A new paradigm for molecular dynamics databases: the COVID-19 database, the legacy of a titanic community effort.

Molecular dynamics (MD) simulations are keeping computers busy around the world, generating a huge amount of data that is typically not open to the scientific community. Pioneering efforts to ensure the safety and reusability of MD data have been based on the use of simple databases providing a limited set of standard analyses on single-short trajectories. Despite their value, these databases do not offer a true solution for the current community of MD users, who want a flexible analysis pipeline and the possibility to address huge non-Markovian ensembles of large systems. Here we present a new paradigm for MD databases, resilient to large systems and long trajectories, and designed to be compatible with modern MD simulations. The data are offered to the community through a web-based graphical user interface (GUI), implemented with state-of-the-art technology, which incorporates system-specific analysis designed by the trajectory providers. A REST API and associated Jupyter Notebooks are integrated into the platform, allowing fully customized meta-analysis by final users. The new technology is illustrated using a collection of trajectories obtained by the community in the context of the effort to fight the COVID-19 pandemic. The server is accessible at https://bioexcel-cv19.bsc.es/#/. It is free and open to all users and there are no login requirements. It is also integrated into the simulations section of the BioExcel-MolSSI COVID-19 Molecular Structure and Therapeutics Hub: https://covid.molssi.org/simulations/ and is part of the MDDB effort (https://mddbr.eu).

Long-term survival in venous thromboembolic disease: rivaroxaban vs. warfarin - propensity score matching study.

BACKGROUND: Venous thromboembolic disease (VTE) is characterized by obstruction of venous blood flow by a thrombus. Survival data, frequency of disease recurrence, and bleeding rate in patients on anticoagulant therapy with warfarin compared to rivaroxaban in the Latin American population are limited in VTE. METHODS: A retrospective cohort study with propensity score matching analysis was conducted in patients with pulmonary embolism and/or deep vein thrombosis anticoagulated with warfarin or rivaroxaban treated. Survival analysis was performed using a Kaplan-Meier curve for each of the intervention groups, and it was compared using a Log Rank test. RESULTS: Of 2193 potentially eligible patients with a suspected diagnosis of VTE, 505 patients entered the analysis; of these, 285 subjects were managed with warfarin and 220 anticoagulated with rivaroxaban. Major bleeding at 12 months occurred in 2.7% (6/220) of patients treated with Rivaroxaban, compared to 10.2% (29/285) in the Warfarin group in the unmatched population (p = 0.001). In the matched population, bleeding at 12 months occurred in 2.9% (6/209) of patients on Rivaroxaban and in 11.0% (23/209) of patients on Warfarin (p = 0.001). The survival rates at 6 months were 97.1% for Rivaroxaban and 97.6% for Warfarin (p = 0.76). At 12 months, the survival rates were 94.7% for Rivaroxaban and 95.7% for Warfarin (p = 0.61). CONCLUSION: In the treatment of VTE, there is no differences on 6 and 12-month survival or a reduction in the occurrence of new thromboembolic events when comparing rivaroxaban to warfarin. However, a lower risk of major bleeding is observed at 12 months with Rivaroxaban.

Five-year serological and clinical evolution of chronic Chagas disease patients in Cochabamba, Bolivia.

BACKGROUND: Chagas disease, caused by the parasite Trypanosoma cruzi, is a neglected infectious disease that exerts the highest public health burden in the Americas. There are two anti-parasitic drugs approved for its treatment-benznidazole and nifurtimox-but the absence of biomarkers to early assess treatment efficacy hinders patients´ follow-up. METHODOLOGY/PRINCIPAL FINDINGS: We conducted a longitudinal, observational study among a cohort of 106 chronically T. cruzi-infected patients in Cochabamba (Bolivia) who completed the recommended treatment of benznidazole. Participants were followed-up for five years, in which we collected clinical and serological data, including yearly electrocardiograms and optical density readouts from two ELISAs (total and recombinant antigens). Descriptive and statistical analyses were performed to understand trends in data, as well as the relationship between clinical symptoms and serological evolution after treatment. Our results showed that both ELISAs documented average declines up to year three and slight inclines for the following two years. The recorded clinical parameters indicated that most patients did not have any significant changes to their cardiac or digestive symptoms after treatment, at least in the timeframe under investigation, while a small percentage demonstrated either a regression or progression in symptoms. Only one participant met the "cure criterion" of a negative serological readout for both ELISAs by the final year. CONCLUSIONS/SIGNIFICANCE: The study confirms that follow-up of benznidazole-treated T. cruzi-infected patients should be longer than five years to determine, with current tools, if they are cured. In terms of serological evolution, the single use of a total antigen ELISA might be a more reliable measure and suffice to address infection status, at least in the region of Bolivia where the study was done. Additional work is needed to develop a test-of-cure for an early assessment of drugs´ efficacy with the aim of improving case management protocols.

