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Ischaemic brain infarction can occur without acute neurological symptoms (covert strokes) or with symptoms (overt strokes), both associated with poor health outcomes. We conducted a pilot study of the incidence of preoperative and postoperative (intraoperative or postoperative) covert strokes, and explored the relationship of postoperative ischaemic brain injury to blood levels of neurofilament light, a biomarker of neuronal damage.We analysed 101 preoperative (within 2 weeks of surgery) and 58 postoperative research MRIs on postoperative days 2-9 from two prospective cohorts collected at the University of Wisconsin (NCT01980511 and NCT03124303). Participants were aged65 yr and undergoing non-intracranial, non-carotid surgery.Preoperative covert stroke was identified in 2/101 participants (2%; Bayesian 95% confidence interval [CI], 0.2-5.4). This rate was statistically different from the postoperative ischaemic brain injury rate of 7/58 (12%, 4.9-21.3%; P=0.01) based on postoperative imaging. However, in a smaller group of participants with paired imaging (n=30), we did not identify the same effect (P=0.67). Patients with postoperative brain injury had elevated peak neurofilament light levels (median [inter-quartile range], 2.34 [2.24-2.64] logAlthough limited by a small sample size, these data suggest that preoperative covert stroke occurs more commonly than previously anticipated. Plasma neurofilament light is a potential screening biomarker for postoperative ischaemic brain injury.

Recent randomised controlled trials have failed to show a benefit in mortality by using processed electroencephalography (pEEG) to guide lighter anaesthesia. We performed a meta-analysis of mortality data from randomised trials of pEEG monitoring to assess the evidence of any protective effect of pEEG-guided light anaesthesia compared with deep anaesthesia in adults aged ≥18 yr.Our study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. In February 2022, we searched three databases (Cochrane CENTRAL, OVID Medline, EMBASE) for RCTs of pEEG monitoring that provided mortality data at 30 days, 90 days, and/or 1 yr or longer.We included 16 articles from 12 RCTs with 48 827 total participants. We observed no statistically significant mortality reduction with light anaesthesia compared with deep anaesthesia in patients aged ≥18 yr when all studies were pooled (odds ratio [OR]=0.99; 95% confidence interval (CI), 0.92-1.08). This result did not change significantly when analysing mortality at 30 days, 90 days, 1 yr or longer. We observed no mortality benefit for pEEG monitoring compared with usual care (OR=1.02; 95% CI, 0.89-1.18), targeting higher pEEG index values compared with lower values (OR=0.89; 95% CI, 0.60-1.32), or low pEEG index value alerts compared with no alerts (OR=1.02; 95% CI, 0.41-2.52).pEEG-guided lighter anaesthesia does not appear to reduce the risk of postoperative mortality. The absence of a plausible rationale for why deeper anaesthesia should increase mortality has hampered appropriate design of definitive clinical trials.CRD42022285195 (PROSPERO).

The prevalence and clinical importance of cardiac abnormalities in dogs with acute pancreatitis (AP) is unknown.Twelve dogs with AP and 60 archived serum samples from dogs with suspected AP.Two-phase study.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.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.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.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.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.

