AZD3152 neutralizes SARS-CoV-2 historical and contemporary variants and is protective in hamsters and well tolerated in adults.

The evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in variants that can escape neutralization by therapeutic antibodies. Here, we describe AZD3152, a SARS-CoV-2-neutralizing monoclonal antibody designed to provide improved potency and coverage against emerging variants. AZD3152 binds to the back left shoulder of the SARS-CoV-2 spike protein receptor binding domain and prevents interaction with the human angiotensin-converting enzyme 2 receptor. AZD3152 potently neutralized a broad panel of pseudovirus variants, including the currently dominant Omicron variant JN.1 but has reduced potency against XBB subvariants containing F456L. In vitro studies confirmed F456L resistance and additionally identified T415I and K458E as escape mutations. In a Syrian hamster challenge model, prophylactic administration of AZD3152 protected hamsters from weight loss and inflammation-related lung pathologies and reduced lung viral load. In the phase 1 sentinel safety cohort of the ongoing SUPERNOVA study (ClinicalTrials.gov: NCT05648110), a single 600-mg intramuscular injection of AZD5156 (containing 300 mg each of AZD3152 and cilgavimab) was well tolerated in adults through day 91. Observed serum concentrations of AZD3152 through day 91 were similar to those observed with cilgavimab and consistent with predictions for AZD7442, a SARS-CoV-2-neutralizing antibody combination of cilgavimab and tixagevimab, in a population pharmacokinetic model. On the basis of its pharmacokinetic characteristics, AZD3152 is predicted to provide durable protection against symptomatic coronavirus disease 2019 caused by susceptible SARS-CoV-2 variants, such as JN.1, in humans.

Do Activities Performed within the Intra-Contrast Rest Interval Affect Neuromuscular Performance during Complex-Contrast Training Protocols?

The aim of this study was to analyze the acute effects of including different exercises within the intra-contrast rest interval (ICRI) of a complex-contrast training (CCT) session. Seventeen recreationally active males completed three different CCT protocols. Programs consisted of a contrast pair combining a moderate-intensity conditioning activity (i.e., a back squat) with a lower-body high-velocity exercise (i.e., a vertical jump) and only differed in the activities performed during the ICRI: 1) passive recovery (CCTPASS); 2) a mobility exercise (CCTMOB); and 3) an upper-body high-intensity strength exercise (i.e., a bench press) (CCTSTR). Countermovement jump and bench press throw metrics were evaluated at baseline and after each set during the workout. The rate of perceived exertion was recorded post-session. Non-significant differences in performance were found between CCTPASS, CCTMOB and CCTSTR throughout the session. Significant declines (p < 0.05) were observed for CMJ peak power in the last 2-3 repetitions of each set, irrespective of the protocol. CCTSTR was perceived as more intense than CCTPASS and CCTMOB (p < 0.05). From a neuromuscular performance perspective, including activities during the ICRI (mobility drills or high-intensity strength exercises) may be a suitable strategy to optimize CCT prescription since the acute responses were similar to those found with passive rest periods. Finally, prescribing a lower number of repetitions per set is recommended to attenuate mechanical performance impairment during CCT protocols, irrespective of the activities completed within the ICRI.

Evaluation of markers of immunity in different metastatic immune microenvironments suggests more suppression within breast to liver metastases in breast cancer.

PURPOSE: Programmed death receptor ligand-1 (PD-L1) expression and tumor mutational burden (TMB) are approved screening biomarkers for immune checkpoint inhibition (ICI) in advanced triple negative breast cancer. We examined these biomarkers along with characterization of the tumor microenvironment (TME) between breast tumors (BrTs), axillary metastases (AxMs), liver metastases (LvMs), non-axillary lymph node metastases, and non-liver metastases to determine differences related to site of metastatic disease. METHODS: 3076 unpaired biopsies from breast cancer patients were analyzed using whole transcriptome sequencing and NextGen DNA depicting TMB within tumor sites. The PD-L1 positivity was determined with VENTANA PD-L1 (SP142) assay. The immune cell fraction within the TME was calculated by QuantiSeq and MCP-counter. RESULTS: Compared to BrT, more LvM samples had a high TMB (≥ 10 mutations/Mb) and fewer LvM samples had PD-L1+ expression. Evaluation of the TME revealed that LvM sites harbored lower infiltration of adaptive immune cells, such as CD4+, CD8+, and regulatory T-cells compared with the BrT foci. We saw differences in innate immune cell infiltration in LvM compared to BrT, including neutrophils and NK cells. CONCLUSIONS: LvMs are less likely to express PD-L1+ tumor cells but more likely to harbor high TMB as compared to BrTs. Unlike AxMs, LvMs represent a more immunosuppressed TME and demonstrate lower gene expression associated with adaptive immunity compared to BrTs. These findings suggest biopsy site be considered when interpreting results that influence ICI use for treatment and further investigation of immune composition and biomarkers expression by metastatic site.

