The Cloning and Characterization of a Three-Finger Toxin Homolog (NXH8) from the Coralsnake Micrurus corallinus That Interacts with Skeletal Muscle Nicotinic Acetylcholine Receptors.

Coralsnakes (Micrurus spp.) are the only elapids found throughout the Americas. They are recognized for their highly neurotoxic venom, which is comprised of a wide variety of toxins, including the stable, low-mass toxins known as three-finger toxins (3FTx). Due to difficulties in venom extraction and availability, research on coralsnake venoms is still very limited when compared to that of other Elapidae snakes like cobras, kraits, and mambas. In this study, two previously described 3FTx from the venom of M. corallinus, NXH1 (3SOC1_MICCO), and NXH8 (3NO48_MICCO) were characterized. Using in silico, in vitro, and ex vivo experiments, the biological activities of these toxins were predicted and evaluated. The results showed that only NXH8 was capable of binding to skeletal muscle cells and modulating the activity of nAChRs in nerve-diaphragm preparations. These effects were antagonized by anti-rNXH8 or antielapidic sera. Sequence analysis revealed that the NXH1 toxin possesses eight cysteine residues and four disulfide bonds, while the NXH8 toxin has a primary structure similar to that of non-conventional 3FTx, with an additional disulfide bond on the first loop. These findings add more information related to the structural diversity present within the 3FTx class, while expanding our understanding of the mechanisms of the toxicity of this coralsnake venom and opening new perspectives for developing more effective therapeutic interventions.

Engineering Metal Halide Perovskite Nanocrystals with BODIPY Dyes for Photosensitization and Photocatalytic Applications.

The sensitization of surface-anchored organic dyes on semiconductor nanocrystals through energy transfer mechanisms has received increasing attention owing to their potential applications in photodynamic therapy, photocatalysis, and photon upconversion. Here, we investigate the sensitization mechanisms through visible-light excitation of two nanohybrids based on CsPbBr3 perovskite nanocrystals (NC) functionalized with borondipyrromethene (BODIPY) dyes, specifically 8-(4-carboxyphenyl)-1,3,5,7-tetramethyl-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (BDP) and 8-(4-carboxyphenyl)-2,6-diiodo-1,3,5,7-tetramethyl-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (I2-BDP), named as NC@BDP and NC@I2-BDP, respectively. The ability of I2-BDP dyes to extract hot hole carriers from the perovskite nanocrystals is comprehensively investigated by combining steady-state and time-resolved fluorescence as well as femtosecond transient absorption spectroscopy with spectroelectrochemistry and quantum chemical theoretical calculations, which together provide a complete overview of the phenomena that take place in the nanohybrid. Förster resonance energy transfer (FRET) dominates (82%) the photosensitization of the singlet excited state of BDP in the NC@BDP nanohybrid with a rate constant of 3.8 ± 0.2 × 1010 s-1, while charge transfer (64%) mediated by an ultrafast charge transfer rate constant of 1.00 ± 0.08 × 1012 s-1 from hot states and hole transfer from the band edge is found to be mainly responsible for the photosensitization of the triplet excited state of I2-BDP in the NC@I2-BDP nanohybrid. These findings suggest that the NC@I2-BDP nanohybrid is a unique energy transfer photocatalyst for oxidizing α-terpinene to ascaridole through singlet oxygen formation.

Post-treatment with maropitant reduces oxidative stress, endoplasmic reticulum stress and neuroinflammation on peripheral nerve injury in rats.