Predictors of severity in severe respiratory infection in children with COVID-19 respiratory infection in a developing country.

On March 11, 2020, the WHO declared the COVID-19 pandemic. This name was given to the disease caused by the SARS-CoV 2 virus at its outbreak in December 2019 in Wuhan, Hubei, China. In Colombia, a significant number of cases have been confirmed. The aim of this study was to evaluate children with respiratory symptoms caused by SARS-CoV2 infection, identifying independent predictors of risk of having a severe illness, thus leading to an early approach and intervention in our patients, especially in children with comorbidities. An analytical cross-sectional study was conducted between April 1, 2020 and March 31, 2021 at a fourth-level referral institution in Bogotá on patients under 18 years of age with respiratory symptoms and a COVID-19 diagnosis confirmed in the laboratory. An explanatory binary logistic regression model was performed with an outcome variable of admission to the intensive care unit. A total of 385 children were included in the study, with ages between 9 months and 17 years of age; 50.1% were male, and the ICR was 9.75 years. 41.6% had some comorbidity, 13.5% were admitted to the pediatric ICU, and 3.6% of the total number of patients died. The predictor variables were: use of antibiotics in the first 24 h, neurological comorbidity, and consolidation shown in the chest X-ray. This explains 38.7% of the variability of the variable. In this cohort of patients with COVID-19-associated respiratory symptoms, we identified predictors of severity, so we consider that these patients require a risk approach that allows timely and adequate care.

High-Throughput Prediction of the Impact of Genetic Variability on Drug Sensitivity and Resistance Patterns for Clinically Relevant Epidermal Growth Factor Receptor Mutations from Atomistic Simulations.

Mutations in the kinase domain of the epidermal growth factor receptor (EGFR) can be drivers of cancer and also trigger drug resistance in patients receiving chemotherapy treatment based on kinase inhibitors. A priori knowledge of the impact of EGFR variants on drug sensitivity would help to optimize chemotherapy and design new drugs that are effective against resistant variants before they emerge in clinical trials. To this end, we explored a variety of in silico methods, from sequence-based to "state-of-the-art" atomistic simulations. We did not find any sequence signal that can provide clues on when a drug-related mutation appears or the impact of such mutations on drug activity. Low-level simulation methods provide limited qualitative information on regions where mutations are likely to cause alterations in drug activity, and they can predict around 70% of the impact of mutations on drug efficiency. High-level simulations based on nonequilibrium alchemical free energy calculations show predictive power. The integration of these "state-of-the-art" methods into a workflow implementing an interface for parallel distribution of the calculations allows its automatic and high-throughput use, even for researchers with moderate experience in molecular simulations.

Consumo de ayudas ergogénicas nutricionales y farmacéuticas en personas que asisten a gimnasios del municipio de Cercado, Cochabamba

Dado el problema de salud pública que plantean los esteroides anabólicos, el consumo de ayudas ergogénicas está aumentando a nivel mundial, no es en Bolivia. Además, existe un consumo desmedido de suplementos nutricionales y farmacéuticos, así como efectos reversibles e irreversibles de los esteroides anabólicos. Objetivos: describir cómo se consumen las ayudas ergogénicas nutricionales y farmacéuticas y cómo los asistentes a gimnasios en el municipio Cercado de Cochabamba perciben sus efectos en su salud. Métodos: se realizó un estudio observacional transversal con 378 participantes mayores de 18 años, (estratificada) divididos en cuatro grupos; Amateur, Fitness, Deportista y en nueve gimnasios y dos grupos (NABBA-IFFB) y deportistas en general en el área metropolitana de Cercado Cochabamba. Resultados: se encontró que el 74,6% consume alguna sustancia que mejoran el rendimiento; el consumo de ayudas ergogénicas nutricionales fue del 57,1%(n=216) y farmacológicas el 17,4% (n=66). El tiempo dedicado a entrenamiento y dieta para el grupo amateur es estadísticamente significativo con un valor de (p<0,05). Los efectos percibidos y reportados por el consumo de ayudas ergogénicas farmacológicas (esteroides anabólicos androgénicos) son principalmente cambios de humor, alteración en la libido y acné. Entre los efectos secundarios irreversibles dos casos de hombres desarrollaron ginecomastia y dos mujeres desarrollaron clítoromegalia. Conclusiones: los usuarios de ejercicio en el gimnasio consumen grandes cantidades de sustancias nutricionales y/o farmacológica que mejoran el rendimiento.