Enhancement of oleanolic acid concentration through acid hydrolysis of saponin-rich extracts from Chenopodium berlandieri.

The study investigated Chenopodium berlandieri to analyze its oleanolic acid (OA) content. Response surface methodology with central composite design was used to improve saponin extraction, varying temperature, ethanol, and sample-to-solvent ratio. Best conditions (65 °C, 50% ethanol, 1:10 ratio) yielded 53.45 ± 0.63 mg/g of extract from Huauzontle seeds. Temperature linearly impacted extract yield, while temperature and ethanol influenced total saponin content. Hydrolyzing saponin-rich extracts produced OA-rich extracts. Characterization via HPLC-ELSD and LC-MS identified OA4 as the most concentrated OA saponin (5.54 ± 0.16 mg/g). OA alone reached 2.02 ± 0.12 mg/g. Acid hydrolysis increased OA content by up to 3.27×, highlighting the potential of hydrolyzed Huauzontle extracts as a natural ingredient for various industries due to enhanced OA content.

NMDA receptor-mediated Ca2+ signaling: Impact on cell cycle regulation and the development of neurodegenerative diseases and cancer.

NMDA receptors are Ca2+-permeable ligand-gated ion channels that mediate fast excitatory transmission in the central nervous system. NMDA receptors regulate the proliferation and differentiation of neural progenitor cells and also play critical roles in neural plasticity, memory, and learning. In addition to their physiological role, NMDA receptors are also involved in glutamate-mediated excitotoxicity, which results from excessive glutamate stimulation, leading to Ca2+ overload, and ultimately to neuronal death. Thus, NMDA receptor-mediated excitotoxicity has been linked to several neurodegenerative diseases such as Alzheimer's, Parkinson's, Huntington's, dementia, and stroke. Interestingly, in addition to its effects on cell death, aberrant expression or activation of NMDA receptors is also involved in pathological cellular proliferation, and is implicated in the invasion and proliferation of various types of cancer. These disorders are thought to be related to the contribution of NMDA receptors to cell proliferation and cell death through cell cycle modulation. This review aims to discuss the evidence implicating NMDA receptor activity in cell cycle regulation and the link between aberrant NMDA receptor activity and the development of neurodegenerative diseases and cancer due to cell cycle dysregulation. The information presented here will provide insights into the signaling pathways and the contribution of NMDA receptors to these diseases, and suggests that NMDA receptors are promising targets for the prevention and treatment of these diseases, which are leading causes of death and disability worldwide.

Pharmacological Characterization of the Zebrafish (Danio Rerio) Histamine H1 Receptor Reveals the Involvement of the Second Extracellular Loop in the Binding of Histamine.

The zebrafish (Danio rerio) histamine H1 receptor gene (zfH1R) was cloned in 2007 and reported to be involved in fish locomotion. Yet, no detailed characterization of its pharmacology and signaling properties have so far been reported. In this study, we pharmacologically characterized the zfH1R expressed in HEK-293T cells by means of [3H]-mepyramine binding and G protein-signaling assays. The zfH1R [dissociation constant (KD), 0.7 nM] displayed similar affinity for the antagonist [3H]-mepyramine as the human histamine H1 receptor (hH1R) (KD, 1.5 nM), whereas the affinity for histamine is 100-fold higher than for the human H1R. The zfH1R couples to Gαq/11 proteins and activates several reporter genes, i.e., NFAT, NFÏ°B, CRE, VEGF, COX-2, SRE, and AP-1, and zfH1R-mediated signaling is prevented by the Gαq/11 inhibitor YM-254890 and the antagonist mepyramine. Molecular modeling of the zfH1R and human H1R shows that the binding pockets are identical, implying that variations along the ligand binding pathway could underly the differences in histamine affinity instead. Targeting differentially charged residues in extracellular loop 2 (ECL2) using site-directed mutagenesis revealed that Arg21045x55 is most likely involved in the binding process of histamine in zfH1R. This study aids the understanding of the pharmacological differences between H1R orthologs and the role of ECL2 in histamine binding and provides fundamental information for the understanding of the histaminergic system in the zebrafish. SIGNIFICANCE STATEMENT: The use of the zebrafish as in vivo models in neuroscience is growing exponentially, which asks for detailed characterization of the aminergic neurotransmitter systems in this model. This study is the first to pharmacologically characterize the zebrafish histamine H1 receptor after expression in HEK-293T cells. The results show a high pharmacological and functional resemblance with the human ortholog but also reveal interesting structural differences and unveils an important role of the second extracellular loop in histamine binding.

