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Abstract Background Bloodstream infection (BSI) is associated with poor outcomes especially when effective antimicrobial therapy and control of infection source are delayed. As the frequency of Enterobacterales producing metallo-β-lactamases (MBL) and/or OXA-48–like carbapenemases is increasing in some United States (US) medical centres, effective antimicrobials to treat the infections caused by these organisms are urgently needed. Aztreonam-avibactam is under clinical development for treatment of infections caused by Gram-negative bacteria, including MBL producers. Objectives To evaluate the antimicrobial susceptibility of Enterobacterales causing BSI in US medical centres and compare the activity of aztreonam-avibactam with ceftazidime-avibactam, meropenem-vaborbactam, imipenem-relebactam, cefiderocol, and other antimicrobials used to treat BSI. Methods 4,802 Enterobacterales were consecutively collected (1/patient) from 72 US medical centres in 2020–2022 and susceptibility tested by broth microdilution. Aztreonam-avibactam was tested with avibactam at a fixed concentration of 4 mg/L. A pharmacokinetic/pharmacodynamic susceptible breakpoint of ≤ 8 mg/L was applied for aztreonam-avibactam for comparison. Carbapenem-resistant Enterobacterales (CRE) isolates were tested for β-lactamase–encoding genes using Next-generation sequencing. Results Aztreonam-avibactam was highly active against Enterobacterales; only 2 isolates showed aztreonam-avibactam MICs > 8 mg/L: 1 meropenem-susceptible E. coli and 1 K. aerogenes (CRE). All carbapenemase producers and 98.0% of CRE were inhibited at an aztreonam-avibactam MIC of ≤ 8 mg/L. CRE susceptibility rates were 81.6% for ceftazidime-avibactam, 65.3% for meropenem-vaborbactam, 61.2% for imipenem-relebactam, and 87.8% for cefiderocol. Aztreonam-avibactam retained activity (MIC, ≤ 8 mg/L) against all (100.0%) meropenem-vaborbactam nonsusceptible (n = 17), 99.5% of imipenem-relebactam nonsusceptible (n = 206), and 90.0% of ceftazidime-avibactam nonsusceptible (n = 10) isolates. The most common carbapenemases were KPC-2/3 (57.1% of CREs), OXA-48–like (16.3%), and NDM (14.3%). A carbapenemase gene was not observed in 12.3% of CREs. Ceftazidime-avibactam and meropenem-vaborbactam were active against 100.0% of KPC producers, but ceftazidime-avibactam showed limited activity against MBL producers and meropenem-vaborbactam showed limited activity against OXA-48–like and MBL producers. The most active non–β-lactam comparators against CRE were gentamicin (49.0% susceptible) and amikacin (44.9% susceptible). Conclusions Aztreonam-avibactam demonstrated potent activity against a large collection of Enterobacterales isolated from patients with BSI in US hospitals, including CRE, MBL producers, and isolates resistant to recently approved β-lactamase inhibitor combinations.

ABSTRACT This study reports the activity of cefiderocol against Enterobacterales, Pseudomonas aeruginosa, and Acinetobacter spp. isolates collected from the United States and Europe, including Israel and Turkey, from 2020 to 2021. Among Enterobacterales, 2.8% were carbapenem nonsusceptible (CNSE); cefiderocol inhibited 96.6%/85.1% [Clinical Laboratory Standards Institute (CLSI)/European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoints] of these isolates. Imipenem-relebactam, meropenem-vaborbactam, and ceftazidime-avibactam displayed susceptibilities lower than cefiderocol against CNSE isolates (67.4–84.6% susceptible, CLSI). Cefiderocol was the only agent active against CNSE isolates carrying metallo-β-lactamase (MBL) carbapenemase or multiple carbapenemase genes (84.6%–92.3% susceptible, CLSI). Approximately 18% of carbapenem-susceptible Escherichia coli, Klebsiella pneumoniae, and Proteus mirabilis carried extended-spectrum-β-lactamases and/or plasmid-borne AmpC-encoding genes; cefiderocol inhibited 99.8%–100.0% (CLSI) of these genotypic groups. Multi-drug resistance (MDR) phenotypes were observed in 16.9% and 52.5% of P. aeruginosa and A. baumannii-calcoaceticus isolates, respectively. Carbapenemase genes were rare (4.9%) among cephalosporin and/or carbapenem nonsusceptible P. aeruginosa, compared to 87.6% carriage in A. baumannii-calcoaceticus, respectively. Against the MDR and carbapenemase-carrying P. aeruginosa and A. baumannii-calcoaceticus subsets, cefiderocol was active against 98.6%/98.7% and 97.1%/97.4% (CLSI), respectively. Only 69 isolates (0.3%) across all species groups were identified as cefiderocol nonsusceptible per CLSI criteria (>4 mg/L). Cefiderocol was the most active agent in vitro against Enterobacterales, P. aeruginosa, and Acinetobacter spp., with uniform activity against all phenotypic- and genotypic-resistant subsets. Coupled with the low incidence of nonsusceptibility observed across species groups, these results demonstrate cefiderocol as an important option for treating infections caused by pathogens with diverse mechanisms of resistance in US and European hospitals.IMPORTANCEThe worldwide spread of multi-drug-resistant Pseudomonas aeruginosa and carbapenem-resistant Enterobacterales and Acinetobacter spp. poses a serious challenge in healthcare settings as infections caused by these organisms are commonly refractory to many frontline therapeutic agents. Multiple global health organizations highlighted these pathogens as critical priorities for new antibiotic development, thus necessitating continued surveillance of the activities of currently available antimicrobial agents and circulating mechanisms of resistance. To meet this need, this study phenotypically and genotypically characterized priority Gram-negative pathogens collected from patients in US and European hospitals to examine the activity of cefiderocol and other currently available treatment options, including carbapenems and β-lactam-β-lactamase inhibitor combinations. The results presented here provide a detailed perspective to healthcare practitioners of cefiderocol’s broad applicability, manifested in high activity and low nonsusceptibility rates, across phenotypic and genotypic organism groups relative to other agents and further support its use against the most intransigent infections.

Background: To compare the effect of primary subcutaneous cellular tissue (SCT) closure on the incidence of seromas in midline laparotomy wounds. Methods: A cross-sectional study was designed. Patients undergoing midline laparotomy during the study period were included. Patient characteristics and closure techniques were recorded. A 30-day post-operative follow- up was included. Results: 83 patients underwent midline laparotomy abdominal surgery during the study period. 38.1% (n 16/42) of patients with only skin closure developed post-operative seromas versus 12.2% (n 5/41) of patients with skin and SCT closure, with an odds ratio of 0.22 (95% confidence interval [CI] 0.07-0.69, p = 0.009). Surgical site infection was 11.9% and 22%, respectively. Conclusions: SCT closure helps decrease post-operative seroma. Despite methodological limitations, this study lays the groundwork for future research with more rigorous methodologies that allow for longitudinal analysis and the confirmation of cause and effect.

Background: Hearing disabilities in pediatrics are a prevalent pathology with a high impact on quality of life. This study describes the internal ear morphometry of a Mexican pediatric population. The aim is to compare sensorineural hearing loss (SNHL) and control groups. Methods: An observational, cross-sectional, retrospective, and comparative study was conducted utilizing HRCT study images. Variables were measured with the Horos for Mac program. All variables were measured in 108 temporal bones (26 girls and 28 boys) and analyzed by groups, laterality, and sex. Results: The overall cochlear length mean was 35.62 ± 4.06 mm. Internal canal width significantly differed between the control and SNHL groups (p = 0.039). Conclusions: Our findings may be useful to determine control and SNHL pediatric population characteristics to facilitate preoperative management of cochlear implant surgery.