Given the public health problem posed by anabolic steroids, the consumption of ergogenic aids is increasing worldwide, not indifferently in Bolivia. In addition, there is an excessive consumption of nutritional and pharmaceutical supplements, as well as reversible and irreversible effects of anabolic steroids. Objectives: to describe how nutritional and pharmaceutical ergogenic aids are consumed and how gym-goers in the Cercado municipality of Cochabamba perceive their effects on their health. Methods: a crosssectional observational study was conducted with 378 participants over 18 years of age, (stratified) divided into four groups; Amateur, Fitness, Athlete and in 9 gyms and 2 groups (NABBA-IFFB) and athletes in general in the metropolitan area of Cercado Cochabamba. Results: it was found that 74.6% consumed some performance-enhancing substance; the consumption of nutritional ergogenic aids was 57.1% (n=216) and pharmacological aids 17.4% (n=66). Time dedicated to training and diet for the amateur group is statistically significant with a value of (p<0.05). The perceived and reported effects of the consumption of pharmacological ergogenic aids (anabolic androgenic steroids) are mainly mood changes, libido alteration and acne. Among the irreversible side effects 2 cases of men developed gynecomastia and 2 women developed clitoromegaly. Conclusions: exercise users in the gym consume large amounts of nutritional and/or pharmacological performance enhancing substances.

Molecular Diagnoses of X-Linked and Other Genetic Hypophosphatemias: Results From a Sponsored Genetic Testing Program.

X-linked hypophosphatemia (XLH), a dominant disorder caused by pathogenic variants in the PHEX gene, affects both sexes of all ages and results in elevated serum fibroblast growth factor 23 (FGF23) and below-normal serum phosphate. In XLH, rickets, osteomalacia, short stature, and lower limb deformity may be present with muscle pain and/or weakness/fatigue, bone pain, joint pain/stiffness, hearing difficulty, enthesopathy, osteoarthritis, and dental abscesses. Invitae and Ultragenyx collaborated to provide a no-charge sponsored testing program using a 13-gene next-generation sequencing panel to confirm clinical XLH or aid diagnosis of suspected XLH/other genetic hypophosphatemia. Individuals aged ≥6 months with clinical XLH or suspected genetic hypophosphatemia were eligible. Of 831 unrelated individuals tested between February 2019 and June 2020 in this cross-sectional study, 519 (62.5%) individuals had a pathogenic or likely pathogenic variant in PHEX (PHEX-positive). Among the 312 PHEX-negative individuals, 38 received molecular diagnoses in other genes, including ALPL, CYP27B1, ENPP1, and FGF23; the remaining 274 did not have a molecular diagnosis. Among 319 patients with a provider-reported clinical diagnosis of XLH, 88.7% (n = 283) had a reportable PHEX variant; 81.5% (n = 260) were PHEX-positive. The most common variant among PHEX-positive individuals was an allele with both the gain of exons 13-15 and c.*231A>G (3'UTR variant) (n = 66/519). Importantly, over 80% of copy number variants would have been missed by traditional microarray analysis. A positive molecular diagnosis in 41 probands (4.9%; 29 PHEX positive, 12 non-PHEX positive) resulted in at least one family member receiving family testing. Additional clinical or family member information resulted in variant(s) of uncertain significance (VUS) reclassification to pathogenic/likely pathogenic (P/LP) in 48 individuals, highlighting the importance of segregation and clinical data. In one of the largest XLH genetic studies to date, 65 novel PHEX variants were identified and a high XLH diagnostic yield demonstrated broad insight into the genetic basis of XLH. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Comparative mitogenome phylogeography of two anteater genera (Tamandua and Myrmecophaga; Myrmecophagidae, Xenarthra): Evidence of discrepant evolutionary traits.