Impact of In Vitro Digestion on the Digestibility, Amino Acid Release, and Antioxidant Activity of Amaranth (Amaranthus cruentus L.) and Cañihua (Chenopodium pallidicaule Aellen) Proteins in Caco-2 and HepG2 Cells.

This study evaluated the impact of in vitro gastrointestinal digestion on the digestibility, amino acid release, and antioxidant activity of proteins from amaranth (Amarantus cruentus L.) and cañihua (Chenopodium pallidicaule Aellen). Antioxidant activity was assessed using ORAC, ABTS, DPPH, and cellular antioxidant activity (CAA) assays in human intestinal Caco-2 and hepatic Hep-G2 cell lines. The results showed that amaranth had higher protein digestibility (79.19%) than cañihua (71.22%). In addition, intestinal digestion promoted the release of essential amino acids, such as leucine, lysine, and phenylalanine, in both protein concentrates. Concentrations of amaranth and cañihua proteins, ranging from 0.125 to 1.0 mg mL-1, were non-cytotoxic in both cell lines. At a concentration of 0.750 mg mL-1, simulated gastrointestinal digestion enhanced cellular antioxidant activity. Intestinal digest fractions containing peptides >5 kDa were the principal contributors to CAA in both cell lines. Notably, cañihua proteins exhibited high CAA, reaching values of 85.55% and 82.57% in Caco-2 and HepG2 cells, respectively, compared to amaranth proteins, which reached 84.68% in Caco-2 and 81.06% in HepG2 cells. In conclusion, both amaranth and cañihua proteins, after simulated gastrointestinal digestion, showcased high digestibility and released peptides and amino acids with potent antioxidant properties, underscoring their potential health benefits.

Impact of SARS-CoV-2 ORF6 and its variant polymorphisms on host responses and viral pathogenesis.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) encodes several proteins that inhibit host interferon responses. Among these, ORF6 antagonizes interferon signaling by disrupting nucleocytoplasmic trafficking through interactions with the nuclear pore complex components Nup98-Rae1. However, the roles and contributions of ORF6 during physiological infection remain unexplored. We assessed the role of ORF6 during infection using recombinant viruses carrying a deletion or loss-of-function (LoF) mutation in ORF6. ORF6 plays key roles in interferon antagonism and viral pathogenesis by interfering with nuclear import and specifically the translocation of IRF and STAT transcription factors. Additionally, ORF6 inhibits cellular mRNA export, resulting in the remodeling of the host cell proteome, and regulates viral protein expression. Interestingly, the ORF6:D61L mutation that emerged in the Omicron BA.2 and BA.4 variants exhibits reduced interactions with Nup98-Rae1 and consequently impairs immune evasion. Our findings highlight the role of ORF6 in antagonizing innate immunity and emphasize the importance of studying the immune evasion strategies of SARS-CoV-2.

Regime de Informação e tipologia documental no âmbito dos serviços de saúde: noções aplicadas à gestão da informação em hospitais federais do estado do Rio de Janeiro / Information Regime and documental typology in the field of health services: notions applied to information management in federal hospitals in the state of Rio de Janeiro / Régimen de Información y tipología documental en el ámbito de los servicios de salud: nociones aplicadas a la gestión de la información en los hospitales federales del estado de Río de Janeiro

Aborda a tipologia documental em sistemas de informação digitais, compreendendo-a como metadado essencial na estrutura de transferência da informação entre serviços, sistemas e redes de atenção e inovação à saúde. Por meio de pesquisa de campo com gestores de dois hospitais federais do Rio de Janeiro, realiza prospecção e análise da gestão de sistemas de informação digitais em saúde. Os resultados revelaram que o emprego do conceito de Regime de Informação e de seus componentes analíticos permite-nos obter uma visão dos recursos informacionais, tecnológicos, humanos e normativos do sistema nacional de saúde, que integram o Sistema Único de Saúde. Destaca a tipologia documental como um dos elementos constituintes dos sistemas de informação nos serviços dos hospitais, cujas interconexões e articulações expressam os aspectos seletivos e decisórios das práticas e ações de informação

