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Improved health-related quality of life (HRQOL) is an important outcome following durable left ventricular assist device (LVAD) implant. However, half of pre-implant HRQOL data are incomplete in The Society of Thoracic Surgeons' Intermacs registry. Pre-implant HRQOL incompleteness may reflect patient status or hospital resources to capture HRQOL data. We hypothesized that pre-implant HRQOL incompleteness predicts 90 day outcomes and serves as a novel quality metric.Risk factors for pre-implant HRQOL (EQ-5D-5L visual analog scale; 12-item Kansas City Cardiomyopathy Questionnaire "KCCQ") incompleteness were examined by stepwise logistic modeling. Direct standardization method was used to calculate adjusted incompleteness rates using a mixed effects logistic model. Hospitals were dichotomized as low or high based on median adjusted incompleteness rates. Andersen-Gill models were used to associate pre-implant HRQOL adjusted incompleteness rate with adverse events within 90 day post-implant.The study cohort included 14,063 patients receiving a primary LVAD (4/2012-8/2017). HRQOL incompleteness at high-rate hospitals was more often due to administrative reasons (risk difference, EQ-5D: 10.1%; KCCQ-12: 11.6%) and less likely due to patient reasons (risk difference, EQ-5D: -8.9%; KCCQ-12: -11.4%). A 10% increase in the adjusted pre-implant EQ-5D incompleteness rate was significantly associated with higher risk of infection-related mortality (HR: 1.09), infection (HR: 1.05), and renal dysfunction (HR: 1.03). A 10% increase in the adjusted pre-implant KCCQ-12 incompleteness rate was significantly associated with higher risk of infection (HR: 1.04).Hospital adjusted pre-implant HRQOL incompleteness was predictive of 90-day post-implant outcomes and may serve as a novel quality metric.

Mitochondrial activity differs markedly between organs, but it is not known how and when this arises. Here we show that cell lineage-specific expression profiles involving essential mitochondrial genes emerge at an early stage in mouse development, including tissue-specific isoforms present before organ formation. However, the nuclear transcriptional signatures were not independent of organelle function. Genetically disrupting intra-mitochondrial protein synthesis with two different mtDNA mutations induced cell lineage-specific compensatory responses, including molecular pathways not previously implicated in organellar maintenance. We saw downregulation of genes whose expression is known to exacerbate the effects of exogenous mitochondrial toxins, indicating a transcriptional adaptation to mitochondrial dysfunction during embryonic development. The compensatory pathways were both tissue and mutation specific and under the control of transcription factors which promote organelle resilience. These are likely to contribute to the tissue specificity which characterizes human mitochondrial diseases and are potential targets for organ-directed treatments.

Background Informed consent forms consist of large blocks of written information that may be difficult for patients to understand. Visual teaching aids are promising, however, they have not been studied as a pre-operative educational tool for common surgical procedures. We pilot tested the use of a visual teaching aid during the informed consent process for a colectomy. Methods A randomized pilot study was performed. Participants were randomized into the visual teaching aid group or standard care. Following the consent process, participants were questioned about potential surgical complications, anxiety, satisfaction, and understanding. Results 30 participants were enrolled. Potential complication recall and patient-reported understanding were improved in the visual group (p = 0.01, p = 0.03). Anxiety levels were reduced in the visual group (p = 0.02). No statistically significant data were found for satisfaction (p = 0.75). Conclusions Utilizing a visual teaching aid during the consent process for colectomy increases patient recall of risks, reduces anxiety, and improves understanding.

In 1926, the German biologist Johanna (Hanni) Hrabowski published a study of the morphology and development of the fetal placenta in lizards that has proven to be of historical importance. Her anatomical descriptions and interpretations identified developmental patterns that differ from other amniotes -- features now recognized as unique attributes of squamate (lizards and snakes) development. Her 1926 monograph presented the first histological comparison of fetal membranes in closely-related oviparous and viviparous reptiles, thereby establishing a comparative framework for understanding placental specializations for viviparity. Hrabowski reported that yolk sac development did not differ between oviparous and viviparous species. The novel, shared components of yolk sac development she identified are now recognized as the foundation for the unique yolk sac placenta of reptiles, the omphaloplacenta. In addition, Hrabowski's extensive ontogenetic sampling and the detail and accuracy of her anatomical descriptions set high standards for subsequent studies of comparative evolutionary embryology.

Metallic, nanocomposite, thin-films with intertwined morphologies can be synthesized via physical vapor deposition of two immiscible metals. Understanding the phase-ordering kinetics controlling the way the microstructure develops is crucial to obtaining reliable and enhanced functionalities in these nanostructured thin-films. Here, we study the complex relationship between the vapor-deposition conditions and the resulting self-assembled nanoscale morphologies by using phase-field simulations. Our phase-field model accounts for the deposition of the incident vapor phase of a binary alloy onto a substrate, surface interdiffusion, and the subsequent spinodal decomposition in the resulting elastically inhomogeneous thin-film. We systematically investigated the effects of deposition rate, dissimilar bulk and surface kinetics, phase fraction, and dissimilar elastic response on the resulting microstructure. Four distinct classes of achievable self-assembled microstructure morphologies are observed throughout: lateral, vertical, random, and nanoprecipitate concentration modulations. Through our systematic investigation of competing mechanisms, we provide insights on the complex relationships between alloy species and deposition conditions to obtain specific nanostructured morphologies of binary, nanocomposite, thin-films.

