Patterns of executive functions and theory of mind in adults with a family history of alcohol use disorder: Combined group and single-case analyses.

BACKGROUND: Impairments in executive function and social cognition are highly prevalent in individuals with an alcohol use disorder (AUD). Some studies show that similar difficulties are displayed by individuals with a positive family history of AUD (FH+) compared with individuals with a negative family history (FH-). Yet, no studies have jointly investigated cognitive and affective theory of mind at the behavioral level. Moreover, some studies show preserved executive and socioemotional functioning in FH+ participants. One possible explanation for these divergent results is that FH+ individuals are cognitively heterogeneous. In this study, we examined the frequency and co-occurrence of difficulties in executive function and social cognition among FH+ individuals at the individual level. METHODS: Sixty FH+ and 60 FH- participants matched on age, sex, and education level were included. They completed tasks assessing executive functions (Stroop, Trail Making Test) and affective and cognitive theory of mind (Movie for the Assessment of Social Cognition). They also completed self-report questionnaires measuring impulsivity, alexithymia, and empathy. Single-case analyses assessed the proportion of FH+ participants with difficulties in executive function and/or theory of mind. RESULTS: FH+ individuals exhibited difficulties in response inhibition and made more errors during theory of mind processing, indicating an absence of mental state representation, compared with FH- individuals. In the FH+ sample, 53.33% had executive function and/or theory of mind difficulties. Those with lower theory of mind scores reported higher alexithymia and lower empathy on self-report measures. CONCLUSIONS: FH+ individuals display heterogeneous executive function and theory of mind abilities. Given that they mostly occur independently of one another, executive function and theory of mind difficulties may be distinct vulnerability markers in AUD.

Neural activations during cognitive and affective theory of mind processing in healthy adults with a family history of alcohol use disorder.

BACKGROUND: Social cognition impairments are a common feature of alcohol use disorders (AUD). However, it remains unclear whether these impairments are solely the consequence of chronic alcohol consumption or whether they could be a marker of vulnerability. METHODS: The present study implemented a family history approach to address this question for a key process of social cognition: theory of mind (ToM). Thirty healthy adults with a family history of AUD (FH+) and 30 healthy adults with a negative family history of AUD (FH-), matched for age, sex, and education level, underwent an fMRI cartoon-vignette paradigm assessing cognitive and affective ToM. Participants also completed questionnaires evaluating anxiety, depressive symptoms, childhood trauma, and alexithymia. RESULTS: Results indicated that FH+ individuals differed from FH- individuals on affective but not cognitive ToM processing, at both the behavioral and neural levels. At the behavioral level, the FH+ group had lower response accuracy for affective ToM compared with the FH- group. At the neural level, the FH+ group had higher brain activations in the left insula and inferior frontal cortex during affective ToM processing. These activations remained significant when controlling for depressive symptoms, anxiety, and childhood trauma. CONCLUSIONS: These findings highlight difficulties during affective ToM processing among first-degree relatives of AUD patients, supporting the idea that some of the impairments exhibited by these patients may already be present before the onset of AUD and may be considered a marker of vulnerability.

Adaptive short-term plasticity in the typical reading network.

The left temporo-parietal cortex (TPC) is crucial for phonological decoding, i.e., for learning and retaining sound-letter mappings, and appears hypoactive in dyslexia. Here, we tested the causal contribution of this area for reading in typical readers with transcranial magnetic stimulation (TMS) and explored the reading network's response with fMRI. By investigating the underlying neural correlates of stimulation-induced modulations of the reading network, we can help improve targeted interventions for individuals with dyslexia. 28 typical adult readers overtly read simple and complex words and pseudowords during fMRI after effective and sham TMS over the left TPC. To explore differences in functional activation and effective connectivity within the reading network, we performed univariate and multivariate analyses, as well as dynamic causal modeling. While TMS-induced effects on reading performance and brain activation showed large individual variability, multivariate analyses revealed a shift in activation in the left inferior frontal cortex for pseudoword reading after effective TMS. Furthermore, TMS increased effective connectivity from the left ventral occipito-temporal cortex to the left TPC. In the absence of effects on reading performance, the observed changes in task-related activity and the increase in functional coupling between the two core reading nodes suggest successful short-term compensatory reorganization in the reading network following TMS-induced disruption. This study is the first to explore neurophysiological changes induced by TMS to a core reading node in typical readers while performing an overt reading task. We provide evidence for remote stimulation effects and emphasize the relevance of functional interactions in the reading network.