It addresses the document typology in digital information systems, understanding it as essential metadata in the structure of information transfer between attention and innovation health services, systems and networks. Through field research with managers of two federal hospitals in Rio de Janeiro, it prospects and analyzes the management of digital health information systems. The results revealed that the use of the concept of Information System and of its analytical components allows us to obtain a vision of the informational, technological, human and normative resources of the national health system, which are part of the Unified Health System. It highlights the documentary typology as one of the constituent elements of information systems in hospital services, whose interconnections and articulations express the selective and decision-making aspects of information practices and actions

Aborda como objeto la tipología documental en los sistemas de información digital, entendiéndola como un metadato esencial en la estructura de transferencia de información entre servicios, sistemas y redes de atención e innovación en salud. A través de una investigación de campo con gerentes de dos hospitales federales de Río de Janeiro, prospecta y analiza la gestión de los sistemas digitales de información en salud. Los resultados revelaran que la utilización del concepto de Régimen de Información y de sus componen-tes analíticos permítenos obtener una visión de los recursos informacionales, tecnológicos, humanos y normativos del sistema nacional de salud, que integram el Sistema Único de Salud. Destaca la tipología documental como uno de los elementos constitutivos de los sistemas de información cuyas interconexiones y articulaciones expresan los aspectos selectivos y decisorios de las prácticas y acciones informativas reali-zadas en este dominio

Modulation of the substrate specificity of the kinase PDK1 by distinct conformations of the full-length protein.

The activation of at least 23 different mammalian kinases requires the phosphorylation of their hydrophobic motifs by the kinase PDK1. A linker connects the phosphoinositide-binding PH domain to the catalytic domain, which contains a docking site for substrates called the PIF pocket. Here, we used a chemical biology approach to show that PDK1 existed in equilibrium between at least three distinct conformations with differing substrate specificities. The inositol polyphosphate derivative HYG8 bound to the PH domain and disrupted PDK1 dimerization by stabilizing a monomeric conformation in which the PH domain associated with the catalytic domain and the PIF pocket was accessible. In the absence of lipids, HYG8 potently inhibited the phosphorylation of Akt (also termed PKB) but did not affect the intrinsic activity of PDK1 or the phosphorylation of SGK, which requires docking to the PIF pocket. In contrast, the small-molecule valsartan bound to the PIF pocket and stabilized a second distinct monomeric conformation. Our study reveals dynamic conformations of full-length PDK1 in which the location of the linker and the PH domain relative to the catalytic domain determines the selective phosphorylation of PDK1 substrates. The study further suggests new approaches for the design of drugs to selectively modulate signaling downstream of PDK1.

Black Bean Hulls as a Byproduct of an Extraction Process to Enhance Nutraceutical and Glycemic-Related Properties of Nixtamalized Maize Tostadas.

Black bean hulls (BBH) are rich in phenolic compounds, such as anthocyanins, which can be incorporated into common staple foods such as maize tostadas, enhancing the nutraceutical properties of these products. This study incorporates black bean hulls to produce nixtamalized maize tostadas with nutraceutical properties. Nixtamalized corn flour (NCF) and black bean hulls (BBH) were characterized in terms of protein, fat, crude and dietary fiber, anthocyanin concentration, and different starch fractions. NCF and BBH depicted 53.7 and 16.8% of total digestible starch (TDS), respectively, and 1.2 and 7.6% of resistant starch (RS), in the same order. BBH was incorporated into nixtamalized flour at 10, 15, and 20% w/w, and the resulting dough was thermo-mechanically characterized. Tostadas with BBH had higher protein, dietary fiber, and anthocyanin concentrations. Enriched tostadas did not show significant changes in texture or other sensory characteristics. However, a reduction in total digestible starch (61.97 up to 59.07%), an increase in resistant starch (0.46 to 2.3% from control tostadas to 20% BBH tostadas), and a reduction in the predicted glycemic index (52 to 49), among other parameters, indicated that BBH is a suitable alternative for developing nutraceutical food products.

