Transcriptional networks specifying homeostatic and inflammatory programs of gene expression in human aortic endothelial cells.

Endothelial cells (ECs) are critical determinants of vascular homeostasis and inflammation, but transcriptional mechanisms specifying their identities and functional states remain poorly understood. Here, we report a genome-wide assessment of regulatory landscapes of primary human aortic endothelial cells (HAECs) under basal and activated conditions, enabling inference of transcription factor networks that direct homeostatic and pro-inflammatory programs. We demonstrate that 43% of detected enhancers are EC-specific and contain SNPs associated to cardiovascular disease and hypertension. We provide evidence that AP1, ETS, and GATA transcription factors play key roles in HAEC transcription by co-binding enhancers associated with EC-specific genes. We further demonstrate that exposure of HAECs to oxidized phospholipids or pro-inflammatory cytokines results in signal-specific alterations in enhancer landscapes and associate with coordinated binding of CEBPD, IRF1, and NFκB. Collectively, these findings identify cis-regulatory elements and corresponding trans-acting factors that contribute to EC identity and their specific responses to pro-inflammatory stimuli

Dynamic fluid shifts induced by fetal bypass

ObjectiveFluid shifts have been suggested to occur with fetal bypass. The degree or mechanisms behind these volume changes (or location) have not been defined. We characterized the preceding and correlated the findings to plasma vasopressin concentrations, the critical peptide of osmoregulation.MethodsSeventeen ovine fetuses (105–111 days' gestation) were started on bypass and followed 2 hours after bypass. Hemodynamics and volume replacements needed to maintain minimum reservoir volume during bypass and normal physiologic parameters after bypass were recorded. Serial blood samples were collected to assess gas exchange and vasopressin levels. Changes in total tissue water content were measured for several organs and the placenta. Plasma volume, fluid shifts, and osmolarity were calculated.ResultsHematocrit values decreased by 15 minutes of bypass to 28% from 33% and then increased to 34% by 120 minutes after bypass, corresponding to a decreased fetal plasma volume of 79 to 72 mL/kg by 120 minutes after bypass. The majority of volume shifts (approximately 100 mL/kg) occurred during bypass, but additional volume replacements were required after bypass to maintain normal hemodynamics, resulting in overall losses of 0.8 mL · kg−1 · min−1. Losses were not accounted for by placental or organ edema. Vasopressin levels increased dramatically with bypass (39–51.5 pg/mL) and were strongly predicted by increased fetal plasma volumes (R2 = 0.90), whereas osmolarity was not significantly associated with plasma volumes.ConclusionFetal bypass leads to significant fluid shifts that correlate strongly with increasing vasopressin levels (but not changes in osmolarity). The placenta is not the primary site of volume loss. Rehydration of the fetus is necessary after bypass

Rapid evaluation of custom instruction selection approaches with FPGA estimation

The main aim of this article is to demonstrate that a fast and accurate FPGA estimation engine is indispensable in design flows for custom instruction (template) selection. The need for a FPGA estimation engine stems from the difficulty in predicting the FPGA performance measures of selected custom instructions. We will present a FPGA estimation technique that partitions the high-level representation of custom instructions into clusters based on the structural organization of the target FPGA, while taking into account general logic synthesis principles adopted by FPGA tools. In this work, we have evaluated a widely used graph covering algorithm with various heuristics for custom instruction selection. In addition, we present an algorithm called Refined Largest Fit First (RLFF) that relies on a graph covering heuristic to select non-overlapping superset templates, which typically incorporate frequently used basic templates. The initial solution is further refined by considering overlapping templates that were ignored previously to see if their introduction could lead to higher performance. While RLFF provides the most efficient cover compared to the ILP method and other graph covering heuristics, FPGA estimation results reveals that RLFF leads to the worst performance in certain applications. It is therefore a worthy proposition to equip design flows with accurate FPGA estimation in order to rapidly determine the most profitable custom instruction approach for a given application.</jats:p

Prognosis of neonatal tetanus in the modern management era: an observational study in 107 Vietnamese infants.

OBJECTIVES: Most data regarding the prognosis in neonatal tetanus originate from regions where limited resources have historically impeded management. It is not known whether recent improvements in critical care facilities in many low- and middle-income countries have affected indicators of a poor prognosis in neonatal tetanus. We aimed to determine the factors associated with worse outcomes in a Vietnamese hospital with neonatal intensive care facilities. METHODS: Data were collected from 107 cases of neonatal tetanus. Clinical features on admission were analyzed against mortality and a combined endpoint of 'death or prolonged hospital stay'. RESULTS: Multivariable analysis showed that only younger age (odds ratio (OR) for mortality 0.69, 95% confidence interval (CI) 0.48-0.98) and lower weight (OR for mortality 0.06, 95% CI 0.01-0.54) were significantly associated with both the combined endpoint and death. A shorter period of onset (OR 0.94, 95% CI 0.88-0.99), raised white cell count (OR 1.17, 95% CI 1.02-1.35), and time between first symptom and admission (OR 3.77, 95% CI 1.14-12.51) were also indicators of mortality. CONCLUSIONS: Risk factors for a poor outcome in neonatal tetanus in a setting with critical care facilities include younger age, lower weight, delay in admission, and leukocytosis

