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We discuss the properties of the non-Hermitian 𝒫𝒯-symmetric two–scalar fields model. We investigate stability areas of this system and properties of vortices that emerge in the system of two interacting scalar fields. The phase diagram of the model contains stable and unstable regions depending on 𝒫𝒯-symmetry breaking, which intercross the regions of U(1)-symmetric and U(1)-broken phases in a nontrivial way. At non-zero quartic couplings, the non-Hermitian model possesses classical vortex solutions in the 𝒫𝒯-symmetric regions. We also consider a close Hermitian analog of the theory and compare the results with the non-Hermitian model.

The Cox regression, a semi‐parametric method of survival analysis, is extremely popular in biomedical applications. The proportional hazards assumption is a key requirement in the Cox model. To accommodate non‐proportional hazards, we propose to parameterize the shape parameter of the baseline hazard function using the additional, separate Cox‐regression term which depends on the vector of the covariates. This parametrization retains the general form of the hazard function over the strata and is similar to one in Devarajan and Ebrahimi (Comput Stat Data Anal. 2011;55:667–676) in the case of the Weibull distribution, but differs for other hazard functions. We call this model the double‐Cox model. We formally introduce the double‐Cox model with shared frailty and investigate, by simulation, the estimation bias and the coverage of the proposed point and interval estimation methods for the Gompertz and the Weibull baseline hazards. For real‐life applications with low frailty variance and a large number of clusters, the marginal likelihood estimation is almost unbiased and the profile likelihood‐based confidence intervals provide good coverage for all model parameters. We also compare the results from the over‐parametrized double‐Cox model to those from the standard Cox model with frailty in the case of the scale‐only proportional hazards. The model is illustrated on an example of the survival after a diagnosis of type 2 diabetes mellitus. The R programs for fitting the double‐Cox model are available on Github. [ABSTRACT FROM AUTHOR]

Abstract Searching for genes contributing to longevity is a typical task in association analysis. A number of methods can be used for finding this association -- from the simplest method based on the technique of contingency tables to more complex algorithms involving demographic data, which allow us to estimate the genotype-specific hazard functions. The independence of individuals is the common assumption in all these methods. At the same time, data on related individuals such as twins are often used in genetic studies. This paper proposes an extension of the relative risk model to encompass twin data. We estimate the power and also discuss what happens if we treat the twin data using the univariate model.

We discuss the gauge field theory approach to protein structure study, which allows a natural way to introduce collective degrees of freedom and nonlinear topological structures. Local symmetry of proteins and its breaking in the medium is considered, what allows to derive Abelian Higgs model of protein backbone, correct folding of which is defined by gauge symmetry breaking due hydrophobic forces. Within this model structure of protein backbone is defined by superposition of one-dimensional topological solitons (kinks), what allows to reproduce the three-dimensional structure of the protein backbone with precision up to 1A and to predict its dynamics.

We investigate aspects of topology in protein folding. For this we numerically simulate the temperature driven folding and unfolding of the slipknotted archaeal virus protein AFV3-109. Due to knottiness the (un)folding is a topological process, it engages the entire backbone in a collective fashion. Accordingly we introduce a topological approach to model the process. Our simulations reveal that the (un)folding of AFV3-109 slipknot proceeds through a folding intermediate that has the topology of a trefoil knot. We observe that the final slipknot causes a slight swelling of the folded AFV3-109 structure. We disclose the relative stability of the strands and helices during both the folding and unfolding processes. We confirm results from previous studies that pointed out that it can be very demanding to simulate the formation of knotty self-entanglement, and we explain how the problems are circumvented: The slipknotted AFV3-109 protein is a very slow folder with a topologically demanding pathway, which needs to be properly accounted for in a simulation description. When we either increase the relative stiffness of bending, or when we decrease the speed of ambient cooling, the rate of slipknot formation rapidly increases. [ABSTRACT FROM AUTHOR]

Background: Hip replacement and hip resurfacing are common surgical procedures with an estimated risk of revision of 4% over 10 year period. Approximately 58% of hip replacements will last 25 years. Some implants have higher revision rates and early identification of poorly performing hip replacement implant brands and cup/head brand combinations is vital. Aims: Development of a dynamic monitoring method for the revision rates of hip implants. Methods: Data on the outcomes following the hip replacement surgery between 2004 and 2012 was obtained from the National Joint Register (NJR) in the UK. A novel dynamic algorithm based on the CUmulative SUM (CUSUM) methodology with adjustment for casemix and random frailty for an operating unit was developed and implemented to monitor the revision rates over time. The Benjamini-Hochberg FDR method was used to adjust for multiple testing of numerous hip replacement implant brands and cup/ head combinations at each time point. Results: Three poorly performing cup brands and two cup/ head brand combinations have been detected. Wright Medical UK Ltd Conserve Plus Resurfacing Cup (cup o), DePuy ASR Resurfacing Cup (cup e), and Endo Plus (UK) Limited EP-Fit Plus Polyethylene cup (cup g) showed stable multiple alarms over the period of a year or longer. An addition of a random frailty term did not change the list of underperforming components. The model with added random effect was more conservative, showing less and more delayed alarms. Conclusions: Our new algorithm is an efficient method for early detection of poorly performing components in hip replacement surgery. It can also be used for similar tasks of dynamic quality monitoring in healthcare. [ABSTRACT FROM AUTHOR]