El difícil camino al diagnóstico del paciente con atrofia muscular espinal / The difficult path to diagnosis of the patient with spinal muscular atrophy

Introducción. Con las nuevas terapias, el diagnóstico temprano de la atrofia muscular espinal (AME) es esencial. El objetivo de este estudio es analizar los distintos componentes que influyen en el retraso diagnóstico. Población y métodos. Se incluyeron pacientes con un diagnóstico molecular de AME tipo I, II y III. Se estudiaron varios parámetros, como la edad al momento de la aparición del primer signo, qué signo fue y el intervalo entre este y el diagnóstico confirmado. Neurólogos especialistas realizaron entrevistas que se complementaron con la revisión de historias clínicas cuando fue necesario. Resultados. Se entrevistaron 112 pacientes. AME I n = 40, AME II n = 48, AME III n = 24. La mediana de edad en meses al momento del reporte del primer signo fue AME I: 1,5 (R 0-7), AME II: 9 (R 2-20), AME III: 18 (R 8-180). Los primeros signos fueron reconocidos por los padres en el 75 % al 85 % de las veces en todos los subtipos. La mediana del tiempo transcurrido entre el primer signo y la primera consulta médica fue menor a un mes en los tres tipos. La mediana de tiempo transcurrido en meses entre el primer signo y el diagnóstico molecular confirmado fue en AME I: 2 (R 0-11), en AME II: 10 (3-46) y en AME III: 31,5 (R 4-288). Conclusiones. Existe un significativo retraso en el diagnóstico de la AME relacionado fundamentalmente a la falta de sospecha clínica. La demora es menor en AME I y mayor en AME III. Otros factores incluyen deficiencias en el sistema de salud.

Introduction. News treatments, make early diagnosis of spinal muscular atrophy (SMA) critical. The objective of this study is to analyze the different factors that influence delay in diagnosis. Population and methods. Patients with a molecular diagnosis of types I, II, and III SMA were included. Several parameters were studied, such as age at onset of first sign, what sign it was, and the time from recognition of first sign to confirmed diagnosis. Neurologists specialized in SMA conducted interviews, supported by the review of medical records when deemed necessary. Results. A total of 112 patients were interviewed. SMA I n = 40, SMA II n = 48, SMA III n = 24. The median age in months at the time of reporting the first sign was SMA I: 1.5 (R: 0­7), SMA II: 9 (R: 2­20), SMA III: 18 (R: 8­180). In all subtypes, first signs were identified by parents from 75% to 85% of the times. The median time from first sign to first medical consultation was less than a month in all 3 types. The median time in months, from first sign to confirmed molecular diagnosis in SMA I was: 2 (R: 0­11), in SMA II: 10 (R: 3­46), in SMA III: 31.5 (R: 4­288). Conclusions. There is a significant delay in SMA diagnosis mainly related to the absence of clinical suspicion. The delay is shorter in SMA I and longer in SMA III. Other factors include deficiencies in the health care system.

Knowledge, Perceptions, and Practices on Risks and Disasters Among Medical Students. A Multicenter Cross-Sectional Study in 9 Latin American and Caribbean Countries.

Purpose: The objective of this study was to describe the level of knowledge, perceptions, and practices in relation to risks and disasters in medical schools in Latin America and the Caribbean. Participants and Methods: Multicenter, observational, analytical, non-probabilistic convenience sample study with 2546 medical students in 9 countries of Latin America and the Caribbean. An online survey was conducted between October 2020 and November 2020, using an instrument validated in each country to assess knowledge, perceptions, and practices regarding risk and disaster prevention measures. Frequencies, percentages, mean and standard deviation (SD) were used for descriptive analysis. Differences resulting from the relationship between the variables studied and the level of knowledge were obtained using the Chi-square test. P-value <0.05 was accepted as statistically significant for all analyses. Results: The highest proportion of responses came from women, third-semester students, and those studying in public universities. Students from Colombia and Honduras had the highest percentage of high levels of knowledge about disasters, while Peruvian students had the highest percentage of low levels of knowledge. Women and students from public universities showed a higher proportion of high levels of knowledge. 52.7% considered that they live in a country with a medium risk of natural disasters, while 91.2% said that Latin American and Caribbean countries are not prepared to face natural disasters. Only 43.6% believe they are prepared to help in the event of a natural disaster. Conclusion: Most of medical students from Latin America and Latin America and the Caribbean have high and medium level of knowledge in risks and disasters. However, the implementation of disaster training programs for medical students has the potential to improve the preparedness, knowledge, and skills that are important for medical personnel to improve their self-confidence, and their ability to respond, resulting in more effective systems.

Baculovirus Display of Peptides and Proteins for Medical Applications.