Chronic neuroinflammation is characterized by increased blood-brain barrier (BBB) permeability, leading to molecular changes in the central nervous system that can be explored with biomarkers of active neuroinflammatory processes. Magnetic resonance imaging (MRI) has contributed to detecting lesions and permeability of the BBB. Ultra-small superparamagnetic particles of iron oxide (USPIO) are used as contrast agents to improve MRI observations. Therefore, we validate the interaction of peptide-88 with laminin, vectorized on USPIO, to explore BBB molecular alterations occurring during neuroinflammation as a potential tool for use in MRI. The specific labeling of NPS-P88 was verified in endothelial cells (hCMEC/D3) and astrocytes (T98G) under inflammation induced by interleukin 1β (IL-1β) for 3 and 24 hours. IL-1β for 3 hours in hCMEC/D3 cells increased their co-localization with NPS-P88, compared with controls. At 24 hours, no significant differences were observed between groups. In T98G cells, NPS-P88 showed similar nonspecific labeling among treatments. These results indicate that NPS-P88 has a higher affinity towards brain endothelial cells than astrocytes under inflammation. This affinity decreases over time with reduced laminin expression. In vivo results suggest that following a 30-minute post-injection, there is an increased presence of NPS-P88 in the blood and brain, diminishing over time. Lastly, EAE animals displayed a significant accumulation of NPS-P88 in MRI, primarily in the cortex, attributed to inflammation and disruption of the BBB. Altogether, these results revealed NPS-P88 as a biomarker to evaluate changes in the BBB due to neuroinflammation by MRI in biological models targeting laminin.

Sugar solutions promote hedonic feeding and increase the risk of obesity and binge-type behavior. In rodents, ingestion of sugar solutions enhances dopamine release to mesolimbic regions, suggesting changes in hedonic intake and brain reward processes. Moreover, dopaminergic D2R/D3R receptors contribute to the hedonic intake of palatable solutions. Although the experimental evidence indicate that the dopaminergic D4 receptor (D4R) modulates feeding at homeostatic levels, it is currently unknown whether D4R also regulate the hedonic intake of sugar solutions. In this study, we evaluated the effect of the central blockade of D4R on the consumption of a 20% sucrose solution, the drinking microstructure parameters, and levels of locomotor activity in sated rats. In the first experiment, male Wistar rats were daily exposed to a 20% sugar solution in the first hour of the light phase of the light:dark cycle. On day 10, rats received i.c.v injections of the D4R antagonist, L-745870 (0, 1 or 2 µg/5 µl) and sucrose consumption and drinking microstructure parameters (latency to start drinking, bouts, drinking duration, bout size, inter-bout interval, time in activity and time in resting) were evaluated. In the second experiment, rats were trained to receive the 20% sucrose solution as described in experiment 1. On day 10, after the 1 h of sucrose access, the rats were placed in the open field for 5-min (habituation phase). Then, rats received i.c.v injections of L-745870 (0, 1 or 2 µg/ 5 µl), and were placed again in the open-field test for 10-min (pharmacological phase). The number or crosses trough squares and number of rears were scored for both the habituation and pharmacological phase. Here we found that administration of L-745870 decreased the consumption of sucrose in a dose-depended manner. Moreover, L-745870-treated rats displayed microstructural changes, including greater number of bouts and reduced drinking duration, bout size and inter-bout intervals. Furthermore, the number of crosses and number of rears in the open field test remained unchanged for habituation and pharmacological phase. Finally, present findings suggest that D4R modulates the consumption of sugar solutions by alteration of hedonic responses, but the contribution of homeostatic systems is discussed. These results open perspectives for the potential use of the D4R antagonists for treating obesity or binge-eating behavior.

Abstract Recently, porphyrin units have been attached to graphene nanoribbons (Por-GNR) enabling a multitude of structures. Here we report first-principles calculations of two prototypical, experimentally feasible, Por-GNR hybrids, one of which displays a small band gap relevant as electrodes in devices. Embedding a Fe atom in the porphyrin causes spin-polarized ground state (S = 1). Using density functional theory and nonequilibrium Green’s function, we examine a 2-terminal setup involving a Fe-Por-GNR between small band gap, Por-GNR electrodes. The coupling between the Fe-d and GNR band states results in a Fano anti-resonance feature in the spin transport, making the conductance highly sensitive to the Fe spin state. We demonstrate how mechanical strain or chemical adsorption on the Fe give rise to spin-crossover to S = 2 and S = 0, directly reflected in the transmission. Our results provide a deep understanding which can open an avenue for carbon-based spintronics and chemical sensing.

We evaluated the activities of aztreonam/avibactam and recently approved β-lactamase inhibitor combinations (BLICs) to compare the antimicrobial susceptibility patterns of Enterobacterales and Pseudomonas aeruginosa isolated from intensive care unit (ICU) and non-ICU patients. Clinical isolates (1/patient) were consecutively collected from 72 United States medical centres in 2020–2022 and susceptibility tested by broth microdilution. The results for 5421 isolates from ICU patients were analysed and compared to those for 20,649 isolates from non-ICU patients. Isolates from ventilator-associated pneumonia patients were analysed separately. Aztreonam/avibactam inhibited 100.0%/>99.9% Enterobacterales and 100.0%/98.3% of carbapenem-resistant Enterobacterales (CRE) from ICU/non-ICU patients at ≤8 mg/L, respectively. The CRE susceptibility rates were 88.5%/82.9% for ceftazidime/avibactam, 82.1%/81.2% for meropenem/vaborbactam, and 78.2%/72.6% for imipenem/relebactam among ICU/non-ICU isolates. Among the P. aeruginosa isolates from ICU/non-ICU patients, the susceptibility rates were 96.3%/97.6% for ceftazidime/avibactam, 97.2/98.4% for ceftolozane/tazobactam, 97.1%/98.0% for imipenem/relebactam, 77.8%/84.6% for piperacillin/tazobactam, and 76.9%/85.8% for meropenem; aztreonam/avibactam inhibited 78.0%/81.9% of P. aeruginosa at ≤8 mg/L. In summary, lower susceptibility rates were observed among ICU than non-ICU isolates. Aztreonam/avibactam exhibited potent in vitro activity and broad-spectrum activity against Enterobacterales from ICU and non-ICU patients, including CRE and isolates non-susceptible to newer BLICs. Against P. aeruginosa, aztreonam/avibactam showed a spectrum of activity comparable to that of piperacillin/tazobactam, meropenem, and ceftazidime.

El articulo muestra reflexiones fenomenológicas a partir de una etnografía-narrativa sobre las experiencias de ensoñación que manifiestan jóvenes latinoamericanos residentes entre los años 2020-2023 en áreas urbanas de la región de Los Lagos, ciudades localizadas en la norpatagonia de Chile, a objeto de comprender las dimensiones culturales de la vida migrante y sus representaciones simbólicas asociadas con el mundo de los sueños. La metodología propuesta es, en un primer momento, pensada desde una etnografía especular que dialogaba con la interdisciplina, sobre todo en la elaboración de talleres participativos, los cuales permitieron la exploración del objeto de estudio desde las subjetividades como prácticas culturales que fueron narradas a través de la descripción densa. Los resultados muestran cómo las prácticas oníricas y las experiencias de ensoñación donde los sujetos interpretan sus experiencias vividas, se asociaban con la proyección de los significados migratorios en torno a sus estadías, deseos y demandas en Chile. Los aportes que hace este trabajo a los estudios migratorios son, precisamente, un tipo de conocimiento nuevo sobre las formas en las que los sujetos se relacionan e interaccionan en espacios de anclaje donde proyectan parte de sus experiencias basadas en el afrontamiento a los nuevos lugares de residencia, representaciones que bien pueden comprenderse como significados de la nostalgia, estados nerviosos y temores asociados con lo desconocido.