Studies of the association between aircraft noise and hypertension are complicated by inadequate control for potential confounders and a lack of longitudinal assessments, and existing evidence is inconclusive.We evaluated the association between long-term aircraft noise exposure and risk of hypertension among post-menopausal women in the Women's Health Initiative Clinical Trials, an ongoing prospective U.S.Day-night average (DNL) and night equivalent sound levels (LThere were 18,783 participants with non-missing DNL exposure and 14,443 with non-missing L

Spurred in part by growing production from renewable sources and adoption of electric vehicles, dynamic pricing programs for electricity are increasingly being used to influence the shape of residential demand. The most common time-variant prices are time-of-use (TOU) prices, which vary by hour of day, and event-based prices, which take effect during idiosyncratic ``critical'' events. We present evidence on the effects of TOU prices and event-based prices when implemented in isolation versus simultaneously. The key finding is that time-variant prices reduce demand during critical events by 19% when event-based pricing is implemented in isolation, but only 5% when TOU and event-based prices are implemented together. The results suggest that price complexity may dull consumer responsiveness to price signals.

Epigenetic mechanisms may underlie air pollution-health outcome associations. We estimated gaseous air pollutant-DNA methylation (DNAm) associations using twelve subpopulations within Women's Health Initiative (WHI) and Atherosclerosis Risk in Communities (ARIC) cohorts (n = 8397; mean age 61.3 years; 83% female; 46% African-American, 46% European-American, 8% Hispanic/Latino). We used geocoded participant address-specific mean ambient carbon monoxide (CO), nitrogen oxides (NO2; NOx), ozone (O3), and sulfur dioxide (SO2) concentrations estimated over the 2-, 7-, 28-, and 365-day periods before collection of blood samples used to generate Illumina 450 k array leukocyte DNAm measurements. We estimated methylome-wide, subpopulation- and race/ethnicity-stratified pollutant-DNAm associations in multi-level, linear mixed-effects models adjusted for sociodemographic, behavioral, meteorological, and technical covariates. We combined stratum-specific estimates in inverse variance-weighted meta-analyses and characterized significant associations (false discovery rate; FDR 0.05). We attempted replication in the Cooperative Health Research in Region of Augsburg (KORA) study and Normative Aging Study (NAS). We observed a -0.3 (95% CI: -0.4, -0.2) unit decrease in percent DNAm per interquartile range (IQR, 7.3 ppb) increase in 28-day mean NO2 concentration at cg01885635 (chromosome 3; regulatory region 290 bp upstream from ZNF621; FDR = 0.03). At intragenic sites cg21849932 (chromosome 20; LIME1; intron 3) and cg05353869 (chromosome 11; KLHL35; exon 2), we observed a -0.3 (95% CI: -0.4, -0.2) unit decrease (FDR = 0.04) and a 1.2 (95% CI: 0.7, 1.7) unit increase (FDR = 0.04), respectively, in percent DNAm per IQR (17.6 ppb) increase in 7-day mean ozone concentration. Results were not fully replicated in KORA and NAS. We identified three CpG sites potentially susceptible to gaseous air pollution-induced DNAm changes near genes relevant for cardiovascular and lung disease. Further harmonized investigations with a range of gaseous pollutants and averaging durations are needed to determine the effect of gaseous air pollutants on DNA methylation and ultimately gene expression.

This single-surgeon retrospective study examined a consecutive series of direct anterior approach total hip arthroplasties (THAs). Differences for the accuracy of acetabular component placement, leg length discrepancy, femoral offset, and absolute global offset difference were measured for patients who underwent hip replacement surgery with either fluoroscopic or robotic guidance.One hundred THAs were included in both the fluoroscopically guided and robotically guided groups in the study. The program TraumaCad was used to analyze the preoperative and 6-week postoperative standing anteroposterior pelvic radiographs used in this study to evaluate the accuracy of component positioning.Robotic-guided surgery demonstrated a small improvement in acetabular inclination error, 3.8° average robotic error vs 4.63° average fluoroscopic error (P.01). There was no statistically significant difference in accuracy for acetabular anteversion, leg length discrepancy, femoral offset, or global offset difference between the 2 groups. There was also no significant difference in the placement of acetabular components into the Lewinnek safe zone or Callanan safe zone. Both fluoroscopically guided and robotically guided THA patients had similar patterns of error, with excessive anteversion and inclination being more common than inadequate anteversion or inclination.The findings from our study question the use of haptic robotic guidance during direct anterior approach THA when compared to fluoroscopic guidance.

Co-deposited, immiscible alloy systems form hierarchical microstructures under specific deposition conditions that accentuate the difference in constituent element mobility. The mechanism leading to the formation of these unique hierarchical morphologies during the deposition process is difficult to identify, since the characterization of these microstructures is typically carried out post-deposition. We employ phase-field modeling to study the evolution of microstructures during deposition combined with microscopy characterization of experimentally deposited thin films to reveal the origin of the formation mechanism of hierarchical morphologies in co-deposited, immiscible alloy thin films. Our results trace this back to the significant influence of a local compositional driving force that occurs near the surface of the growing thin film. We show that local variations in the concentration of the vapor phase near the surface, resulting in nuclei (i.e., a cluster of atoms) on the film’s surface with an inhomogeneous composition, can trigger the simultaneous evolution of multiple concentration modulations across multiple length scales, leading to hierarchical morphologies. We show that locally, the concentration must be above a certain threshold value in order to generate distinct hierarchical morphologies in a single domain.

