Multiple sclerosis in Central America and Caribbean countries: frequency and clinical characterization of an emergent disease.

Background: Multiple Sclerosis (MS) is a common neurological disease among white populations of European origin. Frequencies among Latin Americans continue to be studied, however, epidemiologic, and clinical characterization studies lack from Central American and Caribbean countries. Ethnicity in these countries is uniformly similar with a prevalent Mestizo population. Methods and results: Data from January 2014 to December 2019 from Guatemala, El Salvador, Honduras, Nicaragua, Costa Rica, Panama, Dominican Republic, and Aruba on demographic, clinical, MRI and phenotypic traits were determined in coordinated studies: ENHANCE, a population-based, retrospective, observational study on incidence and clinical characteristics, and from the subgroup with MS national registries (Aruba, Dominican Republic, Honduras, and Panama), data on prevalence, phenotypes and demographics. Expanded Disability Status Scale (EDSS), and therapeutic schemes were included. ENHANCE data from 758 patients disclosed 79.8% of Mestizo ethnicity; 72.4% female; median age at onset 31.0 years and 33.2 at diagnosis. The highest incidence rate was from Aruba, 2.3-3.5 × 100,000 inhabitants, and the lowest, 0.07-0.15 × 100,000, from Honduras. Crude prevalence rates per 100,000 inhabitants fluctuated from 27.3 (Aruba) to 1.0 (Honduras). Relapsing MS accounted for 87.4% of cases; EDSS <3.0 determined in 66.6% (mean disease duration: 9.1 years, SD ± 5.0); CSF oligoclonal bands 85.7%, and 87% of subjects hydroxyvitamin D deficient. Common initial therapies were interferon and fingolimod. Switching from interferon to fingolimod was the most common escalation step. The COVID-19 pandemic affected follow-up aspects of these studies. Conclusion: This is the first study providing data on frequencies and clinical characteristics from 8 countries from the Central American and Caribbean region, addressing MS as an emergent epidemiologic disorder. More studies from these areas are encouraged.

Transparent, plasticized cellulose-glycerol bioplastics for food packaging applications.

Free-standing films have been obtained by drop-casting cellulose-glycerol mixtures (up to 50 wt% glycerol) dissolved in trifluoroacetic acid and trifluoroacetic anhydride (TFA:TFAA, 2:1, v:v). A comprehensive examination of the optical, structural, mechanical, thermal, hydrodynamic, barrier, migration, greaseproof, and biodegradation characteristics of the films was conducted. The resulting cellulose-glycerol blends exhibited an amorphous molecular structure and a reinforced H-bond network, as evidenced by X-ray diffraction analysis and infrared spectroscopy, respectively. The inclusion of glycerol exerted a plasticizing influence on the mechanical properties of the films, while keeping their transparency. Hydrodynamic and barrier properties were assessed through water uptake and water vapor/oxygen transmission rates, respectively, and obtained values were consistent with those of other cellulose-based materials. Furthermore, overall migration levels were below European regulation limits, as stated by using Tenax® as a dry food simulant. In addition, these bioplastics demonstrated good greaseproof performance, particularly at high glycerol content, and potential as packaging materials for bakery products. Biodegradability assessments were carried out by measuring the biological oxygen demand in seawater and high biodegradation rates induced by glycerol were observed.

Review of the Brain's Behaviour after Injury and Disease for Its Application in an Agent-Based Model (ABM).

The brain is the most complex organ in the human body and, as such, its study entails great challenges (methodological, theoretical, etc.). Nonetheless, there is a remarkable amount of studies about the consequences of pathological conditions on its development and functioning. This bibliographic review aims to cover mostly findings related to changes in the physical distribution of neurons and their connections-the connectome-both structural and functional, as well as their modelling approaches. It does not intend to offer an extensive description of all conditions affecting the brain; rather, it presents the most common ones. Thus, here, we highlight the need for accurate brain modelling that can subsequently be used to understand brain function and be applied to diagnose, track, and simulate treatments for the most prevalent pathologies affecting the brain.

Efficacy and safety of biological treatment for inflammatory bowel disease in elderly patients: Results from a GETECCU cohort.

