Altering the intestinal microbiota during a critical developmental window has lasting metabolic consequences.

Acquisition of the intestinal microbiota begins at birth, and a stable microbial community develops from a succession of key organisms. Disruption of the microbiota during maturation by low-dose antibiotic exposure can alter host metabolism and adiposity. We now show that low-dose penicillin (LDP), delivered from birth, induces metabolic alterations and affects ileal expression of genes involved in immunity. LDP that is limited to early life transiently perturbs the microbiota, which is sufficient to induce sustained effects on body composition, indicating that microbiota interactions in infancy may be critical determinants of long-term host metabolic effects. In addition, LDP enhances the effect of high-fat diet induced obesity. The growth promotion phenotype is transferrable to germ-free hosts by LDP-selected microbiota, showing that the altered microbiota, not antibiotics per se, play a causal role. These studies characterize important variables in early-life microbe-host metabolic interaction and identify several taxa consistently linked with metabolic alterations. PAPERCLIP:

Assessing patterns of delirium symptoms reveals a novel subtype among elective surgical patients with postoperative delirium.

OBJECTIVES: Prior studies reported incidence of hypoactive and hyperactive subtypes of postoperative delirium, but did not consider cognitive symptoms of delirium which are highlighted in the DSM-5 criteria for delirium. This study aims to address this gap in the literature by classifying cases of delirium according to their constellation of cognitive and motoric symptoms of delirium using a statistical technique called Latent Class Analysis (LCA). METHODS: Data were from five independent study cohorts (N = 1968) of patients who underwent elective spine, knee/hip, or elective gastrointestinal and thoracic procedures, between 2001 and 2017. Assessments of delirium symptoms were conducted using the long form of the Confusion Assessment Method (CAM) pre- and post-surgery. Latent class analyses of CAM data from the first 2 days after surgery were conducted to determine subtypes of delirium based on patterns of cognitive and motoric symptoms of delirium. We also determined perioperative patient characteristics associated with each latent class of delirium and assessed whether the length of delirium for each of the patterns of delirium symptoms identified by the latent class analysis. RESULTS: The latent class model from postoperative day 1 revealed three distinct patterns of delirium symptoms. One pattern of symptoms, denoted as the Hyperalert class, included patients whose predominant symptoms were being hyperalert or overly sensitive to environmental stimuli and having a low level of motor activity. Another pattern of symptoms, denoted as the Hypoalert class, included patients whose predominant symptom was being hypoalert (lethargic or drowsy). A third pattern of symptoms, denoted as the Cognitive Changes class, included patients who experienced new onset of disorganized thinking, memory impairment, and disorientation. Among 352 patients who met CAM criteria for delirium on postoperative day 1, 34% had symptoms that fit within the Hyperalert latent class, 39% had symptoms that fit within the Hypoalert latent class, and 27% had symptoms that fit within the Cognitive Changes latent class. Similar findings were found when latent class analysis was applied to those who met CAM criteria for delirium on postoperative day 2. Multinomial regression analyses revealed that ASA class, surgery type, and preoperative cognitive status as measured by the Telephone Interview for Cognitive Status (TICS) scores were associated with class membership. Length of delirium differed between the latent classes with the Cognitive Changes latent class having a longer duration compared to the other two classes. CONCLUSIONS: Older elective surgery patients who did not have acute events or illnesses or a diagnosis of dementia prior to surgery displayed varying symptoms of delirium after surgery. Compared to prior studies that described hypoactive and hyperactive subtypes of delirium, we identified a novel subtype of delirium that reflects cognitive symptoms of delirium. The three subtypes of delirium reveal distinct patterns of delirium symptoms which provide insight into varying risks and care needs of patients with delirium, indicating the necessity of future research on reducing risk for cognitive symptoms of delirium.

Experimental laboratory models as tools for understanding modifiable dementia risk.