OBJECTIVE: To determine the effective dose and therapeutic potential of maropitant using through expression of mediators of oxidative stress, inflammatory and of the unfolded protein response (UPR) (bio) markers on spinal cord using a model of neuropathic pain induced through chronic constriction injury (CCI) in rats. STUDY DESIGN: Randomized, blinded, prospective experimental study. ANIMALS: 98 male Wistar rats. METHODS: Rats were anesthetized with sevoflurane and after CCI, they were randomly assigned to the following groups that received: vehicle, 3, 6, 15, 30 e 50 mg/kg/24q of maropitant. The effect on inflammatory mediators (IL10, TNFα), oxidative stress (GPx, CAT, SOD), microglial (IBA-1) and neuronal (NeuN, TACR1) markers was evaluated though immunohistochemistry and expression levels of markers of hypoxia (HIF1α, Nrf2), antioxidant enzymes (Catalse, Sod1 and GPx1), and endoplasmic reticulum stress mediators (GRP78, CHOP and PERK) through qRT-PCR. RESULTS: Intraperitoneal injection (IP) of maropitant inhibited nociception with ID50 values of 4,1 mg/kg (5,85-19,36) in a neuropathic pain model through CCI. A dose of 30 mg/kg/24q was significantly effective in reducing mechanical allodynia 1 to 4h after treatment with nociception inhibition (145,83%). A reduction in the expression of hypoxia factors (HIF1α, Nrf2) was observed, along with an increase in antioxidant activity (CAT, SOD and GPX). Additionally, there was a reduction in inflammatory markes (IL10, TNFα), microglial (IBA-1), and neuronal markers (NeuN, TACR1). CONCLUSION AND CLINICAL RELEVANCE: These findings demonstrate that the determined dose, administered daily for seven days, had an antinociceptive effect, as well as anti-inflammatory and antioxidant activity.

Navigating the Indeterminate Zone: Surgeons' Decision-Making Factors in Treating Vertebral Metastases with Spinal Instability Scores of 7-12.

BACKGROUND: The Spinal Instability Neoplastic Score (SINS) classification system is a validated and the most widely accepted instrument for defining instability in vertebral metastasis (VM), in which lesions scoring between 7 and 12 are defined as indeterminate and the treatment is controversial. This study aimed to determine which variables more frequently are considered by spine surgeons for choosing between the conservative and the surgical treatment of VMs among patients with an indeterminate SINS. METHODS: A single-round online survey was conducted with 10 spine surgeons with expertise in the management of VMs from our AO Spine Region. In this survey, each surgeon independently reviewed demographic and cancer-related variables of 36 real-life cases of patients with vertebral metastases scored between 7 and 12 in the SINS. Bivariate and multivariate analyses were performed to identify significant SINS and non-SINS variables influencing the decision-making on surgical treatment. RESULTS: The most commonly variables considered important were the SINS element "mechanical pain", rated important for 44.4% of the cases, "lesion type" for 36.1%, and "degree of vertebral collapse" and the non-SINS factor "tumor histology" rated for 13.9% of cases. By far the factor most commonly rated unimportant was "posterior element compromise" (in 72.2% of cases). CONCLUSIONS: Surgeons relied on mechanical pain and type of metastatic lesion for treatment choices. Vertebral collapse, spinal malalignment, and mobility were less influential. Spinal mobility was a predictor of surgical versus non-surgical treatment. The only variables not identified either by surgeons themselves or as a predictor of surgery selection was the presence/degree of posterolateral/posterior element involvement.

Factors Associated With Long Survival in Patients With Cancer Admitted to Palliative Care: An Exploratory Study.

Objective: Some patients with cancer admitted to palliative care have relatively long survivals of 1 year or more. The objective of this study was to find out factors associated with prolonged survival. Methods: Retrospective case-control study comparing the available data of patients with cancer who survived more than 1 year after admission in a palliative care service with patients with cancer who survived 6 months or less. The intended proportion was 4 controls for each case. Patients were identified through electronic records from 2012 until 2018. Results: And 1721 patients were identified. Of those patients, 111 (6.4%) survived for at least 1 year, and 363 (21.1%) were included as controls according to the established criteria. The intended proportion could not be reached; the proportion was only 3.3:1. The median survival of cases was 581 days (range: 371-2763), and the median survival of controls was 57 days (range: 1-182). In the multivariable analysis, patients with a hemoglobin ≥ 10.6 g/dL and a creatinine level >95 µmol/L had a higher probability of living more than 1 year. In contrast, patients with abnormal cognition, pain, anorexia, liver metastases, an Eastern Cooperative Oncology Group performance status >1, and a neutrophil/lymphocyte ratio ≥ 3.43 had a low probability of living more than 1 year. Conclusion: Several factors were statistically associated positively or negatively with prolonged survival. However, the data of this study should be confirmed in other studies.