INTRODUCTION: Biological therapies used for the treatment of inflammatory bowel disease (IBD) have shown to be effective and safe, although these results were obtained from studies involving mostly a young population, who are generally included in clinical trials. The aim of our study was to determine the efficacy and safety of the different biological treatments in the elderly population. METHODS: Multicenter study was carried out in the GETECCU group. Patients diagnosed with IBD and aged over 65 years at the time of initiating biological therapy (infliximab, adalimumab, golimumab, ustekinumab or vedolizumab) were retrospectively included. Among the patients included, clinical response was assessed after drug induction (12 weeks of treatment) and at 52 weeks. Patients' colonoscopy data in week 52 were assessment, where available. Regarding complications, development of oncological events during follow-up and infectious processes occurring during biological treatment were collected (excluding bowel infection by cytomegalovirus). RESULTS: A total of 1090 patients were included. After induction, at approximately 12-14 weeks of treatment, 419 patients (39.6%) were in clinical remission, 502 patients (47.4%) had responded without remission and 137 patients (12.9%) had no response. At 52 weeks of treatment 442 patients (57.1%) had achieved clinical remission, 249 patients had responded without remission (32.2%) and 53 patients had no response to the treatment (6.8%). Before 52 weeks, 129 patients (14.8%) had discontinued treatment due to inefficacy, this being significantly higher (p<0.0001) for Golimumab - 9 patients (37.5%) - compared to the other biological treatments analyzed. With respect to tumor development, an oncological event was observed in 74 patients (6.9%): 30 patients (8%) on infliximab, 23 (7.14%) on adalimumab, 3 (11.1%) on golimumab, 10 (6.4%) on ustekinumab, and 8 (3.8%) on vedolizumab. The incidence was significantly lower (p=0.04) for the vedolizumab group compared to other treatments. As regards infections, these occurred in 160 patients during treatment (14.9%), with no differences between the different biologicals used (p=0.61): 61 patients (19.4%) on infliximab, 39 (12.5%) on adalimumab, 5 (17.8%) on golimumab, 22 (14.1%) on ustekinumab, and 34 (16.5%) on vedolizumab. CONCLUSIONS: Biological drug therapies have response rates in elderly patients similar to those described in the general population, Golimumab was the drug that was discontinued most frequently due to inefficacy. In our experience, tumor development was more frequent in patients who used anti-TNF therapies compared to other targets, although its incidence was generally low and that this is in line with younger patients based on previous literature.

Novel Blood Biomarkers for Response Prediction and Monitoring of Stereotactic Ablative Radiotherapy and Immunotherapy in Metastatic Oligoprogressive Lung Cancer.

Up to 80% of patients under immune checkpoint inhibitors (ICI) face resistance. In this context, stereotactic ablative radiotherapy (SABR) can induce an immune or abscopal response. However, its molecular determinants remain unknown. We present early results of a translational study assessing biomarkers of response to combined ICI and SABR (I-SABR) in liquid biopsy from oligoprogressive patients in a prospective observational multicenter study. Cohort A includes metastatic patients in oligoprogression to ICI maintaining the same ICI due to clinical benefit and who receive concomitant SABR. B is a comparative group of oligometastatic patients receiving only SABR. Blood samples are extracted at baseline (T1), after the first (T2) and last (T3) fraction, two months post-SABR (T4) and at further progression (TP). Response is evaluated by iRECIST and defined by the objective response rate (ORR)-complete and partial responses. We assess peripheral blood mononuclear cells (PBMCs), circulating cell-free DNA (cfDNA) and small RNA from extracellular vesicles. Twenty-seven patients could be analyzed (cohort A: n = 19; B: n = 8). Most were males with non-small cell lung cancer and one progressing lesion. With a median follow-up of 6 months, the last ORR was 63% (26% complete and 37% partial response). A decrease in cfDNA from T2 to T3 correlated with a good response. At T2, CD8+PD1+ and CD8+PDL1+ cells were increased in non-responders and responders, respectively. At T2, 27 microRNAs were differentially expressed. These are potential biomarkers of response to I-SABR in oligoprogressive disease.

Multiphotonic Ablation and Electro-Capacitive Effects Exhibited by Candida albicans Biofilms.