Salvage Robotic-assisted Laparoscopic Radical Prostatectomy Following Focal High-Intensity Focused Ultrasound for ISUP 2/3 Cancer.

OBJECTIVE: To report feasibility and outcome of salvage robotic-assisted laparoscopic radical prostatectomy (S-RALP) after focal therapy using high-intensity focused ultrasound (HIFU) treatment compared to primary robotic-assisted laparoscopic radical prostatectomy (pRALP). METHODS: In this bicentric trial patients undergoing S-RALP for detection of WHO2016/ISUP Grade Group 2 or 3 prostate cancer were previously treated in prospective focal HIFU trials. Perioperative data, complications, oncological and functional outcome were analysed. Patients who underwent pRALP were matched in a ratio 2(pRALP):1(S-RALP) according to preoperatively functional, oncological and clinical parameters. RESULTS: A total of 39 patients were included in the study (13S-RALP, 26pRALP). Median operative time in the S-RALP group was 260minutes (pRALP: 257minutes), blood loss was 230ml (pRALP: 300ml). Complications occurred in 46.2% (6/13) of S-RALP patients (pRALP: 26.9%), including four Clavien-Dindo III complications (pRALP: 2/26). In S-RALP adverse histological outcome (≥pT3a, pN+ or R1) was detected in 23.1% (3/13) (pRALP: 26.9%). There was one patient with PSA-persistence (pRALP: 2/26). Regarding functional outcomes there was no difference between the two groups observed (incontinence P=.71, erectile function P=.21). CONCLUSION: S-RALP should be offered to patients with an early relapse after focal HIFU. The early oncological outcome is satisfactory and functional outcome one year postoperatively is similar to pRALP. However, S-RALP is associated with a higher rate of Clavien-Dindo III complications (mainly, placement of a drainage), of which patients should be informed beforehand.

Model reduction techniques for the computation of extended Markov parameterizations for generalized Langevin equations.

The generalized Langevin equation is a model for the motion of coarse-grained particles where dissipative forces are represented by a memory term. The numerical realization of such a model requires the implementation of a stochastic delay-differential equation and the estimation of a corresponding memory kernel. Here we develop a new approach for computing a data-driven Markov model for the motion of the particles, given equidistant samples of their velocity autocorrelation function. Our method bypasses the determination of the underlying memory kernel by representing it via up to about twenty auxiliary variables. The algorithm is based on a sophisticated variant of the Prony method for exponential interpolation and employs the positive real lemma from model reduction theory to extract the associated Markov model. We demonstrate the potential of this approach for the test case of anomalous diffusion, where data are given analytically, and then apply our method to velocity autocorrelation data of molecular dynamics simulations of a colloid in a Lennard-Jones fluid. In both cases, the velocity autocorrelation function and the memory kernel can be reproduced very accurately. Moreover, we show that the algorithm can also handle input data with large statistical noise. We anticipate that it will be a very useful tool in future studies that involve dynamic coarse-graining of complex soft matter systems.

Prospective multicentre study using high intensity focused ultrasound (HIFU) for the focal treatment of prostate cancer: Safety outcomes and complications.

PURPOSE: To investigate focal therapy using High Intensity Focused Ultrasound (HIFU) for the treatment of localized prostate cancer (CaP), we analyzed the safety and complications of this procedure. METHODS: Patients (pts) eligible for this multicenter prospective cohort study suffered from low to intermediate risk localized CaP with no prior treatment. After tumor identification on multiparametric MRI and in prostate biopsy, the lesions were treated with HIFU observing a safety margin of 8 to 10 mm. Adverse events (AE) after 30 and 90 days, as well as the required interventions were assessed and stratified for treatment localizations. RESULTS: Of the 98 men included in the study in two European centers, 35 (35.7%) experienced AEs in the first 30 days after HIFU intervention with Clavien-Dindo grade ≤ II: 15 pts (15.3%) had a postoperative urinary tract infection and 26 pts (26.5%) a urinary retention. Four pts (4.1%) underwent subsequent intervention (Clavien-Dindo grade IIIa/b). The number of late postoperative complications occurring between 30 and 90 days after intervention was low (2.0%). The highest complication rate was associated with tumors located at the anterior base (50.0%). The inclusion of the urethra in the ablation zone led to AEs in 20 out of 41 cases (48.8%) and represented a significant risk factor for complications within 30 days (odds ratio = 2.53; 95% confidence interval: 1.08-5.96; P = 0.033). CONCLUSIONS: Focal therapy of CaP lesions with a robotic HIFU-probe is safe and renders an acceptable rate of minor early AEs. The inclusion of the urethra in the ablation zone leads to an increase in early complications and should be avoided whenever possible.

