To design and establish a prospective biospecimen repository that integrates multi-omics assays with clinical data to study mechanisms of controlled injury and healing.
Elective surgery is an ...opportunity to understand both the systemic and focal responses accompanying controlled and well-characterized injury to the human body. The overarching goal of this ongoing project is to define stereotypical responses to surgical injury, with the translational purpose of identifying targetable pathways involved in healing and resilience, and variations indicative of aberrant peri-operative outcomes.
Clinical data from the electronic medical record combined with large-scale biological data sets derived from blood, urine, fecal matter, and tissue samples are collected prospectively through the peri-operative period on patients undergoing 14 surgeries chosen to represent a range of injury locations and intensities. Specimens are subjected to genomic, transcriptomic, proteomic, and metabolomic assays to describe their genetic, metabolic, immunologic, and microbiome profiles, providing a multidimensional landscape of the human response to injury.
The highly multiplexed data generated includes changes in over 28,000 mRNA transcripts, 100 plasma metabolites, 200 urine metabolites, and 400 proteins over the longitudinal course of surgery and recovery. In our initial pilot dataset, we demonstrate the feasibility of collecting high quality multi-omic data at pre- and postoperative time points and are already seeing evidence of physiologic perturbation between timepoints.
This repository allows for longitudinal, state-of-the-art geno-mic, transcriptomic, proteomic, metabolomic, immunologic, and clinical data collection and provides a rich and stable infrastructure on which to fuel further biomedical discovery.
Purpose
Hepatic steatosis (fatty liver disease) affects 25% of the world's population, particularly people with HIV (PWH). Pharmacoepidemiologic studies to identify medications associated with ...steatosis have not been conducted because methods to evaluate liver fat within digitized images have not been developed. We determined the accuracy of a deep learning algorithm (automatic liver attenuation region‐of‐interest‐based measurement ALARM) to identify steatosis within clinically obtained noncontrast abdominal CT images compared to manual radiologist review and evaluated its performance by HIV status.
Methods
We performed a cross‐sectional study to evaluate the performance of ALARM within noncontrast abdominal CT images from a sample of patients with and without HIV in the US Veterans Health Administration. We evaluated the ability of ALARM to identify moderate‐to‐severe hepatic steatosis, defined by mean absolute liver attenuation <40 Hounsfield units (HU), compared to manual radiologist assessment.
Results
Among 120 patients (51 PWH) who underwent noncontrast abdominal CT, moderate‐to‐severe hepatic steatosis was identified in 15 (12.5%) persons via ALARM and 12 (10%) by radiologist assessment. Percent agreement between ALARM and radiologist assessment of absolute liver attenuation <40 HU was 95.8%. Sensitivity, specificity, positive predictive value, and negative predictive value of ALARM were 91.7% (95%CI, 51.5%–99.8%), 96.3% (95%CI, 90.8%–99.0%), 73.3% (95%CI, 44.9%–92.2%), and 99.0% (95%CI, 94.8%–100%), respectively. No differences in performance were observed by HIV status.
Conclusions
ALARM demonstrated excellent accuracy for moderate‐to‐severe hepatic steatosis regardless of HIV status. Application of ALARM to radiographic repositories could facilitate real‐world studies to evaluate medications associated with steatosis and assess differences by HIV status.
Improving the affinity of a high‐affinity protein–protein interaction is a challenging problem that has practical applications in the development of therapeutic biomolecules. We used a combination of ...structure‐based computational methods to optimize the binding affinity of an antibody fragment to the I‐domain of the integrin VLA1. Despite the already high affinity of the antibody (Kd ∼7 nM) and the moderate resolution (2.8 Å) of the starting crystal structure, the affinity was increased by an order of magnitude primarily through a decrease in the dissociation rate. We determined the crystal structure of a high‐affinity quadruple mutant complex at 2.2 Å. The structure shows that the design makes the predicted contacts. Structural evidence and mutagenesis experiments that probe a hydrogen bond network illustrate the importance of satisfying hydrogen bonding requirements while seeking higher‐affinity mutations. The large and diverse set of interface mutations allowed refinement of the mutant binding affinity prediction protocol and improvement of the single‐mutant success rate. Our results indicate that structure‐based computational design can be successfully applied to further improve the binding of high‐affinity antibodies.
Patients with locally advanced or recurrent rectal cancer often require multimodality treatment. Intraoperative radiation therapy (IORT) is a focal approach which aims to improve local control.
