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BACKGROUND: Postoperative delirium (POD) following surgery is a prevalent and distressing condition associated with adverse patient outcomes and an increased healthcare burden. OBJECTIVES: To assess the effectiveness of the Safe Brain Initiative care bundle (SBI-CB) in reducing POD in the postanesthesia care unit (PACU). DESIGN: A multicenter, quality-improvement initiative with retrospective analysis of collected data. SETTING: The study was conducted in the operating rooms and postanesthesia care units (PACUs) of four hospitals across Denmark and Turkey. PATIENTS: The convenience sample of patients were aged ≥18 years, scheduled for surgery, and could communicate verbally. Age, sex, preoperative delirium, and the American Society for Anesthesiology physical status classification were used in statistical methods to control for potential confounding influences. INTERVENTION: The SBI-CB, 18 delirium-reducing recommendations aligned with international guidelines. The intervention included patient education, staff training, coordination meetings across centers, and a dashboard for the monitoring of outcomes in the PACU. MAIN OUTCOME MEASURES: The primary outcome was the POD trend in the PACU during implementation months, assessed through Nu-DESC screening at up to three time points in the PACU. We also examined the length of hospital stay. RESULTS: Data were collected from 18,697 adult patients across four hospitals. Initial POD incidence in the PACU after the first three months was 16.36% across all sites (n = 1021). POD in the PACU was observed across all age groups, with peak incidence in younger (18-35 years) and older (>75 years) patients. General anesthesia and longer surgical duration (>1 h) were identified as significant risk factors for POD in the PACU. Matched patients who experienced POD in the PACU had longer stays in hospital, with a mean increase from 35 to 69 h (p < 0.001). Implementation of the SBI-CB was associated with a decreased risk of POD in the PACU for each month of SBI-CB implementation (adjusted odds ratio 0.96, 95% confidence interval: [0.94, 0.97], p < 0.001). CONCLUSIONS: The presented pragmatic implementation of a multidisciplinary care bundle, encompassing pre-, intra-, and postoperative measures alongside outcome monitoring, has the potential to significantly reduce the incidence of POD in the PACU. Improved patient outcomes may be achieved for general surgical departments with patient cohorts not typically considered at risk for developing POD. TRIAL REGISTRATION: Clinicaltrials.gov, identifier NCT05765162.
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Protein nanoparticles are effective platforms for antigen presentation and targeting effector immune cells in vaccine development. Encapsulins are a class of protein-based microbial nanocompartments that self-assemble into icosahedral structures with external diameters ranging from 24 to 42 nm. Encapsulins from Myxococcus xanthus were designed to package bacterial RNA when produced in E. coli and were shown to have immunogenic and self-adjuvanting properties enhanced by this RNA. We genetically incorporated a 20-mer peptide derived from a mutant strain of the SARS-CoV-2 receptor binding domain (RBD) into the encapsulin protomeric coat protein for presentation on the exterior surface of the particle, inducing the formation of several nonicosahedral structures that were characterized by cryogenic electron microscopy. This immunogen elicited conformationally relevant humoral responses to the SARS-CoV-2 RBD. Immunological recognition was enhanced when the same peptide was presented in a heterologous prime/boost vaccination strategy using the engineered encapsulin and a previously reported variant of the PP7 virus-like particle, leading to the development of a selective antibody response against a SARS-CoV-2 RBD point mutant. While generating epitope-focused antibody responses is an interplay between inherent vaccine properties and B/T cells, here we demonstrate the use of orthogonal nanoparticles to fine-tune the control of epitope focusing.
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The effects of impurities on reaction precursors for metal-organic framework (MOF) synthesis have not been studied in extensive detail. The impact of these impurities can be an important factor while considering scale-up of these materials. In this work, we study the apparently positive impact of the presence of manganese ions for the synthesis of a Co-based MOF, Massey University Framework-16 (MUF-16). The presence of a trace amount of manganese in the reaction mixture led to consistently high CO2 uptake across multiple batches. Characterization including X-ray diffraction, scanning electron microscopy, Fourier transform infrared-attenuated total reflectance, ultraviolet-visible spectroscopy, thermogravimetric analysis, X-ray photoelectron spectroscopy, and extended X-ray absorption fine structure spectroscopy led us to hypothesize that the differences in CO2 adsorption among materials with differing synthesis routes arise from variations in the local environment around the cobalt metal center. Aided by density functional theory calculations, we speculate that manganese ions get inserted into the structure during crystallization and act as catalysts for ligand substitution, improving the possibility for octahedral coordination of cobalt with the ligand, thus leading to Co-based pristine structures with higher CO2 uptakes.