Influence of Crystallographic Structure and Metal Vacancies on the Oxygen Evolution Reaction Performance of Ni-based Layered Hydroxides.

Nickel-based layered hydroxides (LHs) are a family of efficient electrocatalysts for the alkaline oxygen evolution reaction (OER). Nevertheless, fundamental aspects such as the influence of the crystalline structure and the role of lattice distortion of the catalytic sites remain poorly understood and typically muddled. Herein, we carried out a comprehensive investigation on ɑ-LH, ß-LH and layered double hydroxide (LDH) phases by means of structural, spectroscopical, in-silico and electrochemical studies, which suggest the key aspect exerted by Ni-vacancies in the ɑ-LH structure. Density functional theory (DFT) calculations and X-ray absorption spectroscopy (XAS) confirm that the presence of Ni-vacancies produces acute distortions of the electroactive Ni sites (reflected as the shortening of the Ni-O distances and changes in the O-Ni-O angles), triggering the appearance of Ni localised electronic states on the Fermi level, reducing the Egap, and consequently, increasing the reactivity of the electroactive sites in the ɑ-LH structure. Furthermore, post-mortem Raman and XAS measurements unveil its transformation into a highly reactive oxyhydroxide-like phase that remains stable under ambient conditions. Hence, this work pinpoints the critical role of the crystalline structure as well as the electronic properties of LH structures on their inherent electrochemical reactivity towards OER catalysis. We envision Ni-based ɑ-LH as a perfect platform for hosting trivalent cations, closing the gap toward the next generation of benchmark efficient earth-abundant electrocatalysts.

Preemptive kidney transplantation: why, when, and how? / Transplante renal preemptivo: por que, quando e como?

ABSTRACT Among renal replacement therapies, preemptive kidney transplantation (PKT) presents the best clinical, social, and economic results. However, it is still infrequently chosen as first therapy for patients with irreversible kidney failure. Initiatives in different parts of the world were developed to identify the reasons why PKT is still not widely used and to facilitate the access of patients with end-stage kidney disease to the advantages associated with it. This article addresses the main advantages and difficulties of PKT and discusses when it should be indicated and how to prepare potential recipients for PKT.

Resumo Entre as terapias renais substitutivas, o transplante renal preemptivo (TRP) apresenta os melhores resultados clínicos, sociais e econômicos. No entanto, ainda é raramente escolhido como primeira terapia para pacientes com falência renal irreversível. Foram desenvolvidas iniciativas em diferentes partes do mundo para identificar as razões pelas quais o TRP ainda não é amplamente utilizado e para facilitar o acesso de pacientes com doença renal em estágio terminal às vantagens associadas ao mesmo. Este artigo aborda as principais vantagens e dificuldades do TRP e discute quando ele deve ser indicado e como preparar potenciais receptores para o TRP.

Crystallographic and Geometrical Dependence of Water Oxidation Activity in Co-Based Layered Hydroxides.

Cobalt-based layered hydroxides (LHs) stand out as one of the best families of electroactive materials for the alkaline oxygen evolution reaction (OER). However, fundamental aspects such as the influence of the crystalline structure and its connection with the geometry of the catalytic sites remain poorly understood. Thus, to address this topic, we have conducted a thorough experimental and in silico study on the most important divalent Co-based LHs (i.e., α-LH, ß-LH, and LDH), which allows us to understand the role of the layered structure and coordination environment of divalent Co atoms on the OER performance. The α-LH, containing both octahedral and tetrahedral sites, behaves as the best OER catalyst in comparison to the other phases, pointing out the role of the chemical nature of the crystalline structure. Indeed, density functional theory (DFT) calculations confirm the experimental results, which can be explained in terms of the more favorable reconstruction into an active Co(III)-based oxyhydroxide-like phase (dehydrogenation process) as well as the significantly lower calculated overpotential across the OER mechanism for the α-LH structure (exhibiting lower Egap). Furthermore, ex situ X-ray diffraction and absorption spectroscopy reveal the permanent transformation of the α-LH phase into a highly reactive oxyhydroxide-like stable structure under ambient conditions. Hence, our findings highlight the key role of tetrahedral sites on the electronic properties of the LH structure as well as their inherent reactivity toward OER catalysis, paving the way for the rational design of more efficient and low-maintenance electrocatalysts.

