Targeted tissue delivery of RNA therapeutics using antibody-oligonucleotide conjugates (AOCs).

Although targeting TfR1 to deliver oligonucleotides to skeletal muscle has been demonstrated in rodents, effectiveness and pharmacokinetic/pharmacodynamic (PKPD) properties remained unknown in higher species. We developed antibody-oligonucleotide conjugates (AOCs) towards mice or monkeys utilizing anti-TfR1 monoclonal antibodies (αTfR1) conjugated to various classes of oligonucleotides (siRNA, ASOs and PMOs). αTfR1 AOCs delivered oligonucleotides to muscle tissue in both species. In mice, αTfR1 AOCs achieved a > 15-fold higher concentration to muscle tissue than unconjugated siRNA. A single dose of an αTfR1 conjugated to an siRNA against Ssb mRNA produced > 75% Ssb mRNA reduction in mice and monkeys, and mRNA silencing was greatest in skeletal and cardiac (striated) muscle with minimal to no activity in other major organs. In mice the EC50 for Ssb mRNA reduction in skeletal muscle was >75-fold less than in systemic tissues. Oligonucleotides conjugated to control antibodies or cholesterol produced no mRNA reduction or were 10-fold less potent, respectively. Tissue PKPD of AOCs demonstrated mRNA silencing activity primarily driven by receptor-mediated delivery in striated muscle for siRNA oligonucleotides. In mice, we show that AOC-mediated delivery is operable across various oligonucleotide modalities. AOC PKPD properties translated to higher species, providing promise for a new class of oligonucleotide therapeutics.

A multiscale model of the role of microenvironmental factors in cell segregation and heterogeneity in breast cancer development.

We analyzed a quantitative multiscale model that describes the epigenetic dynamics during the growth and evolution of an avascular tumor. A gene regulatory network (GRN) formed by a set of ten genes that are believed to play an important role in breast cancer development was kinetically coupled to the microenvironmental agents: glucose, estrogens, and oxygen. The dynamics of spontaneous mutations was described by a Yule-Furry master equation whose solution represents the probability that a given cell in the tissue undergoes a certain number of mutations at a given time. We assumed that the mutation rate is modified by a spatial gradient of nutrients. The tumor mass was simulated by means of cellular automata supplemented with a set of reaction diffusion equations that described the transport of microenvironmental agents. By analyzing the epigenetic state space described by the GRN dynamics, we found three attractors that were identified with cellular epigenetic states: normal, precancer and cancer. For two-dimensional (2D) and three-dimensional (3D) tumors we calculated the spatial distribution of the following quantities: (i) number of mutations, (ii) mutation of each gene and, (iii) phenotypes. Using estrogen as the principal microenvironmental agent that regulates cell proliferation process, we obtained tumor shapes for different values of estrogen consumption and supply rates. It was found that he majority of mutations occurred in cells that were located close to the 2D tumor perimeter or close to the 3D tumor surface. Also, it was found that the occurrence of different phenotypes in the tumor are controlled by estrogen concentration levels since they can change the individual cell threshold and gene expression levels. All results were consistently observed for 2D and 3D tumors.

Historical biogeography of the Neotropical noctilionoid bats (Chiroptera: Noctilionoidea), revisited through a geographically explicit analysis.

Biogeographic studies have generally relied on methods that use a few, large predefined areas, which may overlook fine-scale patterns. Here we test previous hypotheses about the biogeographic history of a diverse bat clade regarding its association with major Neotropical geological formations, particularly the Antilles, the South American Dry Diagonal, the Andes and the Panamanian land bridge, by applying a recently available method that uses actual distributions instead of predefined areas. We compiled and curated spatially explicit, georeferenced data of 173 bat species (Mammalia: Chiroptera: Noctilionoidea) from the online database Global Biodiversity Information Facility. By taking a previous comprehensive phylogeny as an evolutionary framework, we performed computationally intensive analyses using the Geographically-explicit Event Model. This method uses the observed species distributions to reconstruct the ancestral areas and biogeographic events at each phylogeny node. We found that sympatric speciation was the most frequently reconstructed event, and involved mainly the Panamanian Isthmus and northern South America (SA), but all sympatry reconstructions were different and specific to each node. Allopatric events were important in the Andes; vicariance caused both west/east and north/south disjunctions that went unnoticed previously. Founder events indicated bidirectional dispersal between the mainland and the Antilles since the Miocene, and across the incomplete Panamanian bridge and the SA Dry Diagonal since the early Pliocene. Overall, we found support for previous hypotheses on the influence of major Neotropical paleogeographic events in the diversification of the group, but additionally revealed multi-scale patterns that are embedded within the mainland and were previously overlooked. Our results highlight a trans-isthmian centre of diversification in the biogeographic history of Noctilionoidea including the Panamanian Isthmus and Northern SA.