Background/Objective: The objective of the study is to determine the morphological characteristics of residual alveolar bone for dental implants in a Hispanic population. Methods: A cross-sectional study was performed with 385 consecutive adult head-and neck computed tomography (CT) studies. The heights of alveolar bone in the maxilla and mandible, width, and bone density were measured. Groups were stratified for analysis according to the bone resorption. Results: A total of 508 alveolar spaces in the maxilla bone and 260 in the mandibular bone were included, with a mean age of 54.2 ± 14.8 years. Statistically significant differences between sexes were found in the width of the maxillary and mandibular second molar, the width in all regions of the mandible, and the height of the second molar. Statistically differences in the maxilla between Grades 3, 4, and 5 of residual ridge resorption in height, width, and density (p = 0.00), and in the mandibula between Grades 3, 4, and 5 of residual ridge resorption in width and density (p = 0.00). Conclusions: Enhancing pre-operative diagnostic accuracy is a cornerstone in ensuring the appropriateness of residual alveolar bone for dental implant placement, effectively mitigating the risks associated with inadequate bone quality. The rising adoption of CT as a complementary pre-operative diagnostic modality brings about a substantial leap in precision when compared to traditional panoramic radiography methods.

ABSTRACT: Objectives: Whole genome and transcriptome analysis of 213 Pseudomonas aeruginosa isolates resistant to antipseudomonal β-lactams collected in 30 countries was performed to evaluate resistance mechanisms against these agents. Methods: Isolates were susceptibility tested by reference broth microdilution. Whole genome and transcriptome sequencing were performed, and data were analysed using open-source tools. A statistical analysis of changes in the expression of >5500 genes was compared to the expression of PAO1. Results: The high-risk clones ST235 and ST111 were the most prevalent among >90 sequence types (STs). Metallo-β-lactamase (MBLs) genes were detected in 40 isolates. AmpC and MexXY were the most common genes overexpressed in approximately 50% of the 173 isolates that did not carry MBLs. Isolates overexpressing pmrA and pmrB, the norspermidine production genes speD2 and speE2, and the operon arnBCADTEF-ugd were noted among strains resistant to ceftolozane-tazobactam and ceftazidime-avibactam, despite the lack of polymyxin resistance often associated to increased expression of these genes. Overexpression of MuxABC-OpmB, OprG, and OprE proteins were associated with resistance to ceftolozane-tazobactam in addition to the usual genes involved in cephalosporin, monobactam, and carbapenem resistance. Statistical analysis identified discrete mutations in ArmZ, OprD, and AmpC that correlated to antipseudomonal β-lactam resistance. Conclusions: P. aeruginosa resistance mechanisms are complex. This analysis suggests the role of multiple genes in resistance to antipseudomonal β-lactams, including some not commonly described.

El uso de la tecnología en la vida cotidiana en la sociedad contemporánea se ha convertido en una herramienta de gran importancia, trayendo consigo, además, la preocupación sobre conductas nocivas en su respectivo uso, con tendencia al abuso o adicción. La vulnerabilidad hacia este comportamiento se observa en población joven, debido a la exposición desde temprana edad y falta de concientización. Objetivo: sistematizar información derivada de estudios empíricos realizados durante los últimos 5 años sobre los factores psicosociales asociados al riesgo de adición a medios tecnológicos. Método: el estudio de enfoque cualitativo, nivel descriptivo y método de revisión bibliográfica sistemática, incluyo como muestra 21 artículos, se empelo la metodologia de revisión basada en los criterios PRISMA. Resultados: las categorías emergentes identificadas a partir de análisis fueron: características comportamentales, rasgos de personalidad, características del contexto social y variables sociodemográficos, rasgos psicopatológicos, autoesquemas (autoestima, autocontrol, autoeficacia), habilidades para la vida, habilidades sociales y socioemocionales, esquemas maladaptativos tempranos y apego, satisfacción con la vida Conclusiones: se evidencia la necesidad de implementar medidas preventivas en los ambientes familiares y escolares desde las edades tempranas con el fin de disminuir el riesgo de tecnoadicción.

Nowadays, different Industry 4.0 technologies have been implemented into diverse industries. However, these implementations are not standardized across similar industries and countries. Consequently, companies are actively looking for assessment instruments—maturity models, roadmaps, frameworks, readiness assessments—to assist in their digital transformation, to determine their Industry 4.0 level, and to identify technologies and strategies that should be implemented in specific areas, thus developing a feasible implementation plan. A review is conducted following the PRISMA (Preferred Reporting Items for Systematic Literature Reviews and Meta-Analyses) methodology to analyze the different research works on assessment instruments focused on Industry 4.0. A total of 538 articles, book chapters, conference proceedings, editorial material, reviews, and reports written in the English language were retrieved. Of these, 132 research papers were examined using a mixed analysis format to generate bibliometrics, and 36 articles were then deeply studied for a complete meta-analysis. The findings and insights of this meta-analysis led to a compilation and summary of dimensions, outcomes, enablers, and key components typically involved in Industry 4.0, which are comprehensively integrated to present the best practices for assessing Industry 4.0 and deploying a digital transformation that can impact productivity, flexibility, sustainability, quality, costs, and time.

Abstract Balancing safety and efficacy is a major consideration for cancer treatments, especially when combining cancer immunotherapy with other treatment modalities such as chemotherapy. Approaches that induce immunogenic cell death (ICD) are expected to eliminate cancer cells by direct cell killing as well as activation of an antitumor immune response. We have developed a gene therapy approach based on p19Arf and interferon-β gene transfer that, similar to conventional inducers of ICD, results in the release of DAMPS and immune activation. Here, aiming to potentiate this response, we explore whether association between our approach and treatment with doxorubicin (Dox), a known inducer of ICD, could further potentiate treatment efficacy without inducing cardiotoxicity, a critical side effect of Dox. Using central composite rotational design analysis, we show that cooperation between gene transfer and chemotherapy killed MCA205 and B16F10 cells and permitted the application of reduced viral and drug doses. The treatments also cooperated to induce elevated levels of ICD markers in MCA205, which correlated with improved efficacy of immunotherapy in vivo. Treatment of subcutaneous MCA205 tumors associating gene transfer and low dose (10 mg/kg) chemotherapy resulted in inhibition of tumor progression. Moreover, the reduced dose did not cause cardiotoxicity as compared to the therapeutic dose of Dox (20 mg/kg). The association of p19Arf/interferon-β gene transfer and Dox chemotherapy potentiated antitumor response and minimized cardiotoxicity.

The use of human bodies for education and research purposes has existed for hundreds of years1. There is a long history of how bodies have been obtained2,3.

ABSTRACT: Background: High-dose cefepime-tazobactam (WCK 4282) is currently under clinical development at a dosage of 2 grams/2 grams every 8 hours with prolonged infusion (90 minutes). Objective: To evaluate the in vitro activity of high-dose cefepime-tazobactam. Methods: A total of 23, 246 gram-negative organisms were collected from 133 medical centers (34 countries) in 2018-2019 and susceptibility was tested by broth microdilution method against cefepime-tazobactam (tazobactam at fixed 8 mg/L) and comparator agents. Results: Cefepime-tazobactam and cefepime inhibited 97.6% and 85.4% of Enterobacterales isolates (n = 18,143) at ≤8 mg/L, respectively. Cefepime-tazobactam activity against Enterobacterales was comparable with meropenem (97.0% susceptible) and greater than ertapenem (95.2% susceptible) or piperacillin-tazobactam (88.0% susceptible). Moreover, cefepime-tazobactam retained potent activity against meropenem-susceptible Enterobacterales isolates that were nonsusceptible to ceftazidime, ceftriaxone, and piperacillin-tazobactam (96.3% inhibited at ≤8 mg/L) or ceftolozane-tazobactam (96.2% inhibited at ≤8 mg/L). Against P. aeruginosa (n = 4,553), the percentage of isolates inhibited at ≤8 mg/L of cefepime-tazobactam (82.7%) was higher than meropenem (76.0%) or piperacillin-tazobactam (76.4%), and the percentage inhibited at the proposed pharmacokinetic/pharmacodynamic breakpoint of ≤16 mg/L (92.2%) was comparable with ceftolozane-tazobactam (93.5%). Conclusions: The results of this in vitro study support the clinical development of cefepime-tazobactam as a carbapenem-sparing option to treat infections caused by Enterobacterales and P. aeruginosa, including multidrug-resistant isolates.