This work reports the modification in the homogeneity of ablation effects with the assistance of nonlinear optical phenomena exhibited by C. albicans ATCC 10231, forming a biofilm. Equivalent optical energies with different levels of intensity were irradiated in comparative samples, and significant changes were observed. Nanosecond pulses provided by an Nd:YAG laser system at a 532 nm wavelength in a single-beam experiment were employed to explore the photodamage and the nonlinear optical transmittance. A nonlinear optical absorption coefficient -2 × 10-6 cm/W was measured in the samples studied. It is reported that multiphotonic interactions can promote more symmetric optical damage derived by faster changes in the evolution of fractional photoenergy transference. The electrochemical response of the sample was studied to further investigate the electronic dynamics dependent on electrical frequency, and an electro-capacitive behavior in the sample was identified. Fractional differential calculations were proposed to describe the thermal transport induced by nanosecond pulses in the fungi media. These results highlight the nonlinear optical effects to be considered as a base for developing photothermally activated phototechnology and high-precision photodamage in biological systems.

Using the Mooney Space to Characterize the Non-Affine Behavior of Elastomers.

The formulation of the entropic statistical theory and the related neo-Hookean model has been a major advance in the modeling of rubber-like materials, but the failure to explain some experimental observations such as the slope in Mooney plots resulted in hundreds of micromechanical and phenomenological models. The origin of the difficulties, the reason for the apparent need for the second invariant, and the reason for the relative success of models based on the Valanis-Landel decomposition have been recently explained. From that insight, a new micro-macro chain stretch connection using the stretch tensor (instead of the right Cauchy-Green deformation tensor) has been proposed and supported both theoretically and from experimental data. A simple three-parameter model using this connection has been suggested. The purpose of this work is to provide further insight into the model, to provide an analytical expression for the Gaussian contribution, and to provide a simple procedure to obtain the parameters from a tensile test using the Mooney space or the Mooney-Rivlin constants. From different papers, a wide variety of experimental tests on different materials and loading conditions have been selected to demonstrate that the simple model calibrated only from a tensile test provides accurate predictions for a wide variety of elastomers under different deformation levels and multiaxial patterns.

Effectiveness and safety of azathioprine for inflammatory pouch disorders: results from the RESERVO study of GETECCU.

Background: The usefulness of thiopurines has been poorly explored in pouchitis and other pouch disorders. Objective: To evaluate the effectiveness and safety of azathioprine as maintenance therapy in inflammatory pouch disorders. Design: This was a retrospective and multicentre study. Methods: We included patients diagnosed with inflammatory pouch disorders treated with azathioprine in monotherapy. Effectiveness was evaluated at 1 year and in the long term based on normalization of stool frequency, absence of pain, faecal urgency or fistula discharge (clinical remission), or any improvement in these symptoms (clinical response). Endoscopic response was evaluated using the Pouchitis Disease Activity Index (PDAI). Results: In all, 63 patients were included [54% males; median age, 49 (28-77) years]. The therapy was used to treat pouchitis (n = 37) or Crohn's disease of the pouch (n = 26). The rate of clinical response, remission and non-response at 12 months were 52%, 30% and 18%, respectively. After a median follow-up of 23 months (interquartile range 11-55), 19 patients (30%) were in clinical remission, and 45 (66%) stopped therapy. Endoscopic changes were evaluated in 19 cases. PDAI score decreased from 3 (range 2-4) to 1 (range 0-3). In all, 21 patients (33%) presented adverse events and 16 (25%) needed to stop therapy. Conclusion: Azathioprine may be effective in the long term for the treatment of inflammatory pouch disorders and could be included as a therapeutic option.

Revalorization of Yerba Mate Residues: Biopolymers-Based Films of Dual Wettability as Potential Mulching Materials.

Biodegradable mulching films are a very attractive solution to agronomical practices intended to achieve more successful crop results. And, in this context, the employment of agricultural and industrial food residues as starting material for their production is an alternative with economic and environmental advantages. This work reports the preparation of bilayer films having two different wettability characteristics from three bio-derived biopolymers: TEMPO-oxidized cellulose nanofibers isolated from infused Yerba Mate residues, Chitosan and Polylactic acid. The infused Yerba Mate residues, the isolated and oxidized cellulose nanofibers, and the films were characterized. Nanofibrillation yield, optical transmittance, cationic demand, carboxyl content, intrinsic viscosity, degree of polymerization, specific surface area and length were studied for the (ligno)cellulose nanofibers. Textural and chemical analysis, thermal and mechanical properties studies, as well as water and light interactions were included in the characterization of the films. The bilayer films are promising materials to be used as mulching films.