Objectives This study aimed to identify: (1) information needs of people with recently diagnosed type 1 or type 2 diabetes mellitus (DM); (2) information needs within different subgroups; and (3) factors associated with information needs concerning DM such as current level of information, health-related quality of life or participation preferences. Design A mixed-method approach combining quantitative and qualitative methods was used. Information needs for different topics and estimated associated factors were described using logistic regression models. Additionally, a qualitative content analysis was performed. Setting Monocentre study. Participants Information needs were assessed and analysed in 138 consecutive participants with DM who took part in the German Diabetes Study (54% type 2 diabetes, 64% male, mean age 46.3±12.3 years, known diabetes duration <1 year). Results Most participants displayed a need for information in all topics provided, especially in diabetes research (86%) and treatment/therapy (80%). Regarding those topics, participants wished for information regarding new treatments that simplify their everyday life. In general, participants preferred topics that focus on the management or handling of DM over topics related to clinical factors of DM, such as causes and complications. A low current level of information and treatment with antihyperglycaemic medication were significantly associated with higher information needs, and diabetes-related comorbidity and higher mental component summary score in the 36-Item Short-Form Health Survey (SF-36) with lower information needs. Conclusion People with recently diagnosed DM display high information needs, which differ according to the current level of information, mode of diabetes treatment, diabetes-related comorbidity and mental component summary score in the SF-36. There appears to be a preference for information, which can help to simplify life with diabetes and for information that corresponds to their level of knowledge. This should be considered in patient information activities. [ABSTRACT FROM AUTHOR]

Aims: Patients with diabetes are probably often unaware of their comorbidities. We estimated agreement between self-reported comorbidities and administrative data. Methods: In a random sample of 464 diabetes patients, data from a questionnaire asking about the presence of 14 comorbidities closely related to diabetes were individually linked with statutory health insurance data. Results: Specificities were >97%, except cardiac insufficiency (94.5%), eye diseases (93.8%), peripheral arterial disease (92.6%), hypertension (90.9%), and peripheral neuropathy (85.8%). Sensitivities were <60%, except amputation (100%), hypertension (83.1%), and myocardial infarction (67.2%). A few positive predictive values were >90% (hypertension, myocardial infarction, and eye disease), and six were below 70%. Six negative predictive values were >90%, and two <70% (hypertension and eye disease). Total agreement was between 42.7% (eye disease) and 100% (dialysis and amputation). Overall, substantial agreement was observed for three morbidities (kappa 0.61-0.80: hypertension, myocardial infarction, and amputation). Moderate agreement (kappa 0.41-0.60) was estimated for angina pectoris, heart failure, stroke, peripheral neuropathy, and kidney disease. Factors associated with agreement were the number of comorbidities, diabetes duration, age, sex, and education. Conclusions: Myocardial infarction and amputation were well reported by patients as comorbidities; eye diseases and foot ulceration rather poorly, particularly in older, male, or less educated patients. Patient information needs improving. [ABSTRACT FROM AUTHOR]

The diabetic foot is a lifelong disease. The longer patients with diabetes and foot ulcers are observed, the higher the likelihood that they will develop comorbidities that adversely influence ulcer recurrence, amputation and survival (for example peripheral arterial disease, renal failure or ischaemic heart disease). The purpose of our study was to quantify person and limb-related disease progression and the time-dependent influence of any associated factors (present at baseline or appearing during observation) based on which effective prevention and/or treatment strategies could be developed. Using a nine-state continuous-time Markov chain model with time-dependent risk factors, all living patients were divided into eight groups based on their ulceration (previous or current) and previous amputation (none, minor or major) status. State nine is an absorbing state (death). If all transitions are fully observable, this model can be decomposed into eight submodels, which can be analyzed using the methods of survival analysis for competing risks. The dependencies of the risk factors (covariates) were included in the submodels using Cox-like regression. The transition intensities and relative risks for covariates were calculated from long-term data of patients with diabetic foot ulcers collected in a single specialized center in North-Rhine Westphalia (Germany). The detected estimates were in line with previously published, but scarce, data. Together with the interesting new results obtained, this indicates that the proposed model may be useful for studying disease progression in larger samples of patients with diabetic foot ulcers. [ABSTRACT FROM AUTHOR]

