The Fontan epidemic: population projections from the Australia and New Zealand Fontan registry

Background: The number and age demographic of the future Fontan population is unknown

Maternal Anti-Dengue IgG Fucosylation Predicts Susceptibility to Dengue Disease in Infants

Infant mortality from dengue disease is a devastating global health burden that could be minimized with the ability to identify susceptibility for severe disease prior to infection. Although most primary infant dengue infections are asymptomatic, maternally derived anti-dengue immunoglobulin G (IgGs) present during infection can trigger progression to severe disease through antibody-dependent enhancement mechanisms. Importantly, specific characteristics of maternal IgGs that herald progression to severe infant dengue are unknown. Here, we define \u3e /=10% afucosylation of maternal anti-dengue IgGs as a risk factor for susceptibility of infants to symptomatic dengue infections. Mechanistic experiments show that afucosylation of anti-dengue IgGs promotes FcgammaRIIIa signaling during infection, in turn enhancing dengue virus replication in FcgammaRIIIa(+) monocytes. These studies identify a post-translational modification of anti-dengue IgGs that correlates with risk for symptomatic infant dengue infections and define a mechanism by which afucosylated antibodies and FcgammaRIIIa enhance dengue infections

Hepatic and renal end-organ damage in the Fontan circulation: a report from the Australian and New Zealand Fontan Registry

Background: Hepatic and renal dysfunction have been observed in survivors of the Fontan procedure, however their incidence and associated factors remain poorly defined. Methods: A total of 152 participants from a Registry of 1528 patients underwent abdominal ultrasound, transient elastography (FibroScan), serum fibrosis score (FibroTest), in vivo Tc-99m DTPA measurement of glomerular filtration rate (mGFR), and urine albumin-creatinine ratio (ACR). Results: Mean age and time since Fontan were 19.8 ± 9.3 and 14.1 ± 7.6 years, respectively. Features suggestive of hepatic fibrosis were observed on ultrasound in 87/143 (61%) and no patient was diagnosed with hepatocellular carcinoma. FibroScan median kPa was ≥10 in 117/133 (88%), ≥15 in 75/133 (56%), and ≥20 in 41/133 (31%). Fifty-four patients (54/118, 46%) had a FibroTest score ≥0.49 (equivalent to ≥F2 fibrosis). FibroTest score correlated with FibroScan value (r = 0.24, p = 0.015) and ACR (r = 0.29, p = 0.002), and patients with ultrasound features of hepatic fibrosis had a higher FibroScan median kPa (19.5 vs 15.4, p = 0.002). Renal impairment was mild (mGFR 60–89 ml/min/1.73 m) in 46/131 (35%) and moderate (mGFR 30–59 ml/min/1.73 m) in 3/131 (2%). Microalbuminuria was detected in 52/139 participants (37%). By multivariable analysis, time since Fontan was associated with increased FibroScan median kPa (β = 0.89, 95% CI 0.54–1.25, p = 0.002) and decreased mGFR (β = −0.77, 95% CI −1.29–0.24, p = 0.005). Conclusions: In the second decade after Fontan hepatic and renal structure and function are abnormal in a significant number of patients: close to 60% have ultrasonographic evidence of structural hepatic abnormalities, 46% have elevated serum hepatic fibrosis scores, and 57% have either reduced glomerular filtration rate or microalbuminuria. Hepatic and renal function should be monitored for potential impacts on outcomes after Fontan completion

Classifying the evolutionary and ecological features of neoplasms

The consensus conference was supported by Wellcome Genome Campus Advanced Courses and Scientific Conferences. C.C.M. is supported in part by US NIH grants P01 CA91955, R01 CA149566, R01 CA170595, R01 CA185138 and R01 CA140657 as well as CDMRP Breast Cancer Research Program Award BC132057. M.J. is supported by NIH grant K99CA201606. K.S.A. is supported by NCI 5R21 CA196460. K. Polyak is supported by R35 CA197623, U01 CA195469, U54 CA193461, and the Breast Cancer Research Foundation. K.J.P. is supported by NIH grants CA143803, CA163124, CA093900 and CA143055. D.P. is supported by the European Research Council (ERC-617457- PHYLOCANCER), the Spanish Ministry of Economy and Competitiveness (BFU2015-63774-P) and the Education, Culture and University Development Department of the Galician Government. K.S.A. is supported in part by the Breast Cancer Research Foundation and NCI R21CA196460. C.S. is supported by the Royal Society, Cancer Research UK (FC001169), the UK Medical Research Council (FC001169), and the Wellcome Trust (FC001169), NovoNordisk Foundation (ID 16584), the Breast Cancer Research Foundation (BCRF), the European Research Council (THESEUS) and Marie Curie Network PloidyNet. T.A.G. is a Cancer Research UK fellow and a Wellcome Trust funded Investigator. E.S.H. is supported by R01 CA185138-01 and W81XWH-14-1-0473. M.Gerlinger is supported by Cancer Research UK and The Royal Marsden/ICR National Institute of Health Research Biomedical Research Centre. M.Ge., M.Gr., Y.Y., and A.So. were also supported in part by the Wellcome Trust [105104/Z/14/Z]. J.D.S. holds the Edward B. Clark, MD Chair in Pediatric Research, and is supported by the Primary Children's Hospital (PCH) Pediatric Cancer Research Program, funded by the Intermountain Healthcare Foundation and the PCH Foundation. A.S. is supported by the Chris Rokos Fellowship in Evolution and Cancer. Y.Y. is a Cancer Research UK fellow and supported by The Royal Marsden/ICR National Institute of Health Research Biomedical Research Centre. E.S.H. was supported in part by PCORI grants 1505–30497 and 1503–29572, NIH grants R01 CA185138, T32 CA093245, and U10 CA180857, CDMRP Breast Cancer Research Program Award BC132057, a CRUK Grand Challenge grant, and the Breast Cancer Research Foundation. A.R.A.A. was funded in part by NIH grant U01CA151924. A.R.A.A., R.G. and J.S.B. were funded in part by NIH grant U54CA193489

