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Background: Complications following total laryngectomy can lead to increased hospital length of stay (LOS) and increased health care costs. Our objective was to determine the efficacy of a clinical care pathway for improving outcomes for patients following total laryngectomy. Methods: This quality improvement study included all adult patients undergoing total laryngectomy-either primary or salvage-at a tertiary referral center between January 2013 and December 2018. The primary outcome was hospital LOS measured in postoperative days. The total and specific postoperative complication frequencies were evaluated, as well as 30-day readmission rates and intensive care unit (ICU) LOS. Results: Sixty-three patients were included in the study: 29 (46.0%) patients before the pathway implementation and 34 (54.0%) patients after pathway implementation. Demographic characteristics between the groups were similar. The prepathway cohort had a higher rate of total complications compared to the postpathway group (relative risk=0.5; 95% CI 0.3-1.0), although the differences in individual complications were similar. The median LOS of 10 days was the same for the 2 cohorts. The median ICU LOS was 1 day greater in the postpathway cohort, but no difference was seen in rates of ICU readmission in the 2 groups. The 30-day readmission rate also was not significant between the 2 groups. Conclusion: Implementation of a postoperative order set pathway for patients undergoing laryngectomy is associated with decreased overall complication rates. Use of a clinical care pathway may improve outcomes in patients undergoing total laryngectomy.

The purpose of the study was to understand the impact of involuntary remote working during the early phases of the COVID-19 pandemic on perceived stress and work-related burnout for workers with and without previous experience of remote work. The authors developed a questionnaire, open from March 23rd to May 19th, 2020, incorporating the Perceived Stress Scale, Copenhagen Burnout Inventory, demographic, and work-related questions. This sample consisted of 256 professionals who self-identified as working at home during the pandemic. Pandemic restrictions increased perceived stress for all participants, but age and gender had significant effects on stress and burnout. Burnout was most significant for respondents already working remotely before COVID-19. The most significant challenges reported were—communication, collaboration, and time management with colleagues via technology. Working from home may contribute to higher levels of perceived stress and work-related burnout, which questions moves by some employers to make working from home a permanent arrangement.

Background Because of their direct patient contact, healthcare workers (HCW) face an unprecedented risk of exposure to COVID-19. The aim of this study was to examine incidence of COVID-19 disease among asymptomatic HCW and community participants in Northern Virginia during 6 months of follow-up. Methods This is a prospective cohort study that enrolled healthy HCW and residents who never had a symptomatic COVID-19 infection prior to enrolment from the community in Northern Virginia from April to November 2020. All participants were invited to enrol in study, and they were followed at 2-, and 6-months intervals. Participants were evaluated by commercial chemiluminescence SARS-CoV-2 serology assays as part of regional health system and public health surveillance program to monitor the spread of COVID-19 disease. Findings Of a total of 1,819 asymptomatic HCW enrolled, 1,473 (96%) had data at two-months interval, and 1,323 (73%) participants had data at 6-months interval. At baseline, 21 (1.15%) were found to have prior COVID-19 exposure. At two-months interval, COVID-19 rate was 2.8% and at six months follow-up, the overall incidence rate increased to 4.8%, but was as high as 7.9% among those who belong to the youngest age group (20–29 years). Seroconversion rates in HCW were comparable to the seropositive rates in the Northern Virginia community. The overall incidence of COVID-19 in the community was 4.5%, but the estimate was higher among Hispanic ethnicity (incidence rate = 15.3%) potentially reflecting different socio-economic factors among the community participants and the HCW group. Using cross-sectional logistic regression and spatio-temporal mixed effects models, significant factors that influence the transmission rate among HCW include age, race/ethnicity, resident ZIP-code, and household exposure, but not direct patient contact. Interpretation In Northern Virginia, the seropositive rate of COVID-19 disease among HCW was comparable to that in the community.