Anti-proliferative and anti-inflammatory effects of the application of baclofen cream, a GABAB receptor agonist, on skin inflammation in mice.

Previous studies have demonstrated the role of γ-aminobutyric acid type B (GABAB) receptors in skin-related conditions and pain. However, most studies have focused on the main effects of GABAB on the central nervous system. Therefore, this study has aimed to determine the potential topical anti-inflammatory and anti-proliferative effects of baclofen cream in an inflammatory skin disease model. The effects of the baclofen cream were evaluated using acute and chronic models of 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced skin inflammation in mouse ears. Histological and immunohistochemical evaluations were performed using an ear oedema assay. The effect of baclofen on keratinocyte proliferation was assessed in PAM212, the murine keratinocyte cell line. The results demonstrate that a single topical application of 5% baclofen, 7.5% baclofen, and 1% dexamethasone each inhibited acute TPA-induced ear oedema (58.94 ± 6.14%, 47.73 ± 11.26%, and 87.33 ± 4.59%, respectively). These results were confirmed by histological analysis. In the chronic model, baclofen (5%) and dexamethasone (1%) each inhibited ear oedema and the maximum inhibitory effect was reached at the end of the experiment (9th day of TPA application) with a percentage inhibition of 54.60 ± 6.15% for baclofen and 71.68 ± 3.45% for dexamethasone, when compared to the vehicle. These results were confirmed by histological analysis. Baclofen and dexamethasone also reduced proliferating cell nuclear antigen expression by 62.01 ± 6.65% and 70.42 ± 6.11%, respectively. However, baclofen did not inhibit keratinocyte proliferation in PAM212 cells. In conclusion, these results demonstrate that baclofen exhibits notable topical antiproliferative and anti-inflammatory properties and could be a potential therapeutic alternative for treating inflammatory and proliferative skin diseases.

Outpatient parenteral antimicrobial therapy with continuous infusion of meropenem: A retrospective analysis of three years of clinical experience / Tratamiento antimicrobiano domiciliario endovenoso con infusión continua de meropenem: un análisis restrospectivo de tres años de experiencia clínica

Introduction: Data regarding outpatient parenteral antimicrobial therapy (OPAT) with continuous infusion of meropenem (CIM) remain scarce and controversial. We aimed to analyze its outcomes. Methods: We conducted a retrospective analysis of a cohort of patients who received OPAT with CIM during a three-year period at a single center in northwest Spain. Demographics, clinical data and OPAT outcomes were recorded. Results: Since January 2017–December 2019, 34 patients received 35 OPAT episodes with CIM. The median age was 75 years, and 18 (51.4%) had a Charlson comorbidity index>2. Twelve (34.3%) had respiratory infection, 11 (31.4%) urinary tract infection, and 12 (34.3%) other infections. Twenty-one (60%) received a dose of 6g/day, and 27 (77.1%) received combined antibiotic therapy. The duration of OPAT with CIM was 10 median days. Pseudomonas aeruginosa was the most frequently (34.3%) isolated microorganism and 10 (28.6%) infections were polymicrobial. During OPAT and hospital at home unit admission, 4 (11.4%) patients had any adverse reaction that required CIM withdrawal, 2 (5.7%) were readmitted, and 3 (8.8%) died (2 infection-related deaths). After 30 days from discharge 6 (18.8%) of 32 not-censored patients had unplanned readmissions (2 infection-related), 6 (18.8%) developed recurrence (3 relapses, 3 reinfections) and 1 (3.1%) died (none-infection-related death). Twenty-three (71.9%) of these 32 patients did not experience unplanned readmission, recurrence or death. Conclusion: CIM can be an option to be administrated in OPAT programs in selected patients. Further studies are warranted to increase evidence regarding its use, and to externally validate our findings.(AU)

