Postprocessed time-delay interferometry for LISA

High-precision interpolation of LISA phase measurements allows signal reconstruction and formulation of time-delay interferometry (TDI) combinations to be conducted in postprocessing. The reconstruction is based on phase measurements made at approximately 10 Hz (for a 1 Hz signal bandwidth) at regular intervals independent of the TDI delay times. Interpolation introduces an error less than 1 × 10-8 with continuous data segments as short as 2 s in duration. The 10 Hz sampling rate represents an increase from the 2 Hz sampling rate needed for the original implementation of TDI. The advantages of this technique include increased flexibility of the data analysis and significantly simplified hardware

Molecular Characterization of Pediatric Restrictive Cardiomyopathy from Integrative Genomics

Pediatric restrictive cardiomyopathy (RCM) is a genetically heterogeneous heart disease with limited therapeutic options. RCM cases are largely idiopathic; however, even within families with a known genetic cause for cardiomyopathy, there is striking variability in disease severity. Although accumulating evidence implicates both gene expression and alternative splicing in development of dilated cardiomyopathy (DCM), there have been no detailed molecular characterizations of underlying pathways dysregulated in RCM. RNA-Seq on a cohort of pediatric RCM patients compared to other forms of adult cardiomyopathy and controls identified transcriptional differences highly common to the cardiomyopathies, as well as those unique to RCM. Transcripts selectively induced in RCM include many known and novel G-protein coupled receptors linked to calcium handling and contractile regulation. In-depth comparisons of alternative splicing revealed splicing events shared among cardiomyopathy subtypes, as well as those linked solely to RCM. Genes identified with altered alternative splicing implicate RBM20, a DCM splicing factor, as a potential mediator of alternative splicing in RCM. We present the first comprehensive report on molecular pathways dysregulated in pediatric RCM including unique/shared pathways identified compared to other cardiomyopathy subtypes and demonstrate that disruption of alternative splicing patterns in pediatric RCM occurs in the inverse direction as DCM

A surface mooring for air–sea interaction research in the Gulf Stream. Part I : mooring design and instrumentation

Author Posting. © American Meteorological Society, 2012. This article is posted here by permission of American Meteorological Society for personal use, not for redistribution. The definitive version was published in Journal of Atmospheric and Oceanic Technology 29 (2012): 1363–1376, doi:10.1175/JTECH-D-12-00060.1.The design of a surface mooring for deployment in the Gulf Stream in the Mid-Atlantic Bight is described. The authors' goals were to observe the surface meteorology; upper-ocean variability; and air–sea exchanges of heat, freshwater, and momentum in and near the Gulf Stream during two successive 1-yr deployments. Of particular interest was quantifying these air–sea fluxes during wintertime events that carry cold, dry air from the land over the Gulf Stream. Historical current data and information about the surface waves were used to guide the design of the surface mooring. The surface buoy provided the platform for both bulk meteorological sensors and a direct covariance flux system. Redundancy in the meteorological sensors proved to be a largely successful strategy to obtain complete time series. Oceanographic instrumentation was limited in size by considerations of drag; and two current meters, three temperature–salinity recorders, and 15 temperature recorders were deployed. Deployment from a single-screw vessel in the Gulf Stream required a controlled-drift stern first over the anchor sites. The first deployment lasted the planned full year. The second deployment ended after 3 months when the mooring was cut by unknown means at a depth of about 3000 m. The mooring was at times in the core of the Gulf Stream, and a peak surface current of over 2.7 m s−1 was observed. The 15-month records of surface meteorology and air–sea fluxes captured the seasonal variability as well as several cold-air outbreaks; the peak observed heat loss was in excess of 1400 W m−2.This work was funded by the National Science Foundation Grant OCE04-24536 as part of the CLIVAR Mode Water Dynamics Experiment (CLIMODE). The Vetlesen Foundation is also acknowledged for the early support of SB.2013-03-0

Clinically relevant variants identified in thoracic aortic aneurysm patients by research exome sequencing

Thoracic aortic aneurysm (TAA) is a genetically heterogeneous disease involving subclinical and progressive dilation of the thoracic aorta, which can lead to life-threatening complications such as dissection or rupture. Genetic testing is important for risk stratification and identification of at risk family members, and clinically available genetic testing panels have been expanding rapidly. However, when past testing results are normal, there is little evidence to guide decision-making about the indications and timing to pursue additional clinical genetic testing. Results from research based genetic testing can help inform this process. Here we present 10 TAA patients who have a family history of disease and who enrolled in research-based exome testing. Nine of these ten patients had previous clinical genetic testing that did not identify the cause of disease. We sought to determine the number of rare variants in 23 known TAA associated genes identified by research-based exome testing. In total, we found 10 rare variants in six patients. Likely pathogenic variants included a TGFB2 variant in one patient and a SMAD3 variant in another. These variants have been reported previously in individuals with similar phenotypes. Variants of uncertain significance of particular interest included novel variants in MYLK and MFAP5, which were identified in a third patient. In total, clinically reportable rare variants were found in 6/10 (60%) patients, with at least 2/10 (20%) patients having likely pathogenic variants identified. These data indicate that consideration of re-testing is important in TAA patients with previous negative or inconclusive results

