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Abstract The Pattern Electroretinogram (PERG) is an essential tool in ophthalmic electrophysiology, providing an objective assessment of the central retinal function. It quantifies the activity of cells in the macula and the ganglion cells of the retina, assisting in the differentiation of macular and optic nerve conditions. In this study, we present the IOBA-PERG dataset, an extensive collection of 1354 transient PERG responses accessible on the PhysioNet repository. These recordings were conducted at the Institute of Applied Ophthalmobiology (IOBA) at University of Valladolid, over an extended period spanning nearly two decades, from 2003 to 2022. The dataset includes 336 records, ensuring at least one PERG signal per eye. The dataset thoughtfully includes demographic and clinical data, comprising information such as age, gender, visual acuity measurements, and expert diagnoses. This comprehensive dataset fills a gap in ocular electrophysiological repositories, enhancing ophthalmology research. Researchers can explore a broad range of eye-related conditions and diseases, leading to enhanced diagnostic accuracy, innovative treatment strategies, methodological advancements, and a deeper understanding of ocular electrophysiology.

ABSTRACT Automated radio telemetry systems (ARTS) have the potential to revolutionise our understanding of animal movement by providing a near‐continuous record of individual locations in the wild. However, localisation errors in ARTS data can be very high, especially in natural landscapes with complex vegetation structure and topography. This curtails the research questions that may be addressed with this technology. We set up an ARTS grid in a valley with heterogeneous vegetation cover in the Colombian high Andes and applied an analytical pipeline to test the effectiveness of localisation methods. We performed calibration trials to simulate animal movement in high‐ or low‐flight, or walking on the ground, and compared workflows with varying decisions related to signal cleaning, selection, smoothing, and interpretation, along with four multilateration approaches. We also quantified the influence of spatial features on the system's accuracy. Results showed large variation in localisation error, ranging between 0.4–43.4 m and 474–1929 m, depending on the localisation method used. We found that the selection of higher radio signal strengths and data smoothing based on the temporal autocorrelation are useful tools to improve accuracy. Moreover, terrain ruggedness, height of movement, vegetation type, and the location of animals inside or outside the grid area influence localisation error. In the case of our study system, thousands of location points were successfully estimated for two high‐altitude hummingbird species that previously lacked movement data. Our case study on hummingbirds suggests ARTS grids can be used to estimate small animals' home ranges, associations with vegetation types, and seasonality in occurrence. We present a comparative localisation pipeline, highlighting the variety of possible decisions while processing radio signal data. Overall, this study provides guidance to improve the resolution of location estimates, broadening the application of this tracking technology in the study of the spatial ecology of wild populations.

The identification of unlabeled neuronal electric signals is one of the most challenging open problems in neuroscience, widely known as Spike Sorting. Motivated to solve this problem, we propose a model-based approach within the mixture modeling framework for clustering oscillatory functional data called MixFMM. The core of the approach is the FMM (Frequency Modulated Möbius) waves, which are non-linear parametric time functions, flexible enough to describe different oscillatory patterns and simple enough to be estimated efficiently. In particular, specific model parameters describe the phase, amplitude and shape of the waveforms. A mixture model is defined using FMM waves as basic functions and gaussian errors, and an EM algorithm is proposed for estimating the parameters. Spike Sorting (SS) has received considerable attention in the literature, and different functional clustering approaches have been considered. We have conducted a fair comparative analysis of the MixFMM with three competitors. Two of them are traditional methods in functional clustering and widely used in Spike Sorting. The third is an approach that has proven superior to many others solving Spike Sorting problems. The datasets used for validation include benchmarking simulated and real cases. The internal and external validation indexes confirm a better performance of the MixFMM on real data sets against the three competitors and an outstanding performance in simulated data against traditional approaches.