Experimental laboratory research has an important role to play in dementia prevention. Mechanisms underlying modifiable risk factors for dementia are promising targets for dementia prevention but are difficult to investigate in human populations due to technological constraints and confounds. Therefore, controlled laboratory experiments in models such as transgenic rodents, invertebrates and in vitro cultured cells are increasingly used to investigate dementia risk factors and test strategies which target them to prevent dementia. This review provides an overview of experimental research into 15 established and putative modifiable dementia risk factors: less early-life education, hearing loss, depression, social isolation, life stress, hypertension, obesity, diabetes, physical inactivity, heavy alcohol use, smoking, air pollution, anesthetic exposure, traumatic brain injury, and disordered sleep. It explores how experimental models have been, and can be, used to address questions about modifiable dementia risk and prevention that cannot readily be addressed in human studies. HIGHLIGHTS: Modifiable dementia risk factors are promising targets for dementia prevention. Interrogation of mechanisms underlying dementia risk is difficult in human populations. Studies using diverse experimental models are revealing modifiable dementia risk mechanisms. We review experimental research into 15 modifiable dementia risk factors. Laboratory science can contribute uniquely to dementia prevention.

Multi-omic profiling reveals early immunological indicators for identifying COVID-19 Progressors.

We sought to better understand the immune response during the immediate post-diagnosis phase of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by identifying molecular associations with longitudinal disease outcomes. Multi-omic analyses identified differences in immune cell composition, cytokine levels, and cell subset-specific transcriptomic and epigenomic signatures between individuals on a more serious disease trajectory (Progressors) as compared to those on a milder course (Non-progressors). Higher levels of multiple cytokines were observed in Progressors, with IL-6 showing the largest difference. Blood monocyte cell subsets were also skewed, showing a comparative decrease in non-classical CD14-CD16+ and intermediate CD14+CD16+ monocytes. In lymphocytes, the CD8+ T effector memory cells displayed a gene expression signature consistent with stronger T cell activation in Progressors. These early stage observations could serve as the basis for the development of prognostic biomarkers of disease risk and interventional strategies to improve the management of severe COVID-19. BACKGROUND: Much of the literature on immune response post-SARS-CoV-2 infection has been in the acute and post-acute phases of infection. TRANSLATIONAL SIGNIFICANCE: We found differences at early time points of infection in approximately 160 participants. We compared multi-omic signatures in immune cells between individuals progressing to needing more significant medical intervention and non-progressors. We observed widespread evidence of a state of increased inflammation associated with progression, supported by a range of epigenomic, transcriptomic, and proteomic signatures. The signatures we identified support other findings at later time points and serve as the basis for prognostic biomarker development or to inform interventional strategies.

A pigtailed macaque model of Kyasanur Forest disease virus and Alkhurma hemorrhagic disease virus pathogenesis.

Kyasanur Forest disease virus (KFDV) and the closely related Alkhurma hemorrhagic disease virus (AHFV) are emerging flaviviruses that cause severe viral hemorrhagic fevers in humans. Increasing geographical expansion and case numbers, particularly of KFDV in southwest India, class these viruses as a public health threat. Viral pathogenesis is not well understood and additional vaccines and antivirals are needed to effectively counter the impact of these viruses. However, current animal models of KFDV pathogenesis do not accurately reproduce viral tissue tropism or clinical outcomes observed in humans. Here, we show that pigtailed macaques (Macaca nemestrina) infected with KFDV or AHFV develop viremia that peaks 2 to 4 days following inoculation. Over the course of infection, animals developed lymphocytopenia, thrombocytopenia, and elevated liver enzymes. Infected animals exhibited hallmark signs of human disease characterized by a flushed appearance, piloerection, dehydration, loss of appetite, weakness, and hemorrhagic signs including epistaxis. Virus was commonly present in the gastrointestinal tract, consistent with human disease caused by KFDV and AHFV where gastrointestinal symptoms (hemorrhage, vomiting, diarrhea) are common. Importantly, RNAseq of whole blood revealed that KFDV downregulated gene expression of key clotting factors that was not observed during AHFV infection, consistent with increased severity of KFDV disease observed in this model. This work characterizes a nonhuman primate model for KFDV and AHFV that closely resembles human disease for further utilization in understanding host immunity and development of antiviral countermeasures.

Presence of Preoperative Neurodegeneration Biofluid Markers in Patients with Postoperative Delirium.