Replacing the Draize eye test: Impedance spectroscopy as a 3R method to discriminate between all GHS categories for eye irritation.

Highly invasive animal based test procedures for risk assessment such as the Draize eye test are under increasing criticism due to poor transferability for the human organism and animal-welfare concerns. However, besides all efforts, the Draize eye test is still not completely replaced by alternative animal-free methods. To develop an in vitro test to identify all categories of eye irritation, we combined organotypic cornea models based on primary human cells with an electrical readout system that measures the impedance of the test models. First, we showed that employing a primary human cornea epithelial cell based model is advantageous in native marker expression to the primary human epidermal keratinocytes derived models. Secondly, by employing a non-destructive measuring system based on impedance spectroscopy, we could increase the sensitivity of the test system. Thereby, all globally harmonized systems categories of eye irritation could be identified by repeated measurements over a period of 7 days. Based on a novel prediction model we achieved an accuracy of 78% with a reproducibility of 88.9% to determine all three categories of eye irritation in one single test. This could pave the way according to the 3R principle to replace the Draize eye test.

Chasing quantitative biases in neutron imaging with scintillator-camera detectors: a practical method with black body grids.

We propose a method for improving the quantification of neutron imaging measurements with scintillator-camera based detectors by correcting for systematic biases introduced by scattered neutrons and other sources such as light reflections in the detector system. This method is fully experimental, using reference measurements with a grid of small black bodies (BB) to measure the bias contributions directly. Using two test samples, one made of lead alloy and having a moderate (20%) neutron transmission and one made of stainless-steel and having a very low (1%) transmission, we evaluated the improvement brought by this method in reducing both the average quantification bias and the uncertainty around this average bias after tomographic reconstruction. The results show that a reduction of the quantification bias of up to one order of magnitude can be obtained. For moderately transparent samples, little sensitivity is observed to the parameters used for the correction. For the more challenging sample with very low transmission, a correct placement of the BB grid is of utmost importance for a successful correction.

A Monte Carlo approach for scattering correction towards quantitative neutron imaging of polycrystals.

The development of neutron imaging from a qualitative inspection tool towards a quantitative technique in materials science has increased the requirements for accuracy significantly. Quantifying the thickness or the density of polycrystalline samples with high accuracy using neutron imaging has two main problems: (i) the scattering from the sample creates artefacts on the image and (ii) there is a lack of specific reference attenuation coefficients. This work presents experimental and simulation results to explain and approach these problems. Firstly, a series of neutron radiography and tomography experiments of iron, copper and vanadium are performed and serve as a reference. These materials were selected because they attenuate neutrons mainly through coherent (Fe and Cu) and incoherent (V) scattering. Secondly, an ad hoc Monte Carlo model was developed, based on beamline, sample and detector parameters, in order to simulate experiments, understand the physics involved and interpret the experimental data. The model, developed in the McStas framework, uses a priori information about the sample geometry and crystalline structure, as well as beamline settings, such as spectrum, geometry and detector type. The validity of the simulations is then verified with experimental results for the two problems that motivated this work: (i) the scattering distribution in transmission imaging and (ii) the calculated attenuation coefficients.

Combining cell-based hydrodynamics with hybrid particle-field simulations: efficient and realistic simulation of structuring dynamics.

We have extended an existing hybrid MD-SCF simulation technique that employs a coarsening step to enhance the computational efficiency of evaluating non-bonded particle interactions. This technique is conceptually equivalent to the single chain in mean-field (SCMF) method in polymer physics, in the sense that non-bonded interactions are derived from the non-ideal chemical potential in self-consistent field (SCF) theory, after a particle-to-field projection. In contrast to SCMF, however, MD-SCF evolves particle coordinates by the usual Newton's equation of motion. Since collisions are seriously affected by the softening of non-bonded interactions that originates from their evaluation at the coarser continuum level, we have devised a way to reinsert the effect of collisions on the structural evolution. Merging MD-SCF with multi-particle collision dynamics (MPCD), we mimic particle collisions at the level of computational cells and at the same time properly account for the momentum transfer that is important for a realistic system evolution. The resulting hybrid MD-SCF/MPCD method was validated for a particular coarse-grained model of phospholipids in aqueous solution, against reference full-particle simulations and the original MD-SCF model. We additionally implemented and tested an alternative and more isotropic finite difference gradient. Our results show that efficiency is improved by merging MD-SCF with MPCD, as properly accounting for hydrodynamic interactions considerably speeds up the phase separation dynamics, with negligible additional computational costs compared to efficient MD-SCF. This new method enables realistic simulations of large-scale systems that are needed to investigate the applications of self-assembled structures of lipids in nanotechnologies.

