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Precursor T-cell neoplasms (T-ALL/LBL) are aggressive hematological malignancies that arise from the malignant transformation of immature thymocytes. Despite the JAK/STAT pathway is recurrently altered in these neoplasms, there are not pharmacological inhibitors officially approved for the treatment of T-ALL/LBL patients that present oncogenic JAK/STAT pathway mutations. In the effort to identify potential therapeutic targets for those patients, we followed an alternative approach and focused on their transcriptional profile. We combined the analysis of molecular data from T-ALL/LBL patients with the generation of hematopoietic cellular models to reveal that JAK/STAT pathway mutations are associated with an aberrant transcriptional profile. Specifically, we demonstrate that JAK/STAT pathway mutations induce the overexpression of the PIM1 gene. Moreover, we show that the pan-PIM inhibitor, PIM447, significantly reduces the leukemogenesis, as well as the aberrant activation of c-MYC and mTOR pathways in cells expressing different JAK/STAT pathway mutations, becoming a potential therapeutic opportunity for a relevant subset of T-ALL/LBL patients.
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Arteries and veins develop different types of occlusive diseases and respond differently to injury. The biological reasons for this discrepancy are not well understood, which is a limiting factor for the development of vein-targeted therapies. This study contrasts human peripheral arteries and veins at the single-cell level, with a focus on cell populations with remodeling potential. Upper arm arteries (brachial) and veins (basilic/cephalic) from 30 organ donors were compared using a combination of bulk and single-cell RNA sequencing, proteomics, flow cytometry, and histology. The cellular atlases of six arteries and veins demonstrated a 7.8× higher proportion of contractile smooth muscle cells (SMCs) in arteries and a trend toward more modulated SMCs. In contrast, veins showed a higher abundance of endothelial cells, pericytes, and macrophages, as well as an increasing trend in fibroblasts. Activated fibroblasts had similar proportions in both types of vessels but with significant differences in gene expression. Modulated SMCs and activated fibroblasts were characterized by the upregulation of MYH10, FN1, COL8A1, and ITGA10. Activated fibroblasts also expressed F2R, POSTN, and COMP and were confirmed by F2R/CD90 flow cytometry. Activated fibroblasts from veins were the top producers of collagens among all fibroblast populations from both types of vessels. Venous fibroblasts were also highly angiogenic, proinflammatory, and hyper-responders to reactive oxygen species. Differences in wall structure further explain the significant contribution of fibroblast populations to remodeling in veins. Fibroblasts are almost exclusively located outside the external elastic lamina in arteries, while widely distributed throughout the venous wall. In line with the above, ECM-targeted proteomics confirmed a higher abundance of fibrillar collagens in veins vs. more basement ECM components in arteries. The distinct cellular compositions and transcriptional programs of reparative populations in arteries and veins may explain differences in acute and chronic wall remodeling between vessels. This information may be relevant for the development of antistenotic therapies.
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Arterias , Miocitos del Músculo Liso , Análisis de la Célula Individual , Remodelación Vascular , Venas , Humanos , Arterias/metabolismo , Venas/metabolismo , Miocitos del Músculo Liso/metabolismo , Fibroblastos/metabolismo , Masculino , Femenino , Persona de Mediana EdadRESUMEN
INTRODUCTION: Deep vein thrombosis (DVT) poses a complex challenge and often leads to postthrombotic syndrome (PTS), a debilitating complication. The emergence of venous stents offers a potential preventive avenue against this complication. This study aimed to provide consensus recommendations on the use of venous stent for DVT. MATERIALS AND METHODS: From June to July 2023, 20 internal medicine, angiology and vascular surgery, and vascular and interventional radiology experts were involved in the Delphi process. Thirty-one recommendations, categorized into three thematic areas, were rigorously evaluated: indications for stent use, stent selection and placement, and monitoring and prevention of complications. Agreement was evaluated using a Likert scale, with consensus defined as agreement by two-thirds of the participants. RESULTS: Consensus was reached for 23 (74.2%) of 31 recommendations. The agreement was centered on considerations, such as stent placement in specific acute DVT scenarios, emphasizing pivotal stent characteristics. However, there were divergences in the recommended stent length to prevent migration and stent characteristics based on iliocaval bifurcation morphology. Notably, there was no consensus on whether patients with DVT caused by a major transient risk factor need more than 3 months of anticoagulation therapy or whether aspirin should be added to anticoagulant treatment after venous stenting. CONCLUSIONS: These consensus recommendations offer practical insights into optimizing venous stent use to prevent PTS in DVT patients. Addressing the critical aspects of stent selection, placement, and postprocedural care, these recommendations contribute to clinical decision-making. The identified divergences underscore the importance of consensus and thus indicate the need for further investigation.