BACKGROUND: The pathophysiology of delirium is incompletely understood, including what molecular pathways are involved in brain vulnerability to delirium. This study examined whether preoperative plasma neurodegeneration markers were elevated in patients who subsequently developed postoperative delirium through a retrospective case-control study. METHODS: Inclusion criteria were patients of 65 yr of age or older, undergoing elective noncardiac surgery with a hospital stay of 2 days or more. Concentrations of preoperative plasma P-Tau181, neurofilament light chain, amyloid ß1-42 (Aß42), and glial fibrillary acidic protein were measured with a digital immunoassay platform. The primary outcome was postoperative delirium measured by the Confusion Assessment Method. The study included propensity score matching by age and sex with nearest neighbor, such that each patient in the delirium group was matched by age and sex with a patient in the no-delirium group. RESULTS: The initial cohort consists of 189 patients with no delirium and 102 patients who developed postoperative delirium. Of 291 patients aged 72.5 ± 5.8 yr, 50.5% were women, and 102 (35%) developed postoperative delirium. The final cohort in the analysis consisted of a no-delirium group (n = 102) and a delirium group (n = 102) matched by age and sex using the propensity score method. Of the four biomarkers assayed, the median value for neurofilament light chain was 32.05 pg/ml for the delirium group versus 23.7 pg/ml in the no-delirium group. The distribution of biomarker values significantly differed between the delirium and no-delirium groups (P = 0.02 by the Kolmogorov-Smirnov test) with the largest cumulative probability difference appearing at the biomarker value of 32.05 pg/ml. CONCLUSIONS: These results suggest that patients who subsequently developed delirium are more likely to be experiencing clinically silent neurodegenerative changes before surgery, reflected by changes in plasma neurofilament light chain biomarker concentrations, which may identify individuals with a preoperative vulnerability to subsequent cognitive decline.

Fine structure and molecular characterization of two new parabasalid species that naturally colonize laboratory mice, Tritrichomonas musculus and Tritrichomonas casperi.

Tritrichomonas muris is a common flagellated protist isolated from the cecum of wild rodents. This commensal protist has been shown previously to alter immune phenotypes in laboratory mice. Other trichomonads, referred to as Tritrichomonas musculis and Tritrichomonas rainier, also naturally colonize laboratory mice and cause immune alterations. This report formally describes two new trichomonads, Tritrichomonas musculus n. sp., and Tritrichomonas casperi n. sp., at the ultrastructural and molecular level. These two protists were isolated from laboratory mice and were differentiated by their size and the structure of their undulating membrane and posterior flagellum. Analysis at the 18S rRNA and trans-ITS genetic loci supported their designation as distinct species, related to T. muris. To assess the true extent of parabasalid diversity infecting laboratory mice, 135 mice bred at the National Institutes of Health (NIH) were screened using pan-parabasalid primers that amplify the trans-ITS region. Forty-four percent of mice were positive for parabasalids, encompassing a total of eight distinct sequence types. Tritrichomonas casperi and Trichomitus-like protists were dominant. T. musculus and T. rainier were also detected, but T. muris was not. Our work establishes a previously underappreciated diversity of commensal trichomonad flagellates that naturally colonize the enteric cavity of laboratory mice.

Postoperative delirium prediction using machine learning models and preoperative electronic health record data.

BACKGROUND: Accurate, pragmatic risk stratification for postoperative delirium (POD) is necessary to target preventative resources toward high-risk patients. Machine learning (ML) offers a novel approach to leveraging electronic health record (EHR) data for POD prediction. We sought to develop and internally validate a ML-derived POD risk prediction model using preoperative risk features, and to compare its performance to models developed with traditional logistic regression. METHODS: This was a retrospective analysis of preoperative EHR data from 24,885 adults undergoing a procedure requiring anesthesia care, recovering in the main post-anesthesia care unit, and staying in the hospital at least overnight between December 2016 and December 2019 at either of two hospitals in a tertiary care health system. One hundred fifteen preoperative risk features including demographics, comorbidities, nursing assessments, surgery type, and other preoperative EHR data were used to predict postoperative delirium (POD), defined as any instance of Nursing Delirium Screening Scale ≥2 or positive Confusion Assessment Method for the Intensive Care Unit within the first 7 postoperative days. Two ML models (Neural Network and XGBoost), two traditional logistic regression models ("clinician-guided" and "ML hybrid"), and a previously described delirium risk stratification tool (AWOL-S) were evaluated using the area under the receiver operating characteristic curve (AUC-ROC), sensitivity, specificity, positive likelihood ratio, and positive predictive value. Model calibration was assessed with a calibration curve. Patients with no POD assessments charted or at least 20% of input variables missing were excluded. RESULTS: POD incidence was 5.3%. The AUC-ROC for Neural Net was 0.841 [95% CI 0. 816-0.863] and for XGBoost was 0.851 [95% CI 0.827-0.874], which was significantly better than the clinician-guided (AUC-ROC 0.763 [0.734-0.793], p < 0.001) and ML hybrid (AUC-ROC 0.824 [0.800-0.849], p < 0.001) regression models and AWOL-S (AUC-ROC 0.762 [95% CI 0.713-0.812], p < 0.001). Neural Net, XGBoost, and ML hybrid models demonstrated excellent calibration, while calibration of the clinician-guided and AWOL-S models was moderate; they tended to overestimate delirium risk in those already at highest risk. CONCLUSION: Using pragmatically collected EHR data, two ML models predicted POD in a broad perioperative population with high discrimination. Optimal application of the models would provide automated, real-time delirium risk stratification to improve perioperative management of surgical patients at risk for POD.

