Semiparametric Multivariate Accelerated Failure Time Model with Generalized Estimating Equations

The semiparametric accelerated failure time model is not as widely used as the Cox relative risk model mainly due to computational difficulties. Recent developments in least squares estimation and induced smoothing estimating equations provide promising tools to make the accelerate failure time models more attractive in practice. For semiparametric multivariate accelerated failure time models, we propose a generalized estimating equation approach to account for the multivariate dependence through working correlation structures. The marginal error distributions can be either identical as in sequential event settings or different as in parallel event settings. Some regression coefficients can be shared across margins as needed. The initial estimator is a rank-based estimator with Gehan's weight, but obtained from an induced smoothing approach with computation ease. The resulting estimator is consistent and asymptotically normal, with a variance estimated through a multiplier resampling method. In a simulation study, our estimator was up to three times as efficient as the initial estimator, especially with stronger multivariate dependence and heavier censoring percentage. Two real examples demonstrate the utility of the proposed method

Series Solution and Minimal Surfaces in AdS

According to the Alday-Maldacena program the strong coupling limit of Super Yang-Mills scattering amplitudes is given by minimal area surfaces in AdS spacetime with a boundary consisting of a momentum space polygon. The string equations in AdS systematically reduce to coupled Toda type equations whose Euclidean classical solutions are then of direct relevance. While in the simplest case of AdS_3 exact solutions were known from earlier studies of the sinh-Gordon equation, there exist at present no similar exact forms for the generalized Toda equations related to AdS_d with d>=4. In this paper we develop a series method for the solution to those equations and evaluate their contribution to the finite piece of the worldsheet area. For the known sinh-Gordon case the method is seen to give results in excellent agreement with the exact answer.Comment: 19 pages, no figures; references added, one note adde

Development and Validation of Apolipoprotein AI-Associated Lipoprotein Proteome Panel for the Prediction of Cholesterol Efflux Capacity and Coronary Artery Disease

BACKGROUND: Cholesterol efflux capacity (CEC) is a measure of HDL function that, in cell-based studies, has demonstrated an inverse association with cardiovascular disease. The cell-based measure of CEC is complex and low-throughput. We hypothesized that assessment of the lipoprotein proteome would allow for precise, high-throughput CEC prediction. METHODS: After isolating lipoprotein particles from serum, we used LC-MS/MS to quantify 21 lipoprotein-associated proteins. A bioinformatic pipeline was used to identify proteins with univariate correlation to cell-based CEC measurements and generate a multivariate algorithm for CEC prediction (pCE). Using logistic regression, protein coefficients in the pCE model were reweighted to yield a new algorithm predicting coronary artery disease (pCAD). RESULTS: Discovery using targeted LC-MS/MS analysis of 105 training and test samples yielded a pCE model comprising 5 proteins (Spearman r = 0.86). Evaluation of pCE in a case-control study of 231 specimens from healthy individuals and patients with coronary artery disease revealed lower pCE in cases (P = 0.03). Derived within this same study, the pCAD model significantly improved classification (P < 0.0001). Following analytical validation of the multiplexed proteomic method, we conducted a case-control study of myocardial infarction in 137 postmenopausal women that confirmed significant separation of specimen cohorts in both the pCE (P = 0.015) and pCAD (P = 0.001) models. CONCLUSIONS: Development of a proteomic pCE provides a reproducible high-throughput alternative to traditional cell-based CEC assays. The pCAD model improves stratification of case and control cohorts and, with further studies to establish clinical validity, presents a new opportunity for the assessment of cardiovascular health

HIV prevalence and undiagnosed infection among a community sample of gay and bisexual men in Scotland, 2005-2011: implications for HIV testing policy and prevention

