EEG connectivity patterns in response to gaming and learning-based cognitive stimulations in Rett syndrome.

BACKGROUND: Functional connectivity is scarcely studied in Rett syndrome (RTT). Explorations revealed associations between RTT's clinical, genetic profiles, and coherence measures, highlighting an unexplored frontier in understanding RTT's neural mechanisms and cognitive processes. AIMS: To evaluate the effects of diverse cognitive stimulations-learning-focused versus gaming-oriented-on electroencephalography brain connectivity in RTT. The comparison with resting states aimed to uncover potential biomarkers and insights into the neural processes associated with RTT. METHODS AND PROCEDURES: The study included 15 girls diagnosed with RTT. Throughout sessions lasting about 25 min, participants alternated between active and passive tasks, using an eyetracker device while their brain activity was recorded with a 20-channel EEG. Results revealed significant alterations during cognitive tasks, notably in delta, alpha and beta bands. Both tasks induced spectral pattern changes and connectivity shifts, hinting at enhanced neural processing. Hemispheric asymmetry decreased during tasks, suggesting more balanced neural processing. Linear and nonlinear connectivity alterations were observed in active tasks compared to resting state, while passive tasks showed no significant changes. CONCLUSIONS AND IMPLICATIONS: Results underscores the potential of cognitive stimulation for heightened cognitive abilities, promoting enhanced brain connectivity and information flow in Rett syndrome. These findings offer valuable markers for evaluating cognitive interventions and suggest gaming-related activities as effective tools for improving learning outcomes.

Association of Moderate-to-Vigorous Physical Activity, Sedentary Time, Fat Percentage, and Physical Fitness with Gait Parameters in Women with Fibromyalgia: The Al-Ándalus Project.

Gait impairments have been found in women with fibromyalgia, reducing the physical activity possibilities in this population and leading to a negative correlation with fibromyalgia impact. The aim of this study was to analyze the individual and independent associations of moderate-to-vigorous physical activity (MVPA), sedentary time, fat percentage, and physical fitness with gait parameters in women with fibromyalgia. A total of 84 women with fibromyalgia were included. MVPA and sedentary time were assessed with accelerometry, fat percentage with bioimpedance analysis, and physical fitness with field-based fitness tests. Gait was assessed during a "6 min walk test" and categorized in velocity, cadence, step length, step cycle duration, unipedal stance phase, and bipedal stance phase. Individual relationships were analyzed by partial correlations and independent relationships by linear regressions, adjusting by age and height. MVPA, sedentary time, fat percentage, and physical fitness were correlated with most gait parameters (rpartial between |0.842| and |0.219|; p ≤ 0.05). Physical fitness was independently associated with all gait parameters (ß between |0.346| and |0.761|; p ≤ 0.002). In addition, MVPA was independently associated with velocity and step length (ß = 0.241 and 0.292; both p = 0.004), and fat percentage was associated with bipedal stance phase (ß = 0.242; p = 0.049). Good levels of MVPA, physical fitness, and adequate weight balance are associated with improved gait parameters in women with fibromyalgia.

Methodological biases in observational hospital studies of COVID-19 treatment effectiveness: pitfalls and potential.