Catch-up validation study of an in vitro skin irritation test method based on an open source reconstructed epidermis (phase II).

To replace the Draize skin irritation assay (OECD guideline 404) several test methods based on reconstructed human epidermis (RHE) have been developed and were adopted in the OECD test guideline 439. However, all validated test methods in the guideline are linked to RHE provided by only three companies. Thus, the availability of these test models is dependent on the commercial interest of the producer. To overcome this limitation and thus to increase the accessibility of in vitro skin irritation testing, an open source reconstructed epidermis (OS-REp) was introduced. To demonstrate the capacity of the OS-REp in regulatory risk assessment, a catch-up validation study was performed. The participating laboratories used in-house generated OS-REp to assess the set of 20 reference substances according to the performance standards amending the OECD test guideline 439. Testing was performed under blinded conditions. The within-laboratory reproducibility of 87% and the inter-laboratory reproducibility of 85% prove a high reliability of irritancy testing using the OS-REp protocol. In addition, the prediction capacity was with an accuracy of 80% comparable to previous published RHE based test protocols. Taken together the results indicate that the OS-REp test method can be used as a standalone alternative skin irritation test replacing the OECD test guideline 404.

Qualidade do leite e perfil das propriedades leiteiras no sul de Santa Catarina: abordagem multivariada / Milk quality and profile of dairy farms in southern Santa Catarina: multivariate approach

O objetivo do presente estudo foi caracterizar as propriedades leiteiras da região do Vale do Braço do Norte, sul de Santa Catarina, Brasil, quanto à qualidade do leite e ao perfil em infraestrutura, manejo e alimentação dos animais. Foram coletadas informações de 50 propriedades leiteiras, obtidas por meio da aplicação de um questionário estruturado, abrangendo questões socioeconômicas dos produtores, manejo do rebanho, estrutura da propriedade, caracterização dos animais, alimentação das vacas além de manejo e higiene da ordenha. As amostras de leite foram submetidas a análises de composição, contagem bacteriana total, contagem de células somáticas e estabilidade do leite ao teste do álcool. Os dados foram analisados pela análise fatorial, discriminante, canônica, e de agrupamento. As propriedades têm como principal característica a agricultura familiar, com área média de 30 hectares; destes, 15,1 são destinados à pecuária leiteira, com média de 23,1 vacas ordenhadas. Na análise fatorial, o primeiro fator representa as relações entre as práticas de higiene na ordenha e de controle/prevenção de mastite, o segundo fator compreende a infraestrutura da fazenda com o nível de produção e o terceiro fator demonstra a relação entre a suplementação concentrada, a produção e a estabilidade do leite ao teste do álcool. A análise de agrupamento formou três grupos, sendo dois compostos por produtores com maior nível tecnológico e outro constituído por pequenos produtores com menor infraestrutura e nível de tecnologia. As propriedades que apresentam infraestrutura mais adequada para a produção, maior adoção das práticas recomendadas de manejo de ordenha e critérios de alimentação mais adequados produzem leite com melhor qualidade.

The aim of this study was to characterize the dairy farms of the Vale do Braço do Norte region, south of Santa Catarina State, Brazil, regarding milk quality and profile of the farms for infrastructure, management and nutrition of the animals. Information about 50 dairy farms was obtained through a survey regarding socio-economic conditions of the farmers, farm structure, characterization of animals, cow feeding and also milking management and hygiene. The milk samples were analyzed for total bacterial count, somatic cell count and stability of milk to ethanol. The data were analyzed in factorial, discriminant, canonical and cluster analysis. The main characteristic of farms is family farming with an average area of 30 hectares, of which 15.1 are destined for dairy farming, where an average of 23.1 cows are milked. On the factor analysis, the first factor represents the relation between hygiene practices during milking and control / prevention of mastitis, the second factor comprises the infrastructure of the farm with the level of production and the third factor shows the ratio of concentrate supplementation, production and stability of the milk to the ethanol test. The cluster analysis formed three groups, two composed of producers with higher technological level and another by small producers with lower infrastructure and level of technology. The dairy farms that have more adequate infrastructure for production, greater adoption of practices recommended for milking management and more appropriate criteria for cow feeding produce better quality milk.