A drug-tunable Flt23k gene therapy for controlled intervention in retinal neovascularization.

Gene therapies that chronically suppress vascular endothelial growth factor (VEGF) represent a new approach for managing retinal vascular leakage and neovascularization. However, constitutive suppression of VEGF in the eye may have deleterious side effects. Here, we developed a novel strategy to introduce Flt23k, a decoy receptor that binds intracellular VEGF, fused to the destabilizing domain (DD) of Escherichia coli dihydrofolate reductase (DHFR) into the retina. The expressed DHFR(DD)-Flt23k fusion protein is degraded unless "switched on" by administering a stabilizer; in this case, the antibiotic trimethoprim (TMP). Cells transfected with the DHFR(DD)-Flt23k construct expressed the fusion protein at levels correlated with the TMP dose. Stabilization of the DHFR(DD)-Flt23k fusion protein by TMP was able to inhibit intracellular VEGF in hypoxic cells. Intravitreal injection of self-complementary adeno-associated viral vector (scAAV)-DHFR(DD)-Flt23k and subsequent administration of TMP resulted in tunable suppression of ischemia-induced retinal neovascularization in a rat model of oxygen-induced retinopathy (OIR). Hence, our study suggests a promising novel approach for the treatment of retinal neovascularization. Schematic diagram of the tunable system utilizing the DHFR(DD)-Flt23k approach to reduce VEGF secretion. a The schematic shows normal VEGF secretion. b Without the ligand TMP, the DHFR(DD)-Flt23k protein is destabilized and degraded by the proteasome. c In the presence of the ligand TMP, DHFR(DD)-Flt23k is stabilized and sequestered in the ER, thereby conditionally inhibiting VEGF. Green lines indicate the intracellular and extracellular distributions of VEGF. Blue lines indicate proteasomal degradation of the DHFR(DD)-Flt23k protein. Orange lines indicate the uptake of cell-permeable TMP. TMP, trimethoprim; VEGF, vascular endothelial growth factor; ER, endoplasmic reticulum.

Centrin2 from the human parasite Toxoplasma gondii is required for its invasion and intracellular replication.

Centrins are EF-hand containing proteins ubiquitously found in eukaryotes and are key components of centrioles/basal bodies as well as certain contractile fibers. We previously identified three centrins in the human parasite Toxoplasma gondii, all of which localized to the centrioles. However, one of them, T. gondii (Tg) Centrin2 (CEN2), is also targeted to structures at the apical and basal ends of the parasite, as well as to annuli at the base of the apical cap of the membrane cortex. The role(s) that CEN2 play in these locations were unknown. Here, we report the functional characterization of CEN2 using a conditional knockdown method that combines transcriptional and protein stability control. The knockdown resulted in an ordered loss of CEN2 from its four compartments, due to differences in incorporation kinetics and structural inheritance over successive generations. This was correlated with a major invasion deficiency at early stages of CEN2 knockdown, and replication defects at later stages. These results indicate that CEN2 is incorporated into multiple cytoskeletal structures to serve distinct functions that are required for parasite survival.