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Extremidad Inferior , Stents , Trombosis de la Vena , Humanos , Stents/efectos adversos , Trombosis de la Vena/prevención & control , Extremidad Inferior/irrigación sanguínea , ConsensoRESUMEN
This paper addresses the dearth of studies examining the status of Operational Excellence (OE) implementation and offers a roadmap for enhancing OE maturity levels. The study encompassed three phases: (1) face-to-face interviews with industry OE experts in 57 companies across seven sectors, (2), classification of companies based on their maturity levels, and (3) development of a roadmap for companies to enhance their OE maturity. Through face-to-face interviews with OE experts in fifty-seven companies across various sectors, the study classified organizations into five maturity levels, with only 7 % reaching the champion level. The proposed roadmap, comprising twenty-three variables across six hierarchical levels, outlines a path for companies to progress towards champion-level OE maturity, with an estimated timeframe of 4.5-5 years from a zero level. This research contributes valuable insights into the OE implementation status in emerging countries and provides practical guidance for organizations aiming to elevate their OE maturity, emphasizing the importance of strategic planning, economic sustainability, environmental sustainability, and social sustainability variables tailored to the specific challenges and opportunities faced by businesses in emerging nations.
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Nqo15 is a subunit of respiratory complex I of the bacterium Thermus thermophilus, with strong structural similarity to human frataxin (FXN), a protein involved in the mitochondrial disease Friedreich's ataxia (FRDA). Recently, we showed that the expression of recombinant Nqo15 can ameliorate the respiratory phenotype of FRDA patients' cells, and this prompted us to further characterize both the Nqo15 solution's behavior and its potential functional overlap with FXN, using a combination of in silico and in vitro techniques. We studied the analogy of Nqo15 and FXN by performing extensive database searches based on sequence and structure. Nqo15's folding and flexibility were investigated by combining nuclear magnetic resonance (NMR), circular dichroism, and coarse-grained molecular dynamics simulations. Nqo15's iron-binding properties were studied using NMR, fluorescence, and specific assays and its desulfurase activation by biochemical assays. We found that the recombinant Nqo15 isolated from complex I is monomeric, stable, folded in solution, and highly dynamic. Nqo15 does not share the iron-binding properties of FXN or its desulfurase activation function.
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Frataxina , Ataxia de Friedreich , Humanos , Complejo I de Transporte de Electrón/metabolismo , Thermus thermophilus/metabolismo , Simulación de Dinámica Molecular , Hierro/metabolismo , Proteínas de Unión a Hierro/metabolismo , Ataxia de Friedreich/metabolismoRESUMEN
INTRODUCTION: Sexuality is an integral part of human health, and sexual dysfunctions are prevalent issues that affect men and women. While reviews on sexual dysfunctions in various diseases have been conducted, overall data are scarce. OBJECTIVES: To update the overall prevalence of sexual dysfunctions from available prevalence studies on both sexes. METHODS: We used a 2-phase selection process to include cross-sectional studies that were conducted on the adult population and published between 2017 and 2022. The extracted data were prevalence, methodology, sample size, and location. Sensitivity and subgroup analyses were conducted to assess heterogeneity. RESULTS: This review analyzed 4407 studies. Twenty-three met the established criteria: 9 on the male population and 14 on the female population. The meta-analysis included 7 articles on males and 13 on females. The prevalence of sexual dysfunction was 31% in men and 41% in women, with significant heterogeneity among the studies. Sociocultural differences and use of varying measurement methods were identified as the main factors contributing to heterogeneity. Subgroup analysis revealed decreased heterogeneity among studies that used the Female Sexual Function Index as a diagnostic tool for females. CONCLUSIONS: The review highlights the notable variability in results due to methodological and geographic variations. Therefore, enhancing the training of professionals and standardizing the recording of patient data-through the Female Sexual Function Index and Male Sexual Health Questionnaire or by developing new ones for this purpose-could improve the consistency of research on sexual health.