We mathematically model, fabricate, and test a counter-gravity heat pipe with a unique header and artery system. The header and artery system augments the capillary limit of traditional heat pipes with homogeneous wicks by incorporating a low resistance pathway for liquid return from the condenser to the evaporator. Unlike other composite wick designs for low resistance liquid return to the evaporator, the header and artery system enables priming of the wick structure for counter-gravity start-up. We tested a stainless steel-water heat pipe with the header and artery system. This header and artery heat pipe demonstrated reliable counter-gravity start-up with a capillary limit augmentation of over four times that of the same heat pipe with a conventional homogeneous wick. This result is in agreement with a theory developed by Chisholm (1978).

The complexity of radiation effects in a material’s microstructure makes developing predictive models a difficult task. In principle, a complete list of all possible reactions between defect species being considered can be used to elucidate damage evolution mechanisms and its associated impact on microstructure evolution. However, a central limitation is that many models use a limited and incomplete catalog of defect energetics and associated reactions. Even for a given model, estimating its input parameters remains a challenge, especially for complex material systems. Here, we present a computational analysis to identify the extent to which defect accumulation, energetics, and irradiation conditions can be determined via forward and reverse regression models constructed and trained from large data sets produced by cluster dynamics simulations. A global sensitivity analysis, via Sobol’ indices, concisely characterizes parameter sensitivity and demonstrates how this can be connected to variability in defect evolution. Based on this analysis and depending on the definition of what constitutes the input and output spaces, forward and reverse regression models are constructed and allow for the direct calculation of defect accumulation, defect energetics, and irradiation conditions. This computational analysis, exercised on a simplified cluster dynamics model, demonstrates the ability to design predictive surrogate and reduced-order models, and provides guidelines for improving model predictions within the context of forward and reverse engineering of mathematical models for radiation effects in a materials’ microstructure.

Objectives mcr-9.1 is a newly described mobile colistin resistance gene. We have noted its presence in multiple species of carbapenem-resistant Enterobacterales (CRE) from our institution. We aimed to determine the clinical features, genomic context and phenotypic impact of mcr-9.1 carriage in a series of patients between 2010 and 2019. Methods We identified 32 patients with mcr-9.1-carrying CRE isolates (mCRE) and collected demographic, antimicrobial exposure and infection data. Whole-genome sequencing (including short and long reads) was performed on 32 isolates. We assessed sequence similarity of mcr-9.1-harbouring plasmids, then compared our findings with plasmids for which sequence data were publicly available. Results There was no colistin exposure in patients prior to isolation of mCRE. mcr-9.1 was identified on IncHI2 plasmids across four different bacterial species and was co-located with blaIMP-4 in 23/30 plasmids studied. mCRE isolates did not demonstrate phenotypic colistin resistance, either at baseline or following sublethal colistin exposure, thus showing that mcr-9.1 alone is not sufficient for resistance. Publicly available sequence data indicated the presence of carbapenemase genes in 236/619 mcr-9.1-carrying genomes (38%). IncHI2 plasmids carrying mcr-9.1 and carbapenemase genes were detected in genomes from North America, Europe, North Africa, Asia and Oceania. Conclusions Spread of mcr-9.1 in CRE from our institution was driven by IncHI2 ‘superplasmids’, so termed because of their large size and their prolific carriage of resistance determinants. These were also detected in global CRE genomes. Phenotypic colistin resistance was not detected in our isolates but remains to be determined from global mCRE.

A coupled phase-field model is presented for simulating physical vapor deposition (PVD) of multi-phase materials, including the effects of phase nucleation. This model is utilized to study the role of initial substrate phase and temperature distributions, which are important experimental deposition parameters, on PVD of a generic allotropic metal with two stable phases. PVD simulations are performed for the deposition of a high temperature phase below its phase transition temperature, and for bicrystal and amorphous substrates with a Gaussian temperature distribution. Several general observations are made from these simulations. During the initial stages of PVD, the substrate phase distribution acts as a template for the growing phases. As the thin film continues to grow, the release of latent heat due to deposition creates a temperature gradient within the film, i.e., regions near the film surface become hotter than near the substrate. Additionally, a substrate with a defined temperature distribution that encompasses temperatures above and below the phase transition temperature, allows for distinguishable regions within the thin film where different phases are stable and continue to grow. Three-dimensional simulations provide additional insight into the role of substrate temperature and phase distribution on the resulting microstructure with different flux rates.

Background Long-term exposure to ambient particulate matter (PM) has been previously linked with higher risk of cardiovascular events. This association may be mediated, at least partly, by increasing the risk of incident hypertension, a key determinant of cardiovascular risk. However, whether long-term exposure to PM is associated with incident hypertension remains unclear. Methods Using national geostatistical models incorporating geographic covariates and spatial smoothing, we estimated annual average concentrations of residential fine (PM 2.5 ), respirable (PM 10 ), and course (PM 10–2.5 ) fractions of particulate matter among 44,255 post-menopausal women free of hypertension enrolled in the Women's Health Initiative (WHI) clinical trials. We used time-varying Cox proportional hazards models to evaluate the association between long-term average residential pollutant concentrations and incident hypertension, adjusting for potential confounding by sociodemographic factors, medical history, neighborhood socioeconomic measures, WHI study clinical site, clinical trial, and randomization arm. Results During 298,383 person-years of follow-up, 14,511 participants developed incident hypertension. The adjusted hazard ratios per interquartile range (IQR) increase in PM 2.5 , PM 10 , and PM 10–2.5 were 1.13 (95% CI: 1.08, 1.17), 1.06 (1.03, 1.10), and 1.01 (95% CI: 0.97, 1.04), respectively. Statistically significant concentration-response relationships were identified for PM 2.5 and PM 10 fractions. The association between PM 2.5 and hypertension was more pronounced among non-white participants and those residing in the Northeastern United States. Conclusions In this cohort of post-menopausal women, ambient fine and respirable particulate matter exposures were associated with higher incidence rates of hypertension. These results suggest that particulate matter may be an important modifiable risk factor for hypertension.

