Intervención de la telemedicina en pacientes peruanos con insuficiencia cardíaca en tiempos de COVID-19 / Telemedicine Intervention in Peruvian Patients with Heart Failure in Times of COVID-19

Introducción: La insuficiencia cardíaca tiene un gran impacto epidemiológico, no solo por su alta morbilidad y mortalidad, sino también por el alto costo en servicios hospitalarios. Las tasas de hospitalización por reagudizaciones y readmisiones luego del alta se han incrementado los últimos años, lo que constituye en la actualidad un problema de salud pública. Objetivo: Evaluar el efecto de la intervención de la telemedicina en pacientes peruanos con insuficiencia cardíaca en tiempos de COVID-19. Métodos: Se utilizó un diseño cuasi experimental con evaluación antes y después de la intervención en 32 pacientes provenientes de Chimbote (Perú), entre los meses de enero a junio del 2021, que aceptaron participar en el estudio y cumplieron con los criterios de inclusión y exclusión. Se utilizó una ficha de recolección de datos que registró las características clínicas de los pacientes, frecuencia de hospitalización y clase funcional, así como el cuestionario de Kansas City que midió la calidad de vida relacionada a salud. En la intervención, se implementaron actividades de telemedicina que comprendió teleconsulta médica de cardiología, telemonitoreo y teleorientación de enfermería, y teleorientación de nutrición. Resultados: Se redujo la frecuencia de hospitalización de 9,4 por ciento a 0 por ciento en los pacientes categorizados en clase funcional III disminuyó de 28,1 por ciento a 15,6 por ciento, y el score general se mejoró de 65,8 a 69,6 puntos. Conclusiones: La intervención de la telemedicina mejoró los resultados sanitarios de los pacientes peruanos con insuficiencia cardíaca(AU)

Introduction: Heart failure has a great epidemiological impact, not only because of its high morbidity and mortality, but also because of the high cost in hospital services. Hospitalization rates for exacerbations and readmissions after discharge have increased in recent years, which is currently a public health problem. Objective: To evaluate the effect of telemedicine intervention in Peruvian patients with heart failure in COVID-19 times. Methods: A quasi-experimental design was used with evaluation before and after the intervention in 32 patients from Chimbote (Peru), between January and June 2021, who agreed to participate in the study and met the inclusion and exclusion criteria. A data collection form was used to record the clinical characteristics of the patients, frequency of hospitalization and functional class, as well as the Kansas City questionnaire that measured health-related quality of life. Telemedicine activities were implemented in the intervention, including cardiology medical teleconsultation, telemonitoring and nursing tele-guidance, and nutrition tele-guidance. Results: The frequency of hospitalization was reduced from 9.4 to 0 percent, while in patients categorized in functional class III it decreased from 28.1 to 15.6 percent. The overall score was improved from 65.8 to 69.6 points. Conclusions: The telemedicine intervention improved health outcomes in Peruvian patients with heart failure(AU)

LC-MS/MS method for the quantitation of a dual PI3K/BRD4 inhibitor SF2523 in mouse plasma: Application to plasma protein binding and metabolism studies.

A sensitive and selective liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) method was developed and validated for the quantitation of dual PI3K/BRD4 inhibitor SF2523 in mouse plasma. The analysis was performed on a UPLC system connected to a Shimadzu 8060 mass spectrometer by electrospray ionization in positive multiple reaction monitoring mode. Chromatographic separation was carried out on an ACE Excel C18 column with a gradient elution containing 0.1% formic acid and methanol as the mobile phase. The linearity was conducted in the concentration range 0.1-500 ng/ml for SF2523 in 100 µl of plasma. The inter- and intra-batch precision (RSD) were both lower than 13.5%, with the accuracy (percentage bias) ranging from -10.03 to 11.56%. The validated method was successfully applied to plasma protein binding and in vitro metabolism studies. SF2523 was highly bound to mouse plasma proteins (>95% bound). Utilizing mouse S9 fractions, a total of seven phase I and II metabolites were identified with hydroxylation found to be the major metabolic pathway. Metabolite identification included analysis of retention behaviors, molecular weight changes and MS/MS fragment patterns of SF2523 and the metabolites. This newly developed and validated method allows the rapid and easy determination of the SF2523 concentration with high sensitivity in a low sample volume and can be applied to future pre-clinical studies.

