions involving genes such as TMPRSS2, RET, FGFR3, ALK, and ESR1 in 6.0% of cases, and we predicted immunogenic peptides, suggesting that fusions may provide leads for targeted drug and immune therapy

Systematics of the Neotropical Genus Leptodactylus Fitzinger, 1826 (Anura: Leptodactylidae): Phylogeny, the Relevance of Non-molecular Evidence, and Species Accounts

A phylogeny of the species-rich clade of the Neotropical frog genus Leptodactylus sensu stricto is presented on the basis of a total evidence analysis of molecular (mitochondrial and nuclear markers) and non-molecular (adult and larval morphological and behavioral characters) sampled from > 80% of the 75 currently recognized species. Our results support the monophyly of Leptodactylus sensu stricto, with Hydrolaetare placed as its sister group. The reciprocal monophyly of Hydrolaetare and Leptodactylus sensu stricto does not require that we consider Hydrolaetare as either a subgenus or synonym of Leptodactylus sensu lato. We recognize Leptodactylus sensu stricto, Hydrolaetare, Adenomera, and Lithodytes as valid monophyletic genera. Our results generally support the traditionally recognized Leptodactylus species groups, with exceptions involving only a few species that are easily accommodated without proposing new groups or significantly altering contents. The four groups form a pectinate tree, with the Leptodactylus fuscus group diverging first, followed by the L. pentadactylus group, which is sister to the L. latrans and L. melanonotus groups. To evaluate the impact of non-molecular evidence on our results, we compared our total evidence results with results obtained from analyses using only molecular data. Although non-molecular evidence comprised only 3.5% of the total evidence matrix, it had a strong impact on our total evidence results. Only one species group was monophyletic in the molecular-only analysis, and support differed in 86% of the 54 Leptodactylus clades that are shared by the results of the two analyses. Even though no non-molecular evidence was included for Hydrolaetare, exclusion of that data partition resulted in that genus being nested within Leptodactylus, demonstrating that the inclusion of a small amount of non-molecular evidence for a subset of species can alter not only the placement of those species, but also species that were not scored for those data. The evolution of several natural history and reproductive traits is considered in the light of our phylogenic framework. Invasion of rocky outcrops, larval oophagy, and use of underground reproductive chambers are restricted to species of the Leptodactylus fuscus and L. pentadactylus groups. In contrast, larval schooling, larval attendance, and more complex parental care are restricted to the L. latrans and L. melanonotus groups. Construction of foam nests is plesiomorphic in Leptodactylus but their placement varies extensively (e.g., underground chambers, surface of waterbodies, natural or excavated basins). Information on species synonymy, etymology, adult and larval morphology, advertisement call, and geographic distribution is summarized in species accounts for the 30 species of the Leptodactylus fuscus group, 17 species of the L. pentadactylus group, eight species of the L. latrans group, and 17 species of the L. melanonotus group, as well as the three species that are currently unassigned to any species group.Se presenta una filogenia del género Leptodactylus, un ciado neotropical rico en especies, basada en análises combinados de datos moleculares (marcadores nuclear y mitocondriales) y no moleculares (caracteres de la morfología de adultos y larvas así como de comportamiento) se muestrearon > 80% de las 75 especies reconocidas. Los resultados apoyan la monofília de Leptodactylus sensu stricto, con Hydrolaetare como su grupo hermano. La monofília recíproca de Hydrolaetare y Leptodactylus no requiere considerar a Hydrolaetare como un subgénero o sinónimo de Leptodactylus sensu lato. Se reconocen Leptodactylus sensu stricto, Hydrolaetare, Adenomera y Lithodytes como géneros monofiléticos válidos. Los resultados en general resuelven los grupos tradicionalmente reconocidos de Leptodactylus, con excepciones de algunas especies que son reasignadas sin la necesidad de proponer nuevos grupos o alterar significativamente el contenido de los grupos tradicionales. Los cuatro grupos de especies forman una topología pectinada donde el grupo de L. fuscus tiene una posición basal, seguido por el grupo de L. pentadactylus que es el grupo hermano al clado formado por los grupo de L. latrans y L. melanonotus. Se estimó el impacto de los datos no moleculares en los resultados, comparándose los resultados de evidencia total con los de los análises de datos moleculares solamente. Los datos no moleculares representan un 3.5% de la matriz de evidencia total, pero estos datos tuvieron un impacto significativo en los resultados del análisis de evidencia total. En el análisis estrictamente molecular solamente un grupo de especies resultó monofilético, y el apoyo difirió en 86% de los 54 ciados de Leptodactylus compartidos entre los dos análises. A pesar que datos no moleculares no fueron incluidos para Hydrolaetare, la exclusión de evidencia no molecular resultó en el género estar dentro de Leptodactylus, demostrando que la inclusión de evidencia no molecular pequeña para un subgrupo de especies altera no solamente la posición topológica de esas especies, sino tambien de las especies para las cuales dichos datos no fueron codificados. La evolución de patrones de historia natural y reprodución se evalúan en el contexto filogenético. La invasión de afloramientos rocosos y la construción de cámaras de reprodución subterraneas está limitada a los grupos de Leptodactylus fuscus y L. pentadactylus, mientras que la oofagia larval está restringida al grupo de L. pentadactylus. Por otro lado, los cárdumenes larvales, la proteción del cárdumen, y otros comportamientos parentales complejos carecterizan al clado formado por los grupos de especies de L. latrans y L. melanonotus. Los resúmenes de especies incluyen información de sinonimias, etimología, morfología de adultos y larvas, cantos, y distribución geográfica para las 30 especies del grupo de Leptodactylus fuscus, 17 especies del grupo L. pentadactylus, ocho especies del grupo de L. latrans, 17 especies del grupo de L. melanonotus, así como para las tres especies que actualmente no se encuentran asociadas a ninguno de los grupos de especies.Taran Grant was supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico Proc. 307001/2011-3 and Fundação de Amparo à Pesquisa do Estado de São Paulo Proc. 2012/10000-5