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Azobenzenes (ABs) are versatile compounds featured in numerous applications for energy storage systems, such as solar thermal storages or phase change materials. Additionally, the reversible one-electron reduction of these diazenes to the nitrogen-based radical anion has been used in battery applications. Although the oxidation of ABs is normally irreversible, 4,4'-diamino substitution allows a reversible 2e- oxidation, which is attributed to the formation of a stable bis-quinoidal structure. Herein, we present a system that shows a bipolar redox behaviour. In this way, ABs can serve not only as anolytes, but also as catholytes. The resulting redox potentials can be tailored by suitable amine- and ring-substitution. For the first time, the solid-state structure of the oxidized form could be characterized by X-ray diffraction.
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PURPOSE OF REVIEW: This review explores the intricacies of ethical anesthesia, exploring the necessity for precision anesthesia and its impact on patient-reported outcomes. The primary objective is to advocate for a defined aim, promoting the implementation of rules and feedback systems. The ultimate goal is to enhance precision anesthesia care, ensuring patient safety through the implementation of a teamwork and the integration of feedback mechanisms. RECENT FINDINGS: Recent strategies in the field of anesthesia have evolved from intraoperative monitorization to a wider perioperative patient-centered precision care. Nonetheless, implementing this approach encounters significant obstacles. The article explores the evidence supporting the need for a defined aim and applicable rules for precision anesthesia's effectiveness. The implementation of the safety culture is underlined. The review delves into the teamwork description with structured feedback systems. SUMMARY: Anesthesia is a multifaceted discipline that involves various stakeholders. The primary focus is delivering personalized precision care. This review underscores the importance of establishing clear aims, defined rules, and fostering effective and well tolerated teamwork with accurate feedback for improving patient-reported outcomes. The Safe Brain Initiative approach, emphasizing algorithmic monitoring and systematic follow-up, is crucial in implementing a fundamental and standardized reporting approach within patient-centered anesthesia care practice.
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Anestesia , Atención Dirigida al Paciente , Humanos , Anestesia/métodos , Anestesia/normas , Anestesia/ética , Anestesia/efectos adversos , Atención Dirigida al Paciente/ética , Atención Dirigida al Paciente/normas , Anestesiología/ética , Anestesiología/normas , Seguridad del Paciente/normas , Medicina de Precisión/métodos , Medicina de Precisión/ética , Medicina de Precisión/normas , Grupo de Atención al Paciente/ética , Grupo de Atención al Paciente/normas , Grupo de Atención al Paciente/organización & administración , Medición de Resultados Informados por el Paciente , Monitoreo Intraoperatorio/métodos , Monitoreo Intraoperatorio/normasRESUMEN
Hepatitis B virus (HBV) is the leading cause of chronic liver pathologies worldwide. HBV nucleocapsid, a key structural component, is formed through the self-assembly of the capsid protein units. Therefore, interfering with the self-assembly process is a promising approach for the development of novel antiviral agents. Applied to HBV, this approach has led to several classes of capsid assembly modulators (CAMs). Here, we report structurally novel CAMs with moderate activity and low toxicity, discovered through a biophysics-guided approach combining docking, molecular dynamics simulations, and a series of assays with a particular emphasis on biophysical experiments. Several of the identified compounds induce the formation of aberrant capsids and inhibit HBV DNA replication in vitro, suggesting that they possess modest capsid assembly modulation effects. The synergistic computational and experimental approaches provided key insights that facilitated the identification of compounds with promising activities. The discovery of preclinical CAMs presents opportunities for subsequent optimization efforts, thereby opening new avenues for HBV inhibition.
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Cápside , Virus de la Hepatitis B , Cápside/metabolismo , Proteínas de la Cápside , Ensamble de Virus , NucleocápsideRESUMEN
Type 1 diabetes (T1D) is a prototypic T cell-mediated autoimmune disease. Because the islets of Langerhans are insulated from blood vessels by a double basement membrane and lack detectable lymphatic drainage, interactions between endocrine and circulating T cells are not permitted. Thus, we hypothesized that initiation and progression of anti-islet immunity required islet neolymphangiogenesis to allow T cell access to the islet. Combining microscopy and single cell approaches, the timing of this phenomenon in mice was situated between 5 and 8 wk of age when activated anti-insulin CD4 T cells became detectable in peripheral blood while peri-islet pathology developed. This "peri-insulitis," dominated by CD4 T cells, respected the islet basement membrane and was limited on the outside by lymphatic endothelial cells that gave it the attributes of a tertiary lymphoid structure. As in most tissues, lymphangiogenesis seemed to be secondary to local segmental endothelial inflammation at the collecting postcapillary venule. In addition to classic markers of inflammation such as CD29, V-CAM, and NOS, MHC class II molecules were expressed by nonhematopoietic cells in the same location both in mouse and human islets. This CD45- MHC class II+ cell population was capable of spontaneously presenting islet Ags to CD4 T cells. Altogether, these observations favor an alternative model for the initiation of T1D, outside of the islet, in which a vascular-associated cell appears to be an important MHC class II-expressing and -presenting cell.