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Disfunciones Sexuales Fisiológicas , Adulto , Humanos , Masculino , Femenino , Prevalencia , Estudios Transversales , Disfunciones Sexuales Fisiológicas/epidemiología , Conducta Sexual , SexualidadRESUMEN
PURPOSE: Patients with isolated distal deep vein thrombosis (DVT) have lower rates of adverse outcomes (death, venous thromboembolism [VTE] recurrence or major bleeding) than those with proximal DVT. It is uncertain if such findings are also observed in patients with cancer. METHODS: Using data from the international Registro Informatizado de la Enfermedad TromboEmbolica venosa registry, we compared the risks of adverse outcomes at 90 days (adjusted odds ratio [aOR]; 95% CI) and 1 year (adjusted hazard ratio [aHR; 95% CI]) in 886 patients with cancer-associated distal DVT versus 5,196 patients with cancer-associated proximal DVT and 5,974 patients with non-cancer-associated distal DVT. RESULTS: More than 90% of patients in each group were treated with anticoagulants for at least 90 days. At 90 days, the adjusted risks of death, VTE recurrence, or major bleeding were lower in patients with non-cancer-associated distal DVT than in patients with cancer-associated distal DVT (reference): aOR = 0.16 (0.11-0.22), aOR = 0.34 (0.22-0.54), and aOR = 0.47 (0.27-0.80), respectively. The results were similar at 1-year follow-up: aHR = 0.12 (0.09-0.15), aHR = 0.39 (0.28-0.55), and aHR = 0.51 (0.32-0.82), respectively. Risks of death, VTE recurrence, and major bleeding were not statistically different between patients with cancer-associated proximal versus distal DVT, both at 90 days: aOR = 1.11 (0.91-1.36), aOR = 1.10 (0.76-1.62), and aOR = 1.18 (0.76-1.83), respectively, and 1 year: aHR = 1.01 (0.89-1.15), aHR = 1.02 (0.76-1.35), and aHR = 1.10 (0.76-1.61), respectively. However, more patients with cancer-associated proximal DVT, compared with cancer-associated distal DVT, developed fatal pulmonary embolism (PE) during follow-up: The risk difference was 0.40% (95% CI, 0.23 to 0.58). CONCLUSION: Cancer-associated distal DVT has serious and relatively comparable outcomes compared with cancer-associated proximal DVT. The lower risk of fatal PE from cancer-associated distal DVT needs further investigation.
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Neoplasias , Embolia Pulmonar , Tromboembolia Venosa , Trombosis de la Vena , Humanos , Tromboembolia Venosa/epidemiología , Tromboembolia Venosa/etiología , Recurrencia , Embolia Pulmonar/complicaciones , Anticoagulantes/uso terapéutico , Hemorragia/complicaciones , Hemorragia/tratamiento farmacológico , Neoplasias/complicaciones , Neoplasias/tratamiento farmacológico , Trombosis de la Vena/etiología , Factores de RiesgoRESUMEN
BACKGROUND: Functional Abdominal Bloating and Distension (FABD) is a multifaceted condition related in part to trapped gas, with changes in the intestinal barrier and small intestinal bacterial overgrowth (SIBO), which lead to gas production. Currently, there are no treatments targeting the etiology of FABD. METHODS: This double-blind, multicenter, randomized study evaluated the safety and efficacy of a product containing xyloglucan and pea proteins (XG + PP) compared with simethicone, both administered orally (three times daily) for 20 consecutive days. Eighty-eight patients with FABD were randomly assigned to the two groups in a 1:1 ratio. Primary outcome was safety; secondary outcomes were (i) efficacy in alleviating the symptoms of FABD and (ii) efficacy in reducing SIBO, as assessed by hydrogen breath test (HBT). RESULTS: No Adverse Events or Serious Unexpected Adverse Reactions were reported during the study. XG + PP showed a faster onset of action and a significant reduction in bloating and abdominal pain compared with simethicone. At Day 20, XG + PP drastically reduced abdominal girth when compared with simethicone, with an average reduction of 4.7 cm versus 1.8 cm. At Day 20, the XG + PP arm showed a significant reduction in HBT compared to baseline. CONCLUSIONS: This study supports the evidence that FABD patients may benefit from a XG + PP-based treatment that acts on etiology and not just the symptoms.