The species within Xenarthra (sloths, anteaters, and armadillos) are quintessential South American mammals. Of the three groups, Vermilingua (anteaters) contains the fewest extant and paleontological species. Here, we sampled and sequenced the entire mitochondrial genomes (mitogenomes) of two Tamandua species (Tamandua tetradactyla and Tamandua mexicana) (n=74) from Central and South America, as well as Myrmecophaga tridactyla (n=41) from South America. Within Tamandua, we detected three different haplogroups. The oldest (THI) contained many specimens with the T. tetradactyla morphotype (but also several with the T. mexicana morphotype) and originated in southeastern South America (currently Uruguay) before moving towards northern South America, where the THII haplogroup originated. THII primarily contained specimens with the T. mexicana morphotype (but also several with the T. tetradactyla morphotype) and was distributed in Central America, Colombia, and Ecuador. THI and THII yielded a genetic distance of 4%. THII originated in either northern South America or "in situ" in Central America with haplogroup THIII, which consisted of ~50% T. mexicana and 50% T. tetradactyla phenotypes. THIII was mostly located in the same areas as THII, i.e., Central America, Ecuador, and Colombia, though mainly in the latter. The three haplogroups overlapped in Colombia and Ecuador. Thus, T. tetradactyla and T. mexicana were not reciprocally monophyletic. For this reason, we considered that a unique species of Tamandua likely exists, i.e., T. tetradactyla. In contrast to Tamandua, M. tridactyla did not show different morphotypes throughout its geographical range in the Neotropics. However, two very divergent genetic haplogroups (MHI and MHII), with a genetic distance of ~10%, were detected. The basal haplogroup, MHI, originated in northwestern South America, whereas the more geographically derived haplogroup, MHII, overlapped with MHI, but also expanded into central and southern South America. Thus, Tamandua migrated from south to north whereas Myrmecophaga migrated from north to south. Our results also showed that temporal mitochondrial diversification for Tamandua began during the Late Pliocene and Upper Pleistocene, but for Myrmecophaga began during the Late Miocene. Furthermore, both taxa showed elevated levels of mitochondrial genetic diversity. Tamandua showed more evidence of female population expansion than Myrmecophaga. Tamandua experienced population expansion ~0.6-0.17 million years ago (Mya), whereas Myrmecophaga showed possible population expansion ~0.3-0.2 Mya. However, both taxa experienced a conspicuous female decline in the last 10 000-20 000 years. Our results also showed little spatial genetic structure for both taxa. However, several analyses revealed higher spatial structure in Tamandua than in Myrmecophaga. Therefore, Tamandua and Myrmecophaga were not subjected to the same biogeographical, geological, or climatological events in shaping their genetic structures.

El Estigma Social Asociado a la Enfermedad de Chagas

Resumen Objetivos: identificar a partir de relatos individuales y familiares los componentes del estigma social asociado a un diagnóstico de Chagas positivo. Métodos: el estudio recopila los testimonios de tres familias a través de entrevistas a profundidad que fueron grabadas, cuyo contenido fue estructurado y luego compartido entre los investigadores a través de un proceso de triangulación. Resultados: se identificaron las diferentes formas de estigma social, experimentado, percibido, anticipado, así como el autoestigma, el estigma por asociación y comportamientos de discriminación; lo que conlleva el aislamiento social, refuerza los miedos tradicionalmente relacionados a esta enfermedad, y provoca tensiones intrafamiliares. El estigma social y el silencio que lo acompaña son serias barreras de acceso a la consulta médica y al tratamiento antiparasitario. Conclusiones: Es importante tomar en cuenta aspectos de tipo psico-socio-cultural en las estrategias de atención integral de Chagas, principalmente en los programas de información, educación, comunicación (IEC) y durante la consulta médica. Para romper el estigma y el silencio que lo acompaña, es indispensable integrar las personas afectadas por Chagas y otros actores de la sociedad civil en el diseño de esas estrategias.

Abstract Objectives: to identify the components of social stigma associated with a positive diagnosis of Chagas disease based on individual and family accounts. Methods: The study compiles the testimonies of 3 families through in-depth interviews that were recorded, the content of which was structured and then shared among the researchers through a process of triangulation. Results: different forms of social stigma, experienced, perceived, anticipated, as well as self-stigma, stigma by association and discriminatory behaviours were identified, leading to social isolation, reinforcing traditional fears associated with the disease, and causing intra-familial tensions. Social stigma and the silence that accompanies it are serious barriers to access to medical consultation and deworming treatment. Conclusions: It is important to take into account psycho-socio-cultural aspects in strategies for comprehensive care of Chagas disease, especially in information, education and communication (IEC) programmes and during the medical consultation. Also, to break the stigma and the silence surrounding it, it's essential to integrate people affected by Chagas and other civil society actors into the conception of these programs.

Implementación de un modelo de comunicación en Chagas basado en la estrategia de educación por pares / Implementation of a communication model in Chagas based on the peer education strategy

OBJETIVOS: el presente estudio evalúa el cambio en las perspectivas, conocimientos, actitudes y prácticas de los familiares de un grupo de pacientes capacitados con la estrategia de educación por pares que fueron tratados en la Plataforma de atención integral de Chagas, y si ese cambio se traduce en un aumento de la demanda de atención integral de Chagas en los servicios de salud del Valle Alto de Cochabamba. MÉTODOS: se comparó los resultados de la encuesta realizada en 32 familiares de 8 pacientes capacitados en 2018 (grupo A) con una encuesta similar realizada en 64 familiares de 16 pacientes tratados en 2017 (grupo B) que no fueron capacitados, pero en cambio recibieron la consejería que provee el personal de salud de forma rutinaria. RESULTADOS: los resultados obtenidos muestran que los familiares de pacientes educadores pares han modificado sus conocimientos, actitudes, prácticas y percepciones sobre la enfermedad de Chagas y este cambio ha influido positivamente la demanda de atención de servicios integrales para dicha enfermedad. CONCLUSIÓN: la estrategia de educación por pares ha demostrado ser eficaz, fácil de aplicar por un personal de enfermería en los 1º y 2º niveles de atención, y que permite llegar a las familias afectadas a un costo relativamente bajo.(AU)