Introducción: Los datos sobre el tratamiento antimicrobiano domiciliario endovenoso (TADE) con infusión continua de meropenem (ICM) son escasos y controvertidos. Nuestro objetivo fue analizar sus resultados. Métodos: Realizamos un análisis retrospectivo de una cohorte de pacientes que recibieron TADE con ICM durante tres años en un centro del noroeste de España. Se registraron datos demográficos, clínicos y resultados. Resultados: Desde enero de 2017 a diciembre de 2019, 34 pacientes recibieron 35 episodios de TADE con ICM. La mediana de edad fue de 75 años y 18 (51,4%) tenían un índice de comorbilidad de Charlson>2. Doce (34,3%) tenían infección respiratoria, 11 (31,4%) urinaria y 12 (34,3%) otras infecciones. Veintiuno (60%) recibieron una dosis de 6g/día y 27 (77,1%) antibioterapia combinada. La duración mediana del TADE con ICM fue de 10 días. Pseudomonas aeruginosa fue el microorganismo aislado más frecuentemente (34,3%) y 10 (28,6%) infecciones fueron polimicrobianas. Durante el TADE, 4 (11,4%) pacientes presentaron alguna reacción adversa que requirió retirada de ICM, 2 (5,7%) reingresaron y 3 (8,8%) fallecieron (2 muertes relacionadas con infección). Tras 30 días desde el alta, 6 (18,8%) de 32 pacientes tuvieron reingresos no programados (2 relacionados con infección), 6 (18,8%) desarrollaron recurrencia (3 recidivas, 3 reinfecciones) y 1 (3,1%) falleció (sin relación con infección). Veintitrés (71,9%) de 32 pacientes no experimentaron reingreso no programado, recidiva o muerte. Conclusión: La ICM puede ser una opción para ser administrada en programas de TADE en pacientes seleccionados. Se necesitan más estudios para aumentar la evidencia sobre su uso y validar externamente nuestros hallazgos.(AU)

Hexagonal Hybrid Bismuthene by Molecular Interface Engineering.

High-quality devices based on layered heterostructures are typically built from materials obtained by complex solid-state physical approaches or laborious mechanical exfoliation and transfer. Meanwhile, wet-chemically synthesized materials commonly suffer from surface residuals and intrinsic defects. Here, we synthesize using an unprecedented colloidal photocatalyzed, one-pot redox reaction a few-layers bismuth hybrid of "electronic grade" structural quality. Intriguingly, the material presents a sulfur-alkyl-functionalized reconstructed surface that prevents it from oxidation and leads to a tuned electronic structure that results from the altered arrangement of the surface. The metallic behavior of the hybrid is supported by ab initio predictions and room temperature transport measurements of individual nanoflakes. Our findings indicate how surface reconstructions in two-dimensional (2D) systems can promote unexpected properties that can pave the way to new functionalities and devices. Moreover, this scalable synthetic process opens new avenues for applications in plasmonics or electronic (and spintronic) device fabrication. Beyond electronics, this 2D hybrid material may be of interest in organic catalysis, biomedicine, or energy storage and conversion.

Unilateral Vocal Fold Paralysis and Voice Therapy: Predictors of Long-Term Quality of Life.

To date, little is known about the long-term predictors of quality of life (QoL) in unilateral vocal fold paralysis (UVFP). The main objective of this study was to evaluate the predictors of long-term QoL in UVFP patients submitted to voice therapy (VT) exclusively. Data from patients diagnosed with UVFP who followed a VT program between 2013 and 2019 were reviewed. Video laryngoscopy (VL) records were obtained at the beginning and at the end of VT. To assess QoL, Voice Handicap Index 30 (VHI-30) score was assessed in three temporal frames: before voice therapy (pre-VT), at the last VT session (post-VT), and in the present (cur-VHI). A longitudinal analysis was performed regarding the evolution of QoL and the factors influencing QoL through time were analyzed. Seventy-eight percent of patients had iatrogenic UVFP. The mean time of follow-up after VT was 3.942 years (range 6 months-7 years). There was a significant improvement in QoL through all time points (F (2,88)=72.179, p<0.001), with VHI-30 decrease from the baseline pre-VT to post-VT(p<0.001) and from post-VT to cur-VT (p=0.0013). In the iatrogenic UVFP population, patients starting VT earlier showed better long-term QoL (p=0.023). UVFP patients with dysphagia at presentation showed significantly worse QoL in the late follow-up (p=0.016). Hence, iatrogenic UVFP patients beginning VT rapidly may show better QoL in the future. Also, our results suggest that dysphagia at UVFP onset may predict higher morbidity later in life.