Psychiatric aeromedical evacuations are one of the leading causes of medical related evacuations of US military personnel from combat. Currently, no studies have examined gender and marital status of individuals who were evacuated from combat for a psychiatric diagnosis. Psychiatric aeromedical evacuation data from 5,957 United States military personnel deployed to Iraq or Afghanistan between 2001 and 2013 were analyzed using chi-square tests of independence, odds ratios (OR), and standardized residuals. Analyses showed that female service members were evacuated at higher rates (178 per 100,000) than males (115 per 100,000). When compared to nonmarried females, married females did not present with increased risk of psychiatric aeromedical evacuation on any diagnosis. Married males, however, were more likely to be evacuated than married females for PTSD (OR = 1.98) and TBI (OR = 1.14). Likewise, married males, compared to nonmarried males, were more likely to be evacuated for PTSD (OR = 1.66) and anxiety (OR = 1.38). Although deployments can be extremely stressful experiences for some military service members, they may be especially so among unmarried females and married males. This study provides a unique contribution to enhancing the understanding of risk factors related to psychiatric aeromedical evacuation for deployed service members.

Increasingly, corporate health promotion programs are implementing wellness programs integrating principles of behavioral economics. Employees of a large firm were provided a customized online incentive program to design their own commitments to meet health goals. This study examines patterns of program participation and engagement in health promotion activities. Subjects were US-based employees of a large, nondurable goods manufacturing firm who were enrolled in corporate health benefits in 2010 and 2011. We assessed measures of engagement with the workplace health promotion program (e.g., incentive points earned, weight loss). To further examine behaviors indicating engagement in health promotion activities, we constructed an aggregate, employee-level engagement index. Regression models were employed to assess the association between employee characteristics and the engagement index, and the engagement index and spending. 4220 employees utilized the online program and made 25,716 commitments. Male employees age 18–34 had the highest level of engagement, and male employees age 55–64 had the lowest level of engagement overall. Prior year health status and prior year spending did not show a significant association with the level of engagement with the program (p > 0.05). Flexible, incentive-based behavioral health and lifestyle programs may reach the broader workforce including those with chronic conditions and higher levels of health spending., Highlights • Employee engagement with online health promotion activities declined with age. • No consistent relationship was found between gender and engagement across age groups. • Employees at all levels of spending, including high spending, used the online program. • Employees with chronic conditions used the online health promotion program.

Species richness varies considerably among the tree of life which can only be explained by heterogeneous rates of diversification (speciation and extinction). Previous approaches use phylogenetic trees to estimate branch-specific diversification rates. However, all previous approaches disregard diversification-rate shifts on extinct lineages although 99% of species that ever existed are now extinct. Here we describe a lineage-specific birth-death-shift process where lineages, both extant and extinct, may have heterogeneous rates of diversification. To facilitate probability computation we discretize the base distribution on speciation and extinction rates intokrate categories. The fixed number of rate categories allows us to extend the theory of state-dependent speciation and extinction models (e.g.,BiSSE and MuSSE) to compute the probability of an observed phylogeny given the set of speciation and extinction rates. To estimate branch-specific diversification rates, we develop two independent and theoretically equivalent approaches: numerical integration with stochastic character mapping and data-augmentation with reversible-jump Markov chain Monte Carlo sampling. We validate the implementation of the two approaches in RevBayes using simulated data and an empirical example study of primates. In the empirical example, we show that estimates of the number of diversification-rate shifts are, unsurprisingly, very sensitive to the choice of prior distribution. Instead, branch-specific diversification rate estimates are less sensitive to the assumed prior distribution on the number of diversification-rate shifts and consistently infer an increased rate of diversification for Old World Monkeys. Additionally, we observe that as few as 10 diversification-rate categories are sufficient to approximate a continuous base distribution on diversification rates. In conclusion, our implementation of the lineage-specific birth-death-shift model in RevBayes provides biologists with a method to estimate branch-specific diversification rates under a mathematically consistent model.