El uso de procedimientos y metodologías estandarizadas para realizar análisis dinámico no lineales (ADNL) está en aumento. En este tipo de análisis, varios de los criterios pueden ser definidos de forma arbitraria o seleccionados a criterio del experto, tal es el caso de la selección de los acelerogramas a ser utilizados como dato de partida para el ADNL. Por ejemplo, para este tipo de análisis, el Eurocódigo 8 (EC-8) sugiere seleccionar, y escalar o ajustar un número de registros de aceleraciones para que su espectro de respuesta sea compatible con el espectro de diseño objetivo. Sin embargo, tanto el EC-8 como diversos documentos normativos, no sugieren la consideración de parámetros sísmicos de la señal o diferentes medidas de intensidad, en el proceso de selección de estos acelerogramas. Es evidente que una selección inadecuada de los parámetros de entrada, incluyendo las acciones sísmicas, generaría resultados poco realistas y sin sentido físico. En este sentido, el presente estudio tiene como objetivo analizar la influencia de la intensidad de Arias (IA) y la duración significativa (Da5-95) en la selección de registros de aceleración compatibles con un espectro de diseño objetivo para la realización de ADNL. De forma particular, estudiamos la variación del daño estructural de un edificio a partir de cuatro acelerogramas, con diferentes IA y Da5-95, ajustados al mismo espectro de diseño. Los resultados demuestran diferencias significativas en el daño esperado. Los registros con mayor intensidad de Arias y duración significativa produjeron un daño estructural mayor a pesar de disponer del mismo espectro de respuesta. Se concluye que es relevante considerar estos parámetros sísmicos en la selección de acelerogramas para su uso en ADNL.

Abstract In biologically diverse ecosystems, an essential process to support competing species to coexist is ecological differentiation. Habitat heterogeneity is, hence, important in establishing species abundance and richness, favoring the coexistence of species due to habitat partition. In this context, shading and species thermal tolerance can be good factors to elucidate the role of habitat heterogeneity in the habitat partition among closely related species. Herein, we study shading effects in microhabitat selection, behavior, and physiological limitation on two species of fiddler crabs (Leptuca leptodactyla and Leptuca uruguayensis). Indeed, shading conditions influenced fiddler crabs species proportion over time, with L. leptodactyla more associated with nonshaded/warmer areas while the L. uruguayensis to shaded/cooler ones. They also adjusted their behavior differently from each other to deal with thermal stress. Finally, we have demonstrated that these effects are related to species' physiological limitations. We conclude that biologically diverse ecosystems, such as intertidal regions from estuaries (e.g., mudflats and mangroves), support the coexistence between closely related species by reducing competition due to habitat partition.

ABSTRACT Tebipenem pivoxil is an oral broad-spectrum carbapenem. This study evaluated the activity of tebipenem and comparators against UTI Enterobacterales from US hospitals (2019–2020). 3,576 Enterobacterales causing UTI in 52 centers in 9 US Census Divisions were included. Susceptibility testing followed the CLSI broth microdilution method. Escherichia coli, Klebsiella pneumoniae, and Proteus mirabilis with an MIC of ≥2 μg/mL for ceftazidime, ceftriaxone, and/or aztreonam were designated ESBL. Isolates were also grouped based on MDR phenotype. Tebipenem, meropenem, and ertapenem had MIC90 against Enterobacterales of 0.06 μg/mL, 0.06 μg/mL and 0.03 μg/mL, respectively. Low susceptibility results for aztreonam (87.1% susceptible), cefazidime (88.1%), ceftriaxone (84.8%), and other agents were observed. Tebipenem and ertapenem were equally potent (MIC90, 0.015 to 0.03 μg/mL) against E. coli and K. pneumoniae, whereas ertapenem showed an MIC 8-fold lower than tebipenem against P. mirabilis. Oral agents, such as amoxicillin-clavulanate, levofloxacin, and trimethoprim-sulfamethoxazole, showed elevated nonsusceptibility rates in the Middle Atlantic region (26, 45, 47, and 41%, respectively). ESBL prevalence varied from 7% to 16%, except in the Middle Atlantic region (42%). The carbapenems were active against ESBL and MDR isolates (93.7 to 96.8% susceptible). Elevated rates of ESBL in UTI pathogens in US hospitals were noted as well as a uniform in vitro potency (MIC90) of tebipenem and the intravenous carbapenems, regardless of phenotype. IMPORTANCE The occurrence of urinary-tract Enterobacterales pathogens producing ESBL enzymes in community and nosocomial settings continues to increase, as does the coresistance to fluoroquinolones, trimethoprim-sulfamethoxazole and nitrofurantoin often exhibited by these pathogens. This scenario complicates the clinical empirical and guided management of UTI by precluding the use of oral and many intravenous options. Oral options appear compromised even among some ESBL-negative isolates, against which the use of parenteral agents may be required. In addition, the interregional variability of susceptibility results of US UTI pathogens provides a less predictable susceptibility pattern to inform empirical treatment decisions. This study evaluated the in vitro activity of tebipenem against contemporary uropathogens, including those resistant to currently available oral options.

Abstract Background It has been reported that the oncoprotein E7 from human papillomavirus type 16 (HPV16-E7) can induce the excessive synthesis of centrosomes through the increase in the expression of PLK4, which is a transcriptional target of E2F1. On the other hand, it has been reported that increasing MPS1 protein stability can also generate an excessive synthesis of centrosomes. In this work, we analyzed the possible role of MPS1 in the amplification of centrosomes mediated by HPV16-E7. Results Employing qRT-PCR, Western Blot, and Immunofluorescence techniques, we found that E7 induces an increase in the MPS1 transcript and protein levels in the U2OS cell line, as well as protein stabilization. Besides, we observed that inhibiting the expression of MPS1 in E7 protein-expressing cells leads to a significant reduction in the number of centrosomes. Conclusions These results indicate that the presence of the MPS1 protein is necessary for E7 protein to increase the number of centrosomes, and possible implications are discussed.

Although a large part of the genome is transcribed, only 1.9% has a protein-coding potential; most of the transcripts are non-coding RNAs such as snRNAs, tRNAs, and rRNAs that participate in mRNA processing and translation. In addition, there are small RNAs with a regulatory role, such as siRNAs, miRNAs, and piRNAs. Finally, the long non-coding RNAs (lncRNAs) are transcripts of more than 200 bp that can positively and negatively regulate gene expression (both in cis and trans), serve as a scaffold for protein recruitment, and control nuclear architecture, among other functions. An essential process regulated by lncRNAs is genome stability. LncRNAs regulate genes associated with DNA repair and chromosome segregation; they are also directly involved in the maintenance of telomeres and have recently been associated with the activity of the centromeres. In cancer, many alterations in lncRNAs have been found to promote genomic instability, which is a hallmark of cancer and is associated with resistance to chemotherapy. In this review, we analyze the most recent findings of lncRNA alterations in cancer, their relevance in genomic instability, and their impact on the resistance of tumor cells to anticancer therapy.