We ...retrospectively reviewed 42 patients treated with IORT following definitive resection of a locally advanced or recurrent rectal cancer from 2000-2009. All patients were treated with the Intrabeam® Photon Radiosurgery System (PRS). A dose of 5 Gy was prescribed to a depth of 1 cm (surface dose range: 13.4-23.1, median: 14.4 Gy). Median survival times were calculated using Kaplan-Meier analysis.
Of 42 patients, 32 had recurrent disease (76%) while 10 had locally advanced disease (24%). Eighteen patients (43%) had tumors fixed to the sidewall. Margins were positive in 19 patients (45%). Median follow-up after IORT was 22 months (range 0.2-101). Median survival time after IORT was 34 months. The 3-year overall survival rate was 49% (43% for recurrent and 65% for locally advanced patients). Local recurrence was evaluable in 34 patients, of whom 32% failed. The 1-year local recurrence rate was 16%. Distant metastasis was evaluable in 30 patients, of whom 60% failed. The 1-year distant metastasis rate was 32%. No intraoperative complications were attributed to IORT. Median duration of IORT was 35 minutes (range: 14-39). Median discharge time after surgery was 7 days (range: 2-59). Hydronephrosis after IORT occurred in 10 patients (24%), 7 of whom had documented concomitant disease recurrence.
The Intrabeam® PRS appears to be a safe technique for delivering IORT in rectal cancer patients. IORT with PRS marginally increased operative time, and did not appear to prolong hospitalization. Our rates of long-term toxicity, local recurrence, and survival rates compare favorably with published reports of IORT delivery with other methods.
We report measurements of the Sunyaev-Zel'dovich (SZ) effect in three high-redshift ( super(0.89 less than or equal to z less than or equal to 1.03)), X-ray selected galaxy clusters. The observations ...were obtained at 30 GHz during the commissioning period of a new, eight-element interferometer-the Sunyaev-Zel'dovich Array (SZA)-built for dedicated SZ effect observations. The SZA observations are sensitive to angular scales larger than those subtended by the virial radii of the clusters. Assuming isothermality and hydrostatic equilibrium for the intracluster medium and gas-mass fractions consistent with those for clusters at moderate redshift, we calculate electron temperatures, gas masses, and total cluster masses from the SZ data. The SZ-derived masses, integrated approximately to the virial radii, are 1.9 sub(-0.1) x 10 super(14) M for Cl J1415.1+3612, 3.4 super(?) sub(-) super(?) sub(0) super(?) sub(.) super(0) sub(5) super(.6) x 10 super(14) M for Cl J1429.0+4241, and 7.2 super(?) sub(-) super(?) sub(0) super(?) sub(.) super(1) sub(9) super(.3) x 10 super(14) M for Cl J1226.9+3332. The SZ-derived quantities are in good agreement with the cluster properties derived from X-ray measurements.
While it may seem intuitive that using an ensemble of multiple conformations of a receptor in structure-based virtual screening experiments would necessarily yield improved enrichment of actives ...relative to using just a single receptor, it turns out that at least in the p38 MAP kinase model system studied here, a very large majority of all possible ensembles do not yield improved enrichment of actives. However, there are combinations of receptor structures that do lead to improved enrichment results. We present here a method to select the ensembles that produce the best enrichments that does not rely on knowledge of active compounds or sophisticated analyses of the 3D receptor structures. In the system studied here, the small fraction of ensembles of up to 3 receptors that do yield good enrichments of actives were identified by selecting ensembles that have the best mean GlideScore for the top 1% of the docked ligands in a database screen of actives and drug-like “decoy” ligands. Ensembles of two receptors identified using this mean GlideScore metric generally outperform single receptors, while ensembles of three receptors identified using this metric consistently give optimal enrichment factors in which, for example, 40% of the known actives outrank all the other ligands in the database.
Introduction
To date, no study has compared laparoscopy (LB) to percutaneous (PB) biopsy for the diagnosis of abdominal lymphoma. The objective of this study is to compare the success rate and safety ...profile of laparoscopic lymph node biopsy to the percutaneous approach in patients with intra-abdominal lymphadenopathy concerning for lymphoma.
Materials and methods
We performed a multi-institution, retrospective review of patients undergoing lymph node biopsy for suspected intra-abdominal lymphoma between 2005 and 2013. Our primary outcome was adequate tissue yield between the two techniques, both for histologic diagnosis and for ancillary studies such as flow cytometry. Secondary outcomes included 30-day morbidity, 30-day readmission rates, the need for additional lymph node biopsy procedures, and length of stay.
Results
All 34 of the LB patients had adequate specimen for histologic diagnosis compared to 92.3 % of patients with a PB (
p
= 0.18). Significantly more patients in the LB group had sufficient tissue for ancillary studies when needed than in the PB group, 95.5 and 68.2 %, respectively (
p
= 0.04). A second biopsy was pursued in 23.1 % of failed PB patients, 0 % with success on second attempt.