&lt;b&gt;Objective&lt;/b&gt;&lt;p&gt;&lt;/p&gt; To examine HIV prevalence, HIV testing behaviour, undiagnosed infection and risk factors for HIV positivity among a community sample of gay men in Scotland.&lt;p&gt;&lt;/p&gt; &lt;b&gt;Methods&lt;/b&gt;&lt;p&gt;&lt;/p&gt; Cross-sectional survey of gay and bisexual men attending commercial gay venues in Glasgow and Edinburgh, Scotland with voluntary anonymous HIV testing of oral fluid samples in 2011. A response rate of 65.2% was achieved (1515 participants).&lt;p&gt;&lt;/p&gt; &lt;b&gt;Results&lt;/b&gt;&lt;p&gt;&lt;/p&gt; HIV prevalence (4.8%, 95% confidence interval, CI 3.8% to 6.2%) remained stable compared to previous survey years (2005 and 2008) and the proportion of undiagnosed infection among HIV-positive men (25.4%) remained similar to that recorded in 2008. Half of the participants who provided an oral fluid sample stated that they had had an HIV test in the previous 12 months; this proportion is significantly higher when compared to previous study years (50.7% versus 33.8% in 2005, p&#60;0.001). Older age (&#62;25 years) was associated with HIV positivity (1.8% in those &#60;25 versus 6.4% in older ages group) as was a sexually transmitted infection (STI) diagnosis within the previous 12 months (adjusted odds ratio 2.13, 95% CI 1.09–4.14). There was no significant association between age and having an STI or age and any of the sexual behaviours recorded.&lt;p&gt;&lt;/p&gt; &lt;b&gt;Conclusion&lt;/b&gt;&lt;p&gt;&lt;/p&gt; HIV transmission continues to occur among gay and bisexual men in Scotland. Despite evidence of recent testing within the previous six months, suggesting a willingness to test, the current opt-out policy may have reached its limit with regards to maximising HIV test uptake. Novel strategies are required to improve regular testing opportunities and more frequent testing as there are implications for the use of other biomedical HIV interventions.&lt;p&gt;&lt;/p&gt

Dark matter direct detection from new interactions in models with spin-two mediators

We consider models where a massive spin-two resonance acts as the mediator between Dark Matter (DM) and the SM particles through the energy-momentum tensor. We examine the effective theory for fermion, vector and scalar DM generated in these models and find novel types of DM-SM interaction never considered before. We identify the effective interactions between DM and the SM quarks when the mediator is integrated out, and match them to the gravitational form factors relevant for spin-independent DM-nucleon scattering. We also discuss the interplay between DM relic density conditions, direct detection bounds and collider searches for the spin-two mediator

Maximum Parsimony on Phylogenetic networks

Abstract Background Phylogenetic networks are generalizations of phylogenetic trees, that are used to model evolutionary events in various contexts. Several different methods and criteria have been introduced for reconstructing phylogenetic trees. Maximum Parsimony is a character-based approach that infers a phylogenetic tree by minimizing the total number of evolutionary steps required to explain a given set of data assigned on the leaves. Exact solutions for optimizing parsimony scores on phylogenetic trees have been introduced in the past. Results In this paper, we define the parsimony score on networks as the sum of the substitution costs along all the edges of the network; and show that certain well-known algorithms that calculate the optimum parsimony score on trees, such as Sankoff and Fitch algorithms extend naturally for networks, barring conflicting assignments at the reticulate vertices. We provide heuristics for finding the optimum parsimony scores on networks. Our algorithms can be applied for any cost matrix that may contain unequal substitution costs of transforming between different characters along different edges of the network. We analyzed this for experimental data on 10 leaves or fewer with at most 2 reticulations and found that for almost all networks, the bounds returned by the heuristics matched with the exhaustively determined optimum parsimony scores. Conclusion The parsimony score we define here does not directly reflect the cost of the best tree in the network that displays the evolution of the character. However, when searching for the most parsimonious network that describes a collection of characters, it becomes necessary to add additional cost considerations to prefer simpler structures, such as trees over networks. The parsimony score on a network that we describe here takes into account the substitution costs along the additional edges incident on each reticulate vertex, in addition to the substitution costs along the other edges which are common to all the branching patterns introduced by the reticulate vertices. Thus the score contains an in-built cost for the number of reticulate vertices in the network, and would provide a criterion that is comparable among all networks. Although the problem of finding the parsimony score on the network is believed to be computationally hard to solve, heuristics such as the ones described here would be beneficial in our efforts to find a most parsimonious network.</p

