Connected consciousness after tracheal intubation in young adults: an international multicentre cohort study

Background: Connected consciousness, assessed by response to command, occurs in at least 5% of general anaesthetic procedures and perhaps more often in young people. Our primary objective was to establish the incidence of connected consciousness after tracheal intubation in young people aged 18e40 yr. The secondary objectives were to assess the nature of these responses, identify relevant risk factors, and determine their relationship to postoperative outcomes. Methods: This was an international, multicentre prospective cohort study using the isolated forearm technique to assess connected consciousness shortly after tracheal intubation. Results: Of 344 enrolled subjects, 338 completed the study (mean age, 30 [standard deviation, 6.3] yr; 232 [69%] female). Responses after intubation occurred in 37/338 subjects (11%). Females (13%, 31/232) responded more often than males (6%, 6/106). In logistic regression, the risk of responsiveness was increased with female sex (odds ratio [OR adjusted ]¼2.7; 95% confidence interval [CI], 1.1e7.6; P¼0.022) and was decreased with continuous anaesthesia before laryngoscopy (OR adjusted ¼0.43; 95% CI, 0.20e0.96; P¼0.041). Responses were more likely to occur after a command to respond (and not to nonsense, 13 subjects) than after a nonsense statement (and not to command, four subjects, P¼0.049). Conclusions: Connected consciousness occured after intubation in 11% of young adults, with females at increased risk. Continuous exposure to anaesthesia between induction of anaesthesia and tracheal intubation should be considered t

Brd4 bridges the transcriptional regulators, Aire and P-TEFb, to promote elongation of peripheral-tissue antigen transcripts in thymic stromal cells

Aire controls immunologic tolerance by inducing a battery of thymic transcripts encoding proteins characteristic of peripheral tissues. Its unusually broad effect is achieved by releasing RNA polymerase II paused just downstream of transcriptional start sites. We explored Aire’s collaboration with the bromodomain-containing protein, Brd4, uncovering an astonishing correspondence between those genes induced by Aire and those inhibited by a small-molecule bromodomain blocker. Aire:Brd4 binding depended on an orchestrated series of posttranslational modifications within Aire’s caspase activation and recruitment domain. This interaction attracted P-TEFb, thereby mobilizing downstream transcriptional elongation and splicing machineries. Aire:Brd4 association was critical for tolerance induction, and its disruption could account for certain point mutations that provoke human autoimmune disease. Our findings evoke the possibility of unanticipated immunologic mechanisms subtending the potent antitumor effects of bromodomain blockers

Theta Synchrony Is Increased near Neural Populations That Are Active When Initiating Instructed Movement

Theta oscillations (3-8 Hz) in the human brain have been linked to perception, cognitive control, and spatial memory, but their relation to the motor system is less clear. We tested the hypothesis that theta oscillations coordinate distributed behaviorally relevant neural representations during movement using intracranial electroencephalography (iEEG) recordings from nine patients ( = 490 electrodes) as they performed a simple instructed movement task. Using high frequency activity (HFA; 70-200 Hz) as a marker of local spiking activity, we identified electrodes that were positioned near neural populations that showed increased activity during instruction and movement. We found that theta synchrony was widespread throughout the brain but was increased near regions that showed movement-related increases in neural activity. These results support the view that theta oscillations represent a general property of brain activity that may also play a specific role in coordinating widespread neural activity when initiating voluntary movement

Thymic regulatory T cells arise via two distinct developmental programs

The developmental programs that generate a broad repertoire of regulatory T cells (Treg cells) able to respond to both self antigens and non-self antigens remain unclear. Here we found that mature Treg cells were generated through two distinct developmental programs involving CD25+ Treg cell progenitors (CD25+ TregP cells) and Foxp3lo Treg cell progenitors (Foxp3lo TregP cells). CD25+ TregP cells showed higher rates of apoptosis and interacted with thymic self antigens with higher affinity than did Foxp3lo TregP cells, and had a T cell antigen receptor repertoire and transcriptome distinct from that of Foxp3lo TregP cells. The development of both CD25+ TregP cells and Foxp3lo TregP cells was controlled by distinct signaling pathways and enhancers. Transcriptomics and histocytometric data suggested that CD25+ TregP cells and Foxp3lo TregP cells arose by coopting negative-selection programs and positive-selection programs, respectively. Treg cells derived from CD25+ TregP cells, but not those derived from Foxp3lo TregP cells, prevented experimental autoimmune encephalitis. Our findings indicate that Treg cells arise through two distinct developmentalprograms that are both required for a comprehensive Treg cell repertoire capable of establishing immunotolerance