Systematic review and meta-analysis of the visual mismatch negativity in schizophrenia.

Mismatch negativity (MMN) is an event-related potential component automatically elicited by events that violate predictions based on prior events. To elicit this component, researchers use stimulus repetition to induce predictions, and the MMN is obtained by subtracting the brain response to rare or unpredicted stimuli from that of frequent stimuli. Under the Predictive Processing framework, one increasingly popular interpretation of the mismatch response postulates that MMN represents a prediction error. In this context, the reduced MMN amplitude to auditory stimuli has been considered a potential biomarker of Schizophrenia, representing a reduced prediction error and the inability to update the mental model of the world based on the sensory signals. It is unclear, however, whether this amplitude reduction is specific for auditory events or if the visual MMN reveals a similar pattern in schizophrenia spectrum disorder. This review and meta-analysis aimed to summarise the available literature on the vMMN in schizophrenia. A systematic literature search resulted in 10 eligible studies that resulted in a combined effect size of g = -.63, CI [-.86, -.41], reflecting lower vMMN amplitudes in patients. These results are in line with the findings in the auditory domain. This component offers certain advantages, such as less susceptibility to overlap with components generated by attentional demands. Future studies should use vMMN to explore abnormalities in the Predictive Processing framework in different stages and groups of the SSD and increase the knowledge in the search for biomarkers in schizophrenia.

Geometry of visuospatial working memory information in miniature gaze patterns.

Stimulus-dependent eye movements have been recognized as a potential confound in decoding visual working memory information from neural signals. Here we combined eye-tracking with representational geometry analyses to uncover the information in miniature gaze patterns while participants (n = 41) were cued to maintain visual object orientations. Although participants were discouraged from breaking fixation by means of real-time feedback, small gaze shifts (<1°) robustly encoded the to-be-maintained stimulus orientation, with evidence for encoding two sequentially presented orientations at the same time. The orientation encoding on stimulus presentation was object-specific, but it changed to a more object-independent format during cued maintenance, particularly when attention had been temporarily withdrawn from the memorandum. Finally, categorical reporting biases increased after unattended storage, with indications of biased gaze geometries already emerging during the maintenance periods before behavioural reporting. These findings disclose a wealth of information in gaze patterns during visuospatial working memory and indicate systematic changes in representational format when memory contents have been unattended.

A cell abundance analysis based on efficient PAM clustering for a better understanding of the dynamics of endometrial remodelling.

BACKGROUND: Single-cell RNA sequencing (scRNA-seq) is a powerful tool for investigating cell abundance changes during tissue regeneration and remodeling processes. Differential cell abundance supports the initial clustering of all cells; then, the number of cells per cluster and sample are evaluated, and the dependence of these counts concerning the phenotypic covariates of the samples is studied. Analysis heavily depends on the clustering method. Partitioning Around Medoids (PAM or k-medoids) represents a well-established clustering procedure that leverages the downstream interpretation of clusters by pinpointing real individuals in the dataset as cluster centers (medoids) without reducing dimensions. Of note, PAM suffers from high computational costs and memory requirements. RESULTS: This paper proposes a method for differential abundance analysis using PAM as a clustering method and negative binomial regression as a statistical model to relate covariates to cluster/cell counts. We used this approach to study the differential cell abundance of human endometrial cell types throughout the natural secretory phase of the menstrual cycle. We developed a new R package -scellpam-, that incorporates an efficient parallel C++ implementation of PAM, and applied this package in this study. We compared the PAM-BS clustering method with other methods and evaluated both the computational aspects of its implementation and the quality of the classifications obtained using distinct published datasets with known subpopulations that demonstrate promising results. CONCLUSIONS: The implementation of PAM-BS, included in the scellpam package, exhibits robust performance in terms of speed and memory usage compared to other related methods. PAM allowed quick and robust clustering of sets of cells with a size ranging from 70,000 to 300,000 cells. https://cran.r-project.org/web/packages/scellpam/index.html . Finally, our approach provides important new insights into the transient subpopulations associated with the fertile time frame when applied to the study of changes in the human endometrium during the secretory phase of the menstrual cycle.

