The Individualized Genetic Barrier Predicts Treatment Response in a Large Cohort of HIV-1 Infected Patients

The success of combination antiretroviral therapy is limited by the evolutionary escape dynamics of HIV-1. We used Isotonic Conjunctive Bayesian Networks (I-CBNs), a class of probabilistic graphical models, to describe this process. We employed partial order constraints among viral resistance mutations, which give rise to a limited set of mutational pathways, and we modeled phenotypic drug resistance as monotonically increasing along any escape pathway. Using this model, the individualized genetic barrier (IGB) to each drug is derived as the probability of the virus not acquiring additional mutations that confer resistance. Drug-specific IGBs were combined to obtain the IGB to an entire regimen, which quantifies the virus' genetic potential for developing drug resistance under combination therapy. The IGB was tested as a predictor of therapeutic outcome using between 2,185 and 2,631 treatment change episodes of subtype B infected patients from the Swiss HIV Cohort Study Database, a large observational cohort. Using logistic regression, significant univariate predictors included most of the 18 drugs and single-drug IGBs, the IGB to the entire regimen, the expert rules-based genotypic susceptibility score (GSS), several individual mutations, and the peak viral load before treatment change. In the multivariate analysis, the only genotype-derived variables that remained significantly associated with virological success were GSS and, with 10-fold stronger association, IGB to regimen. When predicting suppression of viral load below 400 cps/ml, IGB outperformed GSS and also improved GSS-containing predictors significantly, but the difference was not significant for suppression below 50 cps/ml. Thus, the IGB to regimen is a novel data-derived predictor of treatment outcome that has potential to improve the interpretation of genotypic drug resistance tests.

Representation via Probabilities: Models of Probabilistic Modeling

How do probabilistic models represent their targets and how do they allow us to learn about them? The answer to this question depends on a number of details, in particular on the meaning of the probabilities involved. To classify the options, a minimalist conception of representation (Su\'arez 2004) is adopted: Modelers devise substitutes (``sources'') of their targets and investigate them to infer something about the target. Probabilistic models allow us to infer probabilities about the target from probabilities about the source. This leads to a framework in which we can systematically distinguish between different models of probabilistic modeling. I develop a fully Bayesian view of probabilistic modeling, but I argue that, as an alternative, Bayesian degrees of belief about the target may be derived from ontic probabilities about the source. Remarkably, some accounts of ontic probabilities can avoid problems if they are supposed to apply to sources only.

The choice of anesthesia influences oxidative energy metabolism and tissue survival in critically ischemic murine skin

In surgical animal studies anesthesia is used regularly. Several reports in the literature demonstrate respiratory and cardiovascular side effects of anesthesiologic agents. The aim of this study was to compare two frequently used anesthesia cocktails (ketamine/xylazine [KX] versus medetomidine/climazolam/fentanyl [MCF]) in skin flap mouse models. Systemic blood values, local metabolic parameters, and surgical outcome should be analyzed in critical ischemic skin flap models. Systemic hypoxia was found in the animals undergoing KX anesthesia compared with normoxia in the MCF group (sO(2): 89.2% +/- 2.4% versus 98.5% +/- 1.2%, P < 0.01). Analysis of tissue metabolism revealed impaired anaerobic oxygen metabolism and increased cellular damage in critical ischemic flap tissue under KX anesthesia (lactate/pyruvate ratio: KX 349.86 +/- 282.38 versus MCF 64.53 +/- 18.63; P < 0.01 and glycerol: KX 333.50 +/- 83.91 micromol/L versus MCF 195.83 +/- 29.49 micromol/L; P < 0.01). After 6 d, different rates of flap tissue necrosis could be detected (MCF 57% +/- 6% versus KX 68% +/- 6%, P < 0.01). In summary we want to point out that the type of anesthesia, the animal model and the goal of the study have to be well correlated. Comparing the effects of KX and MCF anesthesia in mice on surgical outcome was a novel aspect of our study.

Methodology and models in erosion research: discussion and conclusions

This paper summarises the discussions which took place at the Workshop on Methodology in Erosion Research in Zürich, 2010, and aims, where possible, to offer guidance for the development and application of both in vitro and in situ models for erosion research. The prospects for clinical trials are also discussed. All models in erosion research require a number of choices regarding experimental conditions, study design and measurement techniques, and these general aspects are discussed first. Among in vitro models, simple (single- or multiple-exposure) models can be used for screening products regarding their erosive potential, while more elaborate pH cycling models can be used to simulate erosion in vivo. However, in vitro models provide limited information on intra-oral erosion. In situ models allow the effect of an erosive challenge to be evaluated under intra-oral conditions and are currently the method of choice for short-term testing of low-erosive products or preventive therapeutic products. In the future, clinical trials will allow longer-term testing. Possible methodologies for such trials are discussed.