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Diabetes Mellitus Tipo 1 , Islotes Pancreáticos , Humanos , Ratones , Animales , Células Endoteliales , Antígenos de Histocompatibilidad Clase II , Inflamación/patología , Ratones Endogámicos NODRESUMEN
Protein nanoparticles are effective platforms for antigen presentation and targeting effector immune cells in vaccine development. Encapsulins are a class of protein-based microbial nanocompartments that self-assemble into icosahedral structures with external diameters ranging from 24 to 42 nm. Encapsulins from Mxyococcus xanthus were designed to package bacterial RNA when produced in E. coli and were shown to have immunogenic and self-adjuvanting properties enhanced by this RNA. We genetically incorporated a 20-mer peptide derived from a mutant strain of the SARS-CoV-2 receptor binding domain (RBD) into the encapsulin protomeric coat protein for presentation on the exterior surface of the particle. This immunogen elicited conformationally-relevant humoral responses to the SARS-CoV-2 RBD. Immunological recognition was enhanced when the same peptide was presented in a heterologous prime/boost vaccination strategy using the engineered encapsulin and a previously reported variant of the PP7 virus-like particle, leading to the development of a selective antibody response against a SARS-CoV-2 RBD point mutant. While generating epitope-focused antibody responses is an interplay between inherent vaccine properties and B/T cells, here we demonstrate the use of orthogonal nanoparticles to fine-tune the control of epitope focusing.
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Delirium is common in hospitalised patients, and there is currently no specific treatment. Identifying and treating underlying somatic causes of delirium is the first priority once delirium is diagnosed. Several international guidelines provide clinicians with an evidence-based approach to screening, diagnosis and symptomatic treatment. However, current guidelines do not offer a structured approach to identification of underlying causes. A panel of 37 internationally recognised delirium experts from diverse medical backgrounds worked together in a modified Delphi approach via an online platform. Consensus was reached after five voting rounds. The final product of this project is a set of three delirium management algorithms (the Delirium Delphi Algorithms), one for ward patients, one for patients after cardiac surgery and one for patients in the intensive care unit.
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PURPOSE OF REVIEW: This review navigates the landscape of precision anaesthesia, emphasising tailored and individualized approaches to anaesthetic administration. The aim is to elucidate precision medicine principles, applications, and potential advancements in anaesthesia. The review focuses on the current state, challenges, and transformative opportunities in precision anaesthesia. RECENT FINDINGS: The review explores evidence supporting precision anaesthesia, drawing insights from neuroscientific fields. It probes the correlation between high-dose intraoperative opioids and increased postoperative consumption, highlighting how precision anaesthesia, especially through initiatives like Safe Brain Initiative (SBI), could address these issues. The SBI represents multidisciplinary collaboration in perioperative care. SBI fosters effective communication among surgical teams, anaesthesiologists, and other medical professionals. SUMMARY: Precision anaesthesia tailors care to individual patients, incorporating genomic insights, personalised drug regimens, and advanced monitoring techniques. From EEG to cerebral/somatic oximetry, these methods enhance precision. Standardised reporting, patient-reported outcomes, and continuous quality improvement, alongside initiatives like SBI, contribute to improved patient outcomes. Precision anaesthesia, underpinned by collaborative programs, emerges as a promising avenue for enhancing perioperative care.
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Anestesia , Anestésicos , Humanos , Anestesia/métodos , Encéfalo , Atención Dirigida al Paciente , Atención PerioperativaRESUMEN
Cancer vaccine development is inhibited by a lack of strategies for directing dendritic cell (DC) induction of effective tumor-specific cellular immunity. Pathogen engagement of DC lectins and toll-like receptors (TLRs) shapes immunity by directing T cell function. Strategies to activate specific DC signaling pathways via targeted receptor engagement are crucial to unlocking type 1 cellular immunity. Here, we engineered a glycan-costumed virus-like particle (VLP) vaccine that delivers programmable peptide antigens to induce tumor-specific cellular immunity in vivo. VLPs encapsulating TLR7 agonists and decorated with a selective mannose-derived ligand for the lectin DC-SIGN induced robust DC activation and type 1 cellular immunity, whereas VLPs lacking this key DC-SIGN ligand failed to promote DC-mediated immunity. Vaccination with glycan-costumed VLPs generated tumor antigen-specific Th1 CD4+ and CD8+ T cells that infiltrated solid tumors, inhibiting tumor growth in a murine melanoma model. Thus, VLPs employing lectin-driven immune reprogramming provide a framework for advancing cancer immunotherapies.