Treatment of metastatic squamous cell carcinoma arising in sacrococcygeal pilonidal sinus: a case report series.

Background: Squamous cell carcinoma (SCC) arising in a sacrococcygeal pilonidal sinus is rare, with cases of metastatic disease being even rarer. Among published cases, almost none have reported on systemic treatment. Objective: This disease has a poorer prognosis than other forms of cutaneous SCC; therefore, our objective is to shed some light on the treatment of metastatic disease. Methods: We present a series of nine cases treated at a single center, four of whom received systemic treatment. Additionally, other previously reported cases of metastatic disease are included in an attempt to draw stronger conclusions. Results: Four patients were treated under several treatment regimens, with a median progression-free survival of only 2 months and two instances of partial response (18%). The best result was achieved with cemiplimab. Across all the cases, there was a trend toward a benefit of the use of systemic treatment (HR 0.41, 95% CI 0.15-1.12, p = 0.083; median overall survival 13 vs. 8 months). Limitations: Limitations include the significant lack of information on previously published cases and the extremely heterogeneous nature of the existing information. Conclusion: The initial systemic treatment should be an anti-PD-1, as with other SCCs. After progression on anti-PD-1, there is no strong evidence to support the recommendation of a specific treatment or sequence: options include cetuximab and/or chemotherapy (platinum, paclitaxel, 5-fluorouracyl).

Long-term outcomes of the global tuberculosis and COVID-19 co-infection cohort.

BACKGROUND: Longitudinal cohort data of patients with tuberculosis (TB) and coronavirus disease 2019 (COVID-19) are lacking. In our global study, we describe long-term outcomes of patients affected by TB and COVID-19. METHODS: We collected data from 174 centres in 31 countries on all patients affected by COVID-19 and TB between 1 March 2020 and 30 September 2022. Patients were followed-up until cure, death or end of cohort time. All patients had TB and COVID-19; for analysis purposes, deaths were attributed to TB, COVID-19 or both. Survival analysis was performed using Cox proportional risk-regression models, and the log-rank test was used to compare survival and mortality attributed to TB, COVID-19 or both. RESULTS: Overall, 788 patients with COVID-19 and TB (active or sequelae) were recruited from 31 countries, and 10.8% (n=85) died during the observation period. Survival was significantly lower among patients whose death was attributed to TB and COVID-19 versus those dying because of either TB or COVID-19 alone (p<0.001). Significant adjusted risk factors for TB mortality were higher age (hazard ratio (HR) 1.05, 95% CI 1.03-1.07), HIV infection (HR 2.29, 95% CI 1.02-5.16) and invasive ventilation (HR 4.28, 95% CI 2.34-7.83). For COVID-19 mortality, the adjusted risks were higher age (HR 1.03, 95% CI 1.02-1.04), male sex (HR 2.21, 95% CI 1.24-3.91), oxygen requirement (HR 7.93, 95% CI 3.44-18.26) and invasive ventilation (HR 2.19, 95% CI 1.36-3.53). CONCLUSIONS: In our global cohort, death was the outcome in >10% of patients with TB and COVID-19. A range of demographic and clinical predictors are associated with adverse outcomes.

Scellpam: an R package/C++ library to perform parallel partitioning around medoids on scRNAseq data sets.