The circadian system drives near-24-h oscillations in behaviors and biological processes. The underlying core molecular clock regulates the expression of other genes, and it has been shown that the expression of more than 50 percent of genes in mammals displays 24-h rhythmic patterns, with the specific genes that cycle varying from one tissue to another. Determining rhythmic gene expression patterns in human tissues sampled as single timepoints has several challenges, including the reconstruction of temporal order of highly noisy data. Previous methodologies have attempted to address these challenges in one or a small number of tissues for which rhythmic gene evolutionary conservation is assumed to be preserved. Here we introduce CIRCUST, a novel CIRCular-robUST methodology for analyzing molecular rhythms, that relies on circular statistics, is robust against noise, and requires fewer assumptions than existing methodologies. Next, we validated the method against four controlled experiments in which sampling times were known, and finally, CIRCUST was applied to 34 tissues from the Genotype-Tissue Expression (GTEx) dataset with the aim towards building a comprehensive daily rhythm gene expression atlas in humans. The validation and application shown here indicate that CIRCUST provides a flexible framework to formulate and solve the issues related to the analysis of molecular rhythms in human tissues. CIRCUST methodology is publicly available at https://github.com/yolandalago/CIRCUST/.

Candida auris has emerged as a fungal pathogen that causes nosocomial outbreaks worldwide. Diseases caused by this fungus are of concern, due to its reduced susceptibility to several antifungals. C. auris exhibits paradoxical growth (PG; defined as growth at high, but not intermediate antifungal concentrations) in the presence of caspofungin (CPF). We have characterized the cellular changes associated with adaptation to CPF. Using EUCAST AFST protocols, all C. auris isolates tested showed PG to CPF, although in some isolates it was more prominent. Most isolates also showed a trailing effect (TE) to micafungin and anidulafungin. We identified two FKS genes in C. auris that encode the echinocandins target, namely β-1,3-glucan synthase. FKS1 contained the consensus hot-spot (HS) 1 and HS2 sequences. FKS2 only contained the HS1 region which had a change (F635Y), that has been shown to confer resistance to echinocandins in C. glabrata. PG has been characterized in other species, mainly C. albicans, where high CPF concentrations induced an increase in chitin, cell volume and aggregation. In C. auris CPF only induced a slight accumulation of chitin, and none of the other phenomena. RNAseq experiments demonstrated that CPF induced the expression of genes encoding several GPI-anchored cell wall proteins, membrane proteins required for the stability of the cell wall, chitin synthase and mitogen-activated protein kinases (MAPKs) involved in cell integrity, such as BCK2, HOG1 and MKC1 (SLT2). Our work highlights some of the processes induced in C. auris to adapt to echinocandins.

Summary: Mathematical models of cardiac electrical activity are one of the most important tools for elucidating information about heart diagnostics. In this paper, we present an efficient mathematical formulation for this modeling simple enough to be easily parameterized and rich enough to provide realistic signals. It relies on a five dipole representation of the cardiac electric source, each one associated with the well-known waves of the electrocardiogram signal. Beyond the physical basis of the model, the parameters are physiologically interpretable as they characterize the wave shape, similar to what a physician would look for in signals, thus making them very useful in diagnosis. The model accurately reproduces the electrocardiogram signals of any diseased or healthy heart. This new discovery represents a significant advance in electrocardiography research. It is especially useful for diagnosis, patient follow-up or decision-making on new therapies; is also a promising tool for well-performing, transparent and interpretable AI approaches.

Abstract A novel approach for analysing cardiac rhythm data is presented in this paper. Heartbeats are decomposed into the five fundamental P, Q, R, S and T waves plus an error term to account for artifacts in the data which provides a meaningful, physical interpretation of the heart’s electric system. The morphology of each wave is concisely described using four parameters that allow all the different patterns in heartbeats to be characterized and thus differentiated This multi-purpose approach solves such questions as the extraction of interpretable features, the detection of the fiducial marks of the fundamental waves, or the generation of synthetic data and the denoising of signals. Yet the greatest benefit from this new discovery will be the automatic diagnosis of heart anomalies as well as other clinical uses with great advantages compared to the rigid, vulnerable and black box machine learning procedures, widely used in medical devices. The paper shows the enormous potential of the method in practice; specifically, the capability to discriminate subjects, characterize morphologies and detect the fiducial marks (reference points) are validated numerically using simulated and real data, thus proving that it outperforms its competitors.