Rapid environmental effects on gut nematode susceptibility in rewilded mice.

Genetic and environmental factors shape host susceptibility to infection, but how and how rapidly environmental variation might alter the susceptibility of mammalian genotypes remains unknown. Here, we investigate the impacts of seminatural environments upon the nematode susceptibility profiles of inbred C57BL/6 mice. We hypothesized that natural exposure to microbes might directly (e.g., via trophic interactions) or indirectly (e.g., via microbe-induced immune responses) alter the hatching, growth, and survival of nematodes in mice housed outdoors. We found that while C57BL/6 mice are resistant to high doses of nematode (Trichuris muris) eggs under clean laboratory conditions, exposure to outdoor environments significantly increased their susceptibility to infection, as evidenced by increased worm burdens and worm biomass. Indeed, mice kept outdoors harbored as many worms as signal transducer and activator of transcription 6 (STAT6) knockout mice, which are genetically deficient in the type 2 immune response essential for clearing nematodes. Using 16S ribosomal RNA sequencing of fecal samples, we discovered enhanced microbial diversity and specific bacterial taxa predictive of nematode burden in outdoor mice. We also observed decreased type 2 and increased type 1 immune responses in lamina propria and mesenteric lymph node (MLN) cells from infected mice residing outdoors. Importantly, in our experimental design, different groups of mice received nematode eggs either before or after moving outdoors. This contrasting timing of rewilding revealed that enhanced hatching of worms was not sufficient to explain the increased worm burdens; instead, microbial enhancement and type 1 immune facilitation of worm growth and survival, as hypothesized, were also necessary to explain our results. These findings demonstrate that environment can rapidly and significantly shape gut microbial communities and mucosal responses to nematode infections, leading to variation in parasite expulsion rates among genetically similar hosts.

Midazolam Premedication Immediately Before Surgery Is Not Associated With Early Postoperative Delirium.

BACKGROUND: Postoperative delirium is common among older surgical patients and may be associated with anesthetic management during the perioperative period. The aim of this study is to assess whether intravenous midazolam, a short-acting benzodiazepine used frequently as premedication, increased the incidence of postoperative delirium. METHODS: Analyses of existing data were conducted using a database created from 3 prospective studies in patients aged 65 years or older who underwent elective major noncardiac surgery. Postoperative delirium occurring on the first postoperative day was measured using the confusion assessment method. We assessed the association between the use or nonuse of premedication with midazolam and postoperative delirium using a χ2 test, using propensity scores to match up with 3 midazolam patients for each control patient who did not receive midazolam. RESULTS: A total of 1266 patients were included in this study. Intravenous midazolam was administered as premedication in 909 patients (72%), and 357 patients did not receive midazolam. Those who did and did not receive midazolam significantly differed in age, Charlson comorbidity scores, preoperative cognitive status, preoperative use of benzodiazepines, type of surgery, and year of surgery. Propensity score matching for these variables and American Society of Anesthesiology physical status scores resulted in propensity score-matched samples with 1-3 patients who used midazolam (N = 749) for each patient who did not receive midazolam (N = 357). After propensity score matching, all standardized differences in preoperative patient characteristics ranged from -0.07 to 0.06, indicating good balance on baseline variables between the 2 exposure groups. No association was found between premedication with midazolam and incident delirium on the morning of the first postoperative day in the matched dataset, with odds ratio (95% confidence interval) of 0.91 (0.65-1.29), P = .67. CONCLUSIONS: Premedication using midazolam was not associated with higher incidence of delirium on the first postoperative day in older patients undergoing major noncardiac surgery.

Perceptions, Beliefs, and Experiences of Asians and Micronesian Islanders on Family Health History Genetic Cancer Screening Community Outreach.