BACKGROUND: Partitioning around medoids (PAM) is one of the most widely used and successful clustering method in many fields. One of its key advantages is that it only requires a distance or a dissimilarity between the individuals, and the fact that cluster centers are actual points in the data set means they can be taken as reliable representatives of their classes. However, its wider application is hampered by the large amount of memory needed to store the distance matrix (quadratic on the number of individuals) and also by the high computational cost of computing such distance matrix and, less importantly, by the cost of the clustering algorithm itself. RESULTS: Therefore, new software has been provided that addresses these issues. This software, provided under GPL license and usable as either an R package or a C++ library, calculates in parallel the distance matrix for different distances/dissimilarities ([Formula: see text], [Formula: see text], Pearson, cosine and weighted Euclidean) and also implements a parallel fast version of PAM (FASTPAM1) using any data type to reduce memory usage. Moreover, the parallel implementation uses all the cores available in modern computers which greatly reduces the execution time. Besides its general application, the software is especially useful for processing data of single cell experiments. It has been tested in problems including clustering of single cell experiments with up to 289,000 cells with the expression of about 29,000 genes per cell. CONCLUSIONS: Comparisons with other current packages in terms of execution time have been made. The method greatly outperforms the available R packages for distance matrix calculation and also improves the packages that implement the PAM itself. The software is available as an R package at https://CRAN.R-project.org/package=scellpam and as C++ libraries at https://github.com/JdMDE/jmatlib and https://github.com/JdMDE/ppamlib The package is useful for single cell RNA-seq studies but it is also applicable in other contexts where clustering of large data sets is required.

Extramammary Paget Disease: a Therapeutic Challenge, for a Rare Entity.

PURPOSE OF REVIEW: Extramammary Paget disease (EMPD) is a rare entity which is more frequently localized at the vulva, though it only accounts for 1-2% of vulvar neoplasms. It is a primary cutaneous adenocarcinoma whose cell of origin is still a matter of controversy: it can either arise from apocrine/eccrine glands or from stem cells. The diagnosis demands a biopsy and entails a histopathological analysis by which cells show similar characteristics as breast Paget disease. RECENT FINDINGS: Treatment approach can entail surgery, radiotherapy, photodynamic therapy, systemic chemotherapy, and topical chemotherapy. For metastatic disease, many different chemotherapy regimens have been explored and even targeted therapy can play an important role in this disease. Since almost 30-40% of patients overexpress HER-2, trastuzumab and anti-HER-2 therapies can be employed in this setting. Due to its low incidence, there is almost no specific evidence on therapeutic interventions for this disease. Thus, there is a neat unmet need for molecular characterization of EMPD and diagnostic tools that allow clinicians to guide treatment both in the early and in the advanced disease settings. In this review, we aim to summarize available evidence about diagnosis and treatment of EMPD, both localized and metastatic, and to provide a comprehensive analysis that may help clinicians for therapeutic decisions.

OncoCardioDB: a public and curated database of molecular information in onco-cardiology/cardio-oncology.

Numerous studies have been published which, separately, investigate the influence of molecular features on oncological and cardiac pathologies. Nevertheless, the relationship between both families of diseases at the molecular level is an emerging area within onco-cardiology/cardio-oncology. This paper presents a new open-source database that aims to organize the curated information concerning the molecular features validated in patients involved in both cancer and cardiovascular diseases. Entities like gene, variation, drug, study and others are modelled as objects of a database which is populated with curated information from 83 papers identified by systematic literature searched for up to 2021. Researchers will discover new connections among them to validate hypotheses or suggest new ones. Special care has been taken to use standard nomenclature for genes, pathologies and all the objects for which accepted conventions exist. The database can be consulted via the web with a system of simplified queries, but it also accepts any query. It will be updated and refined with the incorporation of new studies as they become available. Database URL http://biodb.uv.es/oncocardio/.

Association of IFN-γ +874 A/T SNP and hypermethylation of the -53 CpG site with tuberculosis susceptibility.