Three important results concerning the shape and the trends of the human mortality rate were discussed recently in demographic and epidemiological literature. These are the deceleration of the mortality rate at old ages, the tendency to rectangularization of the survival curve, and the decline of the old age mortality observed in the second part of the 20th century. In this paper we show that all these results can be explained by using a model with a new type of heterogeneity associated with individual differences in adaptive capacity. We first illustrate the idea of such a model by considering survival in a mixture of two subpopulations of individuals (called 'labile' and 'stable'). These subpopulations are characterized by different Gompertz mortality patterns, such that their mortality rates cross over. The survival chances of individuals in these subpopulations have different sensitivities to changes in environmental conditions. Then we develop a more comprehensive model in which the mortality rate is related to the adaptive capacity of an organism. We show that the trends in survival patterns experienced by a mixture of such individuals resemble those obtained in an analysis of empirical data on survival in developed countries. Lastly, we present evidence of the existence of subpopulations of phenotypes in both humans and experimental organisms, which were used as prototypes in our models. The existence of such phenotypes provides the possibility that at least part of today's centenarians originated from an initially frail part of the cohort.

Bivariate survival models with discretely distributed frailty based on the major gene concept and applied to the data on related individuals such as twins and sibs can be used to estimate the underlying hazard, the relative risk and the frequency of the longevity allele. To determine the position of the longevity gene, additional genetic markers data are needed. If the action of the longevity allele does not depend on its position in the genome, these two problems can be solved separately using a two-step procedure. We proposed an extension of this method allowing us to search the position of two longevity genes at a chromosome using the bivariate survival data with correlated competing risks combined with genetic markers data. We have studied the properties of the model with two longevity genes located on the same and on different chromosomes using simulated data sets. [ABSTRACT FROM AUTHOR]

Background & Aims: Interactions between genetic and environmental factors are believed to be involved in onset and initiation of inflammatory bowel disease. We analyzed the interaction between gastrointestinal mucosal microbiota and host genes in twin pairs discordant for ulcerative colitis (UC) to study the functional interaction between microbiota and mucosal epithelium. Methods: Biopsy were collected from sigmoid colon of UC patients and their healthy twins (discordant twin pairs) and from twins without UC. Microbiota profiles were determined from analysis of 16S ribosomal DNA libraries; messenger RNA profiles were determined by microarray analysis. Results: Patients with UC had dysbiotic microbiota, characterized by less bacterial diversity and more Actinobacteria and Proteobacteria than that of their healthy siblings; healthy siblings from discordant twins had more bacteria from the Lachnospiraceae and Ruminococcaceae families than twins who were both healthy. In twins who were both healthy, 34 mucosal transcripts correlated with bacterial genera, whereas only 25 and 11 correlated with bacteria genera in healthy individuals and their twins with UC, respectively. Transcripts related to oxidative and immune responses were differentially expressed between patients with UC and their healthy twins. Conclusions: The transcriptional profile of the mucosa appears to interact with the colonic microbiota; this interaction appears to be lost in colon of patients with UC. Bacterial functions, such as butyrate production, might affect mucosal gene expression. Patients with UC had different gene expression profiles and lower levels of biodiversity than their healthy twins, as well as unusual aerobic bacteria. Patients with UC had lower percentages of potentially protective bacterial species than their healthy twins. [ABSTRACT FROM AUTHOR]

In nonlinear regression models, standard optimality functions for experimental designs usually depend on the unknown parameters. Locally optimal designs are not robust with respect to misspecifications of unknown parameters. They can be robustified by using a minimax approach. A comprehensive analysis of the goal function makes it possible to reduce the search space for the inner as well as the outer optimization. We present an efficient and reliable algorithm for calculating balanced equidistant C- and D-optimal minimax designs in a two-parameter logistic dose-response model, which is based on theoretical and empirical investigations of the considered goal functions. [ABSTRACT FROM AUTHOR]

Analyzes approaches to mortality modeling and influence of emerging theories on their structure and scope of applications. Strehler and Mildvan model which relates mortality to inadequate responses to energy demands; Sacher and Trucco model which describes the role of stochasticity and homeostatic mechanisms; Incorporation of heterogeneity and frailty; Evolutionary theory and models of senescence.