Optimizing biogas methanation over nickel supported on ceria-alumina catalyst: Towards CO2-rich biomass utilization for a negative emissions society.

Biogas methanation emerges as a prominent technology for converting biogas into biomethane in a single step. Furthermore, this technology can be implemented at biogas plant locations, supporting local economies and reducing dependence on large energy producers. However, there is a lack of comprehensive studies on biogas methanation, particularly regarding the technical optimization of operational parameters and the profitability analysis of the overall process. To address this gap, our study represents a seminal work on the technical optimization of biogas methanation obtaining an empirical model to predict the performance of biogas methanation. We investigate the influence of operational parameters, such as reaction temperature, H2/CO2 ratio, space velocity, and CO2 share in the biogas stream through an experimental design. Based on previous research we selected a nickel supported on ceria-alumina catalyst; being nickel a benchmark system for methanation process such selection permits a reliable data extrapolation to commercial units. We showcase the remarkable impact of studied key operation parameters, being the temperature, the most critical factor affecting the reaction performance (ca. 2 to 5 times higher than the second most influencing parameter). The impact of the H2/CO2 ratio is also noticeable. The response surfaces and contour maps suggest that a temperature between 350 and 450 °C and an H2/CO2 ratio between 2.5 and 3.2 optimize the reaction performance. Further experimental tests were performed for model validation and optimization leading to a reliable predictive model. Overall, this study provides validated equations for technology scaling-up and techno-economic analysis, thus representing a step ahead towards real-world applications for bio-methane production.

Vesicle formation induced by thermal fluctuations.

The process of fission and vesicle formation depends on the geometry of the membrane that will split. For instance, a flat surface finds it difficult to form vesicles because of the lack of curved regions where to start the process. Here we show that vesicle formation can be promoted by temperature, by using a membrane phase field model with Gaussian curvature. We find a phase transition between fluctuating and vesiculation phases that depends on temperature, spontaneous curvature, and the ratio between bending and Gaussian moduli. We analysed the energy dynamical behaviour of these processes and found that the main driving ingredient is the Gaussian energy term, although the curvature energy term usually helps with the process as well. We also found that the chemical potential can be used to investigate the temperature of the system. Finally we address how temperature changes the condition for spontaneous vesiculation for all geometries, making it happen in a wider range of values of the Gaussian modulus.

Treatment of hydrothermal carbonization process water by electrochemical oxidation: Assessment of process performance.

Herein electrochemical oxidation (EO) is proposed as a novel path to treat the process water obtained from hydrothermal carbonization of olive tree pruning. The aim of this work is to analyze the organic matter removal achieved by the treatment along with the identification of the chemical species formed after the electro-oxidation process at different experimental conditions. Three different tests were performed in a boron doped diamond cell, using Na2SO4 and NaCl as supporting electrolytes to compare the results obtained with the raw process water. The organic matter removal was evaluated by means of total organic carbon and chemical oxygen demand, while Gas Chromatography Mass Spectrometry was used to determine the chemical species present before and after the treatment. The addition of a promoter considerably increased the organic matter removal. In fact, the experiments performed using supporting electrolytes showed the best results in terms of organic matter removal compared to the control experiment (30-40% vs. 17%); This reduction agrees with the volatile fatty acids' measurements. Almost all the chemical species identified in the different feedstocks were partially or totally removed after the EO treatment depending on the experimental conditions. The specific energy consumption and the cost calculated for the treatment is highly dependent on the time of electro-oxidation and the supporting electrolyte used, obtaining values from 1 to 45 €/kg CODremoved. All in all, this work suggests an interesting path towards a further utilization of process water from hydrothermal carbonization processes.

Dipole-dipole interactions control the interfacial rheological response of cyclodextrin/surfactant solutions.