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Glucanos , Proteínas de Guisantes , Simeticona , Xilanos , Humanos , Resultado del Tratamiento , IntestinosRESUMEN
During the COVID-19 outbreak, numerous tools including protein-based vaccines have been developed. The methylotrophic yeast Pichia pastoris (synonymous to Komagataella phaffii) is an eukaryotic cost-effective and scalable system for recombinant protein production, with the advantages of an efficient secretion system and the protein folding assistance of the secretory pathway of eukaryotic cells. In a previous work, we compared the expression of SARS-CoV-2 Spike Receptor Binding Domain in P. pastoris with that in human cells. Although the size and glycosylation pattern was different between them, their protein structural and conformational features were indistinguishable. Nevertheless, since high mannose glycan extensions in proteins expressed by yeast may be the cause of a nonspecific immune recognition, we deglycosylated RBD in native conditions. This resulted in a highly pure, homogenous, properly folded and monomeric stable protein. This was confirmed by circular dichroism and tryptophan fluorescence spectra and by SEC-HPLC, which were similar to those of RBD proteins produced in yeast or human cells. Deglycosylated RBD was obtained at high yields in a single step, and it was efficient in distinguishing between SARS-CoV-2-negative and positive sera from patients. Moreover, when the deglycosylated variant was used as an immunogen, it elicited a humoral immune response ten times greater than the glycosylated form, producing antibodies with enhanced neutralizing power and eliciting a more robust cellular response. The proposed approach may be used to produce at a low cost, many antigens that require glycosylation to fold and express, but do not require glycans for recognition purposes.
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COVID-19 , Saccharomycetales , Vacunas , Humanos , COVID-19/diagnóstico , COVID-19/prevención & control , Prueba de COVID-19 , Pichia/genética , Pichia/metabolismo , SARS-CoV-2/genética , SARS-CoV-2/metabolismo , Proteínas Recombinantes/química , Vacunas/metabolismo , Anticuerpos Neutralizantes/metabolismo , Anticuerpos AntiviralesRESUMEN
INTRODUCTION: COMPACT, a non-interventional study, evaluated the persistence, effectiveness, safety and patient-reported outcomes (PROs) in patients with rheumatoid arthritis (RA), axial-spondyloarthritis (axSpA) or psoriatic arthritis (PsA) treated with SDZ ETN (etanercept [ETN] biosimilar) in Europe and Canada. METHODS: Patients (aged ≥ 18 years) who have been treated with SDZ ETN were categorised on the basis of prior treatment status (groups A-D): patients in clinical remission or with low disease activity under treatment with reference ETN or biosimilar ETN and switched to SDZ ETN; patients who received non-ETN targeted therapies and switched to SDZ ETN; biologic-naïve patients who started SDZ ETN after conventional therapy failure; or disease-modifying anti-rheumatic drug (DMARD)-naïve patients with RA considered suitable for treatment initiation with a biologic and started on treatment with SDZ ETN. The primary endpoint was drug persistence, defined as time from study enrolment until discontinuation of SDZ ETN treatment. RESULTS: Of the 1466 patients recruited, 844 (57.6%) had RA, 334 (22.8%) had axSpA and 288 (19.6%) had PsA. Patients had an ongoing SDZ ETN treatment at the time of enrolment for an observed average of 138 days (range 1-841); 22.7% of patients discontinued SDZ ETN through 12 months of study observation. Overall, all the patients receiving SDZ ETN showed good treatment persistence at 12 months with discontinuation rates of 15.2%, 25.7% and 27.8% in groups A, B and C, respectively. Across all patient groups, no major differences were observed in the disease activity and PRO scores between baseline and month 12. Injection-site reactions were low across the treatment groups. CONCLUSION: These results support the effectiveness and safety of SDZ ETN treatment in patients with RA, axSpA or PsA in real-life conditions. The treatment persistence rates observed were consistent with previously published reports of patients treated with reference or other biosimilar ETN. No new safety signals were identified.