JDP2 overexpression provokes cardiac dysfunction in mice

The transcriptional regulator JDP2 (Jun dimerization protein 2) has been identified as a prognostic marker for patients to develop heart failure after myocardial infarction. We now performed in vivo studies on JDP2-overexpressing mice, to clarify the impact of JDP2 on heart failure progression. Therefore, during birth up to the age of 4 weeks cardiac-specific JDP2 overexpression was prevented by doxycycline feeding in transgenic mice. Then, JDP2 overexpression was started. Already after 1 week, cardiac function, determined by echocardiography, decreased which was also resembled on the cardiomyocyte level. After 5 weeks blood pressure declined, ejection fraction and cardiac output was reduced and left ventricular dilatation developed. Heart weight/body weight, and mRNA expression of ANP, inflammatory marker genes, collagen and fibronectin increased. Collagen 1 protein expression increased, and fibrosis developed. As an additional sign of elevated extracellular matrix remodeling, matrix metalloproteinase 2 activity increased in JDP2 mice. Thus, JDP2 overexpression is deleterious to heart function in vivo. It can be concluded that JDP2 overexpression provokes cardiac dysfunction in adult mice that is accompanied by hypertrophy and fibrosis. Thus, induction of JDP2 is a maladaptive response contributing to heart failure development

Myocarditis related to Campylobacter jejuni infection: A case report

BACKGROUND: Myocarditis can develop as a complication of various infections and is most commonly linked to enterovirus infections. Myocarditis is rarely associated with bacterial infections; salmonellosis and shigellosis have been the most frequently reported bacterial cause. We report a case of myocarditis related to Campylobacter jejuni enteritis. CASE PRESENTATION: A 30-year-old previously healthy man presented with a history of prolonged chest pain radiating to the jaw and the left arm. Five days prior to the onset of chest pain, he developed bloody diarrhea, fever and chills. Creatine kinase (CK) and CK-MB were elevated to 289 U/L and 28.7 μg/L. Troponin I was 30.2 μg/L. The electrocardiogram (ECG) showed T wave inversion in the lateral and inferior leads. The chest pain resolved within 24 hours of admission. The patient had a completely normal ECG stress test. The patient was initiated on ciprofloxacin 500 mg po bid when Campylobacter jejuni was isolated from the stool. Diarrhea resolved within 48 hours of initiation of ciprofloxacin. The diagnosis of Campylobacter enteritis and related myocarditis was made based on the clinical and laboratory results and the patient was discharged from the hospital in stable condition. CONCLUSION: Myocarditis can be a rare but severe complication of infectious disease and should be considered as a diagnosis in patients presenting with chest pain and elevated cardiac enzymes in the absence of underlying coronary disease. It can lead to cardiomyopathy and congestive heart failure. There are only a few reported cases of myocarditis associated with Campylobacter infection

sParEGO – A hybrid optimization algorithm for expensive uncertain multi-objective optimization problems

Evaluations of candidate solutions to real-world problems are often expensive to compute, are characterised by uncertainties arising from multiple sources, and involve simultaneous consideration of multiple conflicting objectives. Here, the task of an optimizer is to find a set of solutions that offer alternative robust trade-offs between objectives, where robustness comprises some user-defined measure of the ability of a solution to retain high performance in the presence of uncertainties. Typically, understanding the robustness of a solution requires multiple evaluations of performance under different uncertain conditions – but such an approach is infeasible for expensive problems with a limited evaluation budget. To overcome this issue, a new hybrid optimization algorithm for expensive uncertain multi-objective optimization problems is proposed. The algorithm – sParEGO – uses a novel uncertainty quantification approach to assess the robustness of a candidate design without having to rely on expensive sampling techniques. Hypotheses on the relative performance of the algorithm compared to an existing method for deterministic problems are tested using two benchmark problems, and provide preliminary indication that sParEGO is an effective technique for identifying robust trade-off surfaces