Predicting Composition of Genetic Circuits with Resource Competition: Demand and Sensitivity.

The design of genetic circuits typically relies on characterization of constituent modules in isolation to predict the behavior of modules' composition. However, it has been shown that the behavior of a genetic module changes when other modules are in the cell due to competition for shared resources. In order to engineer multimodule circuits that behave as intended, it is thus necessary to predict changes in the behavior of a genetic module when other modules load cellular resources. Here, we introduce two characteristics of circuit modules: the demand for cellular resources and the sensitivity to resource loading. When both are known for every genetic module in a circuit library, they can be used to predict any module's behavior upon addition of any other module to the cell. We develop an experimental approach to measure both characteristics for any circuit module using a resource sensor module. Using the measured resource demand and sensitivity for each module in a library, the outputs of the modules can be accurately predicted when they are inserted in the cell in arbitrary combinations. These resource competition characteristics may be used to inform the design of genetic circuits that perform as predicted despite resource competition.

Predictors of failure of high flow nasal cannula failure in acute hypoxemic respiratory failure due to COVID-19.

Hypoxemic respiratory failure is a common manifestation of COVID-19 pneumonia. Early in the COVID-19 pandemic, patients with hypoxemic respiratory failure were, at times, being intubated earlier than normal; in part because the options of heated humidified high flow nasal cannula (HFNC) and non-invasive ventilation (NIV) were considered potentially inadequate and to increase risk of virus aerosolization. To understand the benefits and factors that predict success and failure of HFNC in this population, we evaluated data from the first 30 sequential patients admitted with COVID-19 pneumonia to our center who were managed with HFNC. We conducted Cox Proportional Hazards regression models to evaluate the factors associated with high flow nasal cannula failure (outcome variable), using time to intubation (censoring variable), while adjusting for comorbidities and immunosuppression. In the majority of our patients (76.7%), the use of HFNC failed and the patients were ultimately placed on mechanical ventilation. Those at increased risk of failure had a higher sequential organ failure assessment score, and at least one comorbidity or history of immunosuppression. Our data suggest that high flow nasal cannula may have a role in some patients with COVID-19 presenting with hypoxemic respiratory failure, but careful patient selection is the likely key to its success.

Statin prescription rates and their facility-level variation in patients with peripheral artery disease and ischemic cerebrovascular disease: Insights from the Department of Veterans Affairs.

The 2013 American College of Cardiology/American Heart Association cholesterol guideline recommends moderate to high-intensity statin therapy in patients with peripheral artery disease (PAD) and ischemic cerebrovascular disease (ICVD). We examined frequency and facility-level variation in any statin prescription and in guideline-concordant statin prescriptions in patients with PAD and ICVD receiving primary care in 130 facilities across the Veterans Affairs (VA) health care system between October 2013 and September 2014. Guideline-concordant statin intensity was defined as the prescription of high-intensity statins in patients with PAD or ICVD ≤75 years and at least moderate-intensity statins in those >75 years. We calculated median rate ratios (MRR) after adjusting for patient demographic factors to assess the magnitude of facility-level variation in statin prescribing patterns independent of patient characteristics. Among 194,151 PAD patients, 153,438 patients (79.0%) were prescribed any statin and 79,435 (40.9%) were prescribed a guideline-concordant intensity of statin. PAD patients without ischemic heart disease were prescribed any statin and a guideline-concordant intensity of statin therapy less frequently (69.1% and 28.9%, respectively). Among 339,771 ICVD patients, 265,491 (78.1%) were prescribed any statin and 136,430 (40.2%) were prescribed a guideline-concordant intensity of statin. ICVD patients without ischemic heart disease were prescribed any statin and a guideline-concordant intensity of statin less frequently (70.9% and 30.5%, respectively). MRRs for both PAD and ICVD patients demonstrated a 20% and 28% variation among two facilities in treating two identical patients with statin therapy and guideline-concordant intensity of statin therapy, respectively. The prescription of statins, especially guideline-recommended intensity of statin therapy, is suboptimal in PAD and ICVD patients, with significant facility-level variation not explained by patient-level factors.

Orbital Infarction due to Sickle Cell Disease without Orbital Pain.