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Antirreumáticos , Artritis Psoriásica , Artritis Reumatoide , Espondiloartritis Axial , Biosimilares Farmacéuticos , Enfermedades Reumáticas , Humanos , Etanercept/efectos adversos , Biosimilares Farmacéuticos/efectos adversos , Artritis Psoriásica/tratamiento farmacológico , Resultado del Tratamiento , Antirreumáticos/efectos adversos , Artritis Reumatoide/tratamiento farmacológico , Enfermedades Reumáticas/tratamiento farmacológicoRESUMEN
Throughout computational science, there is a growing need to utilize the continual improvements in raw computational horsepower to achieve greater physical fidelity through scale-bridging over brute-force increases in the number of mesh elements. For instance, quantitative predictions of transport in nanoporous media, critical to hydrocarbon extraction from tight shale formations, are impossible without accounting for molecular-level interactions. Similarly, inertial confinement fusion simulations rely on numerical diffusion to simulate molecular effects such as non-local transport and mixing without truly accounting for molecular interactions. With these two disparate applications in mind, we develop a novel capability which uses an active learning approach to optimize the use of local fine-scale simulations for informing coarse-scale hydrodynamics. Our approach addresses three challenges: forecasting continuum coarse-scale trajectory to speculatively execute new fine-scale molecular dynamics calculations, dynamically updating coarse-scale from fine-scale calculations, and quantifying uncertainty in neural network models.
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In this paper, we describe the development of a Dictyostelium discoideum strain deficient in frataxin protein (FXN). We investigated the conservation of function between humans and D. discoideum and showed that DdFXN can substitute the human version in the interaction and activation of the Fe-S assembly supercomplex. We edited the D. discoideum fxn locus and isolated a defective mutant, clone 8, which presents landmarks of frataxin deficiency, such as a decrease in Fe-S cluster-dependent enzymatic functions, growth rate reduction, and increased sensitivity to oxidative stress. In addition, the multicellular development is affected as well as growing on bacterial lawn. We also assessed the rescuing capacity of DdFXN-G122V, a version that mimics a human variant present in some FA patients. While the expression of DdFXN-G122V rescues growth and enzymatic activity defects, as DdFXN does, multicellular development defects were only partially rescued. The results of the study suggest that this new D. discoideum strain offers a wide range of possibilities to easily explore diverse FA FXN variants. This can facilitate the development of straightforward drug screenings to look for new therapeutic strategies.
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BACKGROUND: An ostomy significantly influences a person's life, altering their biopsychosocial and sexual sphere and affecting their interpersonal relationships. MATERIALS AND METHODS: Through an observational, descriptive, and cross-sectional study, with a questionnaire aimed at professionals from a health area in Madrid, we analyzed: sociodemographic variables, knowledge of the professionals on the subject, referral of the patient according to the professional's assessment and feelings that the subject under study produces in the patient and in professionals. RESULTS: 49% claimed to have no knowledge about sexuality of the ostomyzed patients. 55.9% of those surveyed consider that the healthcare provider is the one who should introduce the topic of sexuality during the clinical interview. 48.5 and 85.2% are unaware of treatments for male and female sexual dysfunction, respectively. CONCLUSIONS: The data show that the training provided in the university centers is insufficient to deal effectively with this issue in the medical consultation. The participants manifest null or minimal knowledge about the sexual sphere in ostomized patients. Knowledge deficiencies are detected in relation to the sexuality of the ostomized patient, difficulty in talking about sex with these patients, and the importance that sanitary professionals give to the patient's sexual sphere, among others.