The complete understanding of the mammalian brain requires exact knowledge of the function of each neuron subpopulation composing its parts. To achieve this goal, an exhaustive, precise, reproducible, and robust neuronal taxonomy should be defined. In this paper, a new circular taxonomy based on transcriptomic features and novel electrophysiological features is proposed. The approach is validated by analysing more than 1850 electrophysiological signals of different mouse visual cortex neurons proceeding from the Allen Cell Types database. The study is conducted on two different levels: neurons and their cell-type aggregation into Cre lines. At the neuronal level, electrophysiological features have been extracted with a promising model that has already proved its worth in neuronal dynamics. At the Cre line level, electrophysiological and transcriptomic features are joined on cell types with available genetic information. A taxonomy with a circular order is revealed by a simple transformation of the first two principal components that allow the characterization of the different Cre lines. Moreover, the proposed methodology locates other Cre lines in the taxonomy that do not have transcriptomic features available. Finally, the taxonomy is validated by Machine Learning methods which are able to discriminate the different neuron types with the proposed electrophysiological features.

The Hodgkin-Huxley model, decades after its first presentation, is still a reference model in neuroscience as it has successfully reproduced the electrophysiological activity of many organisms. The primary signal in the model represents the membrane potential of a neuron. A simple representation of this signal is presented in this paper. The new proposal is an adapted Frequency Modulated Möbius multicomponent model defined as a signal plus error model in which the signal is decomposed as a sum of waves. The main strengths of the method are the simple parametric formulation, the interpretability and flexibility of the parameters that describe and discriminate the waveforms, the estimators' identifiability and accuracy, and the robustness against noise. The approach is validated with a broad simulation experiment of Hodgkin-Huxley signals and real data from squid giant axons. Interesting differences between simulated and real data emerge from the comparison of the parameter configurations. Furthermore, the potential of the FMM parameters to predict Hodgkin-Huxley model parameters is shown using different Machine Learning methods. Finally, promising contributions of the approach in Spike Sorting and cell-type classification are detailed.

This paper analyses COVID-19 patients' dynamics during the first wave in the region of Castilla y León (Spain) with around 2.4 million inhabitants using multi-state competing risk survival models. From the date registered as the start of the clinical process, it is assumed that a patient can progress through three intermediate states until reaching an absorbing state of recovery or death. Demographic characteristics, epidemiological factors such as the time of infection and previous vaccinations, clinical history, complications during the course of the disease and drug therapy for hospitalised patients are considered as candidate predictors. Regarding risk factors associated with mortality and severity, consistent results with many other studies have been found, such as older age, being male, and chronic diseases. Specifically, the hospitalisation (death) rate for those over 69 is 27.2% (19.8%) versus 5.3% (0.7%) for those under 70, and for males is 14.5%(7%) versus 8.3%(4.6%)for females. Among patients with chronic diseases the highest rates of hospitalisation are 26.1% for diabetes and 26.3% for kidney disease, while the highest death rate is 21.9% for cerebrovascular disease. Moreover, specific predictors for different transitions are given, and estimates of the probability of recovery and death for each patient are provided by the model. Some interesting results obtained are that for patients infected at the end of the period the hazard of transition from hospitalisation to ICU is significatively lower (p < 0.001) and the hazard of transition from hospitalisation to recovery is higher (p < 0.001). For patients previously vaccinated against pneumococcus the hazard of transition to recovery is higher (p < 0.001). Finally, internal validation and calibration of the model are also performed.