Case-control studies have associated delirium with blood-brain barrier (BBB) permeability. However, this approach cannot determine whether delirium is attributable to high pre-existing permeability or to perioperative changes. We tested whether perioperative changes in cerebrospinal fluid/plasma albumin ratio (CPAR) and plasma S100B were associated with delirium severity.Participants were recruited to two prospective cohort studies of non-intracranial surgery (NCT01980511, NCT03124303, and NCT02926417). Delirium severity was assessed using the Delirium Rating Scale-98. Delirium incidence was diagnosed with the 3D-Confusion Assessment Method (3D-CAM) or CAM-ICU (CAM for the ICU). CSF samples from 25 patients and plasma from 78 patients were analysed for albumin and S100B. We tested associations between change in CPAR (n=11) and S100B (n=61) and delirium, blood loss, CSF interleukin-6 (IL-6), and CSF lactate.The perioperative increase in CPAR and S100B correlated with delirium severity (CPAR ρ=0.78, P=0.01; S100B ρ=0.41, P0.001), delirium incidence (CPAR P=0.012; S100B P0.001) and CSF IL-6 (CPAR ρ=0.66 P=0.04; S100B ρ=0.75, P=0.025). Linear mixed-effect analysis also showed that decreased levels of S100B predicted recovery from delirium symptoms (P=0.001). Linear regression demonstrated that change in plasma S100B was independently associated with surgical risk, cardiovascular surgery, blood loss, and hypotension. Blood loss also correlated with CPAR (ρ=0.64, P=0.04), S100B (ρ=0.70, P0.001), CSF lactate (R=0.81, P=0.01), and peak delirium severity (ρ=0.36, P=0.01).Postoperative delirium is associated with a breakdown in the BBB. This increased permeability is dynamic and associated with a neuroinflammatory and lactate response. Strategies to mitigate blood loss may protect the BBB.

Supplementary Figures S1 to S5

Purpose:Report relevance of molecular groups to clinicopathologic features, germline SMARCB1/SMARCA4 alterations (GLA), and survival of children with atypical teratoid rhabdoid tumor (ATRT) treated in two multi-institutional clinical trials.Materials and Methods:Seventy-four participants with newly diagnosed ATRT were treated in two trials: infants (SJYC07: age < 3 years; n = 52) and children (SJMB03: age 3–21 years; n = 22), using surgery, conventional chemotherapy (infants), or dose-dense chemotherapy with autologous stem cell rescue (children), and age- and risk-adapted radiotherapy [focal (infants) and craniospinal (CSI; children)]. Molecular groups ATRT-MYC (MYC), ATRT-SHH (SHH), and ATRT-TYR (TYR) were determined from tumor DNA methylation profiles.Results:Twenty-four participants (32%) were alive at time of analysis at a median follow-up of 8.4 years (range, 3.1–14.1 years). Methylation profiling classified 64 ATRTs as TYR (n = 21), SHH (n = 30), and MYC (n = 13), SHH group being associated with metastatic disease. Among infants, TYR group had the best overall survival (OS; P = 0.02). However, outcomes did not differ by molecular groups among infants with nonmetastatic (M0) disease. Children with M0 disease and 2 residual tumor had a 5-year progression-free survival (PFS) of 72.7 ± 12.7% and OS of 81.8 ± 11%. Infants with M0 disease had a 5-year PFS of 39.1 ± 11.5% and OS of 51.8 ± 12%. Those with metastases fared poorly [5-year OS 25 ± 12.5% (children) and 0% (infants)]. SMARCB1 GLAs were not associated with PFS.Conclusions:Among infants, those with ATRT-TYR had the best OS. ATRT-SHH was associated with metastases and consequently with inferior outcomes. Children with nonmetastatic ATRT benefit from postoperative CSI and adjuvant chemotherapy.