Introduction: Tuberculosis (TB) is now the 2nd leading infectious killer after COVID-19 and the 13th leading cause of death worldwide. Moreover, TB is a lethal combination for HIV-patients. Th1 responses and particularly IFN-γ are crucial for immune protection against Mycobacterium tuberculosis infection. Many gene variants for IFNG that confer susceptibility to TB have been described in multiple ethnic populations. Likewise, some epigenetic modifications have been evaluated, being CpG methylation the major epigenetic mark that makes chromatin inaccessible to transcription factors, thus avoiding the initiation of IFNG transcription. Methods: We evaluated both genetic and epigenetic changes involved in IFN-γ production and TB susceptibility in Argentine population. Amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) was performed for the IFN-γ +874 A/T polymorphism (rs2430561) genotyping in 199 healthy donors (HD) and 173 tuberculosis (TB) patients. IFN-γ levels from M. tuberculosis-stimulated PBMCs were measured by ELISA. The methylation status at the -53 CpG site of the IFNG promoter in individuals with latent infection (LTBI), TB and HD was determine by pyrosequencing. Results: Using a case-control study, we found that A allele and, consequently, AA genotype were overrepresented in patients with active disease. Moreover, HD carrying T allele (AT or TT genotype) evidenced an augmented IFN-γ secretion compared to TB patients. Codominance was the genetic model that best fits our results according to the Akaike information criterion (AIC). In addition, increased methylation levels at the -53 CpG site in the IFN-γ promoter were observed in whole blood of patients with active TB compared to LTBI individuals. Discussion: IFN-γ is regulated by genetic variants and epigenetic modifications during TB. Besides, AA genotype of the rs2430561 single nucleotide polymorphism could be considered as a potential TB susceptibility genetic biomarker in Argentina and the methylation of the -53 CpG site could result in a useful predictor of TB reactivation.

Endoscopic suspect of subacute occlusive mesenteric ischemia.

A 74-year-old patient presented to our emergency department with melena for 24 hours, associated with postprandial abdominal pain, predominantly in the epigastrium, for one month. Urgent gastroscopy showed a pale mucosa with loss of vascular pattern in the gastric antrum, as well as several superficial ulcers, Forrest III, at that level and in the duodenal bulb highly suggestive of ischaemia. An abdominal computed tomography angiography (CTA) revealed a filiform celiac trunk, with calcified atherosclerotic plaques in the ostium, superior mesenteric artery and both renal arteries, with absence of enhancement in a large part of the intestinal wall, suggestive of ischaemia. An exploratory laparoscopy confirmed patchy ischaemia of the small intestine, as well as of the cecum, ascending colon, and portion of the transversus. Atherosclerosis is the most common cause of occlusive chronic mesenteric ischaemia. The 'classic triad' consisting of postprandial pain, weight loss and abdominal bruit, is found in only a minority of patients, with a significant percentage of paucisymptomatic patients due to abundant colateral circulation, making diagnosis difficult. The endoscopic finding of edema, erythema or signs of mucosal atrophy, as well as gastric or duodenal ulcers, not justified by other causes can guide us in the diagnosis. However, more distal sections of the digestive tract which are not accessible with the conventional endoscope can often be affected, and the absence of these findings, does not exclude the diagnosis. Abdominal CTA is the gold-standard imaging test. Early diagnosis of mesenteric ischaemia is a challenge in clinical practice. Recognizing its endoscopic signs can facilitate its early diagnosis and treatment.

Asymmetric reinforcement learning facilitates human inference of transitive relations.

Humans and other animals are capable of inferring never-experienced relations (for example, A > C) from other relational observations (for example, A > B and B > C). The processes behind such transitive inference are subject to intense research. Here we demonstrate a new aspect of relational learning, building on previous evidence that transitive inference can be accomplished through simple reinforcement learning mechanisms. We show in simulations that inference of novel relations benefits from an asymmetric learning policy, where observers update only their belief about the winner (or loser) in a pair. Across four experiments (n = 145), we find substantial empirical support for such asymmetries in inferential learning. The learning policy favoured by our simulations and experiments gives rise to a compression of values that is routinely observed in psychophysics and behavioural economics. In other words, a seemingly biased learning strategy that yields well-known cognitive distortions can be beneficial for transitive inferential judgements.

Síndrome del intestino irritable / Irritable bowel syndrome

El síndrome del intestino irritable es uno de los trastornos funcionales intestinales más comunes y tiene un impacto sustancial en la vida diaria de los pacientes, así como un enorme impacto económico en la sociedad. Se caracteriza por dolor abdominal, meteorismo con distensión abdominal y alteración en las evacuaciones intestinales, con predominio de diarrea, estreñimiento o alternancia de estos signos, los cuales no pueden ser explicados por una anormalidad estructural o bioquímica. Se desconoce su etiopatogenia y su mecanismo fisiopatológico. La enfermedad afecta a entre el 5 y el 10% de los individuos sanos en un momento dado y, en la mayoría de las personas, tiene un curso de recaídas y remisiones. En este artículo se revisan algunas de las evidencias principales y más actuales acerca de su epidemiología, factores de riesgo, fisiopatología, manifestaciones clínicas, aproximación diagnóstica y opciones terapéuticas, tanto de tipo dietético como farmacológico y psicoterapéutico.