Oscillatory systems arise in the different biological and medical fields. Mathematical and statistical approaches are fundamental to deal with these processes. The Frequency Modulated Mobiüs approach (FMM), reviewed in this paper, is one of these approaches. Little known as it has been recently developed, it solves a variety of exciting questions with real data; some of them, such as the decomposition of the signal into components and their multiple uses, are of general application, others are specific. Among the exciting specific applications is the automatic interpretation of the electrocardiogram signal. In this paper, a summary of the theoretical, statistical and computational properties of the FMM approach are revised. Additionally, as a novelty, the FMM approach’s usefulness for the analysis of blood pressure signals is shown. For the latter, a new robust estimation algorithm is proposed using FMM models with restrictions. The paper ends with a view about challenges for the future.

Motivation: Gene-expression data obtained from high throughput technologies are subject to various sources of noise and accordingly the raw data are pre-processed before formally analyzed. Normalization of the data is a key pre-processing step, since it removes systematic variations across arrays. There are numerous normalization methods available in the literature. Based on our experience, in the context of oscillatory systems, such as cell-cycle, circadian clock, etc., the choice of the normalization method may substantially impact the determination of a gene to be rhythmic. Thus rhythmicity of a gene can purely be an artifact of how the data were normalized. Since the determination of rhythmic genes is an important component of modern toxicological and pharmacological studies, it is important to determine truly rhythmic genes that are robust to the choice of a normalization method.Results: In this paper we introduce a rhythmicity measure and a bootstrap methodology to detect rhythmic genes in an oscillatory system. Although the proposed methodology can be used for any high-throughput gene expression data, in this paper we illustrate the proposed methodology using several publicly available circadian clock microarray gene-expression datasets. We demonstrate that the choice of normalization method has very little effect on the proposed methodology. Specifically, for any pair of normalization methods considered in this paper, the resulting values of the rhythmicity measure are highly correlated. Thus it suggests that the proposed measure is robust to the choice of a normalization method. Consequently, the rhythmicity of a gene is potentially not a mere artifact of the normalization method used. Lastly, as demonstrated in the paper, the proposed bootstrap methodology can also be used for simulating data for genes participating in an oscillatory system using a reference dataset.Availability: A user friendly code implemented in R language can be downloaded from http://www.eio.uva.es/~miguel/robustdetectionprocedure.html

The incorporation of additional information into discriminant rules is receiving in- creasing attention as the rules including this information perform better than the usual rules. In this paper we introduce an R package called dawai, which provides the functions that allow to define the rules that take into account this additional information expressed in terms of restrictions on the means, to classify the samples and to evaluate the accuracy of the results. Moreover, in this paper we extend the results and definitions given in previous papers (Fernndez, Rueda, and Salvador 2006, Conde, Fernndez, Rueda, and Salvador 2012, Conde, Salvador, Rueda, and Fernndez 2013) to the case of unequal co-variances among the populations, and consequently define the corresponding restricted quadratic discriminant rules. We also define estimators of the accuracy of the rules for the general more than two populations case. The wide range of applications of these procedures is illustrated with two data sets from two different fields, i.e., biology and pattern recognition.

El abordaje quirúrgico adecuado es un aspecto esencial en la cirugía de aorta. Tras realizar múltiples accesos quirúrgicos en cadáveres en fresco para un curso de formación de residentes y revisar la literatura, se desarrolla de forma didáctica y práctica una visión anatómica y quirúrgica de las diferentes vías de acceso a la aorta.

In many applications one may be interested in drawing inferences regarding the order of a collection of points on a unit circle. Due to the underlying geometry of the circle standard constrained inference procedures developed for Euclidean space data are not applicable. Recently, statistical inference for parameters under such order constraints on a unit circle was discussed in Rueda, Fernndez, and Peddada (2009) and Fernndez, Rueda, and Peddada (2012). In this paper we introduce the R package isocir which provides a set of functions that can be used for analyzing angular data subject to order constraints on a unit circle. Since this work is motivated by applications in cell biology, we illustrate the proposed package using a relevant cell cycle data.