Progress in Interferometry for LISA at JPL

Recent advances at JPL in experimentation and design for LISA interferometry include the demonstration of Time Delay Interferometry using electronically separated end stations, a new arm-locking design with improved gain and stability, and progress in flight readiness of digital and analog electronics for phase measurements.Comment: 11 pages, 9 figures, LISA 8 Symposium, Stanford University, 201

Implementation and Sustainment of a Statewide Telemedicine Diabetic Retinopathy Screening Network for Federally Designated Safety-Net Clinics

CONTEXT: Diabetic retinopathy (DR) is the leading cause of incident blindness among working-age adults in the United States. Federally designated safety-net clinics (FDSC) often serve as point-of-contact for patients least likely to receive recommended DR screenings, creating opportunity for targeted interventions to increase screening access and compliance. STUDY DESIGN AND METHODS: With such a goal, we implemented and assessed the longitudinal performance of an FDSC-based telemedicine DR screening (TDRS) network of 22 clinical sites providing nonmydriatic fundus photography with remote interpretation and reporting. Retrospective analysis of patient encounters between February 2014 and January 2019 was performed to assess rates of pathology and referral. A generalized estimating equation logistic regression model was used for subset analysis from audits of pre- and post-implementation screening rates. Finally, patient surveys were conducted and assessed as a measure of intervention acceptability. RESULTS: Of the 13,923 individual telescreening encounters (4327 female, 4220 male, and 5376 unspecified; mean [SD] age, 54.9 [12.5] years) studied, 10,540 were of adequate quality to identify 3532 (33.5%) patients with ocular pathology: 2319 (22.0%) patients had some level of DR with 1604 (15.2%) requiring specialist referral, and 808 (7.7%) patients required referral for other ocular pathologies. The mean screening rate for audited clinics in the year prior to program implementation was 29.9% (641/2147), which increased to 47.7% (1012/2124) in the program’s first year, doubling patients’ odds of being screened (OR 2.2; 95% CI: 1.3–3.7; P = .003). These gains were sustained over four years following implementation (OR 1.9; 95% CI: 1.1–3.1; P = .018) despite varied clinic screening performance (4-year averaged range, 22.9–55.1%). Odds of early detection likewise doubled for patients with consecutive screenings (OR 2.2, 95% CI: 2.0–2.4; P \u3c .001). Finally, surveyed patients preferred TDRS to specialist exams (82.5%; 776/941) and would recommend the service to friends (92.7%; 868/936). CONCLUSION AND RELEVANCE: A statewide, FDSC-centered TDRS network was successfully established and sustained in a medically underserved region of the United States. Our results suggest that large TDRS networks in FDSCs can increase screening access and compliance for otherwise unscreened populations, but outcomes can vary greatly among clinics. Further work to optimize program implementation is needed to maximize this model\u27s impact

Lineage relationship of prostate cancer cell types based on gene expression

<p>Abstract</p> <p>Background</p> <p>Prostate tumor heterogeneity is a major factor in disease management. Heterogeneity could be due to multiple cancer cell types with distinct gene expression. Of clinical importance is the so-called cancer stem cell type. Cell type-specific transcriptomes are used to examine lineage relationship among cancer cell types and their expression similarity to normal cell types including stem/progenitor cells.</p> <p>Methods</p> <p>Transcriptomes were determined by Affymetrix DNA array analysis for the following cell types. Putative prostate progenitor cell populations were characterized and isolated by expression of the membrane transporter ABCG2. Stem cells were represented by embryonic stem and embryonal carcinoma cells. The cancer cell types were Gleason pattern 3 (glandular histomorphology) and pattern 4 (aglandular) sorted from primary tumors, cultured prostate cancer cell lines originally established from metastatic lesions, xenografts LuCaP 35 (adenocarcinoma phenotype) and LuCaP 49 (neuroendocrine/small cell carcinoma) grown in mice. No detectable gene expression differences were detected among serial passages of the LuCaP xenografts.</p> <p>Results</p> <p>Based on transcriptomes, the different cancer cell types could be clustered into a luminal-like grouping and a non-luminal-like (also not basal-like) grouping. The non-luminal-like types showed expression more similar to that of stem/progenitor cells than the luminal-like types. However, none showed expression of stem cell genes known to maintain stemness.</p> <p>Conclusions</p> <p>Non-luminal-like types are all representatives of aggressive disease, and this could be attributed to the similarity in overall gene expression to stem and progenitor cell types.</p