Physical vapor deposition (PVD) simulations are performed using a phase-field model to study microstructure evolution in single-phase polycrystalline materials as a function of deposition conditions. Specifically, this work focuses on the influence of (i) polycrystalline substrate microstructure with low-angle and high-angle grain boundaries (GBs), (ii) incident vapor flux rate, and (iii) model parameters controlling grain evolution dynamics. Simulation results show that low-angle and high-angle GBs in the substrate promote the formation of low-angle and high-angle GBs within the deposited thin film, in qualitative agreement with experimental reports. Changing the vapor flux rate has a significant influence on the deposited microstructure. A relatively low flux rate is found to provide a thin film with no subsurface porosity, smoothed surface roughness, and a mixture of grain sizes. With an increased vapor flux rate, uniformly distributed surface columnar features are observed with subsurface porosity. The GBs migrate during growth to align with these surface features. At the largest flux rate studied, a dendritic style microstructure is formed where the GBs tend to align with and grow along the regions of low phase density within the thin film. Finally, a parametric study is performed on the phase-field model grain evolution parameters to elucidate their role on grain boundary thickness, internal grain variations and grain rotation during simulated PVD.

Background Screening for internal carotid artery stenosis (ICAS) with Doppler ultrasound is commonly used before cardiovascular surgery. Nevertheless, the relationship between ICAS and procedure-related stroke in isolated aortic valve replacement is unclear. Methods We retrospectively reviewed patients with artery stenosis who underwent ICAS screening before surgical (SAVR) or transcatheter aortic valve replacement (TAVR) between January 2007 and August 2014. Logistic regression models were used to determine the relation between post-procedure stroke and total (sum of left and right ICAS) and maximal unilateral ICAS. Age, sex, history of atrial fibrillation, cerebrovascular disease and diabetes, left ventricular ejection fraction, and procedure type were considered as covariates. Two-subgroup analyses were performed in patients who underwent TAVR and SAVR, adjusting for procedure specific details. Results A total of 996 patients underwent ICAS screening before TAVR (n = 467) or SAVR (n = 529). The prevalence of at least ≥70% ICAS was 5.2% (n = 52) and incidence of 30-day stroke was 3.4% (n = 34). Eight patients who underwent carotid intervention before valve replacement and 6 patients with poor Doppler images were excluded from the final analysis. We found no statistically significant association between stroke and either the total or maximal unilateral ICAS for all patients ( p = 0.13 and p = 0.39, respectively) or those undergoing TAVR ( p = 0.27 and p = 0.63, respectively) or SAVR ( p = 0.21 and p = 0.36, respectively). Conclusions We found no statistically significant association between ICAS severity procedure-related stroke after aortic valve replacement. This suggests that universal carotid Doppler screening before isolated TAVR or SAVR is unnecessary.

Fire is the most commonly occurring major accident hazard in the chemical and process industries, with industry accident statistics highlighting the liquid pool fire as the most frequent fire event. Modelling of such phenomena feeds heavily into industry risk assessment and consequence analyses. Traditional simple empirical equations cannot account for the full range of factors influencing pool fire behaviour or increasingly complex plant design. The use of Computational Fluid Dynamics (CFD) modelling enables a greater understanding of pool fire behaviour to be gained numerically and provides the capability to deal with complex scenarios. This paper presents an evaluation of the Fire Dynamics Simulator (FDS) for predictive modelling of liquid pool fire burning rates. Specifically, the work examines the ability of the model to predict temporal variations in the burning rate of open atmosphere pool fires. Fires ranging from 0.4 to 4 m in diameter, involving ethanol and a range of liquid hydrocarbons as fuels, are considered and comparisons of predicted fuel mass loss rates are compared to experimental measurements. The results show that the liquid pyrolysis sub-model in FDS gives consistent model performance for fully predictive modelling of liquid pool fire burning rates, particularly during quasi-steady burning. However, the model falls short of predicting the subtleties associated with each phase of the transient burning process, failing to reliably predict fuel mass loss rates during fire growth and extinction. The results suggest a range of model modifications which could lead to improved prediction of the transient fire growth and extinction phases of burning for liquid pool fires, specifically, investigation of: ignition modelling techniques for high boiling temperature liquid fuels; a combustion regime combining both infinite and finite-rate chemistry; a solution method which accounts for two- or three-dimensional heat conduction effects in the liquid-phase; alternative surrogate fuel compositions for multi-component hydrocarbon fuels; and modification of the solution procedure used at the liquid-gas interface during fire extinction.