Introduction: This study aims to discuss and assess the impact of three prevalent methodological biases: competing risks, immortal-time bias, and confounding bias in real-world observational studies evaluating treatment effectiveness. We use a demonstrative observational data example of COVID-19 patients to assess the impact of these biases and propose potential solutions. Methods: We describe competing risks, immortal-time bias, and time-fixed confounding bias by evaluating treatment effectiveness in hospitalized patients with COVID-19. For our demonstrative analysis, we use observational data from the registry of patients with COVID-19 who were admitted to the Bellvitge University Hospital in Spain from March 2020 to February 2021 and met our predefined inclusion criteria. We compare estimates of a single-dose, time-dependent treatment with the standard of care. We analyze the treatment effectiveness using common statistical approaches, either by ignoring or only partially accounting for the methodological biases. To address these challenges, we emulate a target trial through the clone-censor-weight approach. Results: Overlooking competing risk bias and employing the naïve Kaplan-Meier estimator led to increased in-hospital death probabilities in patients with COVID-19. Specifically, in the treatment effectiveness analysis, the Kaplan-Meier estimator resulted in an in-hospital mortality of 45.6% for treated patients and 59.0% for untreated patients. In contrast, employing an emulated trial framework with the weighted Aalen-Johansen estimator, we observed that in-hospital death probabilities were reduced to 27.9% in the "X"-treated arm and 40.1% in the non-"X"-treated arm. Immortal-time bias led to an underestimated hazard ratio of treatment. Conclusion: Overlooking competing risks, immortal-time bias, and confounding bias leads to shifted estimates of treatment effects. Applying the naïve Kaplan-Meier method resulted in the most biased results and overestimated probabilities for the primary outcome in analyses of hospital data from COVID-19 patients. This overestimation could mislead clinical decision-making. Both immortal-time bias and confounding bias must be addressed in assessments of treatment effectiveness. The trial emulation framework offers a potential solution to address all three methodological biases.

Stepwise introduction of stabilizing mutations reveals nonlinear additive effects in de novo TIM barrels.

Over the past decades, the TIM-barrel fold has served as a model system for the exploration of how changes in protein sequences affect their structural, stability, and functional characteristics, and moreover, how this information can be leveraged to design proteins from the ground up. After numerous attempts to design de novo proteins with this specific fold, sTIM11 was the first validated de novo design of an idealized four-fold symmetric TIM barrel. Subsequent efforts to enhance the stability of this initial design resulted in the development of DeNovoTIMs, a family of de novo TIM barrels with various stabilizing mutations. In this study, we present an investigation into the biophysical and thermodynamic effects upon introducing a varying number of stabilizing mutations per quarter along the sequence of a four-fold symmetric TIM barrel. We compared the base design DeNovoTIM0 without any stabilizing mutations with variants containing mutations in one, two, three, and all four quarters-designated TIM1q, TIM2q, TIM3q, and DeNovoTIM6, respectively. This analysis revealed a stepwise and nonlinear change in the thermodynamic properties that correlated with the number of mutated quarters, suggesting positive nonadditive effects. To shed light on the significance of the location of stabilized quarters, we engineered two variants of TIM2q which contain the same number of mutations but positioned in different quarter locations. Characterization of these TIM2q variants revealed that the mutations exhibit varying effects on the overall protein stability, contingent upon the specific region in which they are introduced. These findings emphasize that the amount and location of stabilized interfaces among the four quarters play a crucial role in shaping the conformational stability of these four-fold symmetric TIM barrels. Analysis of de novo proteins, as described in this study, enhances our understanding of how sequence variations can finely modulate stability in both naturally occurring and computationally designed proteins.

TIROSEC: Molecular, Clinical and Histopathological Profile of Papillary Thyroid Carcinoma in a Colombian Cohort.

INTRODUCTION: In Colombia, thyroid cancer ranks among the highest incidences, yet our population lacks studies on its molecular profile. This study aims to characterize clinical, histopathologic and molecular data in a Colombian cohort with papillary thyroid carcinoma (PTC). METHODS: A retrospective review of clinical history, clinicopathologic characteristics, treatment and 5-10-year follow-up for all patients was done. DNA and RNA were extracted from formalin-fixed paraffin-embedded (FFPE) tissue using the Quick-DNA & RNA FFPE Min iPrep kit (Zymo Research). Next-generation sequencing (NGS) analysis was performed with SOPHiA Solid Tumor Solutions kit (SOPHiA GENETICS). Tumor mutation genomic analysis used SOPHiA DDM™ platform, with descriptive analysis reporting frequencies, means and associations via chi-square analysis. RESULTS: Among 231 sequenced patients, mean age at diagnosis was 46 (± 12.35) years, with higher frequency in women (81.82%). Two cases were reclassified as non-invasive follicular thyroid neoplasm (NIFT-P); an NRAS mutation was found in one of them. Predominant histologic subtype was classic PTC (57.64%) followed by tall cell (28.82%). Of the 229 sequenced carcinomas, mutations were identified in 186 cases, including BRAF, IDH1, RAS and PIK3CA. Notable copy number variations (CNVs) were PDGFRA, CDK4 and KIT, with RET being the most frequent gene fusion, including CCDC6-RET in two classic subtype cases. CONCLUSION: This is the first study in Colombia (TIROSEC) to our knowledge that integrates molecular and histopathologic profiles enriching our local comprehension and knowledge of PTC. The identification of target mutations such as BRAF, RET and NTRK fusions holds the potential to guide targeted therapies for tumor recurrence and predict aggressive behavior.