A recent surface rheological study has shown that aqueous solutions of α-cyclodextrin (αCD) with anionic surfactants (S) display a remarkable viscoelasticity at the liquid/air interface, which has not been observed in similar systems. The dilatational modulus is various orders of magnitude larger than those for the binary mixtures αCD + water and S + water. The rheological response has been qualitatively related to the bulk distribution of species, the 2 : 1 inclusion complexes (αCD2 : S) playing a fundamental role. In this work, we have developed a model that considers dipole-dipole interactions between 2 : 1 inclusion complexes ordered on the liquid/air interface. When the model is applied to the specific experimental conditions, the dependencies on concentration and temperature of the dilatational modulus and the surface tension were found to be in excellent agreement with the data, indicating clearly that dipole-dipole interactions determine and control the rheological behavior of the interface.

Promoting bioeconomy routes: From food waste to green biomethane. A profitability analysis based on a real case study in eastern Germany.

Profitability studies are needed to establish the potential pathways required for viable biomethane production in the Brandenburg region of Germany. This work study the profitability of a potential biomethane production plant in the eastern German region of Brandenburg, through a specific practical scenario with data collected from a regional biogas plant located in Alteno (Schradenbiogas GmbH & Co. KG). Several parameters with potential economic influence such as distance of the production point to the grid, waste utilization percentage, and investment, were analyzed. The results illustrate a negative overall net present value with the scenario of no governmental investment, even when considering trading the CO2 obtained throughout the process. Subsidies needed to reach profitability varied with distance from 13.5 €/MWh to 19.3 €/MWh. For a fixed distance of 15 kms, the importance of percentage of waste utilization was examined. Only 100% of waste utilization and 75% of waste utilization would reach profitability under a reasonable subsidies scheme (16.3 and 18.8 €/MWh respectively). Concerning the importance of investment, a subsidized investment of at least 70% is demanded for positive net present values. Besides, the sensitivity analysis remarks the energy consumption of the biogas upgrading stage, the electricity price, and the energy consumption of biogas production as major parameters to be tackled for the successful implementation of biogas upgrading plants. The results here obtained invite to ponder about potential strategies to further improve the economic viability of this kind of renewable projects. In this line, using the CO2 separated to produce added-value chemicals can be an interesting alternative.

Chemical synthesis and optical, structural, and surface characterization of InP-In2O3 quantum dots.

InP-In2O3 colloidal quantum dots (QDs) synthesized by a single-step chemical method without injection of hot precursors (one-pot) were investigated. Specifically, the effect of the tris(trimethylsilyl)phosphine, P(TMS)3, precursor concentration on the QDs properties was studied to effectively control the size and shape of the samples with a minimum size dispersion. The effect of the P(TMS)3 precursor concentration on the optical, structural, chemical surface, and electronic properties of InP-In2O3 QDs is discussed. The absorption spectra of InP-In2O3 colloids, obtained by both UV-Vis spectrophotometry and photoacoustic spectroscopy, showed a red-shift in the high-energy regime as the concentration of the P(TMS)3 increased. In addition, these results were used to determine the band-gap energy of the InP-In2O3 nanoparticles, which changed between 2.0 and 2.9 eV. This was confirmed by Photoluminescence spectroscopy, where a broad-band emission displayed from 2.0 to 2.9 eV is associated with the excitonic transition of the InP and In2O3 QDs. In2O3 and InP QDs with diameters ranging approximately from 8 to 10 nm and 6 to 9 nm were respectively found by HR-TEM. The formation of the InP and In2O3 phases was confirmed by X-ray Photoelectron Spectroscopy.

The swimming control group in spatial reference memory task: analysis of its motor cortex activity.

Spatial reference memory in rodents is commonly performed in the Morris Water Maze (MWM). The use of control groups on this task is essential in order to subtract brain activity not related to learning. To study the functional contribution of selected brain areas, we assessed neuronal metabolic activity thorough quantitative cytochrome c oxidase histochemistry. This technique allows the measurement of the oxidative metabolism responsible for ATP production. Our objective is to analyse if the swimming control group is an optimal control for the evaluation of spatial reference memory task. To do so, we explore the behaviour in the MWM and the neuronal metabolic activity of motor cortex and its layers, in addition to hippocampus. For this purpose, three groups of Wistar rats were used: reference memory group, swimming control, and cage control. The behavioural results show significant differences between the experimental group and the swimming control group in time spent in the quadrants and swimming speed. In addition, higher neuronal hippocampal metabolic activity (CA1 subfield) was found in the experimental when compared to both controls. However, there are no differences in the motor cortex neuronal metabolic activity of the groups. Therefore, we can assume that the swimming control group effectively isolates the motor activity during the swim and the behavioural results are due to the hippocampal activity related to learning itself and not the physical activity performed in the labyrinth.