Structure-preserving algorithms for solving conservative PDEs with added linear dissipation are generalized to systems with time-dependent damping/driving terms. This study is motivated by several PDE models of physical phenomena, such as Korteweg-de Vries, Klein-Gordon, Schr\"{o}dinger, and Camassa-Holm equations, all with damping/driving terms and time-dependent coefficients. Since key features of the PDEs under consideration are described by local conservation laws, which are independent of the boundary conditions, the proposed (second-order in time) discretizations are developed with the intent of preserving those local conservation laws. The methods are respectively applied to a damped-driven nonlinear Schr\"{o}dinger equation and a damped Camassa-Holm equation. Numerical experiments illustrate the structure-preserving properties of the methods, as well as favorable results over other competitive schemes., Comment: 17 pages, 3 figures

Photometric stereo is a method that seeks to reconstruct the normal vectors of an object from a set of images of the object illuminated under different light sources. While effective in some situations, classical photometric stereo relies on a diffuse surface model that cannot handle objects with complex reflectance patterns, and it is sensitive to non-idealities in the images. In this work, we propose a novel approach to photometric stereo that relies on dictionary learning to produce robust normal vector reconstructions. Specifically, we develop two formulations for applying dictionary learning to photometric stereo. We propose a model that applies dictionary learning to regularize and reconstruct the normal vectors from the images under the classic Lambertian reflectance model. We then generalize this model to explicitly model non-Lambertian objects. We investigate both approaches through extensive experimentation on synthetic and real benchmark datasets and observe state-of-the-art performance compared to existing robust photometric stereo methods., To appear in IEEE Transactions on Computational Imaging

This paper introduces a novel approach to robust surface reconstruction from photometric stereo normal vector maps that is particularly well-suited for reconstructing surfaces from noisy gradients. Specifically, we propose an adaptive dictionary learning based approach that attempts to simultaneously integrate the gradient fields while sparsely representing the spatial patches of the reconstructed surface in an adaptive dictionary domain. We show that our formulation learns the underlying structure of the surface, effectively acting as an adaptive regularizer that enforces a smoothness constraint on the reconstructed surface. Our method is general and may be coupled with many existing approaches in the literature to improve the integrity of the reconstructed surfaces. We demonstrate the performance of our method on synthetic data as well as real photometric stereo data and evaluate its robustness to noise., ICIP 2017

OBJECTIVES/SPECIFIC AIMS: The goal for this project is to determine the feasibility of using a novel multi-photon fiber-coupled microscope to aid surgeons in localizing STN during surgeries. In order to accomplish this goal, we needed to identify the source of a strong autofluorescent signal in the STN and determine whether we could use image classification methods to automatically distinguish STN from surrounding brain regions. METHODS/STUDY POPULATION: We acquired 3 cadaveric brains from the University of Colorado Anschutz Medical Campus, Department of Pathology. Two of these brains were non-PD controls whereas 1 was diagnosed with PD. We dissected a 10 square centimeter region of midbrain surrounding STN, then prepared this tissue for slicing on a vibratome or cryostat. Samples were immuno-labeled for various cellular markers for identification, or left unlabeled in order to observe the autofluorescence for image classification. RESULTS/ANTICIPATED RESULTS: The border of STN is clearly visible based on the density of a strong autofluorescent signal. The autofluorescent signal is visible using 2-photon (850–1040 nm excitation) and conventional confocal microscopy (488–647 nm excitation). We were also able to visualize blood vessels with second harmonic generation. The autofluorescent signal is quenched by high concentrations of Sudan-black B (0.5%–5%), and is primarily localized in microtubule-associated protein-2 (MAP2)+ cells, indicating that it is likely lipofuscin accumulation in neurons. Smaller lipofuscin particles also accumulate in microglia, identified based on ionized calcium binding adopter 1 (Iba1)+ labeling. We anticipate that colocalization analysis will confirm these qualitative observations. Using 2-photon images of the endogenous autofluorescent signal in these samples, we trained a logistic regression-based image classifier using features derived from gray-level co-occurrence matrices. Preliminary testing indicates that our classifier performed well, with a mean accuracy of 0.89 (standard deviation of 0.11) and a Cohen’s Kappa value of 0.76 (standard deviation of 0.24). We are currently using coherent anti-Stokes Raman scattering and third harmonic imaging to identify different features of myelin that can be used to distinguish between these regions and expect similar results. DISCUSSION/SIGNIFICANCE OF IMPACT: Traditional methods for localizing STN during DBS surgery include the use of stereotactic coordinates and multi-electrode recording (MER) during implantation. MERs are incredibly useful in DBS surgeries, but require penetration of brain structures in order to infer location. Using multi-photon microscopy techniques to aid identification of STN during DBS surgeries offers a number of advantages over traditional methods. For example, blood vessels can be clearly identified with second harmonic generation, something that is not possible with MER. Multi-photon microscopy also allows visualization deep into tissue without actually penetrating it. This ability to look within a depth of field is useful for detection of STN borders based on autofluorescent cell density. When combined with traditional stereotactic information, our preliminary image classification methods are a fast, reliable way to provide surgeons with extra information concerning their location in the midbrain. We anticipate that future advancements and refinements to our image classifier will only increase accuracy and the potential applications and value. In summary, these preliminary data support the feasibility of multi-photon microscopy to aid in the identification of target brain regions during DBS surgeries. The techniques described here complement and enhance current stereotactic and electrophysiological methods for DBS surgeries.