A fresh start for IVM: capacitating the oocyte for development using pre-IVM.

BACKGROUND: While oocyte IVM is practiced sporadically it has not achieved widespread clinical practice globally. However, recently there have been some seminal advances in our understanding of basic aspects of oocyte biology and ovulation from animal studies that have led to novel approaches to IVM. A significant recent advance in IVM technology is the use of biphasic IVM approaches. These involve the collection of immature oocytes from small antral follicles from minimally stimulated patients/animals (without hCG-priming) and an ∼24 h pre-culture of oocytes in an advanced culture system ('pre-IVM') prior to IVM, followed by routine IVF procedures. If safe and efficacious, this novel procedure may stand to make a significant impact on human ART practices. OBJECTIVE AND RATIONALE: The objectives of this review are to examine the major scientific advances in ovarian biology with a unique focus on the development of pre-IVM methodologies, to provide an insight into biphasic IVM procedures, and to report on outcomes from animal and clinical human data, including safety data. The potential future impact of biphasic IVM on ART practice is discussed. SEARCH METHODS: Peer review original and review articles were selected from PubMed and Web of Science searches for this narrative review. Searches were performed using the following keywords: oocyte IVM, pre-IVM, biphasic IVM, CAPA-IVM, hCG-triggered/primed IVM, natural cycle IVF/M, ex-vivo IVM, OTO-IVM, oocyte maturation, meiotic competence, oocyte developmental competence, oocyte capacitation, follicle size, cumulus cell (CC), granulosa cell, COC, gap-junction communication, trans-zonal process, cAMP and IVM, cGMP and IVM, CNP and IVM, EGF-like peptide and IVM, minimal stimulation ART, PCOS. OUTCOMES: Minimizing gonadotrophin use means IVM oocytes will be collected from small antral (pre-dominant) follicles containing oocytes that are still developing. Standard IVM yields suboptimal clinical outcomes using such oocytes, whereas pre-IVM aims to continue the oocyte's development ex vivo, prior to IVM. Pre-IVM achieves this by eliciting profound cellular changes in the oocyte's CCs, which continue to meet the oocyte's developmental needs during the pre-IVM phase. The literature contains 25 years of animal research on various pre-IVM and biphasic IVM procedures, which serves as a large knowledge base for new approaches to human IVM. A pre-IVM procedure based on c-type natriuretic peptide (named 'capacitation-IVM' (CAPA-IVM)) has undergone pre-clinical human safety and efficacy trials and its adoption into clinical practice resulted in healthy live birth rates not different from conventional IVF. WIDER IMPLICATIONS: Over many decades, improvements in clinical IVM have been gradual and incremental but there has likely been a turning of the tide in the past few years, with landmark discoveries in animal oocyte biology finally making their way into clinical practice leading to improved outcomes for patients. Demonstration of favorable clinical results with CAPA-IVM, as the first clinically tested biphasic IVM system, has led to renewed interest in IVM as an alternative, low-intervention, low-cost, safe, patient-friendly ART approach, and especially for patients with PCOS. The same new approach is being used as part of fertility preservation in patients with cancer and holds promise for social oocyte freezing.

Electroencephalographic assessment in patients with Rett syndrome during cognitive stimulation by means of eye tracking technology and alternative and augmentative communication systems.