Two models are presented based on the phase-field methodology to simulate thin film growth during physical vapor deposition (PVD), including subsurface microstructure evolution, for isotropic single-phase polycrystalline materials. The first model couples previous phase-field modeling efforts on ballistic deposition of single-phase materials and grain orientation evolution in polycrystalline materials in a sequential simulation algorithm. The second model incorporates both PVD and grain evolution dynamics into a single free energy functional for use in a phase-field model. To illustrate the capability of the proposed models in capturing combined thin film growth and subsurface grain evolution, PVD simulations of a generic single-phase polycrystalline metal are performed on substrates with different grain sizes. In both models, when the initial substrate grain sizes are smaller than the expected surface features, the thin film grains coarsen via grain boundary (GB) migration until the GBs become aligned with the valleys between the columnar surface features. Thus, each columnar feature is associated with a distinct subsurface grain, in qualitative agreement with experimental observations. Differences between the models arise when initial substrate grain sizes are larger than the surface columnar features. For example, when using the single free energy functional approach, grains contain noticeable internal low-angle variations, which are not captured using the coupled model.

Summary Mutations of mtDNA are an important cause of human disease, but few animal models exist. Because mammalian mitochondria cannot be transfected, the development of mice with pathogenic mtDNA mutations has been challenging, and the main strategy has therefore been to introduce mutations found in cell lines into mouse embryos. Here, we describe a phenotype-driven strategy that is based on detecting clonal expansion of pathogenic mtDNA mutations in colonic crypts of founder mice derived from heterozygous mtDNA mutator mice. As proof of concept, we report the generation of a mouse line transmitting a heteroplasmic pathogenic mutation in the alanine tRNA gene of mtDNA displaying typical characteristics of classic mitochondrial disease. In summary, we describe a straightforward and technically simple strategy based on mouse breeding and histology to generate animal models of mtDNA-mutation disease, which will be of great importance for studies of disease pathophysiology and preclinical treatment trials., Graphical Abstract Image 1, Highlights • We present a method to isolate and identify pathogenic mtDNA mutations in mice • We describe a mouse with a pathogenic mutation in the mitochondrial tRNAALA gene • The mice display disrupted mitochondrial translation as a result of the mutation • The mice display molecular and histochemical symptoms of human mitochondrial disease, Kauppila et al. describe a phenotype-based screen in live mice to generate mouse models with pathogenic mtDNA mutations. As proof of concept, they present a mouse with a mutation in the mitochondrial tRNAALA gene that displays molecular and histochemical symptoms of human mitochondrial disease.

Individuals suffering from diabetes have an increased risk of developing cardiovascular complications such as heart failure. Heart failure can be a result of the stiffening of the left ventricle, which occurs when cardiac fibroblasts become "active" and begin to remodel the extracellular matrix (ECM). Fibroblast "activation" can be triggered by the AGE/RAGE signaling cascade. Advanced Glycation End products (AGEs) are produced and accumulate in the ECM over time in a healthy individual, but under hyperglycemic conditions, this process is accelerated. In this study, we investigated how the presence of AGEs in either non-diabetic or diabetic ECM affected fibroblast-mediated matrix remodeling. In order to address this question, diabetic and non-diabetic fibroblasts were embedded in 3D matrices composed of collagen isolated from either non-diabetic or diabetic mice. Fibroblast function was assessed using gel contraction, migration, and protein expression. Non-diabetic fibroblasts displayed similar gel contraction to diabetic cells when embedded in diabetic collagen. Thus, suggesting the diabetic ECM can alter fibroblast function from an "inactive" to "active" state. Addition of AGEs increase the AGE/RAGE cascade leading to increased gel contraction, whereas inhibiting the cascade resulted in little or no gel contraction. These results indicated 1) the ECM from diabetic and non-diabetic mice differ from one another, 2) diabetic ECM can impact fibroblast function and shift them toward an "active" state, and 3) that fibroblasts can modify the ECM through activation of the AGE/RAGE signaling cascade. These results suggested the importance of understanding the impact diabetes has on the ECM and fibroblast function.

The Cardiac Society of Australia and New Zealand (CSANZ) and the Australia and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) have joined together to provide recommendations for institutions and individual operators to assess their ability to initiate and maintain a transcatheter valve program. Transcatheter aortic valve replacement has been developed as an alternative to traditional surgical replacement of the aortic valve in high risk patients, particularly the frail elderly. The position paper has endorsed the important role of a multi-disciplinary "Heart Team" in selecting patients for TAVI as fundamental to the establishment of a successful program. The paper outlines recommendations for the cardiologist to have a background in structural intervention and the surgeon to have experience in high-risk aortic valve replacement. It is further recommended that TAVI programs be established in high volume cardiac surgical centres where on site valve surgery is performed. The paper is intended to provide guidance to individual operators and prospective institutions considering the establishment of a successful TAVI program.

Summary Background The habenula consists of an evolutionarily conserved set of nuclei that control neuromodulator release. In lower vertebrates, the dorsal habenula receives innervation from sensory regions, but the significance of this is unclear. Here, we address the role of the habenula in olfaction by imaging neural activity in larval zebrafish expressing GCaMP3 throughout the habenula and by carrying out behavioral assays. Results Activity in several hundred neurons throughout the habenula was recorded using wide-field fluorescence microscopy, fast focusing, and deconvolution. This enabled the creation of 4D maps of odor-evoked activity. Odors activated the habenula in two broad spatiotemporal patterns. Increasing concentrations of a putative social cue (a bile salt) evoked a corresponding increase in neuronal activity in the right dorsal habenula. In behavioral assays, fish were attracted to intermediate concentration of this cue but avoided higher concentration. Increasing cholinergic activity through nicotine exposure rendered the intermediate concentration aversive in a habenula-dependent manner. Pharmacologically blocking nicotinic receptors or lesioning the right dorsal habenula attenuated avoidance. Conclusions These data provide physiological and functional evidence that the habenula functions as a higher center in zebrafish olfaction and suggest that activity in the right dorsal subdomain gates innate attraction to specific odors.