Quasiuniversal scaling in mouse-brain neuronal activity stems from edge-of-instability critical dynamics.

The brain is in a state of perpetual reverberant neural activity, even in the absence of specific tasks or stimuli. Shedding light on the origin and functional significance of such a dynamical state is essential to understanding how the brain transmits, processes, and stores information. An inspiring, albeit controversial, conjecture proposes that some statistical characteristics of empirically observed neuronal activity can be understood by assuming that brain networks operate in a dynamical regime with features, including the emergence of scale invariance, resembling those seen typically near phase transitions. Here, we present a data-driven analysis based on simultaneous high-throughput recordings of the activity of thousands of individual neurons in various regions of the mouse brain. To analyze these data, we construct a unified theoretical framework that synergistically combines a phenomenological renormalization group approach and techniques that infer the general dynamical state of a neural population, while designing complementary tools. This strategy allows us to uncover strong signatures of scale invariance that are "quasiuniversal" across brain regions and experiments, revealing that all the analyzed areas operate, to a greater or lesser extent, near the edge of instability.

A Latin American consensus meeting on the essentials of mixed pain.

OBJECTIVES: The term "mixed pain" has been established when a mixture of different pain components (e.g. nociceptive, neuropathic, and nociplastic) are present. It has gained more and more acceptance amongst pain experts worldwide, but many questions around the concept of mixed pain are still unsolved. The sensation of pain is very personal. Cultural, social, personal experiences, idiomatic, and taxonomic differences should be taken into account during pain assessment. Therefore, a Latin American consensus committee was formed to further elaborate the essentials of mixed pain, focusing on the specific characteristics of the Latin American population. METHODS: The current approach was based on a systematic literature search and review carried out in Medline. Eight topics about the definition, diagnosis, and treatment of mixed pain were discussed and voted for by a Latin American consensus committee and recommendations were expressed. RESULTS: At the end of the meeting a total of 14 voting sheets were collected. The full consensus was obtained for 21 of 25 recommendations (15 strong agreement and 6 unanimous agreement) formulated for the above described 8 topics (7 of the 8 topics had for all questions at least a strong agreement - 1 topic had no agreement for all 4 questions). CONCLUSION: In a subject as complex as mixed pain, a consensus has been reached among Latin American specialists on points related to the definition and essence of this pain, its diagnosis and treatment. Recommendations for diagnosis and treatment of mixed pain in Latin America were raised.

Prevalence of obesity, diabetes and hypertension in immigrant populations in northeastern Mexico.

Introduction: Hispanic immigrants are a fast-growing population in the United States of America (USA) that disproportionately suffer from chronic diseases. Despite the increasing prevalence of obesity in Latin-American countries, only a few studies have examined the onset of chronic diseases in Mexican and Central American migrants in Mexico. Objective: The objective of this study is to determine the prevalence of obesity, diabetes, and hypertension in Central American immigrants who are in the process of traveling through northeastern Mexico to the United States. Methods: An observational, descriptive, cross-sectional study was conducted among migrants, mostly Central Americans. Migrants who agreed to participate in the study were interviewed face-to-face by researchers to obtain their sociodemographic data. To obtain the prevalence, many health indicators related to obesity, diabetes, and hypertension, including weight, height, fasting glucose, and blood pressure, were measured. Results: In total, 520 migrants were interviewed; sociodemographic data indicated that most participants were men (76%), from Honduras (72.6%), single (61.2%), and have elementary level of education (48.6%). The somatometric evaluation revealed that 28.9% were diagnosed as overweight, 10.7% with obesity, and 3.3% with malnutrition. Of less prevalence, 8.8% were detected with hypertension and 4.6% had fasting hyperglycemia. The mean participant age was 29.11 ± 10.00 years. For each participant, the average weight was 66.72 ± 13.09 kg; the average height was 1.64 ± 0.08 m; the average body mass index (BMI) was 24.59 ± 4.32; the mean systolic and diastolic pressures were 116.26 ± 15.13 and 74 ± 9.65, respectively; and the average glycemia was 100.97 ± 21.99. El Salvador showed the highest proportion of people with diabetes (14.7%). Women who participated in this study had a higher proportion of obesity (23.4%, p = 0.02) and overweight (36.2%) than men (8.4 and 29.2%, respectively). People from Mexico, Nicaragua, and Honduras reported a high prevalence of overweight participants (63.6, 47.4, and 30.7%, respectively), while people from El Salvador and Nicaragua had a high prevalence of obese participants (23.5 and 21.1%, respectively). Conclusion: We found significant differences in the rates of obesity, diabetes, and hypertension between groups of Central American migrants and their place of origin, age, educational level, and gender. Our findings highlight the importance of exploring differences within groups of Central American migrants traveling through northeastern Mexico to the United States, which may explain several health indicators.