OBJECTIVES: this study aims to identify changes in the perspectives, knowledges, attitudes and practices of the relatives of a group of patients treated in the Platform of integral care of Chagas, and trained as peer educators, and if that changes led to an increase of the Chagas demand in the health services of Valle Alto, in Cochabamba department. METHODS: we compared the results of the survey conducted on 32 relatives of 8 patients trained in 2018 (group A) with a similar survey conducted on 64 family members of 16 patients treated in 2017 (group B) who were not specifically trained, but received the counseling routinely provided by the health staff. RESULTS: the results show that relatives of peer educators have modified their knowledge, attitudes, practices and perceptions about Chagas disease and this change has influenced the demand for diagnosis of this disease. CONCLUSIONS: the strategy of peer education has proven to be effective, easy to apply by a nursing staff in the 1ª and 2ª levels of care, and allows reaching affected families at an affordable cost.(AU)

Conducta sexual y reproductiva durante la adolescencia de los estudiantes de la Universidad Mayor de San Simón / Sexual and reproductive behavior during adolescence of students of the San Simon University

OBJETIVOS: analizar los factores relacionados con la conducta sexual de riesgo, durante la adolescencia de los estudiantes de la Universidad Mayor de San Simón, gestión 2018. MÉTODOS: estudio retrospectivo, de cohorte, el muestreó fue no probabilístico con criterios de inclusión y exclusión. Se aplicó una encuesta auto administrada en cuatro sitios diferentes de la universidad. El análisis de los datos se realizó con el programa Epi-info v.7.2, empleando análisis uni y bivariado, como medidas de asociación OR, chi2 con un valor de p significante menor o igual a 0,05. RESULTADOS: la proporción de participantes que iniciaron su vida sexual activa durante la adolescencia fue del 50%, de estos el 31% no utiliza ningún método anticonceptivo y el 69% si utiliza algún método de anticoncepción, de los cuales el 46% prefiere utilizar el preservativo masculino o la píldora del día siguiente. Se encontró una relación significativa del inicio de vida sexual precoz (antes de los 16 años) con las variables: ser varón, provenir de una familia disfuncional, poco acceso a fuentes de información sobre sexualidad, consumo de sustancias psicoactivas antes de la relación sexual y el haber tenido una pareja sexual informal o casual. CONCLUSIÓN: una conducta sexual adecuada en el adolescente depende en gran medida de un entorno familiar funcional y del acceso adecuado a información sobre sexualidad y reproducción. La prevención de embarazos no deseados y de infecciones de transmisión sexual en adolescentes debe centrarse también en el entorno familiar y de la sociedad del adolescente.(AU)

OBJECTIVES: to analyze factors related to sexual risk behavior during the adolescence of students at the San Simón University, management 2018. METHODS: retrospective cohort study, sampling was non-probability with inclusion and exclusion criteria. A self-administered survey wasapplied in 4 different sites of the university. The analysis of the data was carried out with the program Epi-info v.7.2, using uni and bivariate analysis, as association measures OR, chi2 with a significant p value less than or equal to 0.05. RESULTS: the proportion of participants who began their active sexual life during adolescence was 50%, of whom 31% do not use any contraceptive method and 69% if they use any method of contraception, of whom 46% prefer to use the male condom or the morning-after pill. A significant relationship of early sexual debut (before age 16) was found with the variables: being male, coming from a dysfunctional family, little access to sources of information about sexuality, consumption of psychoactive substances before sexual intercourse, and having had an informal or casual sexual partner. CONCLUSIONS: adequate sexual behavior in the adolescent depends to a large extent on a functional family environment and adequate access to information on sexuality and reproduction. The prevention of unwanted pregnancies and sexually transmitted infections in adolescents must also focus on the adolescent's family environment and society.(AU)

Exogenous expression of the glycosyltransferase LARGE1 restores α-dystroglycan matriglycan and laminin binding in rhabdomyosarcoma.