Rett syndrome (RTT) is considered a rare disease despite being the leading genetic disorder to cause severe intellectual disability in women. There is no cure for RTT, so the treatment is symptomatic and supporting, requiring a multidisciplinary approach. Occupational therapy can help girls and their families to improve communication, being one of the main concerns when verbal language and intentional hand movement are impaired or lost. This paper presents a pilot study of cognitive training through the combined use of eye-tracking technology (ETT) and augmentative and alternative communication (AAC) using the Peabody Picture Vocabulary Test (PPVT-IV). The objective was to evaluate brain activation by means of electroencephalography (EEG) during the stimulation of non-verbal communication. EEG data were recorded during an eyes-open resting state (EO-RS) period and during cognitive stimulation via AAC activity. To assess their effect, both signals were compared at the spectral level, focusing on frequency, brain symmetry and connectivity. During the task, a redistribution of power towards fast frequency bands was observed, as well as an improvement in the brain symmetry index (BSI) and functional synchronicity through increased coherence. Therefore, the results of the spectral analysis showed a possible deviation from the pathological pattern, manifesting a positive effect in the use of non-verbal cognitive stimulation activities. In conclusion, it was observed that it is possible to establish a cognitive training system that produces brain activation and favors communication and learning despite intentional language loss.Clinical Relevance- This manifests a method of cognitive training that would induce brain activation in RTT patients with absence of intentional communication. The evaluation system through spectral analysis could complement the standardized protocols to asses communication that are based on verbal and motor production.

Spinal Cord Injury Patients Exhibit Changes in Motor-Related Activity and Topographic Distribution.

Spinal Cord Injury (SCI) is a common disease that usually limits the patient's independence by affecting their motor function. SCI patients usually present neuroplasticity, which allows brain signals transmission through spread pathways. Some innovative rehabilitation therapies, such as functional electrical stimulation (FES) or Brain-computer interfaces (BCIs) jointly with motor neuroprostheses, provide hope for functional restoration. BCIs require the analysis of event-related EEG potentials (ERPs). Movement-related cortical potentials (MRCPs) and event-related desynchroni-zation and synchronization (ERD/ERS) are the most commonly studied ERPs during motor activity. ERPs of healthy subjects may vary from SCI patients. Thus, this study aimed to compare ERPs between healthy subjects and SCI patients during upper-limb movements (forearm supination and pronation, and hand open). Differences between controls and SCI patients were shown in terms of ERPs' amplitude as well as in topographic maps. Changes in amplitude were more substantial in ERD potentials than in MRCPs, while topographic maps showed better localization of all features in healthy patients. The level of SCI injury determines the patients' mobility. A comparison between complete, partial and no motor function subjects showed lower values of feature's amplitudes in the latter group.Clinical Relevance- This demonstrates the existence of significant statistical differences between healthy and SCI subjects, and might be helpful when performing SCI rehabilitation techniques such as designing BCI and neuroprostheses, or analyzing and understanding the brain plasticity process.

Retracing the evolution of a modern periplasmic binding protein.

Investigating the evolution of structural features in modern multidomain proteins helps to understand their immense diversity and functional versatility. The class of periplasmic binding proteins (PBPs) offers an opportunity to interrogate one of the main processes driving diversification: the duplication and fusion of protein sequences to generate new architectures. The symmetry of their two-lobed topology, their mechanism of binding, and the organization of their operon structure led to the hypothesis that PBPs arose through a duplication and fusion event of a single common ancestor. To investigate this claim, we set out to reverse the evolutionary process and recreate the structural equivalent of a single-lobed progenitor using ribose-binding protein (RBP) as our model. We found that this modern PBP can be deconstructed into its lobes, producing two proteins that represent possible progenitor halves. The isolated halves of RBP are well folded and monomeric proteins, albeit with a lower thermostability, and do not retain the original binding function. However, the two entities readily form a heterodimer in vitro and in-cell. The x-ray structure of the heterodimer closely resembles the parental protein. Moreover, the binding function is fully regained upon formation of the heterodimer with a ligand affinity similar to that observed in the modern RBP. This highlights how a duplication event could have given rise to a stable and functional PBP-like fold and provides insights into how more complex functional structures can evolve from simpler molecular components.

Exploring the Protein Sequence Space with Global Generative Models.