Update on Pediatric Sepsis in Mexico.

The main objective of this work was to determine and update the causal agents' antibiotic sensitivity and resistance patterns on pediatric sepsis in a population of northeast Mexico. It is a cross-sectional study showing the results of blood cultures of pediatric patients with a presumptive diagnosis of sepsis were reviewed according to the SOFA criteria during 2020 in a public hospital in Mexico. A total of 207 blood cultures were performed and analyzed. The main isolated microorganisms were Staphylococcus, followed by Klebsiella and Escherichia. Several microorganisms showed 100% of sensitivity to different antibiotics or antifungals, some of them include Vancomycin, Voriconazole, Meropenem, Ciprofloxacin, and Cefotaxime. Bacteria of genre Staphylococcus showed its highest sensitivity rate to Tigecycline with 63.3%. Too Staphylococcus showed the highest resistance rate to Oxacillin with 50%. Although the patterns of sepsis-causing germs are similar to those previously reported, the development of new drugs with greater efficacy is the main contribution.

The BTK/PI3K/BRD4 axis inhibitor SRX3262 overcomes Ibrutinib resistance in mantle cell lymphoma.

Mantle cell lymphoma (MCL) is an aggressive subtype of non-Hodgkin's lymphoma and one of the most challenging blood cancers to combat due to frequent relapse after treatment. Here, we developed the first-in-class BTK/PI3K/BRD4 axis inhibitor SRX3262, which simultaneously blocks three interrelated MCL driver pathways - BTK, PI3K-AKT-mTOR and MYC. SRX3262 concomitantly binds to BTK, PI3K, and BRD4, exhibits potent in vitro and in vivo activity against MCL, and overcomes the Ibrutinib resistance resulting from the BTK-C481S mutation. Our results reveal that SRX3262 inhibits IgM-induced BTK and AKT phosphorylation and abrogates binding of BRD4 to MYC loci. SRX3262 promotes c-MYC destabilization, induces cell cycle arrest and apoptosis, and shows antitumor activity in in vivo xenograft models. Together, our study provides mechanistic insights and rationale for the use of the triple BTK/PI3K/BRD4 activity inhibitors as a new approach to treat MCL.

Optimal Input Representation in Neural Systems at the Edge of Chaos.

Shedding light on how biological systems represent, process and store information in noisy environments is a key and challenging goal. A stimulating, though controversial, hypothesis poses that operating in dynamical regimes near the edge of a phase transition, i.e., at criticality or the "edge of chaos", can provide information-processing living systems with important operational advantages, creating, e.g., an optimal trade-off between robustness and flexibility. Here, we elaborate on a recent theoretical result, which establishes that the spectrum of covariance matrices of neural networks representing complex inputs in a robust way needs to decay as a power-law of the rank, with an exponent close to unity, a result that has been indeed experimentally verified in neurons of the mouse visual cortex. Aimed at understanding and mimicking these results, we construct an artificial neural network and train it to classify images. We find that the best performance in such a task is obtained when the network operates near the critical point, at which the eigenspectrum of the covariance matrix follows the very same statistics as actual neurons do. Thus, we conclude that operating near criticality can also have-besides the usually alleged virtues-the advantage of allowing for flexible, robust and efficient input representations.

Immune amnesia induced by measles and its effects on concurrent epidemics.

