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Background: We aimed to assess perioperative changes in fibrinogen in the cerebrospinal fluid (CSF), their association with markers of blood–brain barrier breakdown and neuroinflammation, and their association with postoperative delirium severity. Methods: We conducted a secondary analysis of the Interventions for Postoperative Delirium-Biomarker 2 (IPOD-B2, NCT02926417) study, a prospective observational cohort study. We included 24 patients aged >21 yr undergoing aortic aneurysm repair. CSF samples were obtained before (n=24) and after surgery (n=13), with some participants having multiple postoperative samples. Our primary outcome was the perioperative change in CSF fibrinogen. Delirium was assessed using the Delirium Rating Scale-Revised-98. Results: CSF fibrinogen increased after surgery (P

Summary: In an era of ‘big data’, we propose that a collaborative network approach will drive a better understanding of the mechanisms of delirium, and more rapid development of therapies. We have formed the International Delirium Pathophysiology & Electrophysiology Network for Data sharing (iDEPEND) group with a key aim to ‘facilitate the study of delirium pathogenesis with electrophysiology, imaging, and biomarkers including data acquisition, analysis, and interpretation’. Our initial focus is on studies of electrophysiology as we anticipate this methodology has great potential to enhance our understanding of delirium. Our article describes this principle and is used to highlight the endeavour to the wider community as we establish key stakeholders and partnerships.

Abstract The human brain displays a rich repertoire of states that emerge from the microscopic interactions of cortical and subcortical neurons. Difficulties inherent within large-scale simultaneous neuronal recording limit our ability to link biophysical processes at the microscale to emergent macroscopic brain states. Here we introduce a microscale biophysical network model of layer-5 pyramidal neurons that display graded coarse-sampled dynamics matching those observed in macroscale electrophysiological recordings from macaques and humans. We invert our model to identify the neuronal spike and burst dynamics that differentiate unconscious, dreaming, and awake arousal states and provide insights into their functional signatures. We further show that neuromodulatory arousal can mediate different modes of neuronal dynamics around a low-dimensional energy landscape, which in turn changes the response of the model to external stimuli. Our results highlight the promise of multiscale modelling to bridge theories of consciousness across spatiotemporal scales.

BackgroundDisconnected consciousness describes a state in which subjective experience (i.e., consciousness) becomes isolated from the external world. It appears frequently during sleep or sedation, when subjective experiences remain vivid but are unaffected by external stimuli. Traditional methods of differentiating connected and disconnected consciousness, such as relying on behavioral responsiveness or on post-anesthesia reports, have demonstrated limited accuracy: unresponsiveness has been shown to not necessarily equate to unconsciousness and amnesic effects of anesthesia and sleep can impair explicit recollection of events occurred during sleep/sedation. Due to these methodological challenges, our understanding of the neural mechanisms underlying sensory disconnection remains limited.MethodsTo overcome these methodological challenges, we employ a distinctive strategy by combining a serial awakening paradigm with auditory stimulation during mild propofol sedation. While under sedation, participants are systematically exposed to auditory stimuli and questioned about their subjective experience (to assess consciousness) and their awareness of the sounds (to evaluate connectedness/disconnectedness from the environment). The data collected through interviews are used to categorize participants into connected and disconnected consciousness states. This method circumvents the requirement for responsiveness in assessing consciousness and mitigates amnesic effects of anesthesia as participants are questioned while still under sedation. Functional MRI data are concurrently collected to investigate cerebral activity patterns during connected and disconnected states, to elucidate sensory disconnection neural gating mechanisms. We examine whether this gating mechanism resides at the thalamic level or results from disruptions in information propagation to higher cortices. Furthermore, we explore the potential role of slow-wave activity (SWA) in inducing disconnected consciousness by quantifying high-frequency BOLD oscillations, a known correlate of slow-wave activity.DiscussionThis study represents a notable advancement in the investigation of sensory disconnection. The serial awakening paradigm effectively mitigates amnesic effects by collecting reports immediately after regaining responsiveness, while still under sedation. Ultimately, this research holds the potential to understand how sensory gating is achieved at the neural level. These biomarkers might be relevant for the development of sensitive anesthesia monitoring to avoid intraoperative connected consciousness and for the assessment of patients suffering from pathologically reduced consciousness.Clinical trial registrationEuropean Union Drug Regulating Authorities Clinical Trials Database (EudraCT), identifier 2020-003524-17.