Abstract Background Brachiocephalic trunk (BCT) variants may have a clinical impact during surgical procedures, some of which could be fatal. The objective of this study was to classify height positions of the BCT and report their prevalence in a Mexican population. Methods Patients: A retrospective, descriptive, observational, and cross-sectional was performed using computed tomography angiography (CTA) of adult (> 18 years of age) patients, without gender distinction, of Mexican origin. Measuring techniques were standardized using the suprasternal notch to analyze linear and maximum heights, linear and curved lengths, and the vertebral origin and bifurcation levels of the BCT. Results A total of 270 CTA were obtained (66.7% men and 33.3% women). A high position of BCT was present in 64.81% (n 175/270). The mean linear medial height was 0.58 ± 1.91 cm, the maximum height of the free edge was 3.85 ± 2.04 cm, side length of the midline at the maximum height of the free edge was 1.46 ± 2.59, linear length 3.72 ± 0.70, and a curve length 3.99 ± 0.79. The BCT origin was most predominant at the T3 (57.9%) and T4 (27.0%) vertebral levels, with the bifurcation at T2 (57.9%) and T1 (36.2%). Conclusions There is a high prevalence of high position BCT in our population. Patients should be assessed before any procedures in the area, due to the potential risk of complications.

Coppice-rotation stands comprise 20 to 30% of the Eucalyptus forests in Brazil and understanding the factors influencing the production ecology of the coppice-rotation is fundamental to improving silvicultural prescriptions. We investigated the effect of harvesting method, stump height and stump cleaning on survival, uniformity, growth, above-ground biomass and light use efficiency in a short rotation of a highly productive E. grandis x E. urophylla clone at two scales in Brazil. At the field experiment scale, treatments were composed of harvesting techniques (Chainsaw and Feller Buncher), stump height (High and Low) and stump cleaning (No harvesting residues over the stump or with residues). The treatments strongly affected growth in height and volume, with less effect on diameter. The largest response came from harvesting method, with mechanized harvesting with a 33% lower mean annual increment (MAI, 33 m³ ha−1 y−1) than harvesting with the chainsaw (50 m³ ha−1 y−1). Stump height did not influence growth in chainsaw clear-cut, but low stumps after Feller Buncher harvesting reduced growth by 23% (30 m³ ha−1 y−1) compared with high stumps (36 m³ ha−1 y−1). Stumps cleaning increased survival only in the semi-mechanized harvest but did not result in a difference in yield. Leaf area index and light use efficiency at the end of rotation were impacted by the clear-cut method, with an average of 3.3 and 2.1 m² m−2, and 0.7 and 0.57 g MJ−1 for chainsaw and Feller Buncher clear cut, respectively. The percentage of stumps that remained intact, the uniformity among individuals, the light capture and the light use efficiency, presented a r² of 67%, 55%, 60% and 86% (p-value

Wnt signaling pathways are recognized for having major roles in tissue patterning and cell proliferation. In the last years, remarkable progress has been made in elucidating the molecular and cellular mechanisms that underlie sequential segmentation and axial elongation in various arthropods, and the canonical Wnt pathway has emerged as an essential factor in these processes. Here we review, with a comparative perspective, the current evidence concerning the participation of this pathway during posterior growth, its degree of conservation among the different subphyla within Arthropoda and its relationship with the rest of the gene regulatory network involved. Furthermore, we discuss how this signaling pathway could regulate segmentation to establish this repetitive pattern and, at the same time, probably modulate different cellular processes precisely coupled to axial elongation. Based on the information collected, we suggest that this pathway plays an organizing role in the formation of the body segments through the regulation of the dynamic expression of segmentation genes, via controlling the caudal gene, at the posterior region of the embryo/larva, that is necessary for the correct sequential formation of body segments in most arthropods and possibly in their common segmented ancestor. On the other hand, there is insufficient evidence to link this pathway to axial elongation by controlling its main cellular processes, such as convergent extension and cell proliferation. However, conclusions are premature until more studies incorporating diverse arthropods are carried out.

Taurine is considered the most abundant free amino acid in the brain. Even though there are endogenous mechanisms for taurine production in neural cells, an exogenous supply of taurine is required to meet physiological needs. Taurine is required for optimal postnatal brain development; however, its brain concentration decreases with age. Synthesis of taurine in the central nervous system (CNS) occurs predominantly in astrocytes. A metabolic coupling between astrocytes and neurons has been reported, in which astrocytes provide neurons with hypotaurine as a substrate for taurine production. Taurine has antioxidative, osmoregulatory, and anti-inflammatory functions, among other cytoprotective properties. Astrocytes release taurine as a gliotransmitter, promoting both extracellular and intracellular effects in neurons. The extracellular effects include binding to neuronal GABAA and glycine receptors, with subsequent cellular hyperpolarization, and attenuation of N-methyl-D-aspartic acid (NMDA)-mediated glutamate excitotoxicity. Taurine intracellular effects are directed toward calcium homeostatic pathway, reducing calcium overload and thus preventing excitotoxicity, mitochondrial stress, and apoptosis. However, several physiological aspects of taurine remain unclear, such as the existence or not of a specific taurine receptor. Therefore, further research is needed not only in astrocytes and neurons, but also in other glial cells in order to fully comprehend taurine metabolism and function in the brain. Nonetheless, astrocyte’s role in taurine-induced neuroprotective functions should be considered as a promising therapeutic target of several neuroinflammatory, neurodegenerative and psychiatric diseases in the near future. This review provides an overview of the significant relationship between taurine and astrocytes, as well as its homeostatic and neuroprotective role in the nervous system.

Objectives: The antimicrobial activity of tedizolid and comparators was evaluated against a large worldwide collection of Staphylococcus aureus and Streptococcus pneumoniae isolates recovered from patients with pneumonia. Methods: Clinical isolates were collected from patients in 96 medical centres in the Asia-Pacific region, Europe, Latin America and the USA between 2017 and 2019, and tested for susceptibility by reference broth microdilution. Results: The most active agents against S. aureus (n = 4667) were tedizolid (100.0% susceptible), linezolid (100.0% susceptible), ceftaroline (96.2% susceptible) and vancomycin (100.0% susceptible), but only tedizolid, linezolid and vancomycin retained activity against >95% of meticillin-resistant S. aureus isolates from all regions. In general, linezolid, ceftriaxone, ceftaroline, levofloxacin, penicillin and vancomycin showed susceptibility rates >95% against S. pneumoniae (n = 3008). However, only linezolid, ceftaroline, levofloxacin and vancomycin remained active (>95% susceptibility) against isolates displaying penicillin-non-susceptible or multidrug-resistant phenotypes. Penicillin-non-susceptible S. pneumoniae isolates were recovered less frequently from patients aged

Objectives: The aim of this study was to investigate the feasibility of saliva sampling as a non-invasive and safer tool to detect severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and to compare its reproducibility and sensitivity with nasopharyngeal swab samples (NPS). The use of sample pools was also investigated. Methods: A total of 2107 paired samples were collected from asymptomatic healthcare and office workers in Mexico City. Sixty of these samples were also analyzed in two other independent laboratories for concordance analysis. Sample processing and analysis of virus genetic material were performed according to standard protocols described elsewhere. A pooling analysis was performed by analyzing the saliva pool and the individual pool components. Results: The concordance between NPS and saliva results was 95.2% (kappa 0.727, p = 0.0001) and 97.9% without considering inconclusive results (kappa 0.852, p = 0.0001). Saliva had a lower number of inconclusive results than NPS (0.9% vs 1.9%). Furthermore, saliva showed a significantly higher concentration of both total RNA and viral copies than NPS. Comparison of our results with those of the other two laboratories showed 100% and 97% concordance. Saliva samples are stable without the use of any preservative, and a positive SARS-CoV-2 sample can be detected 5, 10, and 15 days after collection when the sample is stored at 4 °C. Conclusions: The study results indicate that saliva is as effective as NPS for the identification of SARS-CoV-2-infected asymptomatic patients. Sample pooling facilitates the analysis of a larger number of samples, with the benefit of cost reduction.