Recent advancements in specialized large-scale architectures for training images and language have profoundly impacted the field of computer vision and natural language processing (NLP). Language models, such as the recent ChatGPT and GPT-4, have demonstrated exceptional capabilities in processing, translating, and generating human language. These breakthroughs have also been reflected in protein research, leading to the rapid development of numerous new methods in a short time, with unprecedented performance. Several of these models have been developed with the goal of generating sequences in novel regions of the protein space. In this work, we provide an overview of the use of protein generative models, reviewing (1) language models for the design of novel artificial proteins, (2) works that use non-transformer architectures, and (3) applications in directed evolution approaches.

Beyond performance: the role of task demand, effort, and individual differences in ab initio pilots.

Aviation safety depends on the skill and expertise of pilots to meet the task demands of flying an aircraft in an effective and efficient manner. During flight training, students may respond differently to imposed task demands based on individual differences in capacity, physiological arousal, and effort. To ensure that pilots achieve a common desired level of expertise, training programs should account for individual differences to optimize pilot performance. This study investigates the relationship between task performance and physiological correlates of effort in ab initio pilots. Twenty-four participants conducted a flight simulator task with three difficulty levels and were asked to rate their perceived demand and effort using the NASA TLX. We recorded heart rate, EEG brain activity, and pupil size to assess changes in the participants' mental and physiological states across different task demands. We found that, despite group-level correlations between performance error and physiological responses, individual differences in physiological responses to task demands reflected different levels of participant effort and task efficiency. These findings suggest that physiological monitoring of student pilots might provide beneficial insights to flight instructors to optimize pilot training at the individual level.

Descripción de la micobiota de los tubos endotraqueales de pacientes de unidades de cuidados intensivos en Bogotá, Colombia / Description of the colonizing mycobiota of endotracheal tubes from patients admitted to two intensive care units in Bogotá, Colombia

Introducción. La colonización por microorganismos patógenos de los dispositivos médicos usados en las unidades de cuidados intensivos es un factor de riesgo para el aumento de infecciones asociadas con la atención en salud y, por lo tanto, al de la morbilidad y la mortalidad de los pacientes intubados. En Colombia, no se ha descrito la colonización por hongos de los tubos endotraqueales, con lo cual se podrían considerar nuevas opciones terapéuticas para el beneficio de los pacientes. Objetivo. Describir los hongos que colonizan los tubos endotraqueales de los pacientes en unidades de cuidados intensivos, junto con su perfil de sensibilidad a los antifúngicos. Materiales y métodos. Se realizó un estudio observacional, descriptivo, en dos centros hospitalarios durante 12 meses. Se recolectaron tubos endotraqueales de pacientes de las unidades de cuidados intensivos. Estos fueron procesados para cultivar e identificar hongos, y para establecer su perfil de sensibilidad a los antifúngicos. Resultados. Se analizaron 121 tubos endotraqueales obtenidos de 113 pacientes. De estos, el 41,32 % se encontró colonizado por los hongos Candida albicans (64,61 %), C. no-albicans (30,77 %), Cryptococcus spp. (3,08 %) o mohos (1,54 %). Todos los hongos evaluados presentaron una gran sensibilidad a los antifúngicos, con un promedio del 91 %. Conclusión. Se encontró colonización fúngica en los tubos endotraqueales de pacientes con asistencia respiratoria mecánica. El perfil de sensibilidad en estos pacientes fue favorable. Se requiere un estudio clínico para correlacionar los microorganismos colonizadores y su capacidad de generar infección.

Introduction. Medical device colonization by pathogenic microorganisms is a risk factor for increasing infections associated with health care and, consequently, the morbidity and mortality of intubated patients. In Colombia, fungal colonization of endotracheal tubes has not been described, and this information could lead to new therapeutic options for the benefit of patients. Objective. To describe the colonizing fungi of the endotracheal tubes from patients in the intensive care unit, along with its antifungal sensitivity profile. Materials and methods. We conducted a descriptive, observational study in two health centers for 12 months. Endotracheal tubes were collected from patients in intensive care units. Samples were processed for culture, fungi identification, and antifungal sensitivity profile assessment. Results. A total of 121 endotracheal tubes, obtained from 113 patients, were analyzed: 41.32 % of the tubes were colonized by Candida albicans (64.62%), C. non-albicans (30.77%), Cryptococcus spp. (3.08%) or molds (1.54%). All fungi evaluated showed a high sensitivity to antifungals, with a mean of 91%. Conclusion. Fungal colonization was found in the endotracheal tubes of patients under invasive mechanical ventilation. The antifungal sensitivity profile in these patients was favorable. A clinical study is required to find possible correlations between the colonizing microorganisms and infectivity.