Discussion
When index of suspicion is high or when biopsy is performed for patient previously diagnosed with lymphoma and recurrence/transformation is suspected, LB safely and consistently provides adequate tissue for initial diagnosis and for ancillary studies. In contrast, image-guided PB may be more appropriate for patients for whom ancillary studies are unlikely to add to planned treatments or when there is a high risk of complications from either general anesthesia or patient comorbidities.
The Breakthrough Listen Search for Intelligent Life MacMahon, David H. E.; Price, Danny C.; Lebofsky, Matthew ...
Publications of the Astronomical Society of the Pacific,
04/2018, Letnik:
130, Številka:
986
Journal Article
Recenzirano
The Breakthrough Listen Initiative is undertaking a comprehensive search for radio and optical signatures from extraterrestrial civilizations. An integral component of the project is the design and ...implementation of widebandwidth data recorder and signal processing systems. The capabilities of these systems, particularly at radio frequencies, directly determine survey speed; further, given a fixed observing time and spectral coverage, they determine sensitivity as well. Here, we detail the Breakthrough Listen wide-bandwidth data recording system deployed at the 100 m aperture Robert C. Byrd Green Bank Telescope. The system digitizes up to 6 GHz of bandwidth at 8 bits for both polarizations, storing the resultant 24 GB s−1 of data to disk. This system is among the highest data rate baseband recording systems in use in radio astronomy. A future system expansion will double recording capacity, to achieve a total Nyquist bandwidth of 12 GHz in two polarizations. In this paper, we present details of the system architecture, along with salient configuration and disk-write optimizations used to achieve high-throughput data capture on commodity compute servers and consumer-class hard disk drives.
Estimating the ambient concentration of nitrogen dioxide (NO
) is challenging because NO
generated by local fossil fuel combustion varies greatly in concentration across space and time. This study ...demonstrates an integrated hybrid approach combining dispersion modeling and land use regression (LUR) to predict daily NO
concentrations at a high spatial resolution (e.g., 50 m) in the New York tri-state area. The daily concentration of traffic-related NO
was estimated at the Environmental Protection Agency's NO
monitoring sites in the study area for the years 2015-2017, using the Research LINE source (R-LINE) model with inputs of traffic data provided by the Highway Performance and Management System and meteorological data provided by the NOAA Integrated Surface Database. We used the R-LINE-predicted daily concentrations of NO
to build mixed-effects regression models, including additional variables representing land use features, geographic characteristics, weather, and other predictors. The mixed model was selected by the Elastic Net method. Each model's performance was evaluated using the out-of-sample coefficient of determination (R
) and the square root of mean squared error (RMSE) from ten-fold cross-validation (CV). The mixed model showed a good prediction performance (CV R
: 0.75-0.79, RMSE: 3.9-4.0 ppb). R-LINE outputs improved the overall, spatial, and temporal CV R
by 10.0%, 18.9% and 7.7% respectively. Given the output of R-LINE is point-based and has a flexible spatial resolution, this hybrid approach allows prediction of daily NO
at an extremely high spatial resolution such as city blocks.
This study analyzed clinical success, patency, and limb salvage after endovascular repair in patients treated for chronic limb ischemia presenting with claudication versus critical limb ischemia. ...Between October 2001 and August 2004, 115 patients (mean age 71) underwent endovascular treatment for infrainguinal arterial disease. Techniques included subintimal angioplasty and transluminal angioplasty with or without stents. Lesions were classified according to Transatlantic InterSociety Consensus. Follow-up (mean 11 months) included physical exam, ankle-brachial index, and duplex ultrasound. Patency rates were determined using Kaplan-Meier and compared by log-rank analysis. One hundred ninety-nine lesions were treated in 121 limbs using percutaneous techniques. Comorbidities were similar except higher rates of diabetes mellitus (67% vs 41%, P < 0.001) and chronic renal insufficiency (22% vs 7%, P < 0.05) were found in critical limb ischemia patients. Primary patency for claudicants was 100 per cent, 98 per cent, and 85 per cent at 3, 6, and 12 months and 89 per cent, 80 per cent, and 72 per cent for critical limb ischemia, respectively (P = 0.06). Limb salvage was 91 per cent at 12 months for critical limb ischemia patients. Morbidity was similar between groups, and there was no perioperative mortality. Percutaneous intervention for both claudication and critical limb ischemia provides acceptable 12 month patency with limited morbidity.
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