Cancer carries stigma, taboos, and shame including, for diverse communities, who can have difficulty understanding and communicating about family health history genetic cancer screening (GCS). The Oregon Health Authority ScreenWise Program reached out to our academic-community research team to explore Asians and Micronesian Islanders (MI) perceptions on public health education outreach on GCS due to having previously only worked with the Latinx community. The purpose of the qualitative description pilot study was to elicit perceptions, beliefs, experiences, and recommendations from Asian and MI community leaders and community members regarding family health history GCS outreach in communities. Twenty Asians (Chinese and Vietnamese) and Micronesian Islanders (Chuukese and Marshallese) were recruited from the US Pacific Northwest. Nineteen participants are immigrants with an average 21.4 and 18.5 years having lived in the USA, respectively. Individual in-depth interviews were conducted using a semi-structured, open-ended interview guide and analyzed using conventional content analysis. Three main transcultural themes were identified: (1) degree of knowing and understanding cancer screening versus family health history GCS, (2) needing culturally relevant outreach messaging on family health history GCS, and (3) communication and decision-making regarding discussing with family and health care providers about cancer screening and GCS. Culturally relevant messaging rather than generic messaging is needed for inclusive outreach. Healthcare providers are encouraged to assess a client's family health history routinely because Asian and MI clients may not understand the information requested, may be hesitant to offer, or unable to provide information about their personal or family history of cancer.

Does postoperative delirium following elective noncardiac surgery predict long-term mortality?

OBJECTIVE: to determine whether incident postoperative delirium in elective older surgical patient was associated with increased risk for mortality, controlling for covariates of 5-year mortality. DESIGN: secondary analysis of prospective cohort studies. SETTING: academic Medical Center. SUBJECTS: patients ≥65 years of age undergoing elective non-cardiac surgery. OUTCOMES: postoperative assessments of delirium measured using the Confusion Assessment Method (CAM), mortality within 5 years of the index surgery was determined from National Death Index records. RESULTS: postoperative delirium occurred in 332/1,315 patients (25%). Five years after surgery, 175 patients (13.3%) were deceased. Older age was associated with an increased odds of mortality [odds ratio (OR) 1.90, 95% confidence interval (CI) 1.20-2.70] for those aged 70-79 years compared to those aged <70 years, and OR 3.29, 95% CI 2.14-5.06 for those aged >80 years. Other variables associated with 5-year mortality on bi-variate analyses were white race, self-rated functional status, lower preoperative cognitive status, higher risk score as measured by the American Society of Anesthesiologists (ASA) classification, higher surgical risk score, history of congestive heart failure, myocardial infarction, renal disease, cancer, peripheral vascular disease and postoperative delirium. However, postoperative delirium was not associated with 5-year mortality on multi-variate logistic regression (OR 1.18, 95% CI 0.85-1.65). CONCLUSIONS: our results showed that delirium was not associated with 5-year mortality in elective surgical patients after consideration of co-variates of mortality. Our results suggest the importance of accounting for known preoperative risks for mortality when investigating the relationship between delirium and long-term mortality.

ADAPT-2: A Randomized Clinical Trial to Reduce Intraoperative EEG Suppression in Older Surgical Patients Undergoing Major Noncardiac Surgery.

BACKGROUND: Recent limited evidence suggests that the use of a processed electroencephalographic (EEG) monitor to guide anesthetic management may influence postoperative cognitive outcomes; however, the mechanism is unclear. METHODS: This exploratory, single-center, randomized clinical trial included patients who were ≥65 years of age undergoing elective noncardiac surgery. The study aimed to determine whether monitoring the brain using a processed EEG monitor reduced EEG suppression and subsequent postoperative delirium. The interventional group received processed EEG-guided anesthetic management to keep the Patient State Index (PSI) above 35 computed by the SEDline Brain Function Monitor (Masimo, Inc, Irvine, CA), while the standard care group was also monitored, but the EEG data were blinded from the clinicians. The primary outcome was intraoperative EEG suppression. A secondary outcome was incident postoperative delirium during the first 3 days after surgery. RESULTS: All outcomes were analyzed using the intention-to-treat paradigm. Two hundred and four patients with a mean age of 72 ± 5 years were studied. Minutes of EEG suppression adjusted by the length of surgery was found to be less for the interventional group than the standard care group (median [interquartile range], 1.4% [5.0%] and 2.5% [10.4%]; Hodges-Lehmann estimated median difference [95% confidence interval {CI}] of -0.8% [-2.1 to -0.000009]). The effect of the intervention on EEG suppression differed for those with and without preoperative cognitive impairment (interaction P = .01), with the estimated incidence rate ratio (95% CI) of 0.39 (0.33-0.44) for those with preoperative cognitive impairment and 0.48 (0.44-0.51) for those without preoperative cognitive impairment. The incidence of delirium was not found to be different between the interventional (17%) and the standard care groups (20%), risk ratio = 0.85 (95% CI, 0.47-1.5). CONCLUSIONS: The use of processed EEG to maintain the PSI >35 was associated with less time spent in intraoperative EEG suppression. Preoperative cognitive impairment was associated with a greater percent of surgical time spent in EEG suppression. A larger prospective cohort study to include more cognitively vulnerable patients is necessary to show whether an intervention to reduce EEG suppression is efficacious in reducing postoperative delirium.