Novel insights into mechanisms of food allergy and allergic airway inflammation using experimental mouse models

Over the last decades, considerable efforts have been undertaken in the development of animal models mimicking the pathogenesis of allergic diseases occurring in humans. The mouse has rapidly emerged as the animal model of choice, due to considerations of handling and costs and, importantly, due to the availability of a large and increasing arsenal of genetically modified mouse strains and molecular tools facilitating the analysis of complex disease models. Here, we review latest developments in allergy research that have arisen from in vivo experimentation in the mouse, with a focus on models of food allergy and allergic asthma, which constitute major health problems with increasing incidence in industrialized countries. We highlight recent novel findings and controversies in the field, most of which were obtained through the use of gene-deficient or germ-free mice, and discuss new potential therapeutic approaches that have emerged from animal studies and that aim at attenuating allergic reactions in human patients.

Variation in habitat choice and delayed reproduction: Adaptive queuing strategies or individual quality differences?

In most species, some individuals delay reproduction or occupy inferior breeding positions. The queue hypothesis tries to explain both patterns by proposing that individuals strategically delay breeding (queue) to acquire better breeding or social positions. In 1995, Ens, Weissing, and Drent addressed evolutionarily stable queuing strategies in situations with habitat heterogeneity. However, their model did not consider the non - mutually exclusive individual quality hypothesis, which suggests that some individuals delay breeding or occupy inferior breeding positions because they are poor competitors. Here we extend their model with individual differences in competitive abilities, which are probably plentiful in nature. We show that including even the smallest competitive asymmetries will result in individuals using queuing strategies completely different from those in models that assume equal competitors. Subsequently, we investigate how well our models can explain settlement patterns in the wild, using a long-term study on oystercatchers. This long-lived shorebird exhibits strong variation in age of first reproduction and territory quality. We show that only models that include competitive asymmetries can explain why oystercatchers' settlement patterns depend on natal origin. We conclude that predictions from queuing models are very sensitive to assumptions about competitive asymmetries, while detecting such differences in the wild is often problematic.

Hotshots, hot spots, and female preference: exploring lek formation models with a bower-building cichlid fish

In many animals, males congregate in leks that females visit for the sole purpose of mating. We observed male and female behavior on 3 different-sized leks of the bower-building cichlid fish Nyassachromis cf. microcephalus to test predictions of 3 prominent lek models: the "hotshot," "hot spot," and "female preference" models. In this system, we were able to refine these predictions by distinguishing between indirect mate choice, by which females restrict their set of potential mates in the absence of individual male assessment, and direct mate choice, by which females assess males and their territories through dyadic behavioral interactions. On no lek were males holding central territories favored by indirect or direct mate choice, contrary to the prediction of the hotshot model that leks form because inferior males establish territories surrounding hotshot males preferred by females. Average female encounter rate of males increased with lek size, a pattern typically interpreted as evidence that leks form through female preference for lekking males, rather than because males congregate in hot spots of high female density. Female propensity to engage in premating behavior once courted did not increase with lek size, suggesting female preference for males on larger leks operated through indirect choice rather than direct choice based on individual assessment. The frequency of male-male competitive interactions increased with lek size, whereas their foraging rate decreased, implying a cost to males maintaining territories on larger leks. Together these data most strongly support the female preference model, where females may benefit through indirect mate choice for males able to meet the competitive cost of occupying larger leks.

Who Is Afraid of School Choice?

This study uses survey data to investigate attitudes among Swiss voters to different models offering more freedom of choice in the educational system. There is a clear opposition to the use of taxpayer money to fund private schools, while free choice between public schools seems to appeal to a majority. The opinions appear to be based on a rational calculation of personal utility. For both types of choice, approval rates are lower for middle to high-income groups and individuals with a teaching qualification. Furthermore, residents of small to medium-sized towns are opposed to more school choice. On the support side, approval rates for private school choice are higher among parents of school-age children and residents in urban areas. The results also indicate differences between the country's language regions, attributable to intercultural differences in what people consider the role of the state.

LakeMIP Kivu: evaluating the representation of a large, deep tropical lake by a set of one-dimensional lake models

The African great lakes are of utmost importance for the local economy (fishing), as well as being essential to the survival of the local people. During the past decades, these lakes experienced fast changes in ecosystem structure and functioning, and their future evolution is a major concern. In this study, for the first time a set of one-dimensional lake models are evaluated for Lake Kivu (2.28°S; 28.98°E), East Africa. The unique limnology of this meromictic lake, with the importance of salinity and subsurface springs in a tropical high-altitude climate, presents a worthy challenge to the seven models involved in the Lake Model Intercomparison Project (LakeMIP). Meteorological observations from two automatic weather stations are used to drive the models, whereas a unique dataset, containing over 150 temperature profiles recorded since 2002, is used to assess the model’s performance. Simulations are performed over the freshwater layer only (60 m) and over the average lake depth (240 m), since salinity increases with depth below 60 m in Lake Kivu and some lake models do not account for the influence of salinity upon lake stratification. All models are able to reproduce the mixing seasonality in Lake Kivu, as well as the magnitude and seasonal cycle of the lake enthalpy change. Differences between the models can be ascribed to variations in the treatment of the radiative forcing and the computation of the turbulent heat fluxes. Fluctuations in wind velocity and solar radiation explain inter-annual variability of observed water column temperatures. The good agreement between the deep simulations and the observed meromictic stratification also shows that a subset of models is able to account for the salinity- and geothermal-induced effects upon deep-water stratification. Finally, based on the strengths and weaknesses discerned in this study, an informed choice of a one-dimensional lake model for a given research purpose becomes possible.