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For years, postoperative cognitive outcomes have steadily garnered attention, and in the past decade, they have remained at the forefront. This prominence is primarily due to empirical research emphasizing their potential to compromise patient autonomy, reduce quality of life, and extend hospital stays, and increase morbidity and mortality rates, especially impacting elderly patients. The underlying pathophysiological process might be attributed to surgical and anaesthesiological-induced stress, leading to subsequent neuroinflammation, neurotoxicity, burst suppression and the development of hypercoagulopathy. The beneficial impact of multi-faceted strategies designed to mitigate the surgical and perioperative stress response has been suggested. While certain potential risk factors are difficult to modify (e.g., invasiveness of surgery), others - including a more personalized depth of anaesthesia (EEG-guided), suitable analgesia, and haemodynamic stability - fall under the purview of anaesthesiologists. The ESAIC Safe Brain Initiative research group recommends implementing a bundle of non-invasive preventive measures as a standard for achieving more patient-centred care. Implementing multi-faceted preoperative, intraoperative, and postoperative preventive initiatives has demonstrated the potential to decrease the incidence and duration of postoperative delirium. This further validates the importance of a holistic, team-based approach in enhancing patients' clinical and functional outcomes. This review aims to present evidence-based recommendations for preventing, diagnosing, and treating postoperative neurocognitive disorders with the Safe Brain Initiative approach.
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Delirio , Delirio del Despertar , Humanos , Anciano , Delirio/etiología , Calidad de Vida , Electroencefalografía , Encéfalo , Delirio del Despertar/epidemiología , Complicaciones Posoperatorias/diagnóstico , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/etiología , Trastornos Neurocognitivos/complicacionesRESUMEN
Postoperative delirium is a serious sequela of surgery and surgery-related anaesthesia. One recommended method to prevent postoperative delirium is using bi-frontal EEG recording. The single, processed index of depth of anaesthesia allows the anaesthetist to avoid episodes of suppression EEG and excessively deep anaesthesia. The study data presented here were based on multichannel (19 channels) EEG recordings during anaesthesia. This enabled the analysis of various parameters of global electrical brain activity. These parameters were used to compare microstate topographies under anaesthesia with those in healthy volunteers and to analyse changes in microstate quantifiers and EEG global state space descriptors with increasing exposure to anaesthesia. Seventy-three patients from the Surgery Depth of Anaesthesia and Cognitive Outcome study (SRCTN 36437985) received intraoperative multichannel EEG recordings. Altogether, 720â min of artefact-free EEG data, including 210â min (29.2%) of suppression EEG, were analysed. EEG microstate topographies, microstate quantifiers (duration, frequency of occurrence and global field power) and the state space descriptors sigma (overall EEG power), phi (generalized frequency) and omega (number of uncorrelated brain processes) were evaluated as a function of duration of exposure to anaesthesia, suppression EEG and subsequent development of postoperative delirium. The major analyses involved covariate-adjusted linear mixed-effects models. The older (71 ± 7 years), predominantly male (60%) patients received a median exposure of 210 (range: 75-675) min of anaesthesia. During seven postoperative days, 21 patients (29%) developed postoperative delirium. Microstate topographies under anaesthesia resembled topographies from healthy and much younger awake persons. With increasing duration of exposure to anaesthesia, single microstate quantifiers progressed differently in suppression or non-suppression EEG and in patients with or without subsequent postoperative delirium. The most pronounced changes occurred during enduring suppression EEG in patients with subsequent postoperative delirium: duration and frequency of occurrence of microstates C and D progressed in opposite directions, and the state space descriptors showed a pattern of declining uncorrelated brain processes (omega) combined with increasing EEG variance (sigma). With increasing exposure to general anaesthesia, multiple changes in the dynamics of microstates and global EEG parameters occurred. These changes varied partly between suppression and non-suppression EEG and between patients with or without subsequent postoperative delirium. Ongoing suppression EEG in patients with subsequent postoperative delirium was associated with reduced network complexity in combination with increased overall EEG power. Additionally, marked changes in quantifiers in microstate C and in microstate D occurred. These putatively adverse intraoperative trajectories in global electrical brain activity may be seen as preceding and ultimately predicting postoperative delirium.