SPON2, a newly identified target gene of MACC1, drives colorectal cancer metastasis in mice and is prognostic for colorectal cancer patient survival.

MACC1 (metastasis associated in colon cancer 1) is a prognostic biomarker for tumor progression, metastasis and survival of a variety of solid cancers including colorectal cancer (CRC). Here we aimed to identify the MACC1-induced transcriptome and key players mediating the MACC1-induced effects in CRC. We performed microarray analyses using CRC cells ectopically overexpressing MACC1. We identified more than 1300 genes at least twofold differentially expressed, including the gene SPON2 (Spondin 2) as 90-fold upregulated transcriptional target of MACC1. MACC1-dependent SPON2 expression regulation was validated on mRNA and protein levels in MACC1 high (endogenously or ectopically) and low (endogenously or by knockdown) expressing cells. Chromatin immunoprecipitation analysis demonstrated the binding of MACC1 to the gene promoter of SPON2. In cell culture, ectopic SPON2 overexpression induced cell viability, migration, invasion and colony formation in endogenously MACC1 and SPON2 low expressing cells, whereas SPON2 knockdown reduced proliferative, migratory and invasive abilities in CRC cells with high endogenous MACC1 and SPON2 expression. In intrasplenically transplanted NOD/SCID mice, metastasis induction was analyzed with control or SPON2-overexpressing CRC cells. Tumors with SPON2 overexpression induced liver metastasis (vs control animals without any metastases, P=0.0036). In CRC patients, SPON2 expression was determined in primary tumors (stages I-III), and survival time was analyzed by Kaplan-Meier method. CRC patients with high SPON2 expressing primary tumors demonstrated 8 months shorter metastasis-free survival (MFS) compared with patients with low SPON2 levels (P=0.053). Combining high levels of SPON2 and MACC1 improved the identification of high-risk patients with a 20-month shorter MFS vs patients with low biomarker expression. In summary, SPON2 is a transcriptional target of the metastasis gene MACC1. SPON2 induces cell motility in vitro and CRC metastasis in mice. In patients, SPON2 serves as prognostic indicator for CRC metastasis and survival, and might represent a promising target for therapeutic approaches.

Comparison of osteoclastogenesis and resorption activity of human osteoclasts on tissue culture polystyrene and on natural extracellular bone matrix in 2D and 3D.

Bone homeostasis is maintained by osteoblasts (bone formation) and osteoclasts (bone resorption). While there have been numerous studies investigating mesenchymal stem cells and their potential to differentiate into osteoblasts as well as their interaction with different bone substitute materials, there is only limited knowledge concerning in vitro generated osteoclasts. Due to the increasing development of degradable bone-grafting materials and the need of sophisticated in vitro test methods, it is essential to gain deeper insight into the process of osteoclastogenesis and the resorption functionality of human osteoclasts. Therefore, we focused on the comparison of osteoclastogenesis and resorption activity on tissue culture polystyrene (TCPS) and bovine extracellular bone matrices (BMs). Cortical bone slices were used as two-dimensional (2D) substrates, whereas a thermally treated cancellous bone matrix was used for three-dimensional (3D) experiments. We isolated primary human monocytes and induced osteoclastogenesis by medium supplementation. Subsequently, the expression of the vitronectin receptor (αVß3) and cathepsin K as well as the characteristic actin formation on TCPS and the two BMs were examined. The cell area of human osteoclasts was analyzed on TCPS and on BMs, whereas significantly larger osteoclasts could be detected on BMs. Additionally, we compared the diameter of the sealing zones with the measured diameter of the resorption pits on the BMs and revealed similar diameters of the sealing zones and the resorption pits. We conclude that using TCPS as culture substrate does not affect the expression of osteoclast-specific markers. The analysis of resorption activity can successfully be conducted on cortical as well as on cancellous bone matrices. For new in vitro test systems concerning bone resorption, we suggest the establishment of a 2D assay for high throughput screening of new degradable bone substitute materials with osteoclasts.

Alemtuzumab in chronic lymphocytic leukemia: final results of a large observational multicenter study in mostly pretreated patients.