Background: The limited armamentarium against multidrug-resistant Gram-negative bacilli led to the development of a new generation of β-lactam/β-lactamase inhibitor combinations (BL/BLI). Objectives: To evaluate the in vitro activity of ceftazidime/avibactam, ceftolozane/tazobactam, meropenem/vaborbactam, and imipenem/relebactam against Pseudomonas aeruginosa isolates recovered from patients hospitalized with skin and soft tissue infections (SSTIs) in several countries around the world. Methods: A total of 360 P. aeruginosa isolates were consecutively collected from 47 medical centers located in Western Europe, Eastern Europe, the Asia-Pacific region, and Latin America. Susceptibility testing was performed by broth microdilution method at a monitoring laboratory. EUCAST breakpoints were applied. Results: Ceftazidime/avibactam (98.3% susceptible), ceftolozane/tazobactam (98.6% susceptible), and imipenem/relebactam (98.3% susceptible) were the most active compounds after colistin (100.0% susceptible) and retained activity against isolates nonsusceptible to piperacillin/tazobactam, meropenem, imipenem, and/or ceftazidime. Meropenem-vaborbactam was active against 94.2% of isolates. Ceftazidime/avibactam was the most active BL/BLI against meropenem-nonsusceptible (92.6% susceptible) and imipenem-resistant (93.8% susceptible) isolates, whereas ceftolozane/tazobactam was the most active BL/BLI against piperacillin/tazobactam-resistant (91.1% susceptible) and ceftazidime-resistant (91.7% susceptible) isolates. Conclusions: The recently approved BL/BLIs demonstrated potent activity and broad coverage against contemporary P. aeruginosa isolates from patients with SSTIs.

Objectives: To evaluate the in vitro activity of dalbavancin compared with vancomycin, daptomycin and other agents against a large collection of coagulase-negative staphylococci (CoNS) isolates. Methods: A total of 5088 CoNS causing clinically significant infection were consecutively collected from 122 medical centres in the USA and Europe over 6 years (2014–2019). Isolates were tested for susceptibility by the reference broth microdilution method. Species identification was confirmed by MALDI-TOF. Most isolates were from bloodstream infections (BSIs) (53.5%) or skin/skin structure infections (28.5%). Results: Staphylococcus epidermidis was the most common species overall (54.6%) and for BSI (61.3%). The second most common species were Staphylococcus lugdunensis overall (12.3%) and Staphylococcus hominis for BSI (14.7%). Dalbavancin (MIC50/90, 0.03/0.06 mg/L) inhibited >99.9% of CoNS isolates at ≤0.25 mg/L (susceptible breakpoint for Staphylococcus aureus per CLSI). All species were inhibited at ≤0.25 mg/L dalbavancin, except some S. epidermidis (>99.9%) and Staphylococcus warneri (98.9%) isolates. Staphylococcus capitis and Staphylococcus simulans exhibited the lowest dalbavancin MIC50/90 values (0.015/0.03 mg/L) and Staphylococcus haemolyticus and Staphylococcus saprophyticus the highest (MIC50/90, 0.06/0.12 mg/L); 47.8% of S. epidermidis and 34.7% of S. haemolyticus exhibited decreased susceptibility to vancomycin (MIC ≥ 2 mg/L) and 23.2% of S. capitis and 28.4% of S. warneri showed decreased susceptibility to daptomycin (MIC ≥ 1 mg/L). Conclusion: Antimicrobial susceptibility varied widely among CoNS species. Dalbavancin inhibited >99.9% and 99.1% of isolates at the US-FDA and EUCAST breakpoints, respectively. Clinical studies of dalbavancin for treatment of CoNS infections should be considered based on these in vitro data.

Objective: To evaluate the antimicrobial activity of ceftaroline against Staphylococcus aureus isolated from patients with infective endocarditis (IE). Methods: 23,833 S. aureus isolates were collected consecutively from patients with bloodstream infections (BSI) from 2010 to 2019, via the SENTRY Antimicrobial Surveillance Program, including 396 isolates from patients with a diagnosis of IE. Isolates were collected from 340 medical centers worldwide and susceptibility tested by reference broth microdilution in a monitoring laboratory. Results: The oxacillin resistance (MRSA) rate was 29.0% among IE isolates, and was higher in North America (40.3%) than in Europe (25.4%) or the Latin America/Asia-Pacific region (LATAM-APAC; 18.6%). Ceftaroline was active against 95.2% of IE isolates (MIC50/90, 0.25/1 mg/L), with ceftaroline susceptibility higher in North America (99.2%) and LATAM-APAC (98.3%) than in Europe (92.0%). Among MRSA isolates from IE (n = 115; MIC50/90, 1/2 mg/L), ceftaroline susceptibility was 98.0% in North America, 90.9% in LATAM-APAC, and 68.5% in Europe. Among BSI isolates, MRSA rates were 43.6% in North America and 25.6% in Europe, while ceftaroline susceptibility rates were 98.1% in North America and 95.4% in Europe. Conclusions: Ceftaroline demonstrated potent in vitro activity against a large collection of S. aureus isolates recovered from patients with BSI, including IE.

Abstract An elongated and segmented body plan is a common morphological characteristic of all arthropods and is probably responsible for their high adaptation ability to diverse environments. Most arthropods form their bodies by progressively adding segments, resembling vertebrate somitogenesis. This sequential segmentation relies on a molecular clock that operates in the posterior region of the elongating embryo that combines dynamically with cellular behaviors and tissue rearrangements, allowing the extension of the developing body along its main embryonic axis. Even though the molecular mechanisms involved in elongation and segment formation have been found to be conserved in a considerable degree, cellular processes such as cell division are quite variable between different arthropods. In this study, we show that cell proliferation in the beetle Tribolium castaneum has a nonuniform spatiotemporal patterning during axial elongation. We found that dividing cells are preferentially oriented along the anterior–posterior axis, more abundant and posteriorly localized during thoracic segments formation and that this cell proliferation peak was triggered at the onset of axis elongation. This raise in cell divisions, in turn, was correlated with an increase in the elongation rate, but not with changes in cell density. When DNA synthesis was inhibited over this period, both the area and length of thoracic segments were significantly reduced but not of the first abdominal segment. We discuss the variable participation that different cell division patterns and cell movements may have on arthropod posterior growth and their evolutionary contribution.

Objectives: Escherichia coli, Klebsiella pneumoniae and Proteus mirabilis are urinary tract infection (UTI) pathogens and extended spectrum β-lactamase (ESBL)-producing pathogens exhibit co-resistance to oral fluoroquinolones (FQ) and trimethoprim-sulphamethoxazole (TMP-SMX). This study assessed the prevalence of ESBL phenotypes and co-resistance to FQ and TMP-SMX. Methods: In total, 766 E. coli, 260 K. pneumoniae and 104 P. mirabilis from UTIs in 18 countries were evaluated for susceptibility in the SENTRY surveillance programme, and results interpreted using EUCAST criteria. Results: E. coli, K. pneumoniae and P. mirabilis accounted for 57.1%, 11.3% and 7.8%, respectively, of the isolates. Among E. coli, resistance to levofloxacin and TMP-SMX ranged from 21.8% to 32.7% for all isolates increasing to 66.5–67.0% among those with a ESBL phenotype (17.9% of all UTI E. coli from Europe were ESBL phenotypes). In contrast, all E. coli were susceptible to meropenem. For K. pneumoniae, resistance rates for levofloxacin and TMP-SMX were 32.2–40.0% increasing to 69.1–78.6% for ESBL phenotypes. Meropenem was the most active agent, with 7.7% resistance. Among P. mirabilis resistance to levofloxacin and TMP-SMX was 26–38.5% and increased to 100% for ESBL phenotypes. No meropenem-resistant P. mirabilis were reported. Conclusions: High co-resistance rates were observed for oral antibiotics among ESBL phenotypes raising concerns regarding empiric use of FQ and TMP-SMX for treating resistant UTIs outside of the hospital. In contrast, intravenous carbapenems retain activity against resistant UTI pathogens. New oral options with the spectrum of the carbapenems would address an unmet need for managing resistant UTIs.