Brain metastasis of breast cancer profoundly affects the cognitive and sensory functions as well as morbidity of patients, and the 1 year survival rate among these patients remains less than 20%. However, the pathological mechanism of brain metastasis is as yet poorly understood. In this report, we found that metastatic breast tumour cells in the brain highly expressed IL-1β which then ‘activated’ surrounding astrocytes. This activation significantly augmented the expression of JAG1 in the astrocytes, and the direct interaction of the reactivated astrocytes and cancer stem-like cells (CSCs) significantly stimulated Notch signalling in CSCs. We also found that the activated Notch signalling in CSCs up-regulated HES5 followed by promoting self-renewal of CSCs. Furthermore, we have shown that the blood-brain barrier permeable Notch inhibitor, Compound E, can significantly suppress the brain metastasis in vivo. These results represent a novel paradigm for the understanding of how metastatic breast CSCs re-establish their niche for their self-renewal in a totally different microenvironment, which opens a new avenue to identify a novel and specific target for the brain metastatic disease.

Sparsity-based approaches have been popular in many applications in image processing and imaging. Compressed sensing exploits the sparsity of images in a transform domain or dictionary to improve image recovery from undersampled measurements. In the context of inverse problems in dynamic imaging, recent research has demonstrated the promise of sparsity and low-rank techniques. For example, the patches of the underlying data are modeled as sparse in an adaptive dictionary domain, and the resulting image and dictionary estimation from undersampled measurements is called dictionary-blind compressed sensing, or the dynamic image sequence is modeled as a sum of low-rank and sparse (in some transform domain) components (L+S model) that are estimated from limited measurements. In this work, we investigate a data-adaptive extension of the L+S model, dubbed LASSI, where the temporal image sequence is decomposed into a low-rank component and a component whose spatiotemporal (3D) patches are sparse in some adaptive dictionary domain. We investigate various formulations and efficient methods for jointly estimating the underlying dynamic signal components and the spatiotemporal dictionary from limited measurements. We also obtain efficient sparsity penalized dictionary-blind compressed sensing methods as special cases of our LASSI approaches. Our numerical experiments demonstrate the promising performance of LASSI schemes for dynamic magnetic resonance image reconstruction from limited k-t space data compared to recent methods such as k-t SLR and L+S, and compared to the proposed dictionary-blind compressed sensing method.