Primary cardiac tumors are extremely rare. Although complete surgical resection of malignant primary cardiac tumors results in an improved survival compared with no intervention, the overall prognosis is generally poor, with treatable recurrent primary cardiac sarcomas being extremely rare. We report a patient with a recurrent primary cardiac sarcoma obstructing the left atrium managed with radical cardiac resection, including right pneumonectomy, with 21-month postprocedural survival.

Objectives This study sought to perform clinical and imaging assessments of the DESolve Bioresorbable Coronary Scaffold (BCS). Background BCS, which is drug eluting, may have potential advantages compared with conventional metallic drug-eluting stents. The DESolve system, designed to provide vessel support and neointimal suppression, combines a poly-l-lactic acid–based scaffold with the antiproliferative myolimus. Methods The DESolve First-in-Man (A NON-RANDOMIZED, CONSECUTIVE ENROLLMENT EVALUATION OF THE DESolve MYOLIMUS ELUTING BIORESORBABLE CORONARY STENT IN THE TREATMENT OF PATIENTS WITH DE NOVO NATIVE CORONARY ARTERY LESIONS) trial was a prospective multicenter study enrolling 16 patients eligible for treatment. The principal safety endpoint was a composite of cardiac death, myocardial infarction, and clinically indicated target lesion revascularization. The principal imaging endpoint was in-scaffold late lumen loss (LLL) assessed by quantitative coronary angiography (QCA) at 6 months. Intravascular ultrasound (IVUS) and optical coherence tomography (OCT) imaging was performed at baseline and 6 months; multislice computed tomography (MSCT) was performed at 12 months. Results Acute procedural success was achieved in 15 of 15 patients receiving a study scaffold. At 12 months, there was no scaffold thrombosis and no major adverse cardiac events directly attributable to the scaffold. At 6 months, in-scaffold LLL (by QCA) was 0.19 ± 0.19 mm; neointimal volume (by IVUS) was 7.19 ± 3.56%, with no evidence of scaffold recoil or late malapposition. Findings were confirmed with OCT and showed uniform, thin neointimal coverage (0.12 ± 0.04 mm). At 12 months, MSCT demonstrated excellent vessel patency. Conclusions This study demonstrated the feasibility and efficacy of the DESolve BCS. Results showing low in-scaffold LLL, low % neointimal volume at 6 months, no chronic recoil, and maintenance of lumen patency at 12 months prompt further study. (DESolve First-in-Man; EudraCT number 2011-000027-32)

Laser-induced forward transfer (LIFT) has already been used to fabricate various types of organic light-emitting diodes (OLEDs), and the process itself has been optimised and refined considerably since OLED pixels were first demonstrated. In particular, a dynamic release layer (DRL) of triazene polymer has been used, the environmental pressure has been reduced down to a medium vacuum, and the donor receiver gap has been controlled with the use of spacers. Insight into the LIFT process's effect upon OLED pixel performance is presented here, obtained through optimisation of three-colour polyfluorene-based OLEDs. A marked dependence of the pixel morphology quality on the cathode metal is observed, and the laser transfer fluence dependence is also analysed. The pixel device performances are compared to conventionally fabricated devices, and cathode effects have been looked at in detail. The silver cathode pixels show more heterogeneous pixel morphologies, and a correspondingly poorer efficiency characteristics. The aluminium cathode pixels have greater green electroluminescent emission than both the silver cathode pixels and the conventionally fabricated aluminium devices, and the green emission has a fluence dependence for silver cathode pixels. (C) 2012 Elsevier B.V. All rights reserved.

Background Elevated percent positivity (≥30%) of Legionella in hospital domestic water systems has been suggested as a metric for assessing the risk of health care–acquired Legionnaires' disease (LD). Methods We examined the validity of this metric by analyzing data from peer-reviewed studies containing reports of Legionella prevalence in hospital water (ie, percent positivity) and temporally matched reports of patients with health care–acquired LD. Results Our literature review identified 31 peer-reviewed publications reporting matched data. We abstracted a total of 206 data points, representing 119 hospitals, from these articles. We determined that the proposed 30% positivity metric has 59% sensitivity and 74% specificity (ie, a 41% false-negative rate and a 26% false-positive rate). These notable error rates could have significant implications, given that we identified 16 peer-reviewed articles and 6 government guidance documents that referenced the 30% positivity metric as a risk assessment tool. Conclusions Environmental sampling of hospital water distribution systems for Legionella can be an important component of risk management for LD. However, the possible consequence of using a percent positivity metric with low sensitivity and specificity is that many hospitals might fail to mitigate when a true risk is present, or might unnecessarily allocate limited resources to deal with a negligible risk.