Increasing Annual Cancer Incidence in Patients Age 20-49 Years: A Real-Data Study.

PURPOSE: Data from population-based studies have shown an increased incidence of certain types of neoplasms in patients younger than 50 years (early-onset cancer [EOC]); however, little information is derived from other real-world data sources. In a nonpopulation registry, we analyzed changes in the incidence of several neoplasms in successive generations. METHODS: This cross-sectional study included all patients with a cancer diagnosis registered in one university hospital in Málaga, Spain, between 1998 and 2021, and 18 neoplasms were analyzed. For each neoplasm, the proportion of patients younger than 50 years and age 50 years and older (late-onset cancer [LOC]) of the total number of patients diagnosed each year was determined. In addition, the age limit was lowered to 45-40 years. Changes in these proportions between each year and the following year were assessed by calculating the annual percentage change (APC), and a final assessment of these changes was performed by determining the average APC (AAPC). RESULTS: Of the 24,596 patients, 5,466 (22.2%) had EOC, and 19,130 (77.8%) had LOC. The incidence of all tumors increased throughout the study period in both age groups. The AAPC increase was higher in patients with EOC than in those with LOC for the following neoplasms: head and neck (6.1% v 4.6%), colon (11.0% v 8.2%), testicular (16.3% v -13.1%), non-Hodgkin lymphoma (8.4% v 5.9%), rectum (16.1% v 6.8%), kidney (27.8% v 20.1%), and sarcoma (43.4% v 28.6%). This increase was confirmed in patients younger than 45 years and 40 years. CONCLUSION: Our results are consistent with the data published for most tumor sites analyzed. This global public health problem requires the utmost attention to decrease excess cancer in young patients.

Evaluation of Genetic Variants Associated with the Risk of Thiopurine-Related Pancreatitis: A Case Control Study from ENEIDA Registry.

INTRODUCTION: Risk factors for developing pancreatitis due to thiopurines in patients with inflammatory bowel disease (IBD) are not clearly identified. Our aim was to evaluate the predictive pharmacogenetic risk of pancreatitis in IBD patients treated with thiopurines. METHODS: We conducted an observational pharmacogenetic study of acute pancreatitis events in a cohort study of IBD patients treated with thiopurines from the prospectively maintained ENEIDA registry biobank of GETECCU. Samples were obtained and the CASR, CEL, CFTR, CDLN2, CTRC, SPINK1, CPA1, and PRSS1 genes, selected based on their known association with pancreatitis, were fully sequenced. RESULTS: Ninety-five cases and 105 controls were enrolled; a total of 57% were women. Median age at pancreatitis diagnosis was 39 years. We identified 81 benign variants (50 in cases and 67 in controls) and a total of 35 distinct rare pathogenic and unknown significance variants (10 in CEL, 21 in CFTR, 1 in CDLN2, and 3 in CPA1). None of the cases or controls carried pancreatitis-predisposing variants within the CASR, CPA1, PRSS1, and SPINK1 genes, nor a pathogenic CFTR mutation. Four different variants of unknown significance were detected in the CDLN and CPA1 genes; one of them was in the CDLN gene in a single patient with pancreatitis and 3 in the CPA1 gene in 5 controls. After the analysis of the variants detected, no significant differences were observed between cases and controls. CONCLUSION: In patients with IBD, genes known to cause pancreatitis seem not to be involved in thiopurine-related pancreatitis onset.

Comparative Review of the State of the Art in Research on the Porcine Epidemic Diarrhea Virus and SARS-CoV-2, Scope of Knowledge between Coronaviruses.