Programs for Bayesian inference of phylogeny currently implement a unique and fixed suite of models. Consequently, users of these software packages are simultaneously forced to use a number of programs for a given study, while also lacking the freedom to explore models that have not been implemented by the developers of those programs. We developed a new open-source software package, RevBayes, to address these problems. RevBayes is entirely based on probabilistic graphical models, a powerful generic framework for specifying and analyzing statistical models. Phylogenetic-graphical models can be specified interactively in RevBayes, piece by piece, using a new succinct and intuitive language called Rev. Rev is similar to the R language and the BUGS model-specification language, and should be easy to learn for most users. The strength of RevBayes is the simplicity with which one can design, specify, and implement new and complex models. Fortunately, this tremendous flexibility does not come at the cost of slower computation; as we demonstrate, RevBayes outperforms competing software for several standard analyses. Compared with other programs, RevBayes has fewer black-box elements. Users need to explicitly specify each part of the model and analysis. Although this explicitness may initially be unfamiliar, we are convinced that this transparency will improve understanding of phylogenetic models in our field. Moreover, it will motivate the search for improvements to existing methods by brazenly exposing the model choices that we make to critical scrutiny. RevBayes is freely available at http://www.RevBayes.com [Bayesian inference; Graphical models; MCMC; statistical phylogenetics.].

Grey mullets (Mugilidae, Ovalentariae) are coastal fishes found in near-shore environments of tropical, subtropical, and temperate regions within marine, brackish, and freshwater habitats throughout the world. This group is noteworthy both for the highly conserved morphology of its members---which complicates species identification and delimitation---and also for the uncommon herbivorous or detritivorous diet of most mullets. In this study, we first attempt to identify the number of mullet species, and then---for the resulting species---estimate a densely sampled time-calibrated phylogeny using three mitochondrial gene regions and three fossil calibrations. Our results identify two major subgroups of mullets that diverged in the Paleocene/Early Eocene, followed by an Eocene/Oligocene radiation across both tropical and subtropical habitats. We use this phylogeny to explore the evolution of feeding preference in mullets, which indicates multiple independent origins of both herbivorous and detritivorous diets within this group. We also explore correlations between feeding preference and other variables, including body size, habitat (marine, brackish, or freshwater), and geographic distribution (tropical, subtropical, or temperate). Our analyses reveal: (1) a positive correlation between trophic index and habitat (with herbivorous and/or detritivorous species predominantly occurring in marine habitats); (2) a negative correlation between trophic index and geographic distribution (with herbivorous species occurring predominantly in subtropical and temperate regions), and; (3) a negative correlation between body size and geographic distribution (with larger species occurring predominantly in subtropical and temperate regions).

Multisymplectic methods have recently been proposed as a generalization of symplectic ODE methods to the case of Hamiltonian PDEs. Their excellent long time behavior for a variety of Hamiltonian wave equations has been demonstrated in a number of numerical studies. A theoretical investigation and justification of multisymplectic methods is still largely missing. In this paper, we study linear multisymplectic PDEs and their discretization by means of numerical dispersion relations. It is found that multisymplectic methods in the sense of Bridges and Reich Phys. Lett. A, 284 (2001), pp. 184-193] and Reich J. Comput. Phys., 157 (2000), pp. 473-499], such as Gauss-Legendre Runge-Kutta methods, possess a number of desirable properties such as nonexistence of spurious roots and conservation of the sign of the group velocity. A certain CFL-type restriction on $\Delta t/\Delta x$ might be required for methods higher than second order in time. It is also demonstrated by means of the explicit midpoint method that multistep methods may exhibit spurious roots in the numerical dispersion relation for any value of $\Delta t/\Delta x$ despite being multisymplectic in the sense of discrete variational mechanics [J. E. Marsden, G. P. Patrick, and S. Shkoller, Commun. Math. Phys., 199 (1999), pp. 351-395].