Background Methods to measure patient time spent on health-related activities are currently not well elaborated or standardized. Aim The purpose of this study was to develop a recall questionnaire measuring patient time devoted to diabetes self-care and to examine its feasibility and validity under field conditions. Methods The initial questionnaire was developed on the basis of instruments frequently used to assess self-care behavior in patients with diabetes, evaluated in two focus groups with patients with type 2 diabetes (N = 15) and tested in a random sample of patients with type 2 diabetes (N = 178). To assess the validity of the questionnaire, four hypotheses about expected differences in self-care time across various patient sub-groups were tested. Results The final questionnaire includes thirteen items estimating time spent on regular diabetes-related activities undertaken in the previous seven days. 78% of respondents completed the questionnaire without item non-response or other evident problems. As hypothesized, respondents receiving insulin treatment, those with poor self-rated health and those with diabetes-related emotional distress (PAID-5 score ≥ 8) reported spending more time on diabetes self-care than the rest of the sample. Contrary to our assumption, no differences in time spent on diabetes self-care between employed and retired individuals were detected by the questionnaire. Conclusion The recall questionnaire measuring patient time devoted to a broad range of regular diabetes self-care activities was developed and its feasibility was proved under field conditions. Ideally, the questionnaire should be further validated within a variety of populations. Exploration of the convergent validity between the recall method and prospective diary may be also useful. [ABSTRACT FROM AUTHOR]

Apart from being the most common mechanism of regulating protein function and transmitting signals throughout the cell, phosphorylation has an ability to induce disorder-to-order transition in an intrinsically disordered protein. In particular, it was shown that folding of the intrinsically disordered protein, eIF4E-binding protein isoform 2 (4E-BP2), can be induced by multisite phosphorylation. Here, the principles that govern the folding of phosphorylated 4E-BP2 (pT37pT46 4E-BP2 18-62 ) are investigated by analyzing canonical and replica exchange molecular dynamics trajectories, generated with the coarse-grained united-residue force field, in terms of local and global motions and the time dependence of formation of contacts between C α s of selected pairs of residues. The key residues involved in the folding of the pT37pT46 4E-BP2 18-62 are elucidated by this analysis. The correlations between local and global motions are identified. Moreover, for a better understanding of the physics of the formation of the folded state, the experimental structure of the pT37pT46 4E-BP2 18-62 is analyzed in terms of a kink (heteroclinic standing wave solution) of a generalized discrete nonlinear Schrödinger equation. It is shown that without molecular dynamics simulations the kinks are able to identify not only the phosphorylated sites of protein, the key players in folding, but also the reasons for the weak stability of the pT37pT46 4E-BP2 18-62 .

Phenotypic variation between individuals, such as different mRNA expression levels, is influenced by genetic and nongenetic factors. Although several studies have addressed the interplay between genotypes and expression profiles in various model organisms in the recent years, the detailed and relative contributions of genetic and nongenetic factors in regulating plasticity of gene expression in barrier organs (e.g., skin, gut), which are exposed to continuous environmental challenge, are still poorly understood. Here we systematically monitored the level of genetic control over genomewide mRNA expression profiles in the healthy intestinal mucosa of 10 monozygotic and 10 dizygotic human twin pairs with microarray analyses. Our results, which are supported by real-time PCR and analysis of molecular phylogenetic conservation, indicate that genes associated with energy metabolism and cell and tissue regeneration pathways are under strong genetic control. Conversely, genes associated with immune response seem to be mainly controlled by exogenous factors. Further insights into the relative extent of genetic and nongenetic determinants of transcriptomal profiles and their influence on physiological and pathophysiological mechanisms are crucial to understanding the key role played by gene-environment interactions in health and disease.

The colonic mucosa-associated flora (MAF) in patients with active ulcerative colitis (UC) (n = 13) was investigated by examining 16S rRNA gene signatures during remission and relapse against levels for controls (n = 5). Baseline reduction, temporal instability, and decrease of bacterial richness toward relapse were observed for UC patients, whereas the MAF for controls was stable over time.

The parameters of the Gompertz approximation to the mortality curve are negatively correlated. Strehler and Mildvan [Science 132 (1960) 14] predicted this property of the mortality curve using a mathematical model of mortality and aging and then confirmed it in empirical studies. Despite the fact that their theory was based on the cohort model of mortality the SM correlation was also revealed in the analysis of period mortality data. In fact, most applications of the SM model to human data use Gompertz's approximation to the period mortality rate. Many researchers studying SM correlation consider it a universal demographic law. Such correlation prescribes a certain regularity in mortality changes. All mortality curves must intersect at one point. Mortality decline must produce the rectangularization of survival curves. In this paper we investigated the changes in the patterns of mortality decline in Sweden between 1861 and 1999. We found a difference in patterns of SM correlation for cohort and period mortality data. We investigated trends in survival improvement and found that the tendency to rectangularization of the survival curve existed for only a limited period of time. Then it was gradually replaced by near parallel shift of the survival curve to the right. We found that the pattern of SM correlation was relatively stable only at certain phases of the survival history of male and female populations. We analyzed past and recent patterns of survival changes and discussed possible causes for instability of SM correlation both in cohort and in period mortality data.