Abstract Background The prevalence and clinical importance of cardiac abnormalities in dogs with acute pancreatitis (AP) is unknown. Animals Twelve dogs with AP and 60 archived serum samples from dogs with suspected AP. Methods Two‐phase study. Phase I: Analysis of archived serum samples from dogs with clinical signs of AP and high Spec cPL concentrations. High sensitivity troponin I (TnIH) and N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) concentrations were measured in achieved serum samples. Phase II: Prospective observational study. Dogs with AP underwent echocardiography and Holter monitoring. Serum cardiac troponin I (cTnI) and plasma NT‐proBNP concentrations were measured. Previously described disease severity indices were calculated for each dog. Results Phase I: 41 of 60 dogs suspected of having AP had abnormally high TnIH concentrations and 13 of 60 had abnormally high serum NT‐proBNP concentrations. Higher TnIH concentrations were observed in dogs with Spec cPL concentration >2000 μg/L as compared to those with concentrations of 1000‐2000 μg/L. Phase II: 11 of 12 dogs diagnosed with pancreatitis had abnormal cTnI concentrations (median: 0.384 ng/mL, range: 0.041‐2.966 ng/mL, RI: ≤0.06 ng/mL) and 7 of 12 dogs had plasma NT‐proBNP concentrations above the reference interval (median: 971 pmol/L, range: 250‐2215 pmol/L, RI: ≤900 pmol/L). Supraventricular and ventricular ectopic beats occurred in 3 dogs. Echocardiographic abnormalities were detected in 5 dogs. Cardiovascular variables were not associated with indices of disease severity. Conclusions and Clinical Importance Myocardial injury is common in dogs with AP, but clinical consequences appeared to be uncommon in our small cohort. Cardiac biomarkers should be interpreted with caution in dogs with AP.

The neural mechanisms through which individuals lose sensory awareness of their environment during anesthesia remains poorly understood despite being of vital importance to the field. Prior research has not distinguished between sensory awareness of the environment (connectedness) and consciousness itself. In the current study, we investigated the neural correlates of sensory awareness by contrasting neural responses to an auditory roving oddball paradigm during consciousness with sensory awareness (connected consciousness) and consciousness without sensory awareness (disconnected consciousness). These states were captured using a serial awakening paradigm with the sedative alpha2 adrenergic agonist dexmedetomidine, chosen based on our published hypothesis that suppression of noradrenaline signaling is key to induce a state of sensory disconnection. High-density electroencephalography was recorded from 18 human subjects before and after administration of dexmedetomidine. By investigating event-related potentials and taking advantage of advances in Dynamic Causal Modeling (DCM), we assessed alterations in effective connectivity between nodes of a previously established auditory processing network. We found that during disconnected consciousness, the scalp-level response to standard tones produced a P3 response that was absent during connected consciousness. This P3 response resembled the response to oddball tones seen in connected consciousness. DCM showed that disconnection produced increases in standard tone feedback signaling throughout the auditory network. Simulation analyses showed that these changes in connectivity, most notably the increase in feedback from right superior temporal gyrus to right A1, can explain the new P3 response. Together these findings show that during disconnected consciousness there is a disruption of normal predictive coding processes, so that all incoming auditory stimuli become similarly surprising.

Background: Micro-electrode recordings are often necessary during electrode implantation for deep brain stimulation of the subthalamic nucleus. Dexmedetomidine may be a useful sedative for these procedures, but there is limited information regarding its effect on neural activity in the subthalamic nucleus and on micro-electrode recording quality. Methods: We recorded neural activity in five patients undergoing deep brain stimulation implantation to the subthalamic nucleus. Activity was recorded after subthalamic nucleus identification while patients received dexmedetomidine sedation (loading – 1 μg kg−1 over 10–15 min, maintenance – 0.7 μg kg−1 h−1). We compared the root-mean square (RMS) and beta band (13–30 Hz) oscillation power of multi-unit activity recorded by microelectrode before, during and after recovery from dexmedetomidine sedation. RMS was normalised to values recorded in the white matter. Results: Multi-unit activity decreased during sedation in all five patients. Mean normalised RMS decreased from 2.8 (1.5) to 1.6 (1.1) during sedation (43% drop, p = 0.056). Beta band power dropped by 48.4%, but this was not significant (p = 0.15). Normalised RMS values failed to return to baseline levels during the time allocated for the study (30 min). Conclusions: In this small sample, we demonstrate that dexmedetomidine decreases neuronal firing in the subthalamic nucleus as expressed in the RMS of the multi-unit activity. As multi-unit activity is a factor in determining the subthalamic nucleus borders during micro-electrode recordings, dexmedetomidine should be used with caution for sedation during these procedures. Clinical trial number: NCT01721460.