Germline methodology

BackgroundAccumulating evidence supports sex differences in pharmacodynamic and pharmacokinetic drug profiles. However, recommended anaesthetic drug doses are not sex-adjusted, likely due to limited studies comparing sexes. Our objective was to systematically synthesise studies of anaesthetic key performance indicators (anaesthesia awareness), and markers of relatively lighter anaesthesia, time to emergence and dosing to achieve adequate depth of anaesthesia, for females and males.MethodsMEDLINE, Embase, and the Cochrane library databases. Studies were identified from inception of database to August 2nd, 2022. Controlled clinical trials (randomised and non-randomised) and prospective cohort studies that reported outcomes by sex for awareness with post-operative recall, connected consciousness during anaesthesia, depth of anaesthesia, and emergence from anaesthesia. Two authors undertook search, review, selection, and data abstraction. Risk of bias was assessed using the Newcastle Ottawa Scale. Results were synthesized by random effects meta-analysis where possible, or narrative form. Results were expressed as odds ratios (ORs) and mean differences (MDs) with corresponding 95% confidence intervals (CIs).ResultsOf the 19,749 studies identified from literature search, 66 citations of 64 studies (98,243 participants; 53,143 females and 45,100 males) were eligible for inclusion, of which 44 contributed to meta-analysis. Females had a higher incidence of awareness with post-operative recall (33 studies, OR 1.37, 95%CI 1.09 to 1.75) and connected consciousness during anaesthesia (3 studies, OR 2.09, 95% CI 1.04 to 4.23) than males. Time to emergence was faster in females than in males, including time to eye-opening (10 studies, MD -2.28 min, 95% CI -3.58 to -0.98), and time to response to command (6 studies, MD - 2.84 min, 95% CI -4.07 to -1.62). Data on depth of anaesthesia were heterogenous limiting synthesis to a qualitative review which did not identify differences by sex.ConclusionFemale sex was associated with a greater incidence of anaesthetic awareness, as well as faster emergence from anaesthesia. These data suggest reappraisal of anaesthetic care, including whether similar drug dosing for females and males represents best care. Equitable outcomes for females undergoing general anaesthesia warrants strategic focus in future research.Systematic review registrationPROSPERO CRD42022336087.

Despite many studies of potential delirium biomarkers, delirium pathophysiology remains unclear. Evidence shows that the quality of reporting delirium biomarker studies is sub-optimal. Better reporting of delirium biomarker studies is needed to understand delirium pathophysiology better. To improve robustness, transparency and uniformity of delirium biomarker study reports, the REDEEMS (Reporting Essentials for DElirium bioMarker Studies) guideline was developed by an international group of delirium researchers through a three-stage process, including a systematic review, a three-round Delphi study, and a follow-up consensus meeting. This process resulted in a 9-item guideline to inform delirium fluid biomarker studies. To enhance implementation of the REDEEMS guideline, this Explanation and Elaboration paper provides a detailed explanation of each item. We anticipate that the REDEEMS guideline will help to accelerate our understanding of delirium pathophysiology by improving the reporting of delirium biomarker research and, consequently the capacity to synthesise results across studies.

This scientific commentary refers to ‘Extremes of baseline cognitive function determine the severity of delirium: a population study’ by Tsui et al. (https://doi.org/10.1093/brain/awad062).

Study DesignRetrospective cohort studyObjectivesTo investigate the effect of perioperative gabapentin administration on postoperative pain and opioid use in elderly patients after elective posterior lumbar fusion.MethodsThis was a single-center study of patients over the age of 65 who underwent elective posterior lumbar fusion. The cohort was stratified into two groups based on perioperative gabapentin administration defined as use both in the immediate preoperative period and postoperatively during hospitalization. Mean daily visual analogue scale (VAS) pain scores and mean daily morphine equivalent dosage (MED) during the postoperative hospital stay were compared between these groups using traditional regression and inverse probability weighting.ResultsThere were 350 patients who received gabapentin perioperatively and 78 patients who did not receive gabapentin. Multivariate regression did not demonstrate a difference in daily MED (ß=-6.6 mg, p=0.816) or daily pain scores (ß=0.04, p=0.257) averaged over the first seven postoperative days. Sub-analysis stratifying by each individual postoperative day also did not demonstrate a difference in MED or pain scores.ConclusionThis study did not find perioperative gabapentin administration to be beneficial in reducing postoperative VAS pain scores or opioid use in the acute postoperative period for elderly patients undergoing posterior lumbar fusion. These findings are consistent with recent literature suggesting gabapentin is of minimal benefit in postoperative multimodal analgesia regimens.Level of Evidence3