Somatic Mutational Landscape of Splicing Factor Genes and Their Functional Consequences across 33 Cancer Types

Hotspot mutations in splicing factor genes have been recently reported at high frequency in hematological malignancies, suggesting the importance of RNA splicing in cancer. We analyzed whole-exome sequencing data across 33 tumor types in The Cancer Genome Atlas (TCGA), and we identified 119 splicing factor genes with significant non-silent mutation patterns, including mutation over-representation, recurrent loss of function (tumor suppressor-like), or hotspot mutation profile (oncogene-like). Furthermore, RNA sequencing analysis revealed altered splicing events associated with selected splicing factor mutations. In addition, we were able to identify common gene pathway profiles associated with the presence of these mutations. Our analysis suggests that somatic alteration of genes involved in the RNA-splicing process is common in cancer and may represent an underappreciated hallmark of tumorigenesis

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

Although the MYC oncogene has been implicated in cancer, a systematic assessment of alterations of MYC, related transcription factors, and co-regulatory proteins, forming the proximal MYC network (PMN), across human cancers is lacking. Using computational approaches, we define genomic and proteomic features associated with MYC and the PMN across the 33 cancers of The Cancer Genome Atlas. Pan-cancer, 28% of all samples had at least one of the MYC paralogs amplified. In contrast, the MYC antagonists MGA and MNT were the most frequently mutated or deleted members, proposing a role as tumor suppressors. MYC alterations were mutually exclusive with PIK3CA, PTEN, APC, or BRAF alterations, suggesting that MYC is a distinct oncogenic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such as immune response and growth factor signaling; chromatin, translation, and DNA replication/repair were conserved pan-cancer. This analysis reveals insights into MYC biology and is a reference for biomarkers and therapeutics for cancers with alterations of MYC or the PMN. We present a computational study determining the frequency and extent of alterations of the MYC network across the 33 human cancers of TCGA. These data, together with MYC, positively correlated pathways as well as mutually exclusive cancer genes, will be a resource for understanding MYC-driven cancers and designing of therapeutics

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