ANTECEDENTES: Una ostomía influye significativamente en la vida de la persona, alterando su esfera biopsicosocial y sexual, y afectando a sus relaciones interpersonales. MATERIAL Y MÉTODO: Estudio observacional, descriptivo y transversal. Mediante un cuestionario dirigido a profesionales de un área sanitaria de Madrid, se analizan variables sociodemográficas, conocimientos de los profesionales, derivación del paciente a un especialista según la valoración del profesional encuestado y sentimientos que produce en ellos el tema de estudio. RESULTADOS: El 49% afirma tener conocimientos nulos sobre la sexualidad del paciente ostomizado. El 55.9% de los encuestados considera que el sanitario es quien debe introducir el tema de la sexualidad durante la entrevista clínica. El 48.5 y el 85.2% desconocen tratamientos para la disfunción sexual, masculina y femenina, respectivamente. CONCLUSIÓN: Los datos demuestran que la formación impartida en los centros universitarios es insuficiente para tratar de forma efectiva este tema en la consulta. Los participantes en el estudio muestran nulo o mínimo conocimiento sobre la esfera sexualidad en el paciente ostomizado Se detectan deficiencias de conocimiento en relación con la sexualidad del ostomizado, dificultad para hablar de sexo con el paciente y valor que da el profesional a la esfera sexual en su paciente, entre otras.
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Conducta Sexual , Sexualidad , Femenino , Humanos , Masculino , Estudios Transversales , Emociones , Personal de SaludRESUMEN
Background: There is growing evidence of the significance of gastrointestinal complaints in the impairment of the intestinal mucosal barrier function and inflammation in fibromyalgia (FM) and in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). However, data on intestinal permeability and gut barrier dysfunction in FM and ME/CFS are still limited with conflicting results. This study aimed to assess circulating biomarkers potentially related to intestinal barrier dysfunction and bacterial translocation and their association with self-reported symptoms in these conditions. Methods: A pilot multicenter, cross-sectional cohort study with consecutive enrolment of 22 patients with FM, 30 with ME/CFS and 26 matched healthy controls. Plasma levels of anti-beta-lactoglobulin antibodies (IgG anti-ß-LGB), zonulin-1 (ZO-1), lipopolysaccharides (LPS), soluble CD14 (sCD14) and interleukin-1-beta (IL-1ß) were assayed using ELISA. Demographic and clinical characteristics of the participants were recorded using validated self-reported outcome measures. The diagnostic accuracy of each biomarker was assessed using the receiver operating characteristic (ROC) curve analysis. Results: FM patients had significantly higher levels of anti-ß-LGB, ZO-1, LPS, and sCD14 than healthy controls (all P < 0.0001). In ME/CFS patients, levels of anti-ß-LGB, ZO-1, LPS, and sCD14 were significantly higher than controls, but lower than in FM (all P < 0.01), while there was no significant difference in IL-1ß level. In the FM and ME/CFS cohorts, both anti-ß-LGB and ZO-1 correlated significantly with LPS and sCD14 (P < 0.001 for both). In the FM group, both anti-ß-LGB and ZO-1 were correlated significantly with physical and mental health components on the SF-36 scale (P < 0.05); whereas IL-1ß negatively correlated with the COMPASS-31 score (P < 0.05). In the ME/CFS cohort, ZO-1 was positively correlated with the COMPASS-31 score (P < 0.05). The ROC curve analysis indicated a strong ability of anti-ß-LGB, ZO-1, LPS and sCD14 to predictively distinguish between FM and ME/CFS from healthy controls (P < 0.0001). Conclusion: Biomarkers of intestinal barrier function and inflammation were associated with autonomic dysfunction assessed by COMPASS-31 scores in FM and ME/CFS respectively. Anti-ß-LGB antibodies, ZO-1, LPS, and sCD14 may be putative predictors of intestinal barrier dysfunction in these cohorts. Further studies are needed to assess whether these findings are causal and can therefore be applied in clinical practice.