Corrigendum: New perspectives on an old grouping: the genomic and phenotypic variability of Oxalobacter formigenes and the implications for calcium oxalate stone prevention.

[This corrects the article DOI: 10.3389/fmicb.2022.1011102.].

Can Three-Dimensional Multiple Object Tracking Training Be Used to Improve Simulated Driving Performance? A Pilot Study in Young and Older Adults.

Driving ability has been shown to be dependent on perceptual-cognitive abilities such as visual attention and speed of processing. There is mixed evidence suggesting that training these abilities may improve aspects of driving performance. This preliminary study investigated the feasibility of training three-dimensional multiple object tracking (3D-MOT)-a dynamic, speeded tracking task soliciting selective, sustained and divided attention as well as speed of processing-to improve measures of simulated driving performance in older and younger adults. A sample of 20 young adults (23-33 years old) and 14 older adults (65-76 years old) were randomly assigned to either a 3D-MOT training group or an active control group trained on a perceptual discrimination task as well as 2048. Participants were tested on a driving scenario with skill-testing events previously identified as optimal for cross-sectional comparisons of driving ability. Results replicated previously identified differences in driving behaviour between age groups. A possible trend was observed for the 3D-MOT trained group, especially younger adults, to increase the distance at which they applied their maximum amount of braking in response to dangerous events. This measure was associated with less extreme braking during events, implying that these drivers may have been making more controlled stops. Limitations of sample size and task realism notwithstanding, the present experiment offers preliminary evidence that 3D-MOT training might transfer to driving performance through quicker detection of or reaction to dangerous events and provides a rationale for replication with a larger sample size.

Thermodynamic and kinetic analysis of the LAO binding protein and its isolated domains reveal non-additivity in stability, folding and function.

Substrate-binding proteins (SBPs) are used by organisms from the three domains of life for transport and signalling. SBPs are composed of two domains that collectively trap ligands with high affinity and selectivity. To explore the role of the domains and the integrity of the hinge region between them in the function and conformation of SBPs, here, we describe the ligand binding, conformational stability and folding kinetics of the Lysine Arginine Ornithine (LAO) binding protein from Salmonella thiphimurium and constructs corresponding to its two independent domains. LAO is a class II SBP formed by a continuous and a discontinuous domain. Contrary to the expected behaviour based on their connectivity, the discontinuous domain shows a stable native-like structure that binds l-arginine with moderate affinity, whereas the continuous domain is barely stable and shows no detectable ligand binding. Regarding folding kinetics, studies of the entire protein revealed the presence of at least two intermediates. While the unfolding and refolding of the continuous domain exhibited only a single intermediate and simpler and faster kinetics than LAO, the folding mechanism of the discontinuous domain was complex and involved multiple intermediates. These findings suggest that in the complete protein the continuous domain nucleates folding and that its presence funnels the folding of the discontinuous domain avoiding nonproductive interactions. The strong dependence of the function, stability and folding pathway of the lobes on their covalent association is most likely the result of the coevolution of both domains as a single unit.

Differences between substance-induced psychotic disorders and non-substance-induced psychotic disorders and diagnostic stability. / Diferencias y estabilidad diagnóstica entre trastornos psicóticos inducidos por sustancias y trastornos psicóticos no inducidos.