This retrospective study evaluated the benefit of alemtuzumab monotherapy in unselected patients with advanced B-cell chronic lymphocytic leukemia (CLL) and prolymphocytic leukemia (B-PLL) to definitely describe the impact of this antibody in clinical routine use. Data were collected from 208 consecutive, mainly pretreated, patients with CLL (n = 202), and B-PLL (n = 6) who had received alemtuzumab. Response, progression-free survival (PFS), and overall survival (OS) in various settings were assessed, and toxicities were documented. In these routine patients, a comparably low cumulative dose of alemtuzumab (median, 403 mg) was applied. In CLL, overall response rate was 32 %, and various pre-therapeutic parameters were predictive for inferior response, among them, the prior administration of ≥3 therapy lines (P < 0.001), refractoriness to fludarabine (P = 0.002), and bulky lymphadenopathy (P = 0.003). PFS and OS after start of alemtuzumab were 6.2 and 21.0 months, respectively. Bulky lymphadenopathy was the prominent risk factor for both inferior PFS (P < 0.001) and OS (P = 0.002). In B-PLL, four patients experienced a fatal outcome, whereas two patients had some benefit with alemtuzumab. The main adverse effects were CMV reactivation (20 %) and a broad spectrum of infections, which together were the main reasons for treatment interruption and/or premature termination. In conclusion, alemtuzumab administered even at low dose levels was effective but overall considerably toxic in routine CLL patients. We emphasize that alemtuzumab remains an important therapeutic option in subsets of CLL patients.

Probing timescales during back side ablation of Molybdenum thin films with optical and electrical measurement techniques.

In this study we present a new measurement technique to investigate the timescales of back side ablation of conductive films, using Molybdenum as an application example from photovoltaics. With ultrashort laser pulses at fluences below 0.6 J/cm(2), we ablate the Mo film in the shape of a fully intact Mo 'disc' from a transparent substrate. By monitoring the time-dependent current flow across a specifically developed test structure, we determine the time required for the lift-off of the disc. This value decreases with increasing laser fluence down to a minimum of 21 ± 2 ns. Furthermore, we record trajectories of the discs using a shadowgraphic setup. Ablated discs escape with a maximum velocity of 150 ± 5 m/s whereas droplets of Mo forming at the center of the disc can reach velocities up to 710 ± 11 m/s.

Comparison of an automated respiratory systolic variation test with dynamic preload indicators to predict fluid responsiveness after major surgery.

BACKGROUND: Predicting the response of cardiac output to volume administration remains an ongoing clinical challenge. The objective of our study was to compare the ability to predict volume responsiveness of various functional measures of cardiac preload. These included pulse pressure variation (PPV), stroke volume variation (SVV), and the recently launched automated respiratory systolic variation test (RSVT) in patients after major surgery. METHODS: In this prospective study, 24 mechanically ventilated patients after major surgery were enrolled. Three consecutive volume loading steps consisting of 300 ml 6% hydroxyethylstarch 130/0.4 were performed and cardiac index (CI) was assessed by transpulmonary thermodilution. Volume responsiveness was considered as positive if CI increased by >10%. RESULTS: In total 72 volume loading steps were analysed, of which 41 showed a positive volume response. Receiver operating characteristic (ROC) curve analysis revealed an area under the curve (AUC) of 0.70 for PPV, 0.72 for SVV and 0.77 for RSVT. Areas under the curves of all variables did not differ significantly from each other (P>0.05). Suggested cut-off values were 9.9% for SVV, 10.1% for PPV, and 19.7° for RSVT as calculated by the Youden Index. CONCLUSION: In predicting fluid responsiveness the new automated RSVT appears to be as accurate as established dynamic indicators of preload PPV and SVV in patients after major surgery. The automated RSVT is clinically easy to use and may be useful in guiding fluid therapy in ventilated patients.

Computing absolute free energies of disordered structures by molecular simulation.

We present a Monte Carlo simulation technique by which the free energy of disordered systems can be computed directly. It is based on thermodynamic integration. The central idea is to construct an analytically solvable reference system from a configuration which is representative for the state of interest. The method can be applied to lattice models (e.g., the Ising model) as well as off-lattice molecular models. We focus mainly on the more challenging off-lattice case. We propose a Monte Carlo algorithm, by which the thermodynamic integration path can be sampled efficiently. At the examples of the hard sphere liquid and a hard disk solid with a defect, we discuss several properties of the approach.