Outpatient parenteral antimicrobial therapy with continuous infusion of meropenem: A retrospective analysis of three years of clinical experience.

INTRODUCTION: Data regarding outpatient parenteral antimicrobial therapy (OPAT) with continuous infusion of meropenem (CIM) remain scarce and controversial. We aimed to analyze its outcomes. METHODS: We conducted a retrospective analysis of a cohort of patients who received OPAT with CIM during a three-year period at a single center in northwest Spain. Demographics, clinical data and OPAT outcomes were recorded. RESULTS: Since January 2017-December 2019, 34 patients received 35 OPAT episodes with CIM. The median age was 75 years, and 18 (51.4%) had a Charlson comorbidity index>2. Twelve (34.3%) had respiratory infection, 11 (31.4%) urinary tract infection, and 12 (34.3%) other infections. Twenty-one (60%) received a dose of 6g/day, and 27 (77.1%) received combined antibiotic therapy. The duration of OPAT with CIM was 10 median days. Pseudomonas aeruginosa was the most frequently (34.3%) isolated microorganism and 10 (28.6%) infections were polymicrobial. During OPAT and hospital at home unit admission, 4 (11.4%) patients had any adverse reaction that required CIM withdrawal, 2 (5.7%) were readmitted, and 3 (8.8%) died (2 infection-related deaths). After 30 days from discharge 6 (18.8%) of 32 not-censored patients had unplanned readmissions (2 infection-related), 6 (18.8%) developed recurrence (3 relapses, 3 reinfections) and 1 (3.1%) died (none-infection-related death). Twenty-three (71.9%) of these 32 patients did not experience unplanned readmission, recurrence or death. CONCLUSION: CIM can be an option to be administrated in OPAT programs in selected patients. Further studies are warranted to increase evidence regarding its use, and to externally validate our findings.

Two-dimensional magnetic behaviour in hybrid NiFe-layered double hydroxides by molecular engineering.

Layered double hydroxides (LDHs) are a class of two-dimensional (2D) anionic materials that exhibit remarkable chemical versatility, making them ideal building blocks in the design of complex multifunctional materials. In this line, a NiFe-LDH is probably one of the most important LDHs due to its interesting electrochemical and magnetic properties. However, no direct magnetic measurements of exfoliated NiFe-LDH nanosheets have been reported so far. Herein, we synthesize a hybrid NiFe-LDH family through anion exchange reactions using surfactant molecules in order to increase the interlayer space (ranging from 8 to 31.6 Å), minimizing the interlayer dipolar interactions. By intercalation with octadecylsulphate, we have managed to obtain the largest interlayer space reported for a NiFe-LDH while keeping a similar size, morphology and composition. This wide interlayer separation results in a decrease in temperatures at which spontaneous magnetization (TM) occurs and the blocking temperature (TB), as well as a decrease in the coercive fields (HC). In fact, an abrupt drop in all these magnetic parameters above 30 Å interlayer distance is observed, evidencing complete magnetic decoupling of the layers. We have further validated our molecular engineering approach by characterizing the hybrid materials by Mössbauer spectroscopy and comparing the magnetic analysis results with those for a liquid phase exfoliated NiFe-LDH sample. Overall, this work provides fundamental insights into the magnetism of NiFe-LDHs, showing the potential of molecular engineering for designing hybrid layered magnetic materials approaching the 2D magnetic limit.