Summary: Background: Delirium predicts poor outcomes, however identifying patients with the worst outcomes is challenging. Plasma neurofilament light protein (NfL) is a sensitive indicator of neuronal damage. We undertook an exploratory observational study to determine the association between plasma NfL and delirium in the critically ill. Methods: MoDUS was a randomised placebo-controlled delirium trial of simvastatin done in an UK adult general ICU. We measured NfL levels in plasma samples using a Single molecule array (Simoa) platform. We explored associations between patient's plasma NfL levels and number of delirium days, and clinical outcomes. The control group for baseline NfL were preoperative patients undergoing major surgery. Findings: The majority of critically ill patients already had a high NfL level on admission. Patients with higher plasma NfL levels at days one and three spent more days in delirium or deep sedation. Patients with zero or one day in delirium or deep sedation had day one mean concentrations of 37.8 pg/ml (SD 32.6) compared with 96.5 pg/ml (SD 106.1)) for patients with two days or more, p-value 0.002 linear mixed effects model.Survivors discharged before 14 days had lower mean plasma NfL concentrations compared to those with longer hospital stays and/or who died within six months. The area under ROC curve for predicting death within six months using day one NfL was 0.81 (0.7,0.9). Interpretation: Measurement of plasma NfL within three days of admission may be useful to identify those patients with worse clinical outcomes, and as an enrichment strategy for future delirium interventional trials in the critically ill. Funding: Alzheimer's Society UK, UK Dementia Research Institute.

Background: Perioperative inflammation is associated with perioperative complications, including delirium, that are associated with a reduced number of postoperative days alive and at home at 90 days (DAH90). We tested whether inflammation was associated with DAH90 even when adjusting for perioperative factors, and whether inflammation independently was associated with DAH90 when adjusting for delirium. Methods: We conducted a prospective cohort study of major, non-intracranial surgical patients who were older than 65 yr (n=134). We measured postoperative delirium incidence and severity, and changes in interleukin (IL)-8 and IL-10 in blood plasma. Our primary outcome, DAH90, was analysed using quantile regression. Results: Before adjusting for delirium, a postoperative day 1 increased IL-8 was associated with fewer DAH90 at the 0.75 quantile (β=–0.082; 95% confidence interval [CI], –0.19 to –0.006) after adjusting for demographic (age and sex) and perioperative factors (cardiovascular surgery, National Surgical Quality Improvement Program risk of death, and operative time). IL-10 was similarly associated with DAH90 at the 0.5 (β=–0.026; 95% CI, –0.19 to –0.001) and 0.75 (β= –0.035; 95% CI, –0.07 to –0.006) quantiles. Neither cytokine was significantly associated with DAH90 once delirium and baseline Trail Making Test B were added to the models. Conclusions: Perioperative inflammation predicts DAH90, but when delirium is added to the model inflammation loses significance as a predictor, whereas delirium is significant. Targeting perioperative inflammation may reduce delirium and moderate hospital readmission and mortality. Clinical trial registration: NCT03124303.