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Síndrome de Fatiga Crónica , Fibromialgia , Humanos , Síndrome de Fatiga Crónica/diagnóstico , Traslocación Bacteriana , Estudios Transversales , Receptores de Lipopolisacáridos , Lipopolisacáridos , InflamaciónRESUMEN
Objetivos: la seguridad de los medicamentos en pediatría supone un verdadero reto. Se dispone de escasos estudios que hayan analizado los errores de medicación en los pacientes pediátricos que acuden a los servicios de urgencias. El objetivo de este estudio ha sido caracterizar los errores detectados en estos pacientes, determinando su gravedad, los procesos afectados, los medicamentos implicados y los tipos de errores y causas asociados. Métodos: estudio multicéntrico observacional prospectivo realizado en los servicios de urgencias de 8 hospitales públicos españoles durante 4 meses. Los errores de medicación detectados por los pediatras de urgencias en pacientes entre 0 y 16 años fueron evaluados por un farmacéutico y un pediatra. Los errores de medicación fueron analizados utilizando la Taxonomía Española de Errores de Medicación actualizada. Resultados: en 99.797 visitas a urgencias se detectaron 218 (0,2%) errores de medicación, de los cuales 74 (33,9%) causaron daños (eventos adversos por medicamentos). Los preescolares fueron el grupo poblacional con mayor número de errores de medicación (126/218). Los errores se originaron mayoritariamente en la prescripción (66,1%), por automedicación (16,5%) y por administración equivocada por parte de los familiares (15,6%). Los tipos de errores más frecuentes fueron: «dosis incorrectas» (51,4%) y «medicamento inapropiado» (46,8%). Los antiinfecciosos (63,5%) fueron los fármacos más comúnmente implicados en los errores con daño. Las causas subyacentes asociadas a una mayor proporción de errores de medicación fueron: «falta de conocimiento del medicamento» (63,8%), «falta de seguimiento de los procedimientos» (48,6%) y «falta de información del paciente» (30,3%). Conclusiones: los errores de medicación en la población pediátrica que acude a urgencias se producen en la prescripción, por automedicación y en la administración, provocando daños a los pacientes en un tercio de las ocasiones. ...(AU)
Objectives: Medication safety represents an important challenge in children. There are limited studies on medication errors in pediatric patients visiting emergency departments. To help bridge this gap, we characterized the medication errors detected in these patients, determining their severity, the stages of the medication process in which they occurred, the drugs involved, and the types and causes associated with the errors. Methods: We conducted a multicenter prospective observational study in the pediatric emergency departments of 8 Spanish public hospitals over a 4-month period. Medication errors detected by emergency pediatricians in patients between 0 and 16 years of age were evaluated by a clinical pharmacist and a pediatrician. Each medication error was analyzed according to the updated Spanish Taxonomy of Medication Errors. Results: In 99,797 visits to pediatric emergency departments, 218 (0.2%) medication errors were detected, of which 74 (33.9%) resulted in harm (adverse drug events). Preschoolers were the age group with the most medication errors (126/218). Errors originated mainly in the prescribing stage (66.1%), and also by self-medication (16.5%) and due to wrong administration of the medication by family members (15.6%). Dosing errors (51.4%) and wrong/improper drugs (46.8%) were the most frequent error types. Anti-infective drugs (63.5%) were the most common drugs implicated in medication errors with harm. Underlying causes associated with a higher proportion of medication errors were medication knowledge deficit (63.8%), deviation from procedures/guidelines (48.6%) and lack of patient information (30.3%). Conclusions: Medication errors presented by children attending emergency departments arise from prescriptions, self-medication, and administration, and lead to patient harm in one third of cases. Developing effective interventions based on the types of errors and the underlying causes identified will improve patient safety. (AU)