BACKGROUND: α-Dystroglycan is the highly glycosylated component of the dystrophin-glycoprotein complex (DGC) that binds with high-affinity to extracellular matrix (ECM) proteins containing laminin-G-like (LG) domains via a unique heteropolysaccharide [-GlcA-beta1,3-Xyl-alpha1,3-]n called matriglycan. Changes in expression of components of the DGC or in the O-glycosylation of α-dystroglycan result in muscular dystrophy but are also observed in certain cancers. In mice, the loss of either of two DGC proteins, dystrophin or α-sarcoglycan, is associated with a high incidence of rhabdomyosarcoma (RMS). In addition, glycosylation of α-dystroglycan is aberrant in a small cohort of human patients with RMS. Since both the glycosylation of α-dystroglycan and its function as an ECM receptor require over 18 post-translational processing enzymes, we hypothesized that understanding its role in the pathogenesis of RMS requires a complete analysis of the expression of dystroglycan-modifying enzymes and the characterization of α-dystroglycan glycosylation in the context of RMS. METHODS: A series of cell lines and biopsy samples from human and mouse RMS were analyzed for the glycosylation status of α-dystroglycan and for expression of the genes encoding the responsible enzymes, in particular those required for the addition of matriglycan. Furthermore, the glycosyltransferase LARGE1 was ectopically expressed in RMS cells to determine its effects on matriglycan modifications and the ability of α-dystroglycan to function as a laminin receptor. RESULTS: Immunohistochemistry and immunoblotting of a collection of primary RMS tumors show that although α-dystroglycan is consistently expressed and glycosylated in these tumors, α-dystroglycan lacks matriglycan and the ability to bind laminin. Similarly, in a series of cell lines derived from human and mouse RMS, α-dystroglycan lacks matriglycan modification and the ability to bind laminin. RNAseq data from RMS cell lines was analyzed for expression of the genes known to be involved in α-dystroglycan glycosylation, which revealed that, for most cell lines, the lack of matriglycan can be attributed to the downregulation of the dystroglycan-modifying enzyme LARGE1. Ectopic expression of LARGE1 in these cell cultures restored matriglycan to levels comparable to those in muscle and restored high-affinity laminin binding to α-dystroglycan. CONCLUSIONS: Collectively, our findings demonstrate that a lack of matriglycan on α-dystroglycan is a common feature in RMS due to the downregulation of LARGE1, and that ectopic expression of LARGE1 can restore matriglycan modifications and the ability of α-dystroglycan to function as an ECM receptor.

Automated on-line monitoring of the TiO2-based photocatalytic degradation of dimethyl phthalate and diethyl phthalate.

A fully automated on-line system for monitoring the TiO2-based photocatalytic degradation of dimethyl phthalate (DMP) and diethyl phthalate (DEP) using sequential injection analysis (SIA) coupled to liquid chromatography (LC) with UV detection was proposed. The effects of the type of catalyst (sol-gel, Degussa P25 and Hombikat), the amount of catalyst (0.5, 1.0 and 1.5 g L-1), and the solution pH (4, 7 and 10) were evaluated through a three-level fractional factorial design (FFD) to verify the influence of the factors on the response variable (degradation efficiency, %). As a result of FFD evaluation, the main factor that influences the process is the type of catalyst. Degradation percentages close to 100% under UV-vis radiation were reached using the two commercial TiO2 materials, which present mixed phases (anatase/rutile), Degussa P25 (82%/18%) and Hombikat (76%/24%). 60% degradation was obtained using the laboratory-made pure anatase crystalline TiO2 phase. The pH and amount of catalyst showed minimum significant effect on the degradation efficiencies of DMP and DEP. Greater degradation efficiency was achieved using Degussa P25 at pH 10 with 1.5 g L-1 catalyst dosage. Under these conditions, complete degradation and 92% mineralization were achieved after 300 min of reaction. Additionally, a drastic decrease in the concentration of BOD5 and COD was observed, which results in significant enhancement of their biodegradability obtaining a BOD5/COD index of 0.66 after the photocatalytic treatment. The main intermediate products found were dimethyl 4-hydroxyphthalate, 4-hydroxy-diethyl phthalate, phthalic acid and phthalic anhydride indicating that the photocatalytic degradation pathway involved the hydrolysis reaction of the aliphatic chain and hydroxylation of the aromatic ring, obtaining products with lower toxicity than the initial molecules.

Layered-Expanded Mesostructured Silicas: Generalized Synthesis and Functionalization.

Mesostructured layered silicas have been prepared through a surfactant-assisted procedure using neutral alkylamines as templates and starting from atrane complexes as hydrolytic inorganic precursors. By adjusting the synthetic parameters, this kinetically controlled reproducible one-pot method allows for obtaining both pure and functionalized (inorganic or organically) lamellar silica frameworks. These are easily deconstructed and built up again, which provides a simple way for expanding the interlamellar space. The materials present high dispersibility, which results in stable colloidal suspensions.