Likelihood approximations of implied weights parsimony can be selected over the Mk model by the Akaike information criterion.

A likelihood method that approximates the behaviour of implied weighting is described. This approach provides a likelihood perspective on several aspects of implied weighting, such as guidance for the choice of concavity values, a justification to use different concavities for different numbers of taxa, and a natural basis for extended implied weighting. In this approach, the number of free parameters in the estimation depends on C, the number of characters (in contrast to the standard Mk model, which estimates 2T-3 parameters for T taxa). Depending on the characteristics of the dataset, the likelihood obtained with this approach may in some cases be similar or superior to that of the Mk model, but with fewer parameters being adjusted. Because of that tradeoff, testing against the Mk model by means of the Akaike information criterion on a set of 182 morphological datasets indicated many cases (36) in which the likelihood approximation to implied weighting is the best method, from an information-theoretic point of view. Given that it is expected to produce (almost) the same results as this maximum-likelihood approximation, implied weighting can therefore be seen as a valid alternative to the Mk model often used for morphological datasets, on the basis of a criterion for model fit widely advocated by likelihoodists.

Substrates' and products' inhibition in fructanase production by a new Kluyveromyces marxianus CF15 from Agave tequilana fructan in a batch reactor.

This study focuses on fructanase production in a batch reactor by a new strain isolated from agave juice (K. marxianus var. drosophilarum) employing different Agave tequilana fructan (ATF) concentrations as substrate. The experimental data suggest that the fructanase production may be inhibited or repressed by high substrate (50 g/L) and ethanol (20.7 g/L) concentrations present in culture medium. To further analyze these phenomena an unstructured kinetic mathematical model taking into account substrate and products inhibition was proposed and fitted. The mathematical model considers six reaction kinetics and the ethanol evaporation, and predicts satisfactorily the biomass, fructan, glucose, fructose, ethanol, and fructanase behavior for different raw material initial concentrations. The proposed model is the first to satisfactorily describe the production of fructanase from branched ATF with a new strain of K. marxianus.

Genetic Polymorphisms in Cytokine Genes in Colombian Patients with Ocular Toxoplasmosis.

Toxoplasmosis is caused by infection with the protozoan parasite Toxoplasma gondii, which has the capacity to infect all warm-blooded animals worldwide. Toxoplasmosis is a major cause of visual defects in the Colombian population; however, the association between genetic polymorphisms in cytokine genes and susceptibility to ocular toxoplasmosis has not been studied in this population. This work evaluates the associations between polymorphisms in genes coding for the cytokines tumor necrosis factor alpha (TNF-α) (rs1799964, rs1800629, rs1799724, rs1800630, and rs361525), interleukin 1ß (IL-1ß) (rs16944, rs1143634, and rs1143627), IL-1α (rs1800587), gamma interferon (IFN-γ) (rs2430561), and IL-10 (rs1800896 and rs1800871) and the presence of ocular toxoplasmosis (OT) in a sample of a Colombian population (61 patients with OT and 116 healthy controls). Genotyping was performed with the "dideoxynucleotide (ddNTP) primer extension" technique. Functional-effect predictions of single nucleotide polymorphisms (SNPs) were done by using FuncPred. A polymorphism in the IL-10 gene promoter (-1082G/A) was significantly more prevalent in OT patients than in controls (P = 1.93e-08; odds ratio [OR] = 5.27e+03; 95% confidence interval [CI] = 3.18 to 8.739; Bonferroni correction [BONF] = 3.48e-07). In contrast, haplotype "AG" of the IL-10 gene promoter polymorphisms (rs1800896 and rs1800871) was present at a lower frequency in OT patients (P = 7e-04; OR = 0.10; 95% CI = 0.03 to 0.35). The +874A/T polymorphism of IFN-γ was associated with OT (P = 3.37e-05; OR = 4.2; 95% CI = 2.478 to 7.12; BONF = 6.07e-04). Haplotype "GAG" of the IL-1ß gene promoter polymorphisms (rs1143634, rs1143627, and rs16944) appeared to be significantly associated with OT (P = 0.0494). The IL-10, IFN-γ, and IL-1ß polymorphisms influence the development of OT in the Colombian population.

Recombinant factor VIII Fc fusion protein for immune tolerance induction in patients with severe haemophilia A with inhibitors-A retrospective analysis.

