Citations

Abstract The myocardium is known to be an anisotropic medium where the muscle fiber orientation changes through the thickness of the wall. Shear wave elastography methods use propagating waves which are measured by ultrasound or magnetic resonance imaging (MRI) techniques to characterize the mechanical properties of various tissues. Ultrasound- or MR-based methods have been used and the excitation frequency ranges for these various methods cover a large range from 24–500 Hz. Some of the ultrasound-based methods have been shown to be able to estimate the fiber direction. We constructed a model with layers of elastic, transversely isotropic materials that were oriented at different angles to simulate the heart wall in systole and diastole. We investigated the effect of frequency on the wave propagation and the estimation of fiber direction and wave speeds in the different layers of the assembled models. We found that waves propagating at low frequencies such as 30 or 50 Hz showed low sensitivity to the fiber direction but also had substantial bias in estimating the wave speeds in the layers. Using waves with higher frequency content (>200 Hz) allowed for more accurate fiber direction and wave speed estimation. These results have particular relevance for MR- and ultrasound-based elastography applications in the heart.

Abstract Pancreatic cancer is projected to become the second leading cause of cancer-related death in the United States by 2020. A familial aggregation of pancreatic cancer has been established, but the cause of this aggregation in most families is unknown. To determine the genetic basis of susceptibility in these families, we sequenced the germline genomes of 638 patients with familial pancreatic cancer and the tumor exomes of 39 familial pancreatic adenocarcinomas. Our analyses support the role of previously identified familial pancreatic cancer susceptibility genes such as BRCA2, CDKN2A, and ATM, and identify novel candidate genes harboring rare, deleterious germline variants for further characterization. We also show how somatic point mutations that occur during hematopoiesis can affect the interpretation of genome-wide studies of hereditary traits. Our observations have important implications for the etiology of pancreatic cancer and for the identification of susceptibility genes in other common cancer types. Significance: The genetic basis of disease susceptibility in the majority of patients with familial pancreatic cancer is unknown. We whole genome sequenced 638 patients with familial pancreatic cancer and demonstrate that the genetic underpinning of inherited pancreatic cancer is highly heterogeneous. This has significant implications for the management of patients with familial pancreatic cancer. Cancer Discov; 6(2); 166–75. ©2015 AACR. This article is highlighted in the In This Issue feature, p. 109

AbstractKernel machine based association tests (KAT) have been increasingly used in testing the association between an outcome and a set of biological measurements due to its power to combine multiple weak signals of complex relationship with the outcome through the specification of a relevant kernel. Human genetic and microbiome association studies are two important applications of KAT. However, the classic KAT framework relies on large sample theory, and conservativeness has been observed for small sample studies, especially for microbiome association studies. The common approach for addressing the small sample problem relies on computationally intensive resampling methods. Here, we derive an exact test for KAT with continuous traits, which resolve the small sample conservatism of KAT without the need for resampling. The exact test has significantly improved power to detect association for microbiome studies. For binary traits, we propose a similar approximate test, and we show that the approximate test is very powerful for a wide range of kernels including common variant‐ and microbiome‐based kernels, and the approximate test controls the type I error well for these kernels. In contrast, the sequence kernel association tests have slightly inflated genomic inflation factors after small sample adjustment. Extensive simulations and application to a real microbiome association study are used to demonstrate the utility of our method.

Background. Preterm Premature Rupture of Membranes (PPROM) is a major leading cause of preterm births. While the cause for PPROM remains unidentified, it is anticipated to be due to subclinical infection, since a large proportion of PPROM patients display signs of chorioamnionitis. Since subclinical infections can be facilitated by dysbiosis, our goal was to characterize the vaginal microbiome and amniotic fluid discharge upon PPROM, through latency antibiotic treatment, and until delivery, to detect the presence of pathogens, microbiota alteration, and microbial response to treatment. Methods. Enrolled subjects (15) underwent routine institutional antenatal care for PPROM, including the administration of latency antibiotics. Serial vaginal swabs were obtained from diagnosis of PPROM through delivery and the sequencing of the V3–V5 region of the 16S rRNA gene was performed for all collected samples. Results. The results show that Lactobacilli species were markedly decreased when compared to vaginal swabs collected from uncomplicated pregnancy subjects with a matched gestational time. Prevotella and Peptoniphilus were the most prevalent taxa in PPROM subjects at presentation. The vaginal microbiome of the PPROM subjects varied substantially intra- and inter-subjects. Several taxa were found to be significantly reduced during and after the antibiotic treatment: Weeksella , Lachnospira , Achromobacter , and Pediococcus . In contrast, Peptostreptococcus and Tissierellaceae ph2 displayed a significant increase after the antibiotic treatment. However, the relative abundance of Lactobacillus , Prevotella , and Peptoniphilus was not substantially impacted during the hospitalization of the PPROM subjects. The deficiency of Lactobacillus , and constancy of known pathogenic species, such as Prevotella and Peptoniphilus during and after antibiotics, highlights the persistent dysbiosis and warrants further investigation into mitigating approaches. Discussion. PPROM is responsible for one third of all preterm births. It is thought that subclinical infection is a crucial factor in the pathophysiology of PPROM because 25–40% of patients present signs of chorioamnionitis on amniocentesis. Here we sought to directly assess the bacterial content of the vagina and leaking amniotic fluid of subjects at presentation, throughout treatment and up until delivery, in order to search for common pathogens, microbiota changes, and microbial response to latency antibiotic treatment. We have found that the vaginal microbiome of PPROM subjects is highly variable and displays significant changes to treatment. However, the unchanging deficiency of Lactobacillus , and persistence of known pathogenic species, such as Prevotella and Peptoniphilus from presentation, through antibiotic treatment and up until delivery, highlights the persistent dysbiosis and warrants further investigation into mitigating approaches.