During a cruise from October to November 2019, along the West Antarctic Peninsula, between 64.32 and 68.37°S, we assessed the diversity and composition of the active microbial eukaryotic community within three size fractions: micro- (> 20 μm), nano- (20–5 μm), and pico-size fractions (5–0.2 μm). The communities and the environmental parameters displayed latitudinal gradients, and we observed a strong similarity in the microbial eukaryotic communities as well as the environmental parameters between the sub-surface and the deep chlorophyll maximum (DCM) depths. Chlorophyll concentrations were low, and the mixed layer was shallow for most of the 17 stations sampled. The richness of the microplankton was higher in Marguerite Bay (our southernmost stations), compared to more northern stations, while the diversity for the nano- and pico-plankton was relatively stable across latitude. The microplankton communities were dominated by autotrophs, mostly diatoms, while mixotrophs (phototrophs-consuming bacteria and kleptoplastidic ciliates, mostly alveolates, and cryptophytes) were the most abundant and active members of the nano- and picoplankton communities. While phototrophy was the dominant trophic mode, heterotrophy (mixotrophy, phagotrophy, and parasitism) tended to increase southward. The samples from Marguerite Bay showed a distinct community with a high diversity of nanoplankton predators, including spirotrich ciliates, and dinoflagellates, while cryptophytes were observed elsewhere. Some lineages were significantly related—either positively or negatively—to ice coverage (e.g., positive for Pelagophyceae, negative for Spirotrichea) and temperature (e.g., positive for Cryptophyceae, negative for Spirotrichea). This suggests that climate changes will have a strong impact on the microbial eukaryotic community.

Hot compression experiments were performed on alloy 5182 with small additions of Sc and Zr. The 5182 alloy containing Sc and Zr is critical for expanding the 5182 alloy’s range of applications, and a thorough understanding of its thermal processing behavior is of great importance to avoid processing defects. Alloy microstructure, including grain structures and Al3(ScxZr1−x) dispersoids were analyzed by EBSD and TEM. Stable flow stresses were observed below a strain rate of 1 s−1 for the Sc-Zr containing alloy. The results of constitutive models, with and without strain−compensation, and artificial neural network (ANN) were used to compare to the experimental results. The Al3(ScxZr1−x) dispersoid data was introduced into the ANN model as a nonlinear influence factor. Addition of the Al3(ScxZr1−x) dispersoid information as input data improved the accuracy and practicality of the artificial neural network in predicting the deformation behavior of the alloy. The squared correlation coefficients of ANN prediction data reached 0.99.

Background: Dominant mutations in COL3A1 are known to cause vascular Ehlers–Danlos syndrome (vEDS) by impairing extracellular matrix (ECM) homeostasis. This disruption leads to the fragility of soft connective tissues and a significantly increased risk of life-threatening arterial and organ ruptures. Currently, treatments for vEDS are primarily symptomatic, largely due to a limited understanding of its underlying pathobiology and molecular mechanisms. Methods: In this study, we conducted a comprehensive analysis of the intracellular proteome of vEDS fibroblasts, integrating these findings with our previous transcriptome results to identify key molecular pathways that drive the disease. Additionally, we explored the therapeutic potential of inhibiting miR-29b-3p as a proof of concept. Results: Our integrative multi-omics analysis revealed complex pathological networks, emphasizing the critical role of miRNAs, particularly miR-29b-3p, in impairing ECM organization, autophagy, and cellular stress responses, all of which contribute to the pathogenesis of vEDS. Notably, the inhibition of miR-29b-3p in vEDS fibroblasts resulted in the upregulation of several differentially expressed target genes involved in these critical processes, as well as increased protein expression of essential ECM components, such as collagen types V and I. These changes suggest potential therapeutic benefits aimed at improving ECM integrity and restoring intracellular homeostasis. Conclusions: Overall, our findings advance our understanding of the complex biological mechanisms driving vEDS and lay a solid foundation for future research focused on developing targeted and effective treatment strategies for this life-threatening disorder. [ABSTRACT FROM AUTHOR]

The Ehlers-Danlos syndromes (EDS) represent a group of genetically diverse disorders characterized by the variable combination of joint hypermobility, hyperextensibility of the skin, and connective tissue fragility affecting the skin and other organs. Based on clinical features, 13 different types of EDS have been delineated, 12 of which represent monogenic conditions caused by pathogenic variants in 21 confirmed genes. Pathogenesis is related to disturbances of collagen formation and/or stability. No monogenic cause has been identified for hypermobile EDS (hEDS), a more common EDS type, which is unlikely to represent a single gene disorder in the majority of affected individuals and at present cannot be diagnosed by genetic investigations. Here we summarize the clinical features and the molecular bases of the monogenic EDS types, highlight diagnostic challenges, and provide guidance for the molecular work-up of affected individuals. In general, genetic tests are indicated if clinical features suggest a monogenic EDS type but are usually unrewarding for other cases of hypermobility. [ABSTRACT FROM AUTHOR]