INTRODUCTION: Immune tolerance induction (ITI) is the gold standard for eradication of factor VIII inhibitors in severe haemophilia A; however, it usually requires treatment for extended periods with associated high burden on patients and healthcare resources. AIM: Review outcomes of ITI with recombinant factor VIII Fc fusion protein (rFVIIIFc) in patients with severe haemophilia A and high-titre inhibitors. METHODS: Multicentre retrospective chart review of severe haemophilia A patients treated with rFVIIIFc for ITI. RESULTS: Of 19 patients, 7 were first-time ITI and 12 were rescue ITI. Of 7 first-time patients, 6 had at least 1 high-risk feature for ITI failure. Four of 7 first-time patients were tolerized in a median of 7.8 months. The remaining 3 patients continue on rFVIIIFc ITI. Of 12 rescue patients, 7 initially achieved a negative Bethesda titre (≤0.6) in a median of 3.3 months, 1 had a decrease in Bethesda titre and continues on rFVIIIFc ITI and 4 have not demonstrated a decrease in Bethesda titre. Of these 4, 3 continue on rFVIIIFc ITI and 1 switched to bypass therapy alone. Two initially responsive patients transitioned to other factors due to recurrence. Overall, 16 of 19 patients remain on rFVIIIFc (prophylaxis or ITI). For those still undergoing ITI, longer follow-up is needed to determine final outcomes. No adverse events reported. CONCLUSIONS: Recombinant factor VIII Fc fusion protein demonstrated rapid time to tolerization in high-risk first-time ITI patients. For rescue ITI, rFVIIIFc showed therapeutic benefit in some patients who previously failed ITI with other products. These findings highlight the need to further evaluate the use of rFVIIIFc for ITI.

Weighted parsimony outperforms other methods of phylogenetic inference under models appropriate for morphology.

One of the lasting controversies in phylogenetic inference is the degree to which specific evolutionary models should influence the choice of methods. Model-based approaches to phylogenetic inference (likelihood, Bayesian) are defended on the premise that without explicit statistical models there is no science, and parsimony is defended on the grounds that it provides the best rationalization of the data, while refraining from assigning specific probabilities to trees or character-state reconstructions. Authors who favour model-based approaches often focus on the statistical properties of the methods and models themselves, but this is of only limited use in deciding the best method for phylogenetic inference-such decision also requires considering the conditions of evolution that prevail in nature. Another approach is to compare the performance of parsimony and model-based methods in simulations, which traditionally have been used to defend the use of models of evolution for DNA sequences. Some recent papers, however, have promoted the use of model-based approaches to phylogenetic inference for discrete morphological data as well. These papers simulated data under models already known to be unfavourable to parsimony, and modelled morphological evolution as if it evolved just like DNA, with probabilities of change for all characters changing in concert along tree branches. The present paper discusses these issues, showing that under reasonable and less restrictive models of evolution for discrete characters, equally weighted parsimony performs as well or better than model-based methods, and that parsimony under implied weights clearly outperforms all other methods.

Is the snail shell repair process really influenced by eggshell membrane as a template of foreign scaffold?

Biominerals are inorganic-organic hybrid composites formed via self-assembled bottom up processes under mild conditions. Biominerals show interesting physical properties, controlled hierarchical structures and robust remodeling or repair mechanisms. Biological processes associated with biominerals remain to be developed into practical engineering processes. Therefore, the formation of biominerals is inspiring for the design of materials, especially those fabricated at ambient temperatures. The study described herein involves the influence of chicken outer eggshell membrane on the type of calcium carbonate (CaCO3) polymorph deposited on the shell of the land snail Helix aspersa during the repair process after an injury. A piece of snail shell was removed by perforating a hole from the largest body whorl. The operated area was left either uncovered or covered with either a thermoplastic flexible polyolefin-based film Parafilm® or a piece of chicken eggshell membrane. The repaired shells of control and experimental animals were analyzed using SEM, EDS, Raman and FTIR spectroscopies. We found that in the presence of eggshell membrane, the polymorph deposited on the substratum during the first hours resembles calcite, the polymorph present in eggshell normal formation, but at 24 and 48h, when snail mantle cells produced their normal organic matrix (mainly ß-chitin plus proteins and proteoglycans), the polymorph deposited is aragonite, the characteristic polymorph of Helix shell. Therefore, the eggshell membrane influences the type of polymorph, but only in the initial stages of biomineral deposition, before an organic matrix layer is deposited by the snail.