Baculoviridae is a large family of arthropod-infective viruses. Recombinant baculoviruses have many applications, the best known is as a system for large scale protein production in combination with insect cell cultures. More recently recombinant baculoviruses have been utilized for the display of proteins of interest with applications in medicine. In the present review we analyze the different strategies for the display of proteins and peptides on the surface of recombinant baculoviruses and provide some examples of the different proteins displayed. We analyze briefly the commercially available systems for recombinant baculovirus production and display and discuss the future of this emerging and powerful technology.

Structural and Molecular Determinants for Isoform Bias at Human Histamine H3 Receptor Isoforms.

The human histamine H3 receptor (hH3R) is predominantly expressed in the CNS, where it regulates the synthesis and release of histamine and other neurotransmitters. Due to its neuromodulatory role, the hH3R has been associated with various CNS disorders, including Alzheimer's and Parkinson's disease. Markedly, the hH3R gene undergoes extensive splicing, resulting in 20 isoforms, of which 7TM isoforms exhibit variations in the intracellular loop 3 (IL3) and/or C-terminal tail. Particularly, hH3R isoforms that display variations in IL3 (e.g., hH3R-365) are shown to differentially signal via Gαi-dependent pathways upon binding of biased agonists (e.g., immepip, proxifan, imetit). Nevertheless, the mechanisms underlying biased agonism at hH3R isoforms remain unknown. Using a structure-function relationship study with a broad range of H3R agonists, we thereby explored determinants underlying isoform bias at hH3R isoforms that exhibit variations in IL3 (i.e., hH3R-445, -415, -365, and -329) in a Gαi-dependent pathway (cAMP inhibition). Hence, we systematically characterized hH3R isoforms on isoform bias by comparing various ligand properties (i.e., structural and molecular) to the degree of isoform bias. Importantly, our study provides novel insights into the structural and molecular basis of receptor isoform bias, highlighting the importance to study GPCRs with multiple isoforms to better tailor drugs.

The difficult path to diagnosis of the patient with spinal muscular atrophy. / El difícil camino al diagnóstico del paciente con atrofia muscular espinal.

Introduction. News treatments, make early diagnosis of spinal muscular atrophy (SMA) critical. The objective of this study is to analyze the different factors that influence delay in diagnosis. Population and methods. Patients with a molecular diagnosis of types I, II, and III SMA were included. Several parameters were studied, such as age at onset of first sign, what sign it was, and the time from recognition of first sign to confirmed diagnosis. Neurologists specialized in SMA conducted interviews, supported by the review of medical records when deemed necessary. Results. A total of 112 patients were interviewed. SMA I n = 40, SMA II n = 48, SMA III n = 24. The median age in months at the time of reporting the first sign was SMA I: 1.5 (R: 0-7), SMA II: 9 (R: 2-20), SMA III: 18 (R: 8-180). In all subtypes, first signs were identified by parents from 75% to 85% of the times. The median time from first sign to first medical consultation was less than a month in all 3 types. The median time in months, from first sign to confirmed molecular diagnosis in SMA I was: 2 (R: 0-11), in SMA II: 10 (R: 3-46), in SMA III: 31.5 (R: 4-288). Conclusions. There is a significant delay in SMA diagnosis mainly related to the absence of clinical suspicion. The delay is shorter in SMA I and longer in SMA III. Other factors include deficiencies in the health care system.

Introducción. Con las nuevas terapias, el diagnóstico temprano de la atrofia muscular espinal (AME) es esencial. El objetivo de este estudio es analizar los distintos componentes que influyen en el retraso diagnóstico. Población y métodos. Se incluyeron pacientes con un diagnóstico molecular de AME tipo I, II y III. Se estudiaron varios parámetros, como la edad al momento de la aparición del primer signo, qué signo fue y el intervalo entre este y el diagnóstico confirmado. Neurólogos especialistas realizaron entrevistas que se complementaron con la revisión de historias clínicas cuando fue necesario. Resultados. Se entrevistaron 112 pacientes. AME I n = 40, AME II n = 48, AME III n = 24. La mediana de edad en meses al momento del reporte del primer signo fue AME I: 1,5 (R 0-7), AME II: 9 (R 2-20), AME III: 18 (R 8-180). Los primeros signos fueron reconocidos por los padres en el 75 % al 85 % de las veces en todos los subtipos. La mediana del tiempo transcurrido entre el primer signo y la primera consulta médica fue menor a un mes en los tres tipos. La mediana de tiempo transcurrido en meses entre el primer signo y el diagnóstico molecular confirmado fue en AME I: 2 (R 0-11), en AME II: 10 (346) y en AME III: 31,5 (R 4-288). Conclusiones. Existe un significativo retraso en el diagnóstico de la AME relacionado fundamentalmente a la falta de sospecha clínica. La demora es menor en AME I y mayor en AME III. Otros factores incluyen deficiencias en el sistema de salud.