Biodiesel made from oils is rich in polyunsaturated fatty acids methyl esters, and, consequently, presents high tendency to oxidize. Biodiesel made from fats, on the other hand, is mainly comprised by saturated chains. Although it is highly stable, they easily crystalize at low temperatures. Blends from both can exhibit optimized properties. In this work, oxidative stability, expressed by induction period (IP), and cold filter plugging point (CFPP) of blends from palm, palm kernel, babassu, tallow or lard biodiesels with soy one were measured. Biodiesel samples were prepared by two steps transesterification methodology with KOH catalysis followed by H2SO4. IP increases, as the fat biodiesel content in the blend is higher, as expected. Blends comprised by 60% of fat biodiesel by volume had their IP increased from 1.5 (lard) to 2 times (palm kernel), compared to soy one. At this level, IP was found 8 h or higher, except for palm, which 80% was required. CFPP was observed at 8 °C or lower for the blends containing up to 60% of all the fat biodiesel, except for the palm one, which a 20% content must not be surpassed. Palm kernel 80% biodiesel blend reached the Brazilian specification, that is, IP higher than 12 h and CFPP lower than 5 °C.

Objectives: The in vitro antimicrobial activities of telavancin and comparator antimicrobials were evaluated against recent Staphylococcus aureus (S. aureus) clinical isolates collected in the United States of America (USA). Methods: A total of 15 882 S. aureus isolates were collected (2014–2016) as part of the SENTRY Antimicrobial Surveillance Program from sites located in all US Census Bureau divisions. Broth microdilution MIC values were measured using current reference methods. Data were stratified by year and census division, and resistance rates were analysed for significant trends. Previously published data on methicillin-resistant S. aureus (MRSA) and multidrug-resistant (MDR) MRSA isolates (collected 2011–2013) were merged with the current isolate set to examine longer term resistance trends. Results: Telavancin antimicrobial activity against MRSA and MDR MRSA isolates (MIC50/90 values, 0.03/0.06 μg/mL for both subsets) remained unchanged over the 3-year surveillance period, and all isolates were susceptible to telavancin. No difference in telavancin activity was noted when MIC data were stratified by year or US Census Bureau division. When merged data (2011–2016) were analysed, the MRSA rate decreased for the entire USA and six individual census divisions, although the overall rate remained considerable. The overall US MDR MRSA rate also remained considerable and was unchanged from 2011–2016. Conclusions: The sustained potent activity of telavancin against US S. aureus isolates (100% susceptible) and the high rates of MRSA and MDR MRSA in the USA support the continued use of telavancin to treat indicated serious infections caused by S. aureus.

RAS oncogenes are chief tumorigenic drivers, and their mutation constitutes a universal predictor of poor outcome and treatment resistance. Despite more than 30 years of intensive research since the identification of the first RAS mutation, most attempts to therapeutically target RAS mutants have failed to reach the clinic. In fact, the first mutant RAS inhibitor, Sotorasib, was only approved by the FDA until 2021. However, since Sotorasib targets the KRAS G12C mutant with high specificity, relatively few patients will benefit from this therapy. On the other hand, indirect approaches to inhibit the RAS pathway have revealed very intricate cascades involving feedback loops impossible to overcome with currently available therapies. Some of these mechanisms play different roles along the multistep carcinogenic process. For instance, although mutant RAS increases replicative, metabolic and oxidative stress, adaptive responses alleviate these conditions to preserve cellular survival and avoid the onset of oncogene-induced senescence during tumorigenesis. The resulting rewiring of cellular mechanisms involves the DNA damage response and pathways associated with oxidative stress, which are co-opted by cancer cells to promote survival, proliferation, and chemo- and radioresistance. Nonetheless, these systems become so crucial to cancer cells that they can be exploited as specific tumor vulnerabilities. Here, we discuss key aspects of RAS biology and detail some of the mechanisms that mediate chemo- and radiotherapy resistance of mutant RAS cancers through the DNA repair pathways. We also discuss recent progress in therapeutic RAS targeting and propose future directions for the field.

Introduction: A high riding jugular bulb is the most common anatomical variation of the petrous section of the temporal bone. The objective of our study was to determine the prevalence of dehiscence and high riding jugular bulb (HRJB) in a Mexican population. Material and methods: This is an observational retrospective, cross-sectional, and descriptive study. The presence of High Riding Jugular Bulb was analyzed, taking as reference the basal turn of the cochlea in axial sections and then reformatted in coronal sections to observe the presence or absence of dehiscence. Patients between 0 to 95 years of age were included and classified by age groups for analysis. Infants included patients ≤ 2 years old, children from 3 to 12, teenagers from 13 to 18, and adults included patients >18 years of age. Results: A total of 229 CT (458 ears) were included. The prevalence of HRJB was 38.4%, higher in women (44.6%), and present bilaterally in 7.9% of patients. It is the highest prevalence reported in the literature. Dehiscence was present in 1.3% of the population. Conclusion: High Riding Jugular Bulb and its dehiscence are important anatomical variations associated with several symptoms like unexplained headache and tinnitus. Due to unawareness of these variations in surgery, the lesion to a vessel could be fatal. It is otorhinolaryngologists be aware of the high prevalence for patient safety.

The increase in the antibiotic resistance of bacteria is a serious threat to public health. Photodynamic inactivation (PDI) of micro-organisms is a reliable antimicrobial therapy to treat a broad spectrum of complex infections. The development of new photosensitizers with suitable properties is a key factor to consider in the optimization of this therapy. In this sense, four corroles were designed to study how the number of cationic centers can influence the efficacy of antibacterial photodynamic treatments. First, 5,10,15-Tris(pentafluorophenyl)corrole (Co) and 5,15-bis(pentafluorophenyl)-10-(4-(trifluoromethyl)phenyl)corrole (Co-CF3) were synthesized, and then derivatized by nucleophilic aromatic substitution with 2-dimethylaminoethanol and 2-(dimethylamino)ethylamine, obtaining corroles Co-3NMe2 and Co-CF3-2NMe2, respectively. The straightforward synthetic strategy gave rise to macrocycles with different numbers of tertiary amines that can acquire positive charges in an aqueous medium by protonation at physiological pH. Spectroscopic and photodynamic studies demonstrated that their properties as chromophores and photosensitizers were unaffected, regardless of the substituent groups on the periphery. All tetrapyrrolic macrocycles were able to produce reactive oxygen species (ROS) by both photodynamic mechanisms. Uptake experiments, the level of ROS produced in vitro, and PDI treatments mediated by these compounds were assessed against clinical strains: methicillin-resistant Staphylococcus aureus and Klebsiella pneumoniae. In vitro experiments indicated that the peripheral substitution significantly affected the uptake of the photosensitizers by microbes and, consequently, the photoinactivation performance. Co-3NMe2 was the most effective in killing both Gram-positive and Gram-negative bacteria (inactivation > 99.99%). This work lays the foundations for the development of new corrole derivatives having pH-activable cationic groups and with plausible applications as effective broad-spectrum antimicrobial photosensitizers.