Rationale for the Cytogenomics of Cardiovascular Malformations Consortium: A Phenotype Intensive Registry Based Approach

Cardiovascular malformations (CVMs) are the most common birth defect, occurring in 1%-5% of all live births. Although the genetic contribution to CVMs is well recognized, the genetic causes of human CVMs are identified infrequently. In addition, a failure of systematic deep phenotyping of CVMs, resulting from the complexity and heterogeneity of malformations, has obscured genotype-phenotype correlations and contributed to a lack of understanding of disease mechanisms. To address these knowledge gaps, we have developed the Cytogenomics of Cardiovascular Malformations (CCVM) Consortium, a multi-site alliance of geneticists and cardiologists, contributing to a database registry of submicroscopic genetic copy number variants (CNVs) based on clinical chromosome microarray testing in individuals with CVMs using detailed classification schemes. Cardiac classification is performed using a modification to the National Birth Defects Prevention Study approach, and non-cardiac diagnoses are captured through ICD-9 and ICD-10 codes. By combining a comprehensive approach to clinically relevant genetic analyses with precise phenotyping, the Consortium goal is to identify novel genomic regions that cause or increase susceptibility to CVMs and to correlate the findings with clinical phenotype. This registry will provide critical insights into genetic architecture, facilitate genotype-phenotype correlations, and provide a valuable resource for the medical community

Exome Sequencing Identifies Candidate Genetic Modifiers of Syndromic and Familial Thoracic Aortic Aneurysm Severity

Thoracic aortic aneurysm (TAA) is a genetic disease predisposing to aortic dissection. It is important to identify the genetic modifiers controlling penetrance and expressivity to improve clinical prognostication. Exome sequencing was performed in 27 subjects with syndromic or familial TAA presenting with extreme phenotypes (15 with severe TAA; 12 with mild or absent TAA). Family-based analysis of a subset of the cohort identified variants, genes, and pathways segregating with TAA severity among three families. A rare missense variant in ADCK4 (p.Arg63Trp) segregated with mild TAA in each family. Genes and pathways identified in families were further investigated in the entire cohort using the optimal unified sequence kernel association test, finding significance for the gene COL15A1 (p = 0.025) and the retina homeostasis pathway (p = 0.035). Thus, we identified candidate genetic modifiers of TAA severity by exome-based study of extreme phenotypes, which may lead to improved risk stratification and development of new medical therapies

Evaluation of Multi-Level Barriers and Facilitators in a Large Diabetic Retinopathy Screening Program in Federally Qualified Health Centers: A Qualitative Study

BACKGROUND: Recommended annual diabetic retinopathy (DR) screening for people with diabetes has low rates in the USA, especially in underserved populations. Telemedicine DR screening (TDRS) in primary care clinics could expand access and increase adherence. Despite this potential, studies have observed high variability in TDRS rates among clinics and over time, highlighting the need for implementation supports. Previous studies of determinants of TDRS focus on patients\u27 perspectives, with few studies targeting upstream multi-level barriers and facilitators. Addressing this gap, this qualitative study aimed to identify and evaluate multi-level perceived determinants of TDRS in Federally Qualified Health Centers (FQHCs), to inform the development of targeted implementation strategies. METHODS: We developed a theory-based semi-structured interview tool based on the Consolidated Framework for Implementation Research (CFIR). We conducted 22 key informant interviews with professionals involved in TDRS (administrators, clinicians, staff). The interviews were audio-recorded and transcribed verbatim. Reported barriers and facilitators were organized into emergent themes and classified according to CFIR constructs. Constructs influencing TDRS implementation were rated for each study site and compared across sites by the investigators. RESULTS: Professionals identified 21 main barriers and facilitators under twelve constructs of the five CFIR domains. Several identified themes were novel, whereas others corroborated previous findings in the literature (e.g., lack of time and human resources, presence of a champion). Of the 21 identified themes, 13 were classified under the CFIR’s Inner Setting domain, specifically under the constructs Compatibility and Available Resources. Themes under the Outer Setting domain (constructs External Incentives and Cost) were primarily perceived by administrators, whereas themes in other domains were perceived across all professional categories. Two Inner Setting (Leadership Engagement, Goals and Feedback) and two Process (Champion, Engaging) constructs were found to strongly distinguish sites with high versus low TDRS performance. CONCLUSIONS: This study classified barriers and facilitators to TDRS as perceived by administrators, clinicians, and staff in FQHCs, then identified CFIR constructs that distinguished high- and low-performance clinics. Implementation strategies such as academic detailing and collection and communication of program data and successes to leadership; engaging of stakeholders through involvement in implementation planning; and appointment of intervention champions may therefore improve TDRS implementation and sustainment in resource-constrained settings