Índice de Robson: riesgo de cesárea en un centro de primer nivel en México / Robson index, c-section risk in a first level center in Mexico

Resumen OBJETIVO: Determinar, conforme al Índice de Robson, la tasa de cesáreas en pacientes atendidas, en un periodo de nueve meses, en el Centro de Investigación Materno-Infantil del Grupo de Estudios al Nacimiento. MATERIALES Y MÉTODOS: Estudio retrospectivo, transversal, descriptivo y monocéntrico efectuado en pacientes embarazadas atendidas en el Centro de Investigación Materno Infantil del Grupo de Estudios al Nacimiento, (CIMIGen) que finalizaron el embarazo por cesárea y en quienes se utilizó el índice de Robson para su clasificación. Parámetros de estudio: indicaciones de la cesárea, riesgo de pérdida del bienestar fetal, alta de progresión del trabajo de parto, falla en la inducción del trabajo de parto, macrosomía, periodo intergenésico corto (menos de 18 meses). RESULTADOS: Se obtuvieron 569 pacientes de las que 228 finalizaron el embarazo mediante cesárea y 341 por parto, lo que representó una tasa de cesáreas del 39.9%. Al aplicar el método de clasificación de Robson, los grupos con mayor contribución relativa a la tasa global de cesáreas fueron: grupo 1 (17.62%), grupo 2, subdividido en sus dos categorías: 2a con 19.38% y 2b 17.18%; y el grupo 5.1 (22.91%) y grupo 5.2 (3.96%). Las principales indicaciones de cesárea fueron: 1) riesgo de pérdida del bienestar fetal (18.9%), 2) falta de progresión del trabajo de parto (16.7%), 3) falla en la inducción del trabajo de parto (11.1%), 4) macrosomía (7.2%) y 5) periodo intergenésico corto (7.2%). CONCLUSIONES: El índice de Robson señaló a los grupos 1, 2 y 5 como los mayores contribuyentes a la tasa de cesáreas en CIMIGen. Esta tendencia, grupos 1 y 2 con porcentajes elevados, también se observa en otros centros de atención en México, lo que pudiera indicar una práctica de atención obstétrica que debe revisarse. Esto también se ve en otros países, aunque los porcentajes son distintos pero siguen siendo considerables en los grupos 1, 2 y 5.

Abstract OBJECTIVE: To determine, according to the Robson Index, the caesarean section rate in patients attended, over a period of nine months, at the Maternal and Infant Research Centre of the Childbirth Studies Group. MATERIALS AND METHODS: Retrospective, cross-sectional, descriptive, single-centre study carried out in pregnant patients attended at the Maternal and Infant Research Centre of the Childbirth Study Group (CIMIGen) who terminated gestation by caesarean section and in whom the Robson index was used for classification. Study parameters: indications for caesarean section, risk of loss of fetal well-being, high labour progression, failure of labour induction, macrosomia, short inter-gestational period (less than 18 months). RESULTS: We obtained 569 patients of whom 228 terminated pregnancy by caesarean section and 341 by delivery, representing a caesarean section rate of 39.9%. Applying Robson's classification method, the groups with the highest relative contribution to the overall caesarean section rate were: group 1 (17.62%), group 2, subdivided into its two categories: 2a with 19.38% and 2b 17.18%; and group 5.1 (22.91%) and group 5.2 (3.96%). The main indications for caesarean section were 1) risk of loss of fetal well-being (18.9%), 2) failure of labour to progress (16.7%), 3) failure of induction of labour (11.1%), 4) macrosomia (7.2%) and 5) short inter-gestational period (7.2%). CONCLUSIONS: Robson's index pointed to groups 1, 2 and 5 as the largest contributors to the caesarean section rate at CIMIGen. This trend, groups 1 and 2 with high percentages, is also seen in other facilities in Mexico, which may indicate an obstetric care practice that needs to be reviewed. This is also seen in other countries, although the percentages are different but still considerable in groups 1, 2 and 5.

Morphological, phylogenetic, and genomic evidence reveals the causal agent of thread blight disease of cacao in Peru is a new species of Marasmius in the section Neosessiles, Marasmius infestans sp. nov.