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Humanos , Recién Nacido , Lactante , Preescolar , Niño , Adolescente , Errores de Medicación/efectos adversos , Errores de Medicación/estadística & datos numéricos , Servicios Médicos de Urgencia/estadística & datos numéricos , Seguridad del Paciente , Pediatría , España , Estudios Multicéntricos como Asunto , Estudios ProspectivosRESUMEN
The mitochondrial cysteine desulfurase NFS1 is an essential PLP-dependent enzyme involved in iron-sulfur cluster assembly. The enzyme catalyzes the desulfurization of the l-Cys substrate, producing a persulfide and l-Ala as products. In this study, we set the measurement of the product l-Ala by NMR in vitro by means of 1H NMR spectra acquisition. This methodology provided us with the possibility of monitoring the reaction in both fixed-time and real-time experiments, with high sensitivity and accuracy. By studying I452A, W454A, Q456A, and H457A NFS1 variants, we found that the C-terminal stretch (CTS) of the enzyme is critical for function. Specifically, mutation of the extremely conserved position W454 resulted in highly decreased activity. Additionally, we worked on two singular variants: "GGG" and C158A. In the former, the catalytic Cys-loop was altered by including two Gly residues to increase the flexibility of this loop. This variant had significantly impaired activity, indicating that the Cys-loop motions are fine-tuned in the wild-type enzyme. In turn, for C158A, we found an unanticipated increase in l-Cys desulfurase activity. Furthermore, we carried out molecular dynamics simulations of the supercomplex dedicated to iron-sulfur cluster biosynthesis, which includes NFS1, ACP, ISD11, ISCU2, and FXN subunits. We identified CTS as a key element that established interactions with ISCU2 and FXN concurrently; we found specific interactions that are established when FXN is present, reinforcing the idea that FXN not only forms part of the iron-sulfur cluster assembly site but also modulates the internal motions of ISCU2.
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Proteínas Hierro-Azufre , Humanos , Proteínas Hierro-Azufre/química , Liasas de Carbono-Azufre/metabolismo , Azufre/química , Hierro/química , Proteínas de Unión a Hierro/química , Proteínas de Unión a Hierro/genéticaRESUMEN
BACKGROUND: Disorders of Gut-Brain Interaction (DGBI) are highly prevalent worldwide, but their effect on work productivity has not gained much attention. AIMS AND METHODS: We aimed to compare work productivity and activity impairment (WPAI) in persons with and without DGBI in a large population-based cohort and identify factors independently associated with WPAI in subjects with DGBI. Data were collected from Germany, Israel, Italy, Japan, the Netherlands, Poland, Spain and Sweden via Internet surveys as part of the Rome Foundation Global Epidemiology Study. Apart from the Rome IV diagnostic questionnaire, questionnaires evaluating WPAI related to general health (WPAI:GH), psychological distress (PHQ-4), somatic symptom severity (PHQ-15) and other factors were assessed. RESULTS: Of the 16,820 subjects, 7111 met the criteria for DGBI according to the Rome IV diagnostic questionnaire. Subjects with DGBI were younger (median (interquartile range) age 43 (31-58) vs. 47 (33-62)) and more often female (59.0% vs. 43.7%) compared to subjects without DGBI. Subjects with DGBI had higher absenteeism, presenteeism (poor work productivity due to illness), overall work impairment and activity impairment (p < 0.001) compared with subjects without. For subjects with DGBI affecting more than one anatomical region, WPAI was incrementally higher for each additional region. There were significant differences in WPAI for subjects with DGBI in different countries. Subjects from Sweden had the highest overall work impairment and from Poland the lowest. Using multiple linear regression, male sex, fatigue, psychological distress, somatic symptom severity and number of anatomical regions were independently associated with overall work impairment (p < 0.05 for all). CONCLUSION: In the general population, people with DGBI have substantial WPAI compared with those without DGBI. The reasons for these findings should be explored further, but having multiple DGBI, psychological distress, fatigue and somatic symptom severity seem to contribute to this impairment associated with DGBI.