American Society for Enhanced Recovery and Perioperative Quality Initiative Joint Consensus Statement on Postoperative Delirium Prevention.

Postoperative delirium is a geriatric syndrome that manifests as changes in cognition, attention, and levels of consciousness after surgery. It occurs in up to 50% of patients after major surgery and is associated with adverse outcomes, including increased hospital length of stay, higher cost of care, higher rates of institutionalization after discharge, and higher rates of readmission. Furthermore, it is associated with functional decline and cognitive impairments after surgery. As the age and medical complexity of our surgical population increases, practitioners need the skills to identify and prevent delirium in this high-risk population. Because delirium is a common and consequential postoperative complication, there has been an abundance of recent research focused on delirium, conducted by clinicians from a variety of specialties. There have also been several reviews and recommendation statements; however, these have not been based on robust evidence. The Sixth Perioperative Quality Initiative (POQI-6) consensus conference brought together a team of multidisciplinary experts to formally survey and evaluate the literature on postoperative delirium prevention and provide evidence-based recommendations using an iterative Delphi process and Grading of Recommendations Assessment, Development and Evaluation (GRADE) Criteria for evaluating biomedical literature.

The effects of living in an outdoor enclosure on hippocampal plasticity and anxiety-like behavior in response to nematode infection.

The hippocampus of rodents undergoes structural remodeling throughout adulthood, including the addition of new neurons. Adult neurogenesis is sensitive to environmental enrichment and stress. Microglia, the brain's resident immune cells, are involved in adult neurogenesis by engulfing dying new neurons. While previous studies using laboratory environmental enrichment have investigated alterations in brain structure and function, they do not provide an adequate reflection of living in the wild, in which stress and environmental instability are common. Here, we compared mice living in standard laboratory settings to mice living in outdoor enclosures to assess the complex interactions among environment, gut infection, and hippocampal plasticity. We infected mice with parasitic worms and studied their effects on adult neurogenesis, microglia, and functions associated with the hippocampus, including cognition and anxiety regulation. We found an increase in immature neuron numbers of mice living in outdoor enclosures regardless of infection. While outdoor living prevented increases in microglial reactivity induced by infection in both the dorsal and ventral hippocampus, outdoor mice with infection had fewer microglia and microglial processes in the ventral hippocampus. We observed no differences in cognitive performance on the hippocampus-dependent object location task between infected and uninfected mice living in either setting. However, we found that infection caused an increase in anxiety-like behavior in the open field test but only in outdoor mice. These findings suggest that living conditions, as well as gut infection, interact to produce complex effects on brain structure and function.

Volatile anaesthetics and postoperative delirium in older surgical patients-A secondary analysis of prospective cohort studies.

BACKGROUND: Volatile Anaesthetics (VAs) may be associated with postoperative delirium (POD). However, to date, the effects of VAs on POD are not completely understood. The objective of this study was to investigate the incidence of POD in different VA groups. METHODS: A secondary analysis was conducted using a database created from prospective cohort studies in patients who underwent elective major noncardiac surgery. Patients who received general anaesthesia with desflurane, isoflurane, or sevoflurane were included in the study. POD occurring on either of the first two postoperative days was measured using the Confusion Assessment Method. RESULTS: Five hundred and thirty-two patients were included in this study, with a mean age of 73.5 ± 6.0 years (range, 65-96 years). The overall incidence of POD on either postoperative day 1 or 2 was 41%. A higher incidence of POD was noted in the desflurane group compared with the isoflurane group (Odds Ratio = 3.35, 95% CI = 1.54-7.28). The incidence of POD between the sevoflurane and isoflurane or desflurane group was not statistically significant. CONCLUSION: Each VA may have different effects on postoperative cognition. Further studies using a prospective randomized approach will be necessary to discern whether anaesthetic type or management affects the occurrence of postoperative delirium.