Irritable bowel syndrome. / Síndrome del intestino irritable.

Irritable bowel syndrome is one of the most common functional bowel disorders, and has a substantial impact on patients' daily lives, as well as a big economic impact on society. It is characterised by abdominal pain, bloating and abdominal distention and altered bowel movements, with a predominance of diarrhoea, constipation, or alternation of these signs, which cannot be explained by a structural or biochemical abnormality. Its aetiopathogenesis and pathophysiological mechanism are unknown. The disease affects 5%-10% of healthy individuals at any given time and, in most people, has a relapsing-remitting course. This article reviews some of the main and most current evidence on its epidemiology, risk factors, pathophysiology, clinical manifestations, diagnostic approach, and therapeutic options, both dietary, pharmacological and psychotherapeutic.

Theta rhythmicity governs human behavior and hippocampal signals during memory-dependent tasks.

Memory formation and reinstatement are thought to lock to the hippocampal theta rhythm, predicting that encoding and retrieval processes appear rhythmic themselves. Here, we show that rhythmicity can be observed in behavioral responses from memory tasks, where participants indicate, using button presses, the timing of encoding and recall of cue-object associative memories. We find no evidence for rhythmicity in button presses for visual tasks using the same stimuli, or for questions about already retrieved objects. The oscillations for correctly remembered trials center in the slow theta frequency range (1-5 Hz). Using intracranial EEG recordings, we show that the memory task induces temporally extended phase consistency in hippocampal local field potentials at slow theta frequencies, but significantly more for remembered than forgotten trials, providing a potential mechanistic underpinning for the theta oscillations found in behavioral responses.

The effect of medical and urologic disorders on the survival of patients with metastatic castration resistant prostate cancer treated with abiraterone or enzalutamide.

INTRODUCTION: Androgenic deprivation therapies have been linked to the development of metabolic syndrome (MS) and cardiovascular diseases, which may lead to a poorer survival in patients with metastatic Castration-Resistant Prostate Cancer (mCRPC). We aimed to analyze whether some cardiovascular or neurological disorders, together with other medical and urological complications, may have an effect on survival outcomes, at baseline and during treatment from patients treated with androgen pathway inhibitors (API). MATERIAL AND METHODS: A retrospective study of a consecutive series of patients diagnosed with mCRPC between 2010 and 2018 treated with API in the first line setting in a single center. RESULTS: Seventy-three patients met the inclusion criteria. Baseline prognostic factors associated with worse survival were diabetes mellitus (DM) with insulin needs compared to patients without DM [hazard ratio (HR) = 0.19, p = 0.025], hypertension (HTN) (HR = 0.46, p = 0.035), and a history of stroke (HR = 0.16, p < 0.001). However, previous history of hypercholesterolemia, arrythmias, and cognitive disorders did not result in a significant worsening on survival. During treatment, patients who developed de novo HTN had the best progression free survival (PFS) (HR = 0.38, p = 0.048) and overall survival (OS) (HR 0.08, p = 0.012) compared with patients with previous HTN. Other factors related to worse outcomes included the presence of heart failure (HR = 0.31, p = 0.001), the requirement for major opioids for pain relief (HR = 0.33, p = 0.023), and the presence of bilateral ureterohydronephrosis (HR = 0.12, p = 0.008). CONCLUSIONS: Some comorbidities may be strongly involved in patient outcomes when receiving API for mCRPC. In this sense, collaborative networking between specialists and caregivers treating prostate cancer (PC) patients should be recommended, focusing on MS features, cardiovascular and neurological disorders in order to anticipate medical and surgical complications.