Equivalence Principle Implications of Modified Gravity Models

Theories that attempt to explain the observed cosmic acceleration by modifying general relativity all introduce a new scalar degree of freedom that is active on large scales, but is screened on small scales to match experiments. We show that if such screening occurrs via the chameleon mechanism such as in f(R), it is possible to have order one violation of the equivalence principle, despite the absence of explicit violation in the microscopic action. Namely, extended objects such as galaxies or constituents thereof do not all fall at the same rate. The chameleon mechanism can screen the scalar charge for large objects but not for small ones (large/small is defined by the gravitational potential and controlled by the scalar coupling). This leads to order one fluctuations in the inertial to gravitational mass ratio. In Jordan frame, it is no longer true that all objects move on geodesics. In contrast, if the scalar screening occurrs via strong coupling, such as in the DGP braneworld model, equivalence principle violation occurrs at a much reduced level. We propose several observational tests of the chameleon mechanism: 1. small galaxies should fall faster than large galaxies, even when dynamical friction is negligible; 2. voids defined by small galaxies would be larger compared to standard expectations; 3. stars and diffuse gas in small galaxies should have different velocities, even on the same orbits; 4. lensing and dynamical mass estimates should agree for large galaxies but disagree for small ones. We discuss possible pitfalls in some of these tests. The cleanest is the third one where mass estimate from HI rotational velocity could exceed that from stars by 30 % or more. To avoid blanket screening of all objects, the most promising place to look is in voids.Comment: 27 pages, 4 figures, minor revisions, references added. Accepted for publication in Phys. Rev.

Design of a Novel Low Cost Point of Care Tampon (POCkeT) Colposcope for Use in Resource Limited Settings

Introduction: Current guidelines by WHO for cervical cancer screening in low- and middle-income countries involves visual inspection with acetic acid (VIA) of the cervix, followed by treatment during the same visit or a subsequent visit with cryotherapy if a suspicious lesion is found. Implementation of these guidelines is hampered by a lack of: trained health workers, reliable technology, and access to screening facilities. A low cost ultra-portable Point of Care Tampon based digital colposcope (POCkeT Colposcope) for use at the community level setting, which has the unique form factor of a tampon, can be inserted into the vagina to capture images of the cervix, which are on par with that of a state of the art colposcope, at a fraction of the cost. A repository of images to be compiled that can be used to empower front line workers to become more effective through virtual dynamic training. By task shifting to the community setting, this technology could potentially provide significantly greater cervical screening access to where the most vulnerable women live. The POCkeT Colposcope’s concentric LED ring provides comparable white and green field illumination at a fraction of the electrical power required in commercial colposcopes. Evaluation with standard optical imaging targets to assess the POCkeT Colposcope against the state of the art digital colposcope and other VIAM technologies. Results: Our POCkeT Colposcope has comparable resolving power, color reproduction accuracy, minimal lens distortion, and illumination when compared to commercially available colposcopes. In vitro and pilot in vivo imaging results are promising with our POCkeT Colposcope capturing comparable quality images to commercial systems. Methods: Rapid 3D printing, consumer grade light sources, and cameras were used to construct the TVDC. The TVDC’s concentric LED ring provides comparable white and green field illumination at a fraction of the electrical power required in commercial colposcopes, and crossed polarizers provide a reduction in glare. Evaluation was performed using standard optical imaging targets to assess the TVDC against the state of the art digital colposcope and other VIA technologies. Results: Our TVDC has comparable resolving power, color reproduction accuracy, minimal lens distortion, and illumination when compared to commercially available colposcopes. In vitro and pilot in vivo imaging results are promising with our TVDC capturing images of comparable quality to commercial systems. Conclusion: The TVDC is capable of capturing images suitable for cervical lesion analysis. Our portable low cost system will be useful for increasing access to cervical cancer screening and diagnostics in resource-limited settings by providing a more readily portable and easy to use device for medical personnel.The image data and support information that is published in the article "Design of a Novel Low Cost Trans-Vaginal Digital Colposcope for use in Resource Limited Settings" are available at: http://dukespace.lib.duke.edu/dspace/handle/10161/8357.National Institutes of Health (US) 5R21CA162747-0

Development and validation of a risk score for hospitalization for heart failure in patients with Type 2 Diabetes Mellitus

<p>Abstract</p> <p>Background</p> <p>There are no risk scores available for predicting heart failure in Type 2 diabetes mellitus (T2DM). Based on the Hong Kong Diabetes Registry, this study aimed to develop and validate a risk score for predicting heart failure that needs hospitalisation in T2DM.</p> <p>Methods</p> <p>7067 Hong Kong Chinese diabetes patients without history of heart failure, and without history and clinical evidence of coronary heart disease at baseline were analyzed. The subjects have been followed up for a median period of 5.5 years. Data were randomly and evenly assigned to a training dataset and a test dataset. Sex-stratified Cox proportional hazard regression was used to obtain predictors of HF-related hospitalization in the training dataset. Calibration was assessed using Hosmer-Lemeshow test and discrimination was examined using the area under receiver's operating characteristic curve (aROC) in the test dataset.</p> <p>Results</p> <p>During the follow-up, 274 patients developed heart failure event/s that needed hospitalisation. Age, body mass index (BMI), spot urinary albumin to creatinine ratio (ACR), HbA_1c, blood haemoglobin (Hb) at baseline and coronary heart disease during follow-up were predictors of HF-related hospitalization in the training dataset. HF-related hospitalization risk score = 0.0709 × age (year) + 0.0627 × BMI (kg/m²) + 0.1363 × HbA_1c(%) + 0.9915 × Log₁₀(1+ACR) (mg/mmol) - 0.3606 × Blood Hb(g/dL) + 0.8161 × CHD during follow-up (1 if yes). The 5-year probability of heart failure = 1-S₀(5)^{EXP{0.9744 × (Risk Score - 2.3961)}}. Where S₀(5) = 0.9888 if male and 0.9809 if female. The predicted and observed 5-year probabilities of HF-related hospitalization were similar (p > 0.20) and the adjusted aROC was 0.920 for 5 years of follow-up.</p> <p>Conclusion</p> <p>The risk score had adequate performance. Further validations in other cohorts of patients with T2DM are needed before clinical use.</p