I use a new sample of families linked between the 1860 and 1880 U.S. censuses to study the impact of migration to frontier cities on job holding. Using variation in transportation costs between different regions of the country to generate exogenous migration, I find frontier city migration had significant job-holding benefits. The impact of migration on job holding was 68% greater for immigrants than for the native born. Expectations about job holding were the most important factor in the decision to migrate to a frontier city. Clerical workers, unskilled blue-collar workers, immigrants, and the poor were also the most likely to migrate. These results show the benefits of geographic mobility and suggest the contribution of frontier cities to economic opportunity in America's past.

A simple 1-D model has been developed for the velocity of flyers in vacuum generated by laser-induced forward transfer (LIFT) with a dynamic release layer (DRL). It is an extension of a laser ablation model for metal flyer plates based on the Gurney model of explosive output for driving metal fragments. The model has been extended to the bilayer system of a DRL overlain with a transfer layer. The suitability of the model has been checked with experimental velocity data obtained from shadowgraphy. The experiments used bilayer samples of triazene polymer/aluminium, ablated from the backside through the substrate at reduced pressure (5 × 10−2 mbar). The results suggest that the Gurney energy approach provides the basis of a viable, physically relevant, algebraic model for LIFT, but other loss mechanisms still need be incorporated, particularly thermal loss into the fused silica substrate.

Transient, repetitive ischemia (RI) stimulates coronary collateral growth (CCG) in normal, healthy (SD) rats, which requires p38 MAPK activation. In contrast, RI does not induce CCG in the metabolic syndrome (JCR) rats, which is associated with lack of p38 MAPK activation. The functional consequences of p38 MAPK activation in CCG remain unknown. Theoretically, effective collateral growth would require extracellular matrix remodeling; however, direct assessment as well as identification of proteases responsible for this degradation are lacking. In this study, we investigated the role of p38 MAPK in the regulation of matrix metalloproteinases 2 and 9 (MMPs 2 and 9) and their requirement for CCG in SD vs. JCR rats. The rats underwent the RI protocol (8 LAD occlusions, 40 sec each, every 20 min, in 8 hr cycles for 0, 3, 6, or 9 days). MMP expression was measured in the ischemic, collateral-dependent zone (CZ) and the normal zone (NZ) by Western blot, and MMP activity by zymography. Expression and activation of MMP 2 and 9 were significantly increased (~3.5 fold) on day 3 of RI in the CZ of SD rats. In vivo p38 MAPK inhibition completely blocked RI-induced MMP 2 and 9 expression and activation. MMP activation correlated with increased degradation of components of the basement membrane and the vascular elastic laminae: elastin (~3 fold), laminin (~3 fold) and type IV collagen (~2 fold). This was blocked by MMP 2 and 9 inhibition, which also abolished RI-induced CCG. In contrast, in JCR rats, RI did not induce expression or activation of MMP 2 or 9 and there was no associated degradation of elastin, laminin or type IV collagen. In conclusion, MMP 2 and 9 activation is essential for CCG and is mediated, in part, by p38 MAPK. Furthermore, compromised CCG in the metabolic syndrome may be partially due to the lack of p38 MAPK-dependent activation of MMP 2 and 9 and resultant decreased extracellular matrix degradation.

Reduction or binding of Fe(III) by agent(s) produced by a highly toxigenic strain of Alexandrium excavatum was detected at approximately the same levels in culture filtrates of this dinoflagellate grown either axenically or non-axenically. Nanomolar concentrations of pure Paralytic Shellfish Poisons (PSP) produced by this phytoplankton, the carbamate toxins saxitoxin, 2/3 gonyautoxin or the N-sulfamoyl carbamate toxins C1/C2, added to a Schwyn and Neilands (1987) assay mixture did not stimulate Fe(III) reduction or binding. In contrast, additions of the N-sulfamoyl carbamate toxin, gonyautoxin V (GTXV also known as B1) alone resulted in a several-fold increase in this activity. The level of activity per cell was considerably higher for those cultures grown in media deficient in iron than in those whose growth was restricted by decreases of either N or P.

Exposure of exponentially growing cells of a toxigenic dinoflagellate strain, Alexandrium fundyense , to ammonium chloride concentrations comparable to levels of ammonia observed in Bay of Fundy waters induced formation in a few days of large numbers of double-walled, circular cysts (termed forced cysts). The A. fundyense forced cysts were distinctly different from the asexual pellicle cysts, and the sexual resting cysts (hypnocysts) described by Anderson and Wall (1978) . The circular shape of these forced cysts and their relatively rapid formation suggest that they were not products of fusion while their resistance to adverse conditions and, when returned to optimal conditions, their subsequent rapid germination to form viable cultures within 14 days, point to an important long-term survival role in response to rapidly changing nutritional and environmental circumstances as well as in the waxing and waning of local toxic dinoflagellate blooms. The relative ease of producing the forced cysts and their fairly rapid germination suggest that these cysts could be suitable vehicles for investigations of the physiology and biochemistry of encystment and excystment in the species producing them. Chemical analyses of forced cysts harvested from cultures of this A. fundyense strain showed large variabilities in selected storage products: iron ranged from 0.03 pg to 17.40 pg Fe/cyst corresponding to 0.04–61.25% of the cyst dry weight; nitrogen levels ranged from 109 pg to 3183 pg/cyst and phosphorus ranged from 0.55 pg to 5.70 pg/cyst. Total paralytic shellfish poisons for these A. fundyense cysts consisted of the same toxins apparent in the vegetative cells, i.e. C1C2 toxins, GTX 2/3, saxitoxin and neosaxitoxin, and ranged from 4.4 fmol to 333 fmol/fg cyst dry wt.