Nanoparticle@Metal-Organic Frameworks as a Template for Hierarchical Porous Carbon Sponges.

The preparation of hierarchical porous carbon sponges (HCS) from metal oxide nanoparticle@metal-organic frameworks is reported. ZnO nanoparticles are partially converted to zeolitic imidazolate framework-8 (ZIF-8) crystals in presence of n-butylamine to obtain ZnO@ZIF-8 porous hybrids. After direct carbonization, followed by ZnO acidic etching, ZnO@ZIF-8 crystals were converted to submicrometric HCS. Due to the high surface area and accessible porosity, combining micro- and mesoporosity of HCS, their application for the extraction of water pollutants was studied by preparing HCS/polymer membranes, and showed a high efficiency for the fast (650 L m-2 h-1 ) removal of plastic degradation by-products (DBP, dibutyl phthalate. DEHP, bis(2-n-ethylhexyl)phthalate). DBP and DEHP breakthroughs were lower than 3 % after the filtration of 100 mL of water containing simultaneously both phthalates at a high concentration level (300 µg L-1 , each). HCS/polymer membranes were reusable up to 5 times, maintaining their extraction capacity, with relative errors of 6 % for DBP, and <1 % for DEHP.

Determination of phthalates in bottled water by automated on-line solid phase extraction coupled to liquid chromatography with uv detection.

An on-line solid phase extraction coupled to liquid chromatography with UV detection (SPE/LC-UV) method was automated by the multisyringe flow-injection analysis (MSFIA) system for the determination of three phthalic acid esters (PAEs). The PAEs determined in drinking water stored in polyethylene terephthalate (PET) bottles of ten commercial brands were dimethyl phthalate (DMP), diethyl phthalate (DEP) and dibutyl phthalate (DBP). C18-bonded silica membrane was used for isolation and enrichment of the PAEs in water samples. The calibration range of the SPE/LC-UV method was 2.5-100µgL-1 for DMP and DEP and 10-100µgL-1 for DBP with correlation coefficients (r) ranging from 0.9970 to 0.9975. Limits of detection (LODs) were between 0.7 and 2.4µgL-1. Inter-day reproducibility performed at two concentration levels (10 and 100µgL-1) expressed as relative standard deviation (%RSD) were found in the range of 0.9-4.0%. The solvent volume was reduced to 18mL with a total analysis time of 48min per sample. The major species detected in bottled water samples was DBP reaching concentrations between 20.5 and 82.8µgL-1. The recovery percentages for the three analytes in drinking water were 80-115%. The migration test showed a great variation in the sum of migrated PAEs level (10.2-50.6µgL-1) among the PET bottle brands analyzed indicating that the presence of these contaminants in the plastic containers may depend on raw materials and the conditions used during their production process.

Rapid diagnostic tests duo as alternative to conventional serological assays for conclusive Chagas disease diagnosis.

Chagas disease is caused by the parasite Trypanosoma cruzi. It affects several million people, mainly in Latin America, and severe cardiac and/or digestive complications occur in ~30% of the chronically infected patients. Disease acute stage is mostly asymptomatic and infection goes undiagnosed. In the chronic phase direct parasite detection is hampered due to its concealed presence and diagnosis is achieved by serological methods, like ELISA or indirect hemagglutination assays. Agreement in at least two tests must be obtained due to parasite wide antigenic variability. These techniques require equipped labs and trained personnel and are not available in distant regions. As a result, many infected people often remain undiagnosed until it is too late, as the two available chemotherapies show diminished efficacy in the advanced chronic stage. Easy-to-use rapid diagnostic tests have been developed to be implemented in remote areas as an alternative to conventional tests. They do not need electricity, nor cold chain, they can return results within an hour and some even work with whole blood as sample, like Chagas Stat-Pak (ChemBio Inc.) and Chagas Detect Plus (InBIOS Inc.). Nonetheless, in order to qualify a rapidly diagnosed positive patient for treatment, conventional serological confirmation is obligatory, which might risk its start. In this study two rapid tests based on distinct antigen sets were used in parallel as a way to obtain a fast and conclusive Chagas disease diagnosis using whole blood samples. Chagas Stat-Pak and Chagas Detect Plus were validated by comparison with three conventional tests yielding 100% sensitivity and 99.3% specificity over 342 patients seeking Chagas disease diagnosis in a reference centre in Sucre (Bolivia). Combined used of RDTs in distant regions could substitute laborious conventional serology, allowing immediate treatment and favouring better adhesion to it.

Role of dystroglycan in limiting contraction-induced injury to the sarcomeric cytoskeleton of mature skeletal muscle.