This review presents comparative information corresponding to the progress in knowledge of some aspects of infection by the porcine epidemic diarrhea virus (PEDV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) coronaviruses. PEDV is an alphacoronavirus of great economic importance due to the million-dollar losses it generates in the pig industry. PEDV has many similarities to the SARS-CoV-2 betacoronavirus that causes COVID-19 disease. This review presents possible scenarios for SARS-CoV-2 based on the collected literature on PEDV and the tools or strategies currently developed for SARS-CoV-2 that would be useful in PEDV research. The speed of the study of SARS-CoV-2 and the generation of strategies to control the pandemic was possible due to the knowledge derived from infections caused by other human coronaviruses such as severe acute respiratory syndrome (SARS) and middle east respiratory syndrome (MERS). Therefore, from the information obtained from several coronaviruses, the current and future behavior of SARS-CoV-2 could be inferred and, with the large amount of information on the virus that causes COVID-19, the study of PEDV could be improved and probably that of new emerging and re-emerging coronaviruses.

Phylogenetic and Molecular Analysis of the Porcine Epidemic Diarrhea Virus in Mexico during the First Reported Outbreaks (2013-2017).

The characteristics of the whole PEDV genome that has circulated in Mexico from the first outbreak to the present are unknown. We chose samples obtained from 2013 to 2017 and sequenced them, which enabled us to identify the genetic variation and phylogeny in the virus during the first four years that it circulated in Mexico. A 99% identity was found among the analyzed pandemic strains; however, the 1% difference affected the structure of the S glycoprotein, which is essential for the binding of the virus to the cellular receptor. The S protein induces the most efficacious antibodies; hence, these changes in structure could be implicated in the clinical antecedents of the outbreaks. Antigenic changes could also help PEDV avoid neutralization, even in the presence of previous immunity. The characterization of the complete genome enabled the identification of three circulating strains that have a deletion in ORF1a, which is present in attenuated Asian vaccine strains. The phylogenetic analysis of the complete genome indicates that the first PEDV outbreaks in Mexico were caused by INDEL strains and pandemic strains related to USA strains; however, the possibility of the entry of European strains exists, which may have caused the 2015 and 2016 outbreaks.

An Agent-Based Model to Reproduce the Boolean Logic Behaviour of Neuronal Self-Organised Communities through Pulse Delay Modulation and Generation of Logic Gates.

The human brain is arguably the most complex "machine" to ever exist. Its detailed functioning is yet to be fully understood, let alone modelled. Neurological processes have logical signal-processing and biophysical aspects, and both affect the brain's structure, functioning and adaptation. Mathematical approaches based on both information and graph theory have been extensively used in an attempt to approximate its biological functioning, along with Artificial Intelligence frameworks inspired by its logical functioning. In this article, an approach to model some aspects of the brain learning and signal processing is presented, mimicking the metastability and backpropagation found in the real brain while also accounting for neuroplasticity. Several simulations are carried out with this model to demonstrate how dynamic neuroplasticity, neural inhibition and neuron migration can reshape the brain's logical connectivity to synchronise signal processing and obtain certain target latencies. This work showcases the importance of dynamic logical and biophysical remodelling in brain plasticity. Combining mathematical (agents, graph theory, topology and backpropagation) and biomedical ingredients (metastability, neuroplasticity and migration), these preliminary results prove complex brain phenomena can be reproduced-under pertinent simplifications-via affordable computations, which can be construed as a starting point for more ambitiously accurate simulations.

A simple agent-based hybrid model to simulate the biophysics of glioblastoma multiforme cells and the concomitant evolution of the oxygen field.