It has been recently discovered that the measles virus can damage pre-existing immunological memory, destroying B lymphocytes and reducing the diversity of non-specific B cells of the infected host. In particular, this implies that previously acquired immunization from vaccination or direct exposition to other pathogens could be partially erased in a phenomenon named 'immune amnesia', whose effects can become particularly worrisome given the actual rise of anti-vaccination movements. Here, we present the first attempt to incorporate immune amnesia into standard models of epidemic spreading by proposing a simple model for the spreading of two concurrent pathogens causing measles and another generic disease. Different analyses confirm that immune amnesia can have important consequences for epidemic spreading, significantly altering the vaccination coverage required to reach herd immunity. We also uncover the existence of novel propagating and endemic phases induced by immune amnesia. Finally, we discuss the meaning and consequences of our results and their relation with, e.g. immunization strategies, together with the possibility that explosive types of transitions may emerge, making immune-amnesia effects particularly dramatic. This work opens the door to further developments and analyses of immune-amnesia effects, contributing also to the theory of interacting epidemics on complex networks.

Blockade of SARS-CoV-2 infection in vitro by highly potent PI3K-α/mTOR/BRD4 inhibitor.

Pathogenic viruses like SARS-CoV-2 and HIV hijack the host molecular machinery to establish infection and survival in infected cells. This has led the scientific community to explore the molecular mechanisms by which SARS-CoV-2 infects host cells, establishes productive infection, and causes life-threatening pathophysiology. Very few targeted therapeutics for COVID-19 currently exist, such as remdesivir. Recently, a proteomic approach explored the interactions of 26 of 29 SARS-CoV-2 proteins with cellular targets in human cells and identified 67 interactions as potential targets for drug development. Two of the critical targets, the bromodomain and extra-terminal domain proteins (BETs): BRD2/BRD4 and mTOR, are inhibited by the dual inhibitory small molecule SF2523 at nanomolar potency. SF2523 is the only known mTOR PI3K-α/(BRD2/BRD4) inhibitor with potential to block two orthogonal pathways necessary for SARS-CoV-2 pathogenesis in human cells. Our results demonstrate that SF2523 effectively blocks SARS-CoV-2 replication in lung bronchial epithelial cells in vitro , showing an IC 50 value of 1.5 µM, comparable to IC 50 value of remdesivir (1.1 µM). Further, we demonstrated that the combination of doses of SF2523 and remdesivir is highly synergistic: it allows for the reduction of doses of SF2523 and remdesivir by 25-fold and 4-fold, respectively, to achieve the same potency observed for a single inhibitor. Because SF2523 inhibits two SARS-CoV-2 driven pathogenesis mechanisms involving BRD2/BRD4 and mTOR signaling, our data suggest that SF2523 alone or in combination with remdesivir could be a novel and efficient therapeutic strategy to block SARS-CoV-2 infection and hence be beneficial in preventing severe COVID-19 disease evolution. ONE SENTENCE SUMMARY: Evidence of in silico designed chemotype (SF2523) targeting PI3K-α/mTOR/BRD4 inhibits SARS-CoV-2 infection and is highly synergistic with remdesivir.

Anti-inflammatory and antiviral roles of hydrogen sulfide: Rationale for considering H2 S donors in COVID-19 therapy.

The COVID-19 pandemic caused by SARS-Cov-2 demands rapid, safe and effective therapeutic options. In the last decades, the endogenous gasotransmitter hydrogen sulfide (H2 S) has emerged as modulator of several biological functions and its deficiency has been associated with different disorders. Therefore, many H2 S-releasing agents have been developed as potential therapeutic tools for diseases related with impaired H2 S production and/or activity. Some of these compounds are in advanced clinical trials. Presently, the pivotal role of H2 S in modulating the inflammatory response and pro-inflammatory cytokine cascade is well recognized, and the usefulness of some H2 S-donors for the treatment of acute lung inflammation has been reported. Recent data is elucidating several mechanisms of action, which may account for antiviral effects of H2 S. Noteworthy, some preliminary clinical results suggest an inverse relationship between endogenous H2 S levels and severity of COVID-19. Therefore, repurposing of H2 S-releasing drugs may be a potential therapeutic opportunity for treatment of COVID-19. LINKED ARTICLES: This article is part of a themed issue on The Pharmacology of COVID-19. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.21/issuetoc.

Design of thienopyranone-based BET inhibitors that bind multiple synthetic lethality targets.