Test Your Memory is sensitive to cognitive change but lacks prospective validity.

OBJECTIVE: To determine the prospective validity of Test Your Memory (TYM) and its sensitivity to change in cognitive state. METHODS: This longitudinal prospective study followed 71 patients with subjective cognitive symptoms and 48 with mild cognitive impairment for a mean time period of 35.2 ± 15 months. Subjects did not have dementia or depression at the beginning of follow-up and each participant was given the TYM at least two times. A psychometric threshold was established to determine presence of a cognitive deficit (z-score ≤ 1.5 on at least one cognitive domain) and the Disability Assessment for Dementia scale was used to ensure full functional ability. The criterion for deterioration was a change in the stage on the Global Deterioration Scale. RESULTS: Sixty-one patients remained cognitively stable and 58 worsened. There were no differences between them with respect to sex, educational attainment, the initial stage on the GDS, or the score on the first TYM. Subjects who worsened were older than those who did not. The TYM increased an average of 0.04 points per month in patients who remained stable or improved (95% CI, -0.01 to 0.08) and decreased an average of 0.14 points per month in those whose condition worsened (95% CI, -0.19 to -0.09). Subjects with mild cognitive impairment who worsened displayed a sharper loss of TYM points than did subjects with subjective cognitive symptoms. CONCLUSIONS: While the TYM lacks prospective validity, it is sensitive to changes in cognitive state.

Validation of a Spanish version of the Test Your Memory.

OBJECTIVE: To validate a Spanish version of the TYM, a self-administered cognitive screening test designed for the detection of Alzheimer's disease and mild cognitive defect. METHODS: A cross-sectional study was conducted in a neurology outpatient clinic. The TYM was administered to individuals of 50 years o more who came to the clinic for whatever the symptom. Their cognitive state was evaluated regardless of the outcome of TYM. They were categorized into 3 groups: 1) Cognitively normal (739), 2) with mild cognitive impairment (183), 3) with dementia (127). An analysis of items was made and the psychometric properties of the TYM were defined. There was a cross-validation, and the predictive validity of the TYM score, adjusted to the demographic variables, was determined by evaluating their performance in ROC curves. RESULTS: The internal consistency, interobserver reliability, short term and long-term test-retest reliability were adequate. The TYM correlated with the MMSE (r=0.779, P<.0001). The cross validation showed consistent results. With the TYM Score adjusted according to the educational level, a sensitivity of 0.86 with a specificity of 0.88 in the cut-off point of ≤40/50 was obtained to identify subjects with cognitive impairment, and a sensitivity of 0.94 with a specificity of 0.89 in the cut-off point of ≤36/50 to identify subjects with dementia. CONCLUSIONS: The TYM is a self-administered global cognitive test, possessing excellent psychometric properties and good predictive validity. It can be used as a cognitive screening test in subjects with 4 years or more of formal education.

[Standardization of the Test Your Memory and evaluation of their concordance with the outcome of the psychometric examination]. / Normalización del Test Your Memory y evaluación de su concordancia con los resultados del examen psicométrico.

OBJECTIVE: To explore the relationship between scores on the Test Your Memory (TYM) battery and findings from a more exhaustive neurocognitive assessment. METHODS: The TYM and fourteen psychometric tests were administered to 84 subjects aged 50 or older who attended an outpatient neurology clinic due to cognitive symptoms. Each patient's cognitive state was determined independently from his/her score on the TYM (CDR 0, n=25; CDR 0.5, n=45; CDR 1, n=14). We analysed concurrent validity of TYM scores and results from the psychometric tests, as well as the degree of concordance between the two types of measurement, by contrasting normalised data from each instrument. RESULTS: Although the intraclass correlation coefficient was 0.67 (confidence interval 95%, 0.53-0.77), analysis of the Bland-Altman plot and the curve on the survival-agreement plot (Luiz et al. method) demonstrates that the individual distances between the two methods exhibit excessive dispersion from a clinical viewpoint. TYM-based predictions of the mean z-score on psychometric tests differed substantially from real results in 30% of the subjects. Concordance of 95% can only be achieved by accepting absolute inter-instrument differences of up to 0.87 as identical values. Furthermore, the TYM underestimates cognitive performance for low values and overestimates it for high values. CONCLUSIONS: The TYM is a cognitive screening test which should not be used to predict results on psychometric tests or to detect cognitive changes in clinical trials.