The death of a child in the emergency department (ED) is one of the most challenging problems facing ED clinicians. This revised technical report and accompanying policy statement reaffirm principles of patient- and family-centered care. Recent literature is examined regarding family presence, termination of resuscitation, bereavement responsibilities of ED clinicians, support of child fatality review efforts, and other issues inherent in caring for the patient, family, and staff when a child dies in the ED. Appendices are provided that offer an approach to bereavement activities in the ED, carrying out forensic responsibilities while providing compassionate care, communicating the news of the death of a child in the acute setting, providing a closing ritual at the time of terminating resuscitation efforts, and managing the child with a terminal condition who presents near death in the ED.

Cognitive deficits in various domains have been shown in patients with bipolar disorder and schizophrenia. The purpose of the present study was to examine if residual psychopathology explained the difference in cognitive function between clinically stable patients with schizophrenia and bipolar disorder. We compared the performance on tests of attention, visual and verbal memory, and executive function of 25 patients with schizophrenia in remission and 25 euthymic bipolar disorder patients with that of 25 healthy controls. Mediation analysis was used to see if residual psychopathology could explain the difference in cognitive function between the patient groups. Both patient groups performed significantly worse than healthy controls on most cognitive tests. Patients with bipolar disorder displayed cognitive deficits that were milder but qualitatively similar to those of patients with schizophrenia. Residual negative symptoms mediated the difference in performance on cognitive tests between the two groups. Neither residual general psychotic symptoms nor greater antipsychotic doses explained this relationship. The shared variance explained by the residual negative and cognitive deficits that the difference between patient groups may be explained by greater frontal cortical neurophysiological deficits in patients with schizophrenia, compared to bipolar disorder. Further longitudinal work may provide insight into pathophysiological mechanisms that underlie these deficits.

Historical biogeography is increasingly studied from an explicitly statistical perspective, using stochastic models to describe the evolution of species range as a continuous-time Markov process of dispersal between and extinction within a set of discrete geographic areas. The main constraint of these methods is the computational limit on the number of areas that can be specified. We propose a Bayesian approach for inferring biogeographic history that extends the application of biogeographic models to the analysis of more realistic problems that involve a large number of areas. Our solution is based on a “data-augmentation” approach, in which we first populate the tree with a history of biogeographic events that is consistent with the observed species ranges at the tips of the tree. We then calculate the likelihood of a given history by adopting a mechanistic interpretation of the instantaneous-rate matrix, which specifies both the exponential waiting times between biogeographic events and the relative probabilities of each biogeographic change. We develop this approach in a Bayesian framework, marginalizing over all possible biogeographic histories using Markov chain Monte Carlo (MCMC). Besides dramatically increasing the number of areas that can be accommodated in a biogeographic analysis, our method allows the parameters of a given biogeographic model to be estimated and different biogeographic models to be objectively compared. Our approach is implemented in the program, BayArea. [ancestral area analysis; Bayesian biogeographic inference; data augmentation; historical biogeography; Markov chain Monte Carlo.]

Background: Serotonin (5-HT) modulates cholinergic neurotransmission and exacerbates airway smooth muscle (ASM) contraction in normal animal and nonasthmatic human tissue. Exposure to house dust mite allergen (HDMA) and ozone (O3) leads to airway hyperreactivity and 5-HT-positive cells in the airway epithelium of infant rhesus monkeys. Research shows that concomitant exposure in allergic animals has an additive effect on airway hyperreactivity. Objectives: In this study, the hypothesis is that the exposure of allergic infant rhesus monkeys to HDMA, O3 and in combination, acting through 5-HT receptors, enhances 5-HT modulation of postganglionic cholinergic ASM contraction. Methods: Twenty-four HDMA-sensitized infant monkeys were split into 4 groups at the age of 1 month, and were exposed to filtered air (FA), HDMA, O3 or in combination (HDMA+O3). At the age of 6 months, airway rings were harvested and postganglionic, and parasympathetic-mediated ASM contraction was evaluated using electrical-field stimulation (EFS). Results: 5-HT exacerbated the EFS response within all exposure groups, but had no effect in the FA group. 5-HT2, 5-HT3 and 5-HT4 receptor agonists exacerbated the response. 5-HT concentration-response curves performed after incubation with specific receptor antagonists confirmed the involvement of 5-HT2, 5-HT3 and 5-HT4 receptors. Conversely, a 5-HT1 receptor agonist attenuated the tension across all groups during EFS, and in ASM contracted via exogenous acetylcholine. Conclusions: HDMA, O3 and HDMA+O3 exposure in a model of childhood allergic asthma enhances 5-HT exacerbation of EFS-induced ASM contraction through 5-HT2, 5-HT3 and 5-HT4 receptors. A nonneurogenic inhibitory pathway exists, unaffected by exposure, mediated by 5-HT1 receptors located on ASM.