BACKGROUND AND OBJECTIVES: Glioblastoma multiforme (GBM) is one of the most aggressive cancers of the central nervous system. It is characterized by a high mitotic activity and an infiltrative ability of the glioma cells, neovascularization and necrosis. GBM evolution entails the continuous interplay between heterogeneous cell populations, chemotaxis, and physical cues through different scales. In this work, an agent-based hybrid model is proposed to simulate the coupling of the multiscale biological events involved in the GBM invasion, specifically the individual and collective migration of GBM cells and the concurrent evolution of the oxygen field and phenotypic plasticity. An asset of the formulation is that it is conceptually and computationally simple but allows to reproduce the complexity and the progression of the GBM micro-environment at cell and tissue scales simultaneously. METHODS: The migration is reproduced as the result of the interaction between every single cell and its micro-environment. The behavior of each individual cell is formulated through genotypic variables whereas the cell micro-environment is modeled in terms of the oxygen concentration and the cell density surrounding each cell. The collective behavior is formulated at a cellular scale through a flocking model. The phenotypic plasticity of the cells is induced by the micro-environment conditions, considering five phenotypes. RESULTS: The model has been contrasted by benchmark problems and experimental tests showing the ability to reproduce different scenarios of glioma cell migration. In all cases, the individual and collective cell migration and the coupled evolution of both the oxygen field and phenotypic plasticity have been properly simulated. This simple formulation allows to mimic the formation of relevant hallmarks of glioblastoma multiforme, such as the necrotic cores, and to reproduce experimental evidences related to the mitotic activity in pseudopalisades. CONCLUSIONS: In the collective migration, the survival of the clusters prevails at the expense of cell mitosis, regardless of the size of the groups, which delays the formation of necrotic foci and reduces the rate of oxygen consumption.

Clinical and treatment outcomes of a second subcutaneous or intravenous anti-TNF in patients with ulcerative colitis treated with two consecutive anti-TNF agents: data from the ENEIDA registry.

Background: Infliximab seems to be the most efficacious of the three available anti-TNF agents for ulcerative colitis (UC) but little is known when it is used as the second anti-TNF. Objectives: To compare the clinical and treatment outcomes of a second subcutaneous or intravenous anti-TNF in UC patients. Design: Retrospective observational study. Methods: Patients from the ENEIDA registry treated consecutively with infliximab and a subcutaneous anti-TNF (or vice versa), naïve to other biological agents, were identified and grouped according to the administration route of the first anti-TNF into IVi (intravenous initially) or SCi (subcutaneous initially). Results: Overall, 473 UC patients were included (330 IVi and 143 SCi). Clinical response at week 14 was 42.7% and 48.3% in the IVi and SCi groups (non-statistically significant), respectively. Clinical remission rates at week 52 were 32.8% and 31.4% in the IVi and SCi groups (nonsignificant differences), respectively. A propensity-matched score analysis showed a higher clinical response rate at week 14 in the SCi group and higher treatment persistence in the IVi group. Regarding long-term outcomes, dose escalation and discontinuation due to the primary failure of the first anti-TNF and more severe disease activity at the beginning of the second anti-TNF were inversely associated with clinical remission. Conclusion: The use of a second anti-TNF for UC seems to be reasonable in terms of efficacy, although it is particularly reduced in the case of the primary failure of the first anti-TNF. Whether the second anti-TNF is infliximab or subcutaneous does not seem to affect efficacy.

OBJECTIVES: To compare the clinical and treatment outcomes of a second subcutaneous or intravenous anti-TNF in UC patients. DESIGN: Retrospective observational study. METHODS: Patients from the ENEIDA registry treated consecutively with infliximab and a subcutaneous anti-TNF (or vice versa), naïve to other biological agents, were identified and grouped according to the administration route of the first anti-TNF into IVi (intravenous initially) or SCi (subcutaneous initially). RESULTS: Overall, 473 UC patients were included (330 IVi, 143 SCi). Clinical response at week 14 was 42.7% and 48.3% in the IVi and SCi groups (non-statistically significant), respectively. Clinical remission rates at week 52 were 32.8% and 31.4%, in the IVi and SCi groups (nonsignificant differences), respectively. A propensity-matched score analysis showed a higher clinical response rate at week 14 in the SCi group and higher treatment persistence in the IVi group. Regarding long-term outcomes, dose escalation and discontinuation due to the primary failure of the first anti-TNF and more severe disease activity at the beginning of the second anti-TNF were inversely associated with clinical remission. CONCLUSION: The use of a second anti-TNF for UC seems to be reasonable in terms of efficacy, although it is particularly reduced in the case of the primary failure of the first anti-TNF. Whether the second anti-TNF is infliximab or subcutaneous does not seem to affect efficacy.

Clinical and treatment outcomes of a second subcutaneous or intravenous anti-TNF in patients with ulcerative colitis treated with two consecutive anti-TNF agents. Data from the ENEIDA registry Background: Infliximab seems to be the most efficacious of the three available anti-TNF agents for ulcerative colitis (UC), but little is known when it is used as the second anti-TNF.