Probabilistic contingency learning with limbic or prefrontal damage

AB A fundamental capacity of the human brain is to learn relations (contingencies) between environmental stimuli and the consequences of their occurrence. Some contingencies are probabilistic; that is, they predict an event in some situations but not in all. Animal studies suggest that damage to limbic structures or the prefrontal cortex may disturb probabilistic learning. The authors studied the learning of probabilistic contingencies in amnesic patients with limbic lesions, patients with prefrontal cortex damage, and healthy controls. Across 120 trials, participants learned contingent relations between spatial sequences and a button press. Amnesic patients had learning comparable to that of control subjects but failed to indicate what they had learned. Across the last 60 trials, amnesic patients and control subjects learned to avoid a noncontingent choice better than frontal patients. These results indicate that probabilistic learning does not depend on the brain structures supporting declarative memory.

Clinical versus pre-clinical FE models for vertebral body strength predictions

The finite element analysis is an accepted method to predict vertebral body compressive strength. This study compares measurements obtained from in vitro tests with the ones from two different simulation models: clinical quantitative computer tomography (QCT) based homogenized finite element (hFE) models and pre-clinical high-resolution peripheral QCT-based (HR-pQCT) hFE models. About 37 vertebral body sections were prepared by removing end-plates and posterior elements, scanned with QCT (390/450μm voxel size) as well as HR-pQCT (82μm voxel size), and tested in compression up to failure. Non-linear viscous damage hFE models were created from QCT/HT-pQCT images and compared to experimental results based on stiffness and ultimate load. As expected, the predictability of QCT/HR-pQCT-based hFE models for both apparent stiffness (r2=0.685/0.801r2=0.685/0.801) and strength (r2=0.774/0.924r2=0.774/0.924) increased if a better image resolution was used. An analysis of the damage distribution showed similar damage locations for all cases. In conclusion, HR-pQCT-based hFE models increased the predictability considerably and do not need any tuning of input parameters. In contrast, QCT-based hFE models usually need some tuning but are clinically the only possible choice at the moment.

Determinants of antithrombotic choice for patent foramen ovale in cryptogenic stroke

Objective: We examined the influence of clinical, radiologic, and echocardiographic characteristics on antithrombotic choice in patients with cryptogenic stroke (CS) and patent foramen ovale (PFO), hypothesizing that features suggestive of paradoxical embolism might lead to greater use of anticoagulation. Methods: The Risk of Paradoxical Embolism Study combined 12 databases to create the largest dataset of patients with CS and known PFO status. We used generalized linear mixed models with a random effect of component study to explore whether anticoagulation was preferentially selected based on the following: (1) younger age and absence of vascular risk factors, (2) “high-risk” echocardiographic features, and (3) neuroradiologic findings. Results: A total of 1,132 patients with CS and PFO treated with anticoagulation or antiplatelets were included. Overall, 438 participants (39%) were treated with anticoagulation with a range (by database) of 22% to 54%. Treatment choice was not influenced by age or vascular risk factors. However, neuroradiologic findings (superficial or multiple infarcts) and high-risk echocardiographic features (large shunts, shunt at rest, and septal hypermobility) were predictors of anticoagulation use. Conclusion: Both antithrombotic regimens are widely used for secondary stroke prevention in patients with CS and PFO. Radiologic and echocardiographic features were strongly associated with treatment choice, whereas conventional vascular risk factors were not. Prior observational studies are likely to be biased by confounding by indication.

Increasing the career choice readiness of young adolescents: an evaluation study

A career workshop that applies models of the Cognitive Information Processing Approach (Sampson, Reardon, Peterson, & Lenz, 2004) and incorporates critical ingredients (Brown and Ryan Krane, 2000) to promote the career choice readiness of young adolescents was developed and evaluated with 334 Swiss students in seventh grade applying a Solomon four group design with a three-month follow-up. Participants significantly increased their performance in terms of career decidedness, career planning, career exploration, and vocational identity. Implications for evaluation research and counselling practice are presented.

The relation of secondary student's career choice readiness to a six-phase model of career decision-making

Based on common aspects of recent models of career decision-making (CDM) a sixphase model of CDM for secondary students is presented and empirically evaluated. The study tested the hypothesis that students who are in later phases possess more career choice readiness and consider different numbers of career alternatives. 266 Swiss secondary students completed measures tapping phase of CDM, career choice readiness, and number of considered career options. Career choice readiness showed an increase with phase of CDM. Later phases were generally associated with a larger increase in career choice readiness. Number of considered career options showed a curve-linear development with fewer options considered at the beginning and at the end of the process. Male students showed a larger variability in their distribution among the process with more male than female students in the first and last phase of the process. Implications for theory and practice are presented.