Dystroglycan (DG) is a highly expressed extracellular matrix receptor that is linked to the cytoskeleton in skeletal muscle. DG is critical for the function of skeletal muscle, and muscle with primary defects in the expression and/or function of DG throughout development has many pathological features and a severe muscular dystrophy phenotype. In addition, reduction in DG at the sarcolemma is a common feature in muscle biopsies from patients with various types of muscular dystrophy. However, the consequence of disrupting DG in mature muscle is not known. Here, we investigated muscles of transgenic mice several months after genetic knockdown of DG at maturity. In our study, an increase in susceptibility to contraction-induced injury was the first pathological feature observed after the levels of DG at the sarcolemma were reduced. The contraction-induced injury was not accompanied by increased necrosis, excitation-contraction uncoupling, or fragility of the sarcolemma. Rather, disruption of the sarcomeric cytoskeleton was evident as reduced passive tension and decreased titin immunostaining. These results reveal a role for DG in maintaining the stability of the sarcomeric cytoskeleton during contraction and provide mechanistic insight into the cause of the reduction in strength that occurs in muscular dystrophy after lengthening contractions.

Clinical Genetic Testing for the Cardiomyopathies and Arrhythmias: A Systematic Framework for Establishing Clinical Validity and Addressing Genotypic and Phenotypic Heterogeneity.

Advances in DNA sequencing have made large, diagnostic gene panels affordable and efficient. Broad adoption of such panels has begun to deliver on the promises of personalized medicine, but has also brought new challenges such as the presence of unexpected results, or results of uncertain clinical significance. Genetic analysis of inherited cardiac conditions is particularly challenging due to the extensive genetic heterogeneity underlying cardiac phenotypes, and the overlapping, variable, and incompletely penetrant nature of their clinical presentations. The design of effective diagnostic tests and the effective use of the results depend on a clear understanding of the relationship between each gene and each considered condition. To address these issues, we developed simple, systematic approaches to three fundamental challenges: (1) evaluating the strength of the evidence suggesting that a particular condition is caused by pathogenic variants in a particular gene, (2) evaluating whether unusual genotype/phenotype observations represent a plausible expansion of clinical phenotype associated with a gene, and (3) establishing a molecular diagnostic strategy to capture overlapping clinical presentations. These approaches focus on the systematic evaluation of the pathogenicity of variants identified in clinically affected individuals, and the natural history of disease in those individuals. Here, we applied these approaches to the evaluation of more than 100 genes reported to be associated with inherited cardiomyopathies and arrhythmias including hypertrophic cardiomyopathy, dilated cardiomyopathy, arrhythmogenic right ventricular dysplasia or cardiomyopathy, long QT syndrome, short QT syndrome, Brugada, and catecholaminergic polymorphic ventricular tachycardia, and to a set of related syndromes such as Noonan Syndrome and Fabry disease. These approaches provide a framework for delivering meaningful and accurate genetic test results to individuals with hereditary cardiac conditions.

Prevalence of Chagas heart disease in a region endemic for Trypanosoma cruzi: evidence from a central Bolivian community.

BACKGROUND: Though the incidence of new Trypanosoma cruzi infections has decreased significantly in endemic regions in the Americas, medical professionals continue to encounter a high burden of resulting Chagas disease among infected adults. The current prevalence of Chagas heart disease in a community setting is not known; nor is it known how recent insecticide vector control measures may have impacted the progression of cardiac disease in an infected population. OBJECTIVES: We sought to determine the current prevalence of T. cruzi infection and associated Chagas heart disease in a Bolivian community endemic for T. cruzi. METHODS: Nested within a community serosurvey in rural and periurban communities in central Bolivia, we performed a cross-sectional cardiac substudy to evaluate adults for historical, clinical, and electrocardiographic evidence of cardiac disease. All adults between the ages of 20 and 60 years old with T. cruzi infection and those with a clinical history, physical exam, or electrocardiogram consistent with cardiac abnormalities were also scheduled for echocardiography. RESULTS: Of the 604 cardiac substudy participants with definitive serology results, 183 were seropositive for infection with T. cruzi (30.3%). Participants who were seropositive for T. cruzi infection were more likely to have conduction system defects (1.6% vs. 0% for complete right bundle branch block and 10.4% vs. 1.9% for any bundle branch block; p = 0.008 and p < 0.001, respectively). However, there was no statistically significant difference in the prevalence of bradycardia among seropositive versus seronegative participants. Echocardiogram findings were not consistent with a high burden of Chagas cardiomyopathy: valvulopathies were the most common abnormality, and few participants were found to have low ejection fraction or left ventricular dilatation. No participants had significant heart failure. CONCLUSIONS: Though almost one-third of adults in the community were seropositive for T. cruzi infection, few had evidence of Chagas heart disease.