En este artículo se analiza la relación entre una serie de expectativas medidas en personas que buscan trabajo y la duración de su situación de desempleo, considerando también las variables edad y sexo. Para ello se propone un modelo explicativo de la conducta motivada de los desempleados donde las expectativas tienen un papel preponderante. Se utiliza como medida cognitiva la escala Expectativas de Control Percibido en Búsqueda de Empleo (ECPBE) y como método de estudio estadístico el análisis de supervivencia (regresión de Cox). Los resultados muestran una relación significativa entre la motivación y la duración del desempleo encontrándose que las personas con puntuaciones altas en el ECPBE tardan como media 14 meses menos en conseguir trabajo que los que puntúan bajo. También se confirman valores más altos que la media en la duración del desempleo para mujeres y los mayores de 30 años.

A literatura sobre formação de professores de ciências não tem tratado suficientemente a situação do mundo quanto a uma percepção global de seus graves problemas atuais. O presente artigo consiste essencialmente de um programa de atividades a ser desenvolvido com professores em formação e em exercício, que visa favorecer uma reflexão coletiva e conscientização sobre essa problemática. Nesta perspectiva é apontado um conjunto de referências e questões para um debate fundamentado sobre vários dos fatores associados à degradação da vida e sobre possíveis medidas para o enfrentamento da emergência planetária. Investigações preliminares sobre a utilização do programa proposto têm revelado resultados favoráveis quanto à percepção de que a educação científica tem a contribuir para pensar e construir o futuro na direção de uma melhoria da qualidade de vida.The literature about science teachers' training program hasn't properly explored the world's situation regarded to a global perception of its serious present problems. This article consists basically of a program of activities to be developed in partnership with graduated and graduating teachers, which aims to stimulate a group reflection over those matters. Under this perspective, a group of references and questions is indicated for a debate based on many factors connected to life's degradation and possible decisions to be taken in order to face the planetary emergency. Primary studies about the use of the proposed program have shown auspicious results regarding the perception that the scientific education can contribute to the thinking and building the future towards a better life quality.

Oscillatory systems in biology are tightly regulated process where the individual components (e.g. genes) express in an orderly manner by virtue of their functions. The temporal order among the components of an oscillatory system may potentially be disrupted for various reasons (e.g. environmental factors). As a result some components of the system may go out of order or even cease to participate in the oscillatory process. In this article, we develop a novel framework to evaluate whether the temporal order is unchanged in different populations (or experimental conditions). We also develop methodology to estimate the order among the components with a suitable notion of "confidence." Using publicly available data on S. pombe, S. cerevisiae and Homo sapiens we discover that the temporal order among the genes cdc18; mik1; hhf1; hta2; fkh2 and klp5 is evolutionarily conserved from yeast to humans.

Tuberculous paradoxical reaction presents as clinical deterioration during appropriate tuberculosis therapy and is a separate entity from treatment failure and drug resistance. We describe a case of central nervous system paradoxical reaction following tuberculous meningoencephalitis treatment in an immunocompromised patient with systemic lupus erythematosus.

Background Evidence indicates a strong link between Zika virus (ZikV) and neurological complications. Acute myelitis, optic neuritis, polyneuropathy, and encephalomyelitis that mimic inflammatory idiopathic demyelination disorders (IIDD) after ZikV infection have been reported in Brazil. Objective The present study aims to investigate the possible occurrence of molecular mimicry between ZikV antigens and Multiple Sclerosis (MS) autoantigens, the most frequent IIDD of the central nervous system (CNS). Methods A retrospective cohort study with 305 patients admitted due to suspected arbovirus infection in Rio de Janeiro was performed, all subjects were submitted to neurological examination, and a biological sample was collected for serologic and molecular diagnostic. Bioinformatics tools were used to analyze the peptides shared between ZikV antigens and MS autoantigens. Results Of 305 patients, twenty-six were positive for ZikV and 4 presented IDD patterns found in MS cases. Sequence homology comparisons by bioinformatics approach between NS5 ZikV and PLP MS protein revealed a homology of 5/6 consecutive amino acids (CSSVPV/CSAVPV) with 83% identity, deducing a molecular mimicry. Analysis of the 3D structures revealed a similar conformation with alpha helix presentation. Conclusions Molecular mimicry between NS5 Zika virus antigen and PLP MS autoantigens emerge as a possible mechanism for IDD spectrum in genetically susceptible individuals.