Machine Learning Identifies Stemness Features Associated with Oncogenic Dedifferentiation.

Cancer progression involves the gradual loss of a differentiated phenotype and acquisition of progenitor and stem-cell-like features. Here, we provide novel stemness indices for assessing the degree of oncogenic dedifferentiation. We used an innovative one-class logistic regression (OCLR) machine-learning algorithm to extract transcriptomic and epigenetic feature sets derived from non-transformed pluripotent stem cells and their differentiated progeny. Using OCLR, we were able to identify previously undiscovered biological mechanisms associated with the dedifferentiated oncogenic state. Analyses of the tumor microenvironment revealed unanticipated correlation of cancer stemness with immune checkpoint expression and infiltrating immune cells. We found that the dedifferentiated oncogenic phenotype was generally most prominent in metastatic tumors. Application of our stemness indices to single-cell data revealed patterns of intra-tumor molecular heterogeneity. Finally, the indices allowed for the identification of novel targets and possible targeted therapies aimed at tumor differentiation

Injury Rates Among Division I Baseball Players With and Without SPEC Program Guidance

Athlete monitoring and proper strength and conditioning should serve not only to manage fatigue and increase athletic performance but decrease injury rates as well. In cooperation with the East Tennessee State University (ETSU) Sport Science Program, the Sports Performance Enhancement Consortium (SPEC) provides athlete monitoring and strength & conditioning services to ETSU Athletics. Since October 2008, the SPEC program has provided evidence based monitoring and strength and conditioning (S&C) services to ETSU baseball. This represents the first investigation of the potential for the SPEC program to influence injury rates among Division I athletes at ETSU. The number of spring season game-time injuries and athletic exposures were determined for ETSU baseball during the 7-year period from 2004-2010. Injuries were classified as Game-Time Injury (GTI) and/or Training Related Game-Time Injury (TRGTI). In order to qualify as a GTI, the injury must have occurred during and as a direct result of playing in a game. GTIs include contact and non-contact injuries. Injuries that may have been influenced by the strength and conditioning program were classified as TRGTI. During spring seasons from 2004-2010, these injuries included strains, sprains, dislocations (non-contact), inflammation, and impingements. Classification as a TRGTI required all of the following criteria to be fulfilled, 1) the injury must have occurred during and as a direct result of playing in a game, 2) the injury must not result from contact, 3) the injury must have been potentially related to and/or prevented through training. For the purposes of this investigation, only injuries sustained during spring season games were considered. A single athletic exposure (A-E) was defined as 1 athlete participating in 1 competition where the potential for injury existed and was not dependent upon the length of time an athlete participated in the competition. For the purposes of this investigation, only A-Es occurring during spring season games were considered. A-Es for practice sessions were not available. Injury rate is defined as the number of injuries divided by the number of A-Es. In this investigation, injury rate is expressed at injuries per 100 A-Es. Since ETSU Baseball injury data is available for the last seven spring seasons, and only two seasons have included SPEC involvement, a description of total injuries and injury rates can be provided. Of the 7 seasons reported, the 2009 and 2010 spring seasons were associated with the lowest GTI, TRGTI and game-time injuries (total injuries and training related injuries) and lowest injury rates (total injury rate and training related injury rate). During the spring 2010 season, not a single TRGTI was reported. If significant injury reductions can be achieved through the SPEC program over a broad range of sports, it may suggest that programs similar to SPEC could be used in sport at a variety of levels to increase performance and reduce injury rates and decrease the costs associated with the treatment of sport related injuries