The impact of metallothionein-II on microglial response to tumor necrosis factor-alpha (TNFα) and downstream effects on neuronal regeneration.

BACKGROUND: The extracellular environment plays an important role in supporting the regeneration of axons after injury. Metallothionein-II (MTII) is a metal-binding protein known for its neuroprotective effect by directly stimulating the growth of axons after injury. Previous studies have shown that MTII also modulates the response of astrocytes and microglia after injury. However, a detailed analysis describing how MTII modulates the interaction between microglia and neurons is lacking. METHODS: We introduced fluorescently labelled MTII into the cortex at the time of needlestick injury to investigate the cellular uptake of MTII using immunohistochemistry with antibodies against cell-type-specific markers. The role of MTII in modulating the effect of microglia on axon outgrowth following an inflammatory response is further investigated using a co-culture model involving primary rodent microglia pre-treated with TNFα and primary rodent cortical neurons. The axon lengths were assessed 24 h after the plating of the neurons onto treated microglia. We also utilised siRNA to knockdown the expression of LRP1, which allows us to investigate the role of LRP1 receptors in the MTII-mediated effect of microglia on axon outgrowth. RESULTS: Fluorescently labelled MTII was found to be associated with neurons, astrocytes and microglia following injury in vivo. Microglia-neuron co-culture experiments demonstrated that exogenous MTII altered the response of microglia to TNFα. The neurons plated onto the TNFα-stimulated microglia pre-treated with MTII have shown a significantly longer axonal length compare to the TNFα-stimulated microglia without the MTII treatment. This suggested that MTII reduce cytokine-stimulated activation of microglia, which would ordinarily impair neurite outgrowth. This inhibitory effect of MTII on activated microglia was blocked by siRNA-mediated downregulation of LRP1 receptor expression in microglia, suggesting that MTII acts via the LRP1 receptor on microglia. CONCLUSIONS: This study demonstrates that exogenous MTII acts via the LRP1 receptor to alter the inflammatory response of microglia following TNFα stimulation, providing a more supportive environment for axon growth.

Processed Electroencephalogram Monitoring and Postoperative Delirium: A Systematic Review and Meta-analysis.

WHAT WE ALREADY KNOW ABOUT THIS TOPIC: WHAT THIS ARTICLE TELLS US THAT IS NEW: BACKGROUND:: Postoperative delirium complicates approximately 15 to 20% of major operations in patients at least 65 yr old and is associated with adverse outcomes and increased resource utilization. Furthermore, patients with postoperative delirium might also be at risk of developing long-term postoperative cognitive dysfunction. One potentially modifiable variable is use of intraoperative processed electroencephalogram to guide anesthesia. This systematic review and meta-analysis examines the relationship between processed electroencephalogram monitoring and postoperative delirium and cognitive dysfunction. METHODS: A systematic search for randomized controlled trials was conducted using Ovid MEDLINE, PubMed, EMBASE, Cochrane Library, and Google search using the keywords processed electroencephalogram, Bispectral Index, postoperative delirium, postoperative cognitive dysfunction. Screening and data extraction were conducted by two independent reviewers, and risk of bias was assessed. Postoperative delirium combined-effect estimates calculated with a fixed-effects model were expressed as odds ratios with 95% CIs. RESULTS: Thirteen of 369 search results met inclusion criteria. Postoperative cognitive dysfunction data were excluded in meta-analysis because of heterogeneity of outcome measurements; results were discussed descriptively. Five studies were included in the quantitative postoperative delirium analysis, with data pooled from 2,654 patients. The risk of bias was low in three studies and unclear for the other two. The use of processed electroencephalogram-guided anesthesia was associated with a 38% reduction in odds for developing postoperative delirium (odds ratio = 0.62; P < 0.001; 95% CI, 0.51 to 0.76). CONCLUSIONS: Processed electroencephalogram-guided anesthesia was associated with a decrease in postoperative delirium. The mechanism explaining this association, however, is yet to be determined. The data are insufficient to assess the relationship between processed electroencephalogram monitoring and postoperative cognitive dysfunction.