Background Multiple sclerosis (MS) is an inflammatory, degenerative, demyelinating disease that ranges from benign to rapidly progressive forms. A striking characteristic of the disease is the clinical-radiological paradox. Objectives The present study was conducted to determine whether, in our cohort, the clinical-radiological paradox exists and whether lesion location is related to clinical disability in patients with MS. Methods Retrospective data from 95 patients with MS (60 women and 35 men) treated at a single center were examined. One head-and-spine magnetic resonance imaging (MRI) examination from each patient was selected randomly, and two independent observers calculated lesion loads (LLs) on T2/fluid attenuation inversion recovery sequences manually, considering the whole brain and four separate regions (periventricular, juxtacortical, posterior fossa, and spinal cord). The LLs were compared with the degree of disability, measured by the Kurtzke Expanded Disability Status Scale (EDSS), at the time of MRI examination in the whole cohort and in patients with relapsing-remitting (RR), primarily progressive, and secondarily progressive MS. Results High LLs correlated with high EDSS scores in the whole cohort (r = 0.34; p

Chikungunya virus (CHIKV) is a re-emergent arbovirus that causes a disease characterized primarily by fever, rash and severe persistent polyarthralgia, although

Objective This study aims to evaluate “in vivo” the integrity of the normal-appearing spinal cord (NASC) in patients with multiple sclerosis (MS) compared to controls, using diffusion tensor MR imaging. Methods We studied 32 patients with MS and 17 without any neurologic disorder. Fractional anisotropy (FA), axial diffusivity (AD), radial diffusivity (RD) and mean diffusivity (MD) were calculated within regions of interest at C2 and C7 levels in the four columns of the spinal cord. Results At C2, FA value was decreased in MS patients. Besides, RD value was higher in MS than in controls. At C7, MD values were increased in MS. Conclusion The NASC in the right column of the cervical spinal cord showed abnormal FA, RD and MD values, which is possibly related to demyelination, since the FA abnormality was related to the RD and not to the AD.

ABSTRACT Background: The genetic predisposition to multiple sclerosis (MS) is associated with HLA alleles, especially HLA-DRB1*15:01. Objective: To identify associations between findings in magnetic resonance imaging (MRI) and genetic features in a Brazilian cohort of patients with MS. Methods: We retrospectively studied data from 95 consecutive patients with MS. Two independent observers who were blinded to the clinical data identified black holes and enhanced lesions on T1 MRI sequences, and counted and measured contrast-enhanced lesions on T2 and Flair (fluid attenuation inversion recovery) sequences. Cases were classified according to lesion size, number, and volume. The HLA-DRB1, HLA-DQB1, and HLA-DQA1 alleles, and the rs4774, rs3087456, rs6897932, rs731236, and rs1033182 single nucleotide polymorphisms were identified by polymerase chain reaction amplification with sequence-specific primers using the One Lambda Inc. Kit, Canoga Park, CA, USA. Results: Patients with the HLA-DQA1*04:01 allele had lesion load (adjusted for age, sex, and MS duration) above median compared with patients with other HLA-DQA1 alleles (p=0.02). There were no differences among all the other HLA alleles and single nucleotide polymorphisms and lesion load. Conclusions: The correlation of the HLA-DQA1*04:01 allele with a higher lesion load on T2/Flair MRI sequences suggests that the presence of this allele is associated with the risk of greater MS severity.