The activities of dalbavancin and comparator agents were evaluated against Staphylococcus aureus isolated from the lower respiratory tract of cystic fibrosis (CF) and non-CF patients with pneumonia. Bacterial isolates (n = 357) were collected from CF patients in 36 medical centers worldwide (2018–2019) and susceptibility tested using reference broth microdilution. Susceptibility results from these isolates were compared with those for 725 S. aureus isolates consecutively collected from non-CF patients with pneumonia from the same medical centers over the same period. Only isolates determined to be the probable cause of pneumonia were included in the study. Susceptibility profiles were very similar among isolates from CF and non-CF patients. Dalbavancin exhibited potent activity (MIC50/90, 0.03/0.03 mg/L) and complete coverage (100.0% susceptibility) against isolates from CF and non-CF patients. Ceftaroline (MIC50/90, 0.25/1 mg/L) was active against 97.8% and 98.1% of isolates from CF and non-CF patients, respectively. Oxacillin resistance (MRSA) rates were 27.7% among CF and 28.7% among non-CF patients. Among MRSA isolates from CF/non-CF patients (n = 99/208), susceptibility to ceftaroline, clindamycin, levofloxacin, and tetracycline were 91.9%/93.3%, 58.6%/64.4%, 40.4%/29.3%, and 83.8%/89.4%, respectively. Dalbavancin demonstrated high potency against S. aureus from CF and non-CF patients and may represent a valuable treatment option for CF patients with MRSA pulmonary infection.

Marijuana (Cannabis sp.) is among the most recurred controlled substances in the world, and there is a growing tendency to legalize its possession and use; however, the genotoxic effects of marijuana remain under debate. A clear definition of marijuana's genotoxic effects remains obscure by the simultaneous consumption of tobacco and other recreational substances. In order to assess the genotoxic effects of marijuana and to prevent the bias caused by the use of substances other than cannabis, we recruited marijuana users that were sub-divided into three categories: (1) users of marijuana-only (M), (2) users of marijuana and tobacco (M+T), and (3) users of marijuana plus other recreative substances or illicit drugs (M+O), all the groups were compared against a non-user control group. We quantified DNA damage by detection of γH2AX levels and quantification of micronuclei (MN), one of the best-established methods for measuring chromosomal DNA damage. We found increased levels of γH2AX in peripheral blood lymphocytes from the M and M+T groups, and increased levels of MNs in cultures from M+T group. Our results suggest a DNA damage increment for M and M+T groups but the extent of chromosomal damage (revealed here by the presence of MNs and NBuds) might be related to the compounds found in tobacco. We also observed an elevated nuclear division index in all marijuana users in comparison to the control group suggesting a cytostatic dysregulation caused by cannabis use. Our study is the first in Mexico to assess the genotoxicity of marijuana in mono-users and in combination with other illicit drugs.

The use of flexible bronchoscopy (FB) with bronchoalveolar lavage (BAL) to diagnose and manage pulmonary complications has been shown to be safe in adult cancer patients, but whether its use is safe in pediatric cancer patients remains unclear. Thus, to describe the landscape of FB outcomes in pediatric cancer patients and to help define the populations most likely to benefit from the procedure, we undertook a retrospective review of FBs performed in patients younger than 21 years treated at our institution from 2002 to 2017. We found that a greater volume of total fluid instilled during BAL was significantly associated with increased probabilities of positive BAL culture (p=0.042), positive bacterial BAL culture (p=0.037), and positive viral BAL culture (p=0.0496). In more than half of the FB cases, findings resulted in alterations in antimicrobial treatment. Our study suggests that for pediatric cancer patients, FB is safe, likely provides diagnostic and/or therapeutic benefits, and has implications for treatment decisions.

Purpose: To assess the relationship and prognostic value of the neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) with poor final best-corrected visual acuity (BCVA) after surgical repair of open globe injuries (OGI) in adults.Design: Retrospective analysis of data from an ongoing prospective cohort of consecutive patients.Methods: In a tertiary university hospital, 197 eyes of 197 patients were included between 2013 and 2017. NLR and PLR were obtained from pre-operative blood tests to analyze its relationship with poor final BCVA.Results: Severe visual impairment (SVI) was defined as ≤20/200, and was observed in 96 (48.7%) patients after surgical repair of OGI. SVI patients had higher NLR (7.4 ± 6.6 vs. 4.0 ± 3.2, p < 0.001), and PLR (167 ± 92 vs. 139 ± 64; p = 0.021) than non-SVI. NLR ≥ 3.47 and PLR ≥ 112.2 were the best cut-off values for SVI, were univariate risk factors for SVI, and had sensitivity: 69.0, 71.4, and specificity: 63.6, 44.8, respectively. In multivariate analysis, only OTS, athalamia, and hyphema remained as risk factors. NLR had significant correlation with ocular trauma score (OTS) (r = −0.389, p < 0.001) and final BCVA (r = 0.345, p < 0.001).Limitations: Simultaneous trauma in other parts of the body that could influence the laboratory findings.Conclusion: Patients with SVI after a repaired OGI had increased pre-operative NLR and PLR levels. High NLR and PLR are risk factors for SVI in univariate analysis. It is confirmed that low OTS is a risk factor for SVI. High NLR and PLR could be used as a prognostic tool to identify patients at higher risk for SVI after repair of OGI.

Las dificultades de succión, deglución y alimentación han sido ampliamente estudiadas en población pediátrica portadora de alguna condición congénita o adquirida. La severidad y variedad de signos y síntomas, orientan a la evaluación y tratamiento con relativa baja complejidad, si se cuenta con los especialistas y equipamiento necesario. Se transforma en un desafío mayor el enfrentamiento de alteraciones de deglución y alimentación en recién nacidos y lactantes que no presentan condiciones neurológicas, genéticas o metabólicas. Las dificultades se relacionan con fallas en la seguridad, eficiencia y la conducta del niño al alimentarse. En este artículo se revisa el desarrollo de la alimentación, su relación con el tracto aéreo digestivo y el impacto en la adquisición del habla.También se detallan criterios de evaluación e intervención, con énfasis en el manejo de equipos multidisciplinarios e incorporación activa de la familia.

Introduction: The Outcome Measures in Rheumatoid Arthritis Clinical Trials (OMERACT) and Rheumatoid Arthritis Magnetic Resonance Imaging Score (RAMRIS), with the EULAR-OMERACT-2005 MR-Atlas, demonstrate characteristics and lesion degrees (synovitis, erosions, bone marrow edema [BME]) in rheumatoid arthritis (R.A.) clinical diagnosis for follow-up and treatment response. Our study’s objective was to use RAMRIS in patients from three R.A. phases to detect lesions according to their tissue characterization (fluid levels in tissue) using different magnetic resonance imaging (MRI) sequences. Methods: Sixty contrast-enhanced MRIs from R.A. patients (clinical suspect arthralgia [CSA] – 38%, early R.A. [ERA] – 37%, and established [R.A.] – 25%) were evaluated according to the American College of Rheumatology (ACR-EULAR)-2010 criteria. R.A. lesions evaluation was performed with RAMRIS/Atlas/scoring; our analysis added the presence of lesions in the thumb and wrist (tenosynovitis, synovitis, erosions, and BME), proposing an “extended RAMRIS.” Results: Overall, 83% (50/60) women, mean 42 ± 13.5 (19-70) years-of-age, from 1731 evaluated sites, 964 lesions were identified. Synovitis 46% (445/964) was most frequently found in the carpal bones 72% (321/445). Extended RAMRIS demonstrated tenosynovitis and erosions in 1st carpometacarpal, 1st metacarpophalangeal, and hand-wrist tenosynovitis. Gadolinium contrast showed synovial and erosions enhancement indicating active lesions, most predominantly in ERA. Conclusions: Extended RAMRIS score was not statistically different (p = 0.43) from RAMRIS-2005. However, it considers all hand-wrist bone joint sites and tendon lesions needed for assessing a more accurate degree of disease development. A proposed extended RAMRIS should be considered.