BACKGROUND AND PURPOSE: CADASIL (cerebral autosomal dominant arteriopathy subcortical infarcts and leukoencephalopathy) is a genetic disorder hallmarked by ischemic stroke and vascular dementia. Characteristic pathological changes in the vasculature include thickening of small arteries and accumulation of heterogeneous material within the vessel wall. We tested whether endothelial von Willebrand factor (vWF) accumulates in CADASIL vessels and whether exposure of smooth muscle cells to vWF alters the expression of smooth muscle gene expression. METHODS: Brain sections obtained at autopsy from six North American CADASIL patients were examined using immunohistochemistry for vWF and IgG. Rat aortic smooth muscle cells (A7R5 cells) were tested for binding to infrared-tag labeled vWF. Finally, A7R5 cells were exposed to vWF, and expression of mature smooth muscle marker genes was analyzed by quantitative reverse transcriptase PCR. RESULTS: vWF is expressed in the penetrating arterial walls in all CADASIL samples. IgG, a marker of serum extravasation, was present only in a minority of arterial walls. vWF binds to smooth muscle cells in vitro, and low concentrations of vWF rapidly activate c-fos, EGR, TSP1, and c-myc while specifically inhibiting RNA encoding smooth muscle actin, calponin, and SM22. CONCLUSIONS: These data demonstrate that vWF, likely produced by the endothelium, permeates the vessel wall of CADASIL brains. Exposure of smooth muscle cells to vWF results in reduction of specific RNAs required for normal vascular homeostasis. This is the first report of accumulation of a protein within CADASIL vessels that inhibits vascular gene expression and implicates a role for vWF beyond hemostasis.

For the archaeon Methanococcus maripaludis, a fully sequenced and annotated model species of hydrogenotrophic methanogen, we report validation of quantitative protein level expression ratios on a proteome-wide basis. Using an approach based on quantitative multidimensional capillary HPLC and quadrupole ion trap mass spectrometry, coverage of gene expression approached that currently achievable with transcription microarrays. Comprehensive mass-spectrometry-based proteomics and spotted cDNA arrays were used to compare global protein and mRNA levels in a wild-type (S2) and mutant strain (S40) of M. maripaludis. Using linear regression with 652 expression ratios generated by both the proteomic and microarray methods, a product moment correlation coefficient of 0.24 was observed. The correlation improved to 0.61 if only genes showing significant expression changes were included. A novel two-stage method of outlier detection was employed for the protein measurements when Dixon’s Q-test by itself failed to give satisfactory results. The log2 transformations of the number of peptides or isotopic peptide pairs associated with each ORF, divided by the predicted molecular weight, were found to have moderately positive correlations with two bioinformatic predictors of gene expression based on codon bias. We detected peptides derived from 939 proteins or 55% of the genome coding capacity. Of these, 60 were over-expressed and 34 were under-expressed in the mutant. Of the 1722 ORFs encoded in the genome, 1597 or 93% were probed by cDNA arrays. Of these, 50 were more highly expressed and 45 showed lower expression levels in the mutant relative to the wild-type. 15 ORFs were shown to be over-expressed by both methods and 2 ORFs were shown to be over-expressed by proteomics and under-expressed by microarray.