Several hypotheses have been proposed to explain the comorbidity between psychotic disorders and substance use, one of them being the capacity of some to induce psychotic symptoms, although the transition from psychotic episodes induced by substances to schizophrenia has been less studied. In this study, differential variables between patients with induced and non-induced psychosis are determined, and the evolution and change of diagnosis of those induced to schizophrenia in the follow-up is analyzed. This is an observational case-control study with 238 patients admitted to the acute care unit for psychotic episodes between December 2003 and September 2011. The group of non-substance-induced psychotic disorders (NSIPD) included 127 patients, with 111 in the substance-induced (SIPD) group, according to the International Classification of Diseases. Sociodemographic and clinical characteristics, personal and family history, substance use, diagnostic stability and progression were compared. The NSIPD group showed higher scores in severity and in negative symptoms and more family history of psychosis. The SIPD group presented more personal history of personality disorder and family history of addictions and more positive symptoms At 6 years of follow-up, 40.9% of ISDP changed to a diagnosis of schizophrenia, presenting more family history of psychotic disorders and worse progression with more visits to the emergency department and readmissions, than subjects who maintained diagnostic stability. Therefore, special attention should be paid to this group of patients because of the potential severity and the increased risk of developing a chronic psychotic disorder.

Se han propuesto distintas hipótesis para explicar la comorbilidad entre trastornos psicóticos y por consumo de sustancias, siendo una de ellas la capacidad de algunas de inducir cuadros psicóticos, aunque la transición de episodios psicóticos inducidos por sustancias a esquizofrenia ha sido menos estudiada. En este trabajo se determinan variables diferenciales entre individuos con psicosis inducidas y no inducidas, y se analiza la evolución y el cambio de diagnóstico de las inducidas a esquizofrenia en el seguimiento. Es un estudio observacional de casos y controles con 238 pacientes ingresados en la unidad de agudos de un Hospital General de Madrid (España) por episodios psicóticos entre diciembre de 2003 y septiembre de 2011. Se incluyeron 127 en el grupo de trastornos psicóticos no inducidos por sustancias (TPNIS) y 111 en el de inducidos por sustancias (TPIS), según la Clasificación Internacional de Enfermedades. Se compararon características sociodemográficas, clínicas, antecedentes personales y familiares, de consumo de sustancias, estabilidad diagnóstica y evolución. El grupo de TPNIS presentó mayores puntuaciones en gravedad y sintomatología negativa mientras que el de TPIS tuvo más antecedentes personales de trastorno de personalidad y familiares de adicciones, y más sintomatología positiva. A los seis años un 40,9% de TPIS cambió a diagnóstico de esquizofrenia, presentando más antecedentes familiares de trastornos psicóticos y de adicciones, y una peor evolución con más visitas a urgencias y reingresos que los sujetos con estabilidad diagnóstica. Por tanto, habrá que prestar especial atención a este grupo de sujetos por su potencial gravedad y por el mayor riesgo de desarrollar un trastorno psicótico crónico.

Manifold analysis of the P-wave changes induced by pulmonary vein isolation during cryoballoon procedure.

BACKGROUND/AIM: In atrial fibrillation (AF) ablation procedures, it is desirable to know whether a proper disconnection of the pulmonary veins (PVs) was achieved. We hypothesize that information about their isolation could be provided by analyzing changes in P-wave after ablation. Thus, we present a method to detect PV disconnection using P-wave signal analysis. METHODS: Conventional P-wave feature extraction was compared to an automatic feature extraction procedure based on creating low-dimensional latent spaces for cardiac signals with the Uniform Manifold Approximation and Projection (UMAP) method. A database of patients (19 controls and 16 AF individuals who underwent a PV ablation procedure) was collected. Standard 12-lead ECG was recorded, and P-waves were segmented and averaged to extract conventional features (duration, amplitude, and area) and their manifold representations provided by UMAP on a 3-dimensional latent space. A virtual patient was used to validate these results further and study the spatial distribution of the extracted characteristics over the whole torso surface. RESULTS: Both methods showed differences between P-wave before and after ablation. Conventional methods were more prone to noise, P-wave delineation errors, and inter-patient variability. P-wave differences were observed in the standard leads recordings. However, higher differences appeared in the torso region over the precordial leads. Recordings near the left scapula also yielded noticeable differences. CONCLUSIONS: P-wave analysis based on UMAP parameters detects PV disconnection after ablation in AF patients and is more robust than heuristic parameterization. Moreover, additional leads different from the standard 12-lead ECG should be used to detect PV isolation and possible future reconnections better.