Recent trials are conflicting as to whether titration of anaesthetic dose using electroencephalography monitoring reduces postoperative delirium. Titration to anaesthetic dose itself might yield clearer conclusions. We analysed our observational cohort to clarify both dose ranges for trials of anaesthetic dose and biological plausibility of anaesthetic dose influencing delirium.We analysed the use of sevoflurane in an ongoing prospective cohort of non-intracranial surgery. Of 167 participants, 118 received sevoflurane and were aged65 yr. We tested associations between age-adjusted median sevoflurane (AMS) minimum alveolar concentration fraction or area under the sevoflurane time×dose curve (AUC-S) and delirium severity (Delirium Rating Scale-98). Delirium incidence was measured with 3-minute Diagnostic Confusion Assessment Method (3D-CAM) or CAM-ICU. Associations with previously identified delirium biomarkers (interleukin-8, neurofilament light, total tau, or S100B) were tested.Delirium severity did not correlate with AMS (Spearman's ρ=-0.014, P=0.89) or AUC-S (ρ=0.093, P=0.35), nor did delirium incidence (AMS Wilcoxon P=0.86, AUC-S P=0.78). Further sensitivity analyses including propofol dose also demonstrated no relationship. Linear regression confirmed no association for AMS in unadjusted (log (IRR)=-0.06 P=0.645) or adjusted models (log (IRR)=-0.0454, P=0.735). No association was observed for AUC-S in unadjusted (log (IRR)=0.00, P=0.054) or adjusted models (log (IRR)=0.00, P=0.832). No association of anaesthetic dose with delirium biomarkers was identified (P0.05).Sevoflurane dose was not associated with delirium severity or incidence. Other biological mechanisms of delirium, such as inflammation and neuronal injury, appear more plausible than dose of sevoflurane.NCT03124303, NCT01980511.

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.

Background ContextPostoperative delirium is a clinically significant acute disorder of consciousness especially prevalent in older adult patients, of which more than 100,000 per year undergo spinal fusion surgery. There are no proven preventative therapies, and delirium is associated with increased postoperative complications, functional decline, morbidity, and mortality.PurposeTo identify perioperative risk factors for postoperative delirium (POD) after lumbar spinal fusion procedures in patients aged 65 or older.Study DesignRetrospective ReviewPatient Sample702 patients who underwent lumbar spinal fusion surgery from 11/13/2017 to 1/30/2021.Outcome MeasuresThe primary outcome was the presence of postoperative delirium assessed by the Delirium Observation Screening Scale (DOSS) and Confusion Assessment Method for the ICU (CAM-ICU).MethodsDemographic, surgical, and perioperative data were obtained from the electronic medical records. The primary outcome was presence of postoperative delirium. Univariate and multivariate analyses were performed. A binomial logistic regression model was designed using a custom written MATLAB script.ResultsOf the 702 patients included in the study, 173 (24.6%) developed POD. Our analysis revealed that older age (p < 0.001), lower preoperative hemoglobin (p < 0.001), and higher ASA grade (p < 0.001), were significant preoperative risk factors for developing POD. The only significant intraoperative risk factor was a higher number of spinal levels that were instrumented (p < 0.001). Higher pain scores on postoperative day 1 (p < 0.001), and lower postoperative hemoglobin (p < 0.001) were associated with increased POD; as were ICU admission (p < 0.001) and increased length of ICU stay (p < 0.001). Patients who developed POD had a longer hospital stay (p < 0.001) with lower rates of discharge to home as opposed to an inpatient facility (p < 0.001).ConclusionsRisk factors for older adults undergoing lumbar spinal fusion surgery include advanced age, lower preoperative and postoperative hemoglobin, higher ASA grade, greater extent of surgery, and higher postoperative pain scores. Patients with delirium had a higher incidence of postoperative ICU admission, increased length of stay, decreased likelihood of discharge to home and increased mortality, all consistent with prior studies. Further studies will determine whether adequate management of anemia and pain lead to a reduction in the incidence of postoperative delirium in these patients.

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.

This cohort study examines major surgical admissions and quality of life.