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The thermal distillation of crude oil mixtures is an energy-intensive process, accounting for nearly 1% of global energy consumption. Membrane-based separations are an appealing alternative or tandem process to distillation due to intrinsic energy efficiency advantages. We developed a family of spirocyclic polytriazoles from structurally diverse monomers for membrane applications. The resulting polymers were prepared by a convenient step-growth method using copper-catalysed azide-alkyne cycloaddition, providing very fast reaction rates, high molecular weights and solubilities in common organic solvents and non-interconnected microporosity. Fractionation of whole Arabian light crude oil and atmospheric tower bottom feeds using these materials enriched the low-boiling-point components and removed trace heteroatom and metal impurities (comparable performance with the lighter feed as the commercial polyimide, Matrimid), demonstrating opportunities to reduce the energy cost of crude oil distillation with tandem membrane processes. Membrane-based molecular separation under these demanding conditions is made possible by high thermal stability and a moderate level of dynamic chain mobility, leading to transient interconnections between micropores, as revealed by the calculations of static and swollen pore structures.
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Self-assembling virus-like particles (VLPs) can tolerate a wide degree of genetic and chemical manipulation to their capsid protein to display a foreign molecule polyvalently. We previously reported the successful incorporation of foreign peptide sequences in the junction loop and onto the C-terminus of PP7 dimer VLPs, as these regions are accessible for surface display on assembled capsids. Here, we report the implementation of a library-based approach to test the assembly tolerance of PP7 dimer capsid proteins to insertions or terminal extensions of randomized 15-mer peptide sequences. By performing two iterative rounds of assembly-based selection, we evaluated the degree of favorability of all 20 amino acids at each of the 15 randomized positions. Deep sequencing analysis revealed a distinct preference for the inclusion of hydrophilic peptides and negatively charged amino acids (Asp and Glu) and the exclusion of positively charged peptides and bulky and hydrophobic amino acid residues (Trp, Phe, Tyr, and Cys). Within the libraries tested here, we identified 4000 to 22,000 unique 15-mer peptide sequences that can successfully be displayed on the surface of the PP7 dimer capsid. Overall, the use of small initial libraries consisting of no more than a few million members yielded a significantly larger number of unique and assembly-competent VLP sequences than have been previously characterized for this class of nucleoprotein particle.
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Aminoácidos , Péptidos , Secuencia de Aminoácidos , Cápside , Proteínas de la Cápside/genética , PolímerosRESUMEN
Postoperative delirium (POD) is an adverse but often preventable complication of surgery and surgery-related anaesthesia, and increasingly prevalent. This article provides an overview on non-pharmacological preventive measures, divided into individualized and non-individualized measures. Non-individualized measures, such as the most minimally invasive surgical procedure, avoidance of unnecessary fasting before surgery, and the most tolerable anaesthesia are used to minimize the risk of POD in all patients. Based on the results of preoperative screenings for risk factors such as frailty or cognitive impairment, individualized measures may encompass prehabilitation, treatment of specific risk factors, operation room companionship or cognitive, motor, and sensory stimulation as well as social support. This article additionally lists several examples of best practice approaches already implemented in German-speaking countries and websites for further readings.
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Anestesia , Anestesiología , Delirio del Despertar , Fragilidad , Humanos , Delirio del Despertar/prevención & control , AyunoRESUMEN
Membrane-based organic solvent separations are rapidly emerging as a promising class of technologies for enhancing the energy efficiency of existing separation and purification systems. Polymeric membranes have shown promise in the fractionation or splitting of complex mixtures of organic molecules such as crude oil. Determining the separation performance of a polymer membrane when challenged with a complex mixture has thus far occurred in an ad hoc manner, and methods to predict the performance based on mixture composition and polymer chemistry are unavailable. Here, we combine physics-informed machine learning algorithms (ML) and mass transport simulations to create an integrated predictive model for the separation of complex mixtures containing up to 400 components via any arbitrary linear polymer membrane. We experimentally demonstrate the effectiveness of the model by predicting the separation of two crude oils within 6-7% of the measurements. Integration of ML predictors of diffusion and sorption properties of molecules with transport simulators enables for the rapid screening of polymer membranes prior to physical experimentation for the separation of complex liquid mixtures.
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Abandonment of diversity, equity and inclusion programs undermines fairness and the productivity of research.