Human gammaherpesviruses such as Epstein-Barr virus (EBV) cause lifelong infections and associated diseases, by virtue of their ability to establish latent infection. Many studies performed in the past years in murine herpesvirus 68 (MHV-68) model of infection suggested that the limited immunity generated against isolated viral components by subunit vaccines cannot counteract the multiple immune evasion strategies operated by gammaherpesviruses. Indeed, a significant inhibition of long-term latency establishment could be observed in mice vaccinated with strains of genetically modified MHV-68 defective in reactivation or establishment of latency. In this study, we focused on the effects of interferon-α (IFN-α) on both the lytic and latent phase of MHV-68 infection, as exerted by the constitutive release of IFN-α1 by a clone of MHV-68 genetically modified to produce this cytokine (MHV-68mIFNα1). Although the MHV-68mIFNα1 recombinant virus exhibited in vitro replication features indistinguishable from those of the wild type MHV-68, its pathological properties were severely attenuated in vivo in immunocompetent mice and not in mice rendered genetically unresponsive to type I IFN, suggesting that a stronger immune response was primed in the presence of the cytokine. Notably, MHV-68mIFNα1 attenuation did not result in a reduced level of long-term spleen latency establishment. These results prompted us to evaluate the efficacy of MHV-68mIFNα1 in a prophylactic vaccination regimen aimed at inhibiting the symptoms of acute virus infection and the establishment of long-term latency after MHV-68 challenge. Our results show that mice vaccinated with MHV-68mIFNα1, administered as a live-attenuated or partially inactivated (by Psoralen and UV treatment) vaccine, were protected against the challenge with wt MHV-68 from all phases of infection. The ability of MHV-68mIFNα1 to produce IFN-α at the site of the infection, thus efficiently stimulating the immune system in case of virus reactivation from latency, makes this recombinant virus a safer live-attenuated vaccine as compared to the previously reported latency-deficient clones.

The tachykinins are implicated in neurogenic inflammation and the neuropeptide substance P in particular has been shown to be a proinflammatory mediator. A role for the tachykinins in host response to viral infection has been previously demonstrated using either TAC1- or NK1 receptor-deficient transgenic mice. However, due to redundancy in the peptide-receptor complexes we wished determine whether a deficiency in TAC1 and NK1(R) in combination exhibited an enhanced phenotype. TAC1 and NK1(R)-deficient mice were therefore crossed to generate transgenic mice in both (NK1(-/-)×TAC1(-/-)). As expected, after infection with the respiratory pathogen murine gammaherpesvirus (MHV-68), TAC1 and NK1(R)-deficient mice were more susceptible to infection than wild-type C57BL/6 controls. However, unexpectedly, NK1(-/-)×TAC1(-/-) mice were more resistant to infection arguing for a lack of feedback inhibition through alternative receptors in these mice. Histopathological examination did not show any great differences in the inflammatory responses between groups of infected animals, except for the presence of focal perivascular B cell accumulations in lungs of all the knockout mice. These were most pronounced in the NK1(-/-)×TAC1(-/-) mice. These results confirm an important role for TAC1 and NK1(R) in the control of viral infection but reinforce the complex nature of the peptide-receptor interactions.

Tachykinins encoded by the preprotachykinin A (TAC1) gene such as substance P (SP) and neurokinin A (NKA) are involved in neurogenic inflammatory processes via predominantly neurokinins 1 and 2 (NK1 and NK2) receptor activation, respectively. Endokinins and hemokinins encoded by the TAC4 gene also have remarkable selectivity and potency for the NK1 receptors and might participate in inflammatory cell functions. The aim of the present study was to investigate endotoxin-induced airway inflammation and consequent bronchial hyper-reactivity in TAC1(-/-), NK1(-/-) and also in double knockout (TAC1(-/-)/NK1(-/-)) mice. Sub-acute interstitial lung inflammation was evoked by intranasal Escherichia coli lipopolysaccharide (LPS) in the knockout mice and their wildtype C57BL/6 counterparts 24 h before measurement. Respiratory parameters were measured with unrestrained whole body plethysmography. Bronchoconstriction was induced by inhalation of the muscarinic receptor agonist carbachol and Penh (enhanced pause) correlating with airway resistance was calculated. Lung interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) concentrations were measured with ELISA. Histological evaluation was performed and a composite morphological score was determined. Myeloperoxidase (MPO) activity in the lung was measured with spectrophotometry to quantify the number of infiltrating neutrophils/macrophages. Airway hyper-reactivity was significantly reduced in the TAC1(-/-) as well as the TAC1(-/-)/NK1(-/-) groups. However, LPS-induced histological inflammatory changes (perivascular/peribronchial oedema, neutrophil infiltration and goblet cell hyperplasia), MPO activity and TNF-alpha concentration were markedly diminished only in TAC1(-/-) mice. Interestingly, the concentrations of both cytokines, IL-1beta and TNF-alpha, were significantly greater in the NK1(-/-) group. These data clearly demonstrated on the basis of histology, MPO and cytokine measurements that TAC1 gene-derived tachykinins, SP and NKA, play a significant role in the development of endotoxin-induced murine airway inflammation, but not solely via NK1 receptor activation. However, in inflammatory bronchial hyper-responsiveness other tachykinins, such as hemokinin-1 acting through NK1 receptors also might be involved.