Sickle cell disease is a hemoglobinopathy that results in paroxysmal arteriolar occlusion and tissue infarction that can manifest in a plurality of tissues. Rarely, these infarcted crises manifest in the bony orbit. Orbital infarction usually presents with acute onset of periorbital tenderness, swelling, erythema, and pain. Soft tissue swelling can result in proptosis and attenuation of extraocular movements. Expedient diagnosis of sickle cell orbital infarction is crucial because this is a potentially sight-threatening entity. Diagnosis can be delayed since the presentation has physical and radiographic findings mimicking various infectious and traumatic processes. We describe a patient who presented with sickle cell orbital crisis without pain. This case highlights the importance of maintaining a high index of suspicion in patients with known sickle cell disease or of African descent born outside the United States in a region where screening for hemoglobinopathy is not routine, even when the presentation is not classic.

Signatures of the Primordial Universe from Its Emptiness: Measurement of Baryon Acoustic Oscillations from Minima of the Density Field.

Sound waves from the primordial fluctuations of the Universe imprinted in the large-scale structure, called baryon acoustic oscillations (BAOs), can be used as standard rulers to measure the scale of the Universe. These oscillations have already been detected in the distribution of galaxies. Here we propose to measure BAOs from the troughs (minima) of the density field. Based on two sets of accurate mock halo catalogues with and without BAOs in the seed initial conditions, we demonstrate that the BAO signal cannot be obtained from the clustering of classical disjoint voids, but it is clearly detected from overlapping voids. The latter represent an estimate of all troughs of the density field. We compute them from the empty circumsphere centers constrained by tetrahedra of galaxies using Delaunay triangulation. Our theoretical models based on an unprecedented large set of detailed simulated void catalogues are remarkably well confirmed by observational data. We use the largest recently publicly available sample of luminous red galaxies from SDSS-III BOSS DR11 to unveil for the first time a >3σ BAO detection from voids in observations. Since voids are nearly isotropically expanding regions, their centers represent the most quiet places in the Universe, keeping in mind the cosmos origin and providing a new promising window in the analysis of the cosmological large-scale structure from galaxy surveys.

Intentional left subclavian artery coverage during thoracic endovascular aortic repair for traumatic aortic injury.

BACKGROUND: Thoracic endovascular aortic repair (TEVAR) is widely used for treatment of traumatic aortic injury (TAI). Stent graft coverage of the left subclavian artery (LSA) may be required in up to 40% of patients. We evaluated the long-term effects of intentional LSA coverage (LSAC) on symptoms and return to normal activity in TAI patients compared with a similarly treated group whose LSA was uncovered (LSAU). METHODS: Patients were identified from a prospective institutional trauma registry between September 2005 and July 2012. TAI was confirmed using computed tomography angiography. The electronic medical records, angiograms, and computed tomography angiograms were reviewed in a retrospective fashion. In-person or telephone interviews were conducted using the SF-12v2 (Quality Metrics, Lincoln, RI) to assess quality of life. An additional questionnaire was used to assess specific LSA symptoms and the ability to return to normal activities. Data were analyzed by Spearman rank correlation and multiple linear and logistic regression analysis with appropriate transformations using SAS software (SAS Institute, Cary, NC). RESULTS: During the study period, 82 patients (57 men; mean age 40.5 ± 20 years, mean Injury Severity Score, 34 ± 10.0) underwent TEVAR for treatment of TAI. Among them, LSAC was used in 32 (39.5%) and LSAU in 50. A group of the LSAU patients (n = 22) served as matched controls in the analysis. We found no statistically significant difference in SF-12v2 physical health scores (ρ = -0.08; P = .62) between LSAC and LSAU patients. LSAC patients had slightly better mental health scores (ρ = 0.62; P = .037) than LSAU patients. LSAC patients did not have an increased likelihood of experiencing pain (ρ = -0.0056; P = .97), numbness (ρ = -0.12; P = .45), paresthesia (ρ = -0.11; P = .48), fatigue (ρ = -0.066; P = .69), or cramping (ρ = -0.12; P = .45). We found no difference between groups in the ability to return to activities. The mean follow-up time was 3.35 years. Six LSAC patients (19%) died during the follow-up period of unrelated causes. CONCLUSIONS: Intentional LSAC during TEVAR for TAI appears safe, without compromising mental or physical health outcomes. Furthermore, LSAC does not increase the long-term risk of upper extremity symptoms or impairment of normal activities.