Development of small molecule compounds that target several cancer drivers has shown great therapeutic potential. Here, we developed a new generation of highly potent thienopyranone (TP)-based inhibitors for the BET bromodomains (BDs) of the transcriptional regulator BRD4 that have the ability to simultaneously bind to phosphatidylinositol-3 kinase (PI3K) and/or cyclin-dependent kinases 4/6 (CDK4/6). Analysis of the crystal structures of the complexes, NMR titration experiments and IC50 measurements reveal the molecular basis underlying the inhibitory effects and selectivity of these compounds toward BDs of BRD4. The inhibitors show robust cytotoxic effects in multiple cancer cell lines and induce cell-cycle arrest and apoptosis. We further demonstrate that concurrent disruption of the acetyllysine binding function of BRD4 and the kinase activities of PI3K and CDK4/6 by the TP inhibitor improves efficacy in several cancer models. Together, these findings provide further compelling evidence that these multi-action inhibitors are efficacious and more potent than single inhibitory chemotypes.

Effect of rituximab on disease activity in latin American patients with anti-aquaporin-4 (+) neuromyelitis optica spectrum disorder.

OBJECTIVES: The aim of the present study is to explore the efficacy of rituximab in patients with Neuromyelitis Optica spectrum disorders (NMOsd) with positive AQP4-IgG serostatus. PATIENTS AND METHODS: In this single center retrospective study, we recruited seropositive anti-AQP4 NMOsd patients who received treatment with Rituximab (RTX) for at least 2 years. Demographics were described and annualized relapse rate (AAR) and survival analysis were performed for time to relapse with Rituximab. All p values ≤0.05 we considered statistically significant. RESULTS: A total of 15 patients (100 % female) were identified. Mean age of disease onset was 34 ±â€¯11 years, mean time of disease was 8.11 ±â€¯4.04 years and the median number of relapses was 5 (2-16). Ten patients received an immunosuppressive agent before RTX. Mean age of RTX initiation was 37 ±â€¯12 with a mean treatment duration of 52 ±â€¯28 months. The median ARR before and after treatment with RTX was 2.08 vs 0.00, respectively, with a difference of -2.08 (p < 0.001) CONCLUSIONS: This study shows a statistically significant reduction in the ARR and an increase in the relapse-free rate in AQP4-IgG NMOsd patients treated with RTX. These findings support the use of rituximab in our population, and indirectly suggests that its prompt use could modify the course of the disease.

SG1002 and Catenated Divalent Organic Sulfur Compounds as Promising Hydrogen Sulfide Prodrugs.

Significance: Sulfur has a critical role in protein structure/function and redox status/signaling in all living organisms. Although hydrogen sulfide (H2S) and sulfane sulfur (SS) are now recognized as central players in physiology and pathophysiology, the full scope and depth of sulfur metabolome's impact on human health and healthy longevity has been vastly underestimated and is only starting to be grasped. Since many pathological conditions have been related to abnormally low levels of H2S/SS in blood and/or tissues, and are amenable to treatment by H2S supplementation, development of safe and efficacious H2S donors deserves to be undertaken with a sense of urgency; these prodrugs also hold the promise of becoming widely used for disease prevention and as antiaging agents. Recent Advances: Supramolecular tuning of the properties of well-known molecules comprising chains of sulfur atoms (diallyl trisulfide [DATS], S8) was shown to lead to improved donors such as DATS-loaded polymeric nanoparticles and SG1002. Encouraging results in animal models have been obtained with SG1002 in heart failure, atherosclerosis, ischemic damage, and Duchenne muscular dystrophy; with TC-2153 in Alzheimer's disease, schizophrenia, age-related memory decline, fragile X syndrome, and cocaine addiction; and with DATS in brain, colon, gastric, and breast cancer. Critical Issues: Mode-of-action studies on allyl polysulfides, benzyl polysulfides, ajoene, and 12 ring-substituted organic disulfides and thiosulfonates led several groups of researchers to conclude that the anticancer effect of these compounds is not mediated by H2S and is only modulated by reactive oxygen species, and that their central model of action is selective protein S-thiolation. Future Directions: SG1002 is likely to emerge as the H2S donor of choice for acquiring knowledge on this gasotransmitter's effects in animal models, on account of its unique ability to efficiently generate H2S without byproducts and in a slow and sustained mode that is dose independent and enzyme independent. Efficient tuning of H2S donation characteristics of DATS, dibenzyl trisulfide, and other hydrophobic H2S prodrugs for both oral and parenteral administration will be achieved not only by conventional structural modification of a lead molecule but also through the new "supramolecular tuning" paradigm.