Among the archaea, Methanococcus maripaludis has the unusual ability to use l - or d -alanine as a nitrogen source. To understand how this occurs, we tested the roles of three adjacent genes encoding homologs of alanine dehydrogenase, alanine racemase, and alanine permease. To produce mutations in these genes, we devised a method for markerless mutagenesis that builds on previously established genetic tools for M . maripaludis . The technique uses a negative selection strategy that takes advantage of the ability of the M . maripaludis hpt gene encoding hypoxanthine phosphoribosyltransferase to confer sensitivity to the base analog 8-azahypoxanthine. In addition, we developed a negative selection method to stably incorporate constructs into the genome at the site of the upt gene encoding uracil phosphoribosyltransferase. Mutants with in-frame deletion mutations in the genes for alanine dehydrogenase and alanine permease lost the ability to grow on either isomer of alanine, while a mutant with an in-frame deletion mutation in the gene for alanine racemase lost only the ability to grow on d -alanine. The wild-type gene for alanine dehydrogenase, incorporated into the upt site, complemented the alanine dehydrogenase mutation. Hence, the permease is required for the transport of either isomer, the dehydrogenase is specific for the l isomer, and the racemase converts the d isomer to the l isomer. Phylogenetic analysis indicated that all three genes had been acquired by lateral gene transfer from the low-moles-percent G+C gram-positive bacteria.

Background To compare one-year all-cause and uterine fibroid (UF)-related direct costs in patients treated with one of the following three uterine-sparing procedures: magnetic resonance-guided focused ultrasound (MRgFUS), uterine artery embolization (UAE) and myomectomy. Methods This retrospective observational cohort study used healthcare claims for several million individuals with healthcare coverage from employers in the MarketScan Database for the period 2003–2010. UF patients aged 25–54 on their first UF procedure (index) date with 366-day baseline experience, 366-day follow-up period, continuous health plan enrollment during baseline and follow-up, and absence of any baseline UF procedures were included in the final sample. Cost outcomes were measured by allowed charges (sum of insurer-paid and patient-paid amounts). UF-related cost was defined as difference in mean cost between study cohorts and propensity-score-matched control cohorts without UF. Multivariate adjustment of cost outcomes was conducted using generalized linear models. Results The study sample comprised 14,426 patients (MRgFUS = 14; UAE = 4,092; myomectomy = 10,320) with a higher percent of older patients in MRgFUS cohort (71% vs. 50% vs. 12% in age-group 45–54, P

Background Cognitive deficits in various domains have been consistently replicated in patients with schizophrenia. Most studies looking at the relationship between cognitive dysfunction and functional disability are from developed countries. Studies from developing countries are few. The purpose of the present study was to compare the neurocognitive function in patients with schizophrenia who were in remission with that of normal controls and to determine if there is a relationship between measures of cognition and functional disability. Methods This study was conducted in the Psychiatric Unit of a General Hospital in Mumbai, India. Cognitive function in 25 patients with schizophrenia in remission was compared to 25 normal controls. Remission was confirmed using the brief psychiatric rating scale (BPRS) and scale for the assessment of negative symptoms (SANS). Subjects were administered a battery of cognitive tests covering aspects of memory, executive function and attention. The results obtained were compared between the groups. Correlation analysis was used to look for relationship between illness factors, cognitive function and disability measured using the Indian disability evaluation and assessment scale. Results Patients with schizophrenia showed significant deficits on tests of attention, concentration, verbal and visual memory and tests of frontal lobe/executive function. They fared worse on almost all the tests administered compared to normal controls. No relationship was found between age, duration of illness, number of years of education and cognitive function. In addition, we did not find a statistically significant relationship between cognitive function and scores on the disability scale. Conclusion The data suggests that persistent cognitive deficits are seen in patients with schizophrenia under remission. The cognitive deficits were not associated with symptomatology and functional disability. It is possible that various factors such as employment and family support reduce disability due to schizophrenia in developing countries like India. Further studies from developing countries are required to explore the relationship between cognitive deficits, functional outcome and the role of socio-cultural variables as protective factors.