The thread blight disease (TBD) of cacao ( Theobroma cacao) in the department of Amazonas, Peru was recently reported to be caused by Marasmius tenuissimus (sect. Neosessiles). This same species is known to be the main causal agent of TBD in West Africa. However, some morphological characteristics, such as the presence of rhizomorphs, the almost exclusively white color, and pileus sizes less than 5 mm, among others, differ to the description of M. tenuissimus. Therefore, we aimed to conduct a taxonomic revision of the cacao-TBD causal agent in Peru, by using thorough micro and macro morphological, phylogenetic, and nuclear and mitochondrial genomic approaches. We showed that the causal agent of TBD of cacao in Amazonas, Peru, belongs to a new species, Marasmius infestans sp. nov. This study enriches our knowledge of species in the sect. Neosessiles, and strongly suggests that the M. tenuissimus species complex is highly diverse.

Sporadic hemangioblastoma of cauda equina: A case report and brief literature review.

Background: Hemangioblastomas (HBs) are rare lesions accounting for 1%-5% of all spinal cord tumors, and are mostly associated with Von Hippel-Lindau (VHL) syndrome. Localization in the cauda equina is uncommon. Aim: In this manuscript, we aimed to describe a rare case of sporadic intradural extramedullary HB of the cauda equina and present a literature review. Mathods: A systematic research was performed on PubMed, MEDLINE, and Google Scholar, using the keywords "spinal HB" and "cauda equina tumors." The previous literature is integrated by the description of the present case. A 49-year-old female presented in August 2020 to our institution with a magnetic resonance imaging (MRI) which showed an intradural mass at L1/2 level and angiography that showing a nidus of serpiginous vessels inside the lesion. Symptoms were right sciatica and paresthesia in right L5 radicular dermatome for more than 3 months. Neurological examination revealed claudicatio spinalis and hypoesthesia on right L5 dermatome and weakness of right anterior tibialis muscle. Microsurgical en bloc resection of lesion was performed with adjuvant neurophysiological intraoperative monitoring. The histological examination provided the diagnosis of HB. Results: After surgery, symptoms and neurological impairment gradually improved. Postoperative MRI showed no residual tumor. Conclusions: Although intradural extramedullary HB of the cauda equina without VHL syndrome is a rare pathological entity, this diagnosis must be taken in consideration when a mass affects cauda equina. Preoperative embolization is an option to minimize intraoperative bleeding. Radiosurgery seems to prevent recurrences when the tumor is not completely excised. A complete surgical removal of the lesion is usually possible and it leads to a low likelihood of recurrence.

Impact of SARS-CoV-2 ORF6 and its variant polymorphisms on host responses and viral pathogenesis.

We and others have previously shown that the SARS-CoV-2 accessory protein ORF6 is a powerful antagonist of the interferon (IFN) signaling pathway by directly interacting with Nup98-Rae1 at the nuclear pore complex (NPC) and disrupting bidirectional nucleo-cytoplasmic trafficking. In this study, we further assessed the role of ORF6 during infection using recombinant SARS-CoV-2 viruses carrying either a deletion or a well characterized M58R loss-of-function mutation in ORF6. We show that ORF6 plays a key role in the antagonism of IFN signaling and in viral pathogenesis by interfering with karyopherin(importin)-mediated nuclear import during SARS-CoV-2 infection both in vitro , and in the Syrian golden hamster model in vivo . In addition, we found that ORF6-Nup98 interaction also contributes to inhibition of cellular mRNA export during SARS-CoV-2 infection. As a result, ORF6 expression significantly remodels the host cell proteome upon infection. Importantly, we also unravel a previously unrecognized function of ORF6 in the modulation of viral protein expression, which is independent of its function at the nuclear pore. Lastly, we characterized the ORF6 D61L mutation that recently emerged in Omicron BA.2 and BA.4 and demonstrated that it is able to disrupt ORF6 protein functions at the NPC and to impair SARS-CoV-2 innate immune evasion strategies. Importantly, the now more abundant Omicron BA.5 lacks this loss-of-function polymorphism in ORF6. Altogether, our findings not only further highlight the key role of ORF6 in the antagonism of the antiviral innate immune response, but also emphasize the importance of studying the role of non-spike mutations to better understand the mechanisms governing differential pathogenicity and immune evasion strategies of SARS-CoV-2 and its evolving variants. ONE SENTENCE SUMMARY: SARS-CoV-2 ORF6 subverts bidirectional nucleo-cytoplasmic trafficking to inhibit host gene expression and contribute to viral pathogenesis.