Structures of permuted halves of a modern ribose-binding protein.

Periplasmic binding proteins (PBPs) are a class of proteins that participate in the cellular transport of various ligands. They have been used as model systems to study mechanisms in protein evolution, such as duplication, recombination and domain swapping. It has been suggested that PBPs evolved from precursors half their size. Here, the crystal structures of two permuted halves of a modern ribose-binding protein (RBP) from Thermotoga maritima are reported. The overexpressed proteins are well folded and show a monomer-dimer equilibrium in solution. Their crystal structures show partially noncanonical PBP-like fold type I conformations with structural deviations from modern RBPs. One of the half variants forms a dimer via segment swapping, suggesting a high degree of malleability. The structural findings on these permuted halves support the evolutionary hypothesis that PBPs arose via a duplication event of a flavodoxin-like protein and further support a domain-swapping step that might have occurred during the evolution of the PBP-like fold, a process that is necessary to generate the characteristic motion of PBPs essential to perform their functions.

Cannabinoid receptor type 2 gene is associated with comorbidity of schizophrenia and cannabis dependence and fatty acid amide hydrolase gene is associated with cannabis dependence in the Spanish population. / El gen del receptor cannabinoide tipo 2 se asocia con la comorbilidad entre esquizofrenia y dependencia de cannabis y el gen de la enzima amidohidrolasa de ácidos grasos se asocia con la dependencia de cannabis en población española.

The endocannabinoid system has been associated with various psychiatric disorders, such as schizophrenia or addictive disorders. Recent studies have found that some polymorphisms in the cannabinoid receptor type 2 (CNR2), cannabinoid receptor type 1 (CNR1) and fatty acid amide hydrolase (FAAH) genes could play an important role as risk factors in the etiology of these diseases. We analysed different cannabinoid gene polimorphisms from non-substance using patients diagnosed with schizophrenia (n = 379), schizophrenic patients with cannabis use disorders (n = 124), cannabis users who did not have psychoses (n = 71), and 316 controls from various Spanish hospitals and health centres. We found a statistical association between polymorphisms rs35761398 and rs12744386 in the CNR2 gene and comorbidity of schizophrenia and cannabis dependence, as well as an association between loss of heterozygosity (overdominance) for polymorphism rs324420 in the FAAH gene and cannabis dependence in a Spanish population sample. The rs35761398 and rs12744386 polymorphisms in the CNR2 gene are genetic risk factors for schizophrenia in cannabis-dependent subjects. Loss of heterozygosity for polymorphism rs324420 in the FAAH gene is a genetic risk factor for cannabis dependence in this population.

El sistema cannabinoide se ha asociado con varios trastornos psiquiátricos como la esquizofrenia y las adicciones. Diversos estudios han observado que algunos polimorfismos del receptor cannabinoide tipo 2 (CNR2), del receptor cannabinoide tipo 1 (CNR1) y del gen de la enzima amido hidrolasa de ácidos grasos (FAAH) pueden ser factores de riesgo de estos trastornos. Hemos analizado diversos polimorfismos del sistema cannabinoide en pacientes diagnosticados de esquizofrenia sin trastorno por uso de sustancias (n = 379), esquizofrenia con trastorno por uso de cannabis (n = 124), dependientes de cannabis sin psicosis asociada (n = 71) y un grupo de control (316) procedentes de diversos hospitales y centros de asistencia sanitaria españoles. Hemos encontrado una asociación entre los polimorfismos rs35761398 y rs12744386 del CNR2 con la presencia de esquizofrenia y trastorno por uso de cannabis comórbido y una pérdida de heterocigosidad en el polimorfismo rs324420 del gen FAAH con la dependencia de cannabis en población española. Los polimorfismos rs35761398 y rs12744386 en CNR2 son factores de riesgo para esquizofrenia en sujetos dependientes de cannabis. La pérdida de heterocigosidad en el polimorfismo rs324420 en el gen FAAH es un factor de riesgo para la dependencia de cannabis.