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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. Author summary: Kyasanur Forest disease virus (KFDV) and Alkhurma hemorrhagic disease virus (AHFV) are tick-borne flaviviruses that cause viral hemorrhagic fevers in India and the Arabian Peninsula, respectively. Bonnet macaques and black-faced langurs are susceptible to KFDV infection, but these animals do not experience hemorrhagic signs as seen in human cases with KFDV. This work characterizes for the first time experimental infection of KFDV and AHFV in pigtailed macaques (PTMs). Infected PTMs can develop moderate to severe disease that models multiple features of human disease, including some hemorrhagic signs. Together these data describe the PTM model for KFDV and AHFV as a valuable tool for future work to study viral pathogenesis and for assessing the efficacy of vaccines and antivirals. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. Much of the literature on immune response post-SARS-CoV-2 infection has been in the acute and post-acute phases of infection. 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Postoperative delirium is prevalent in older patients and associated with worse outcomes. Recent data in animal studies demonstrate increases in inflammatory markers in plasma and cerebrospinal fluid (CSF) even after aseptic surgery, suggesting that inflammation of the central nervous system may be part of the pathogenesis of postoperative cognitive changes. We investigated the hypothesis that neuroinflammation was an important cause for postoperative delirium and cognitive dysfunction after major non-cardiac surgery.Methods: After Institutional Review Board approval and informed consent, we recruited patients undergoing major knee surgery who received spinal anesthesia and femoral nerve block with intravenous sedation. All patients had an indwelling spinal catheter placed at the time of spinal anesthesia that was left in place for up to 24 h. Plasma and CSF samples were collected preoperatively and at 3, 6, and 18 h postoperatively. Cytokine levels were measured using ELISA and Luminex. Postoperative delirium was determined using the confusion assessment method, and cognitive dysfunction was measured using validated cognitive tests (word list, verbal fluency test, digit symbol test).Results: Ten patients with complete datasets were included. One patient developed postoperative delirium, and six patients developed postoperative cognitive dysfunction. Postoperatively, at different time points, statistically significant changes compared to baseline were present in IL-5, IL-6, I-8, IL-10, monocyte chemotactic protein (MCP)-1, macrophage inflammatory protein (MIP)-1α, IL-6/IL-10, and receptor for advanced glycation end products in plasma and in IFN-γ, IL-6, IL-8, IL-10, MCP-1, MIP-1α, MIP-1β, IL-8/IL-10, and TNF-α in CSF.Conclusions: Substantial pro- and anti-inflammatory activity in the central neural system after surgery was found. If confirmed by larger studies, persistent changes in cytokine levels may serve as biomarkers for novel clinical trials. [ABSTRACT FROM AUTHOR]

Summary 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 [ABSTRACT FROM AUTHOR]

The Gram-positive, spore-forming pathogen Clostridium difficile is the leading definable cause of healthcare-associated diarrhea worldwide. C. difficile infections are difficult to treat because of their frequent recurrence, which can cause life-threatening complications such as pseudomembranous colitis. The spores of C. difficile are responsible for these high rates of recurrence, since they are the major transmissive form of the organism and resistant to antibiotics and many disinfectants. Despite the importance of spores to the pathogenesis of C. difficile, little is known about their composition or formation. Based on studies in Bacillus subtilis and other Clostridium spp., the sigma factors σF, σE, σG, and σK are predicted to control the transcription of genes required for sporulation, although their specific functions vary depending on the organism. In order to determine the roles of σF, σE, σG, and σK in regulating C. difficile sporulation, we generated loss-of-function mutations in genes encoding these sporulation sigma factors and performed RNA-Sequencing to identify specific sigma factor-dependent genes. This analysis identified 224 genes whose expression was collectively activated by sporulation sigma factors: 183 were σF-dependent, 169 were σE-dependent, 34 were σG-dependent, and 31 were σK-dependent. In contrast with B. subtilis, C. difficile σE was dispensable for σG activation, σG was dispensable for σK activation, and σF was required for post-translationally activating σG. Collectively, these results provide the first genome-wide transcriptional analysis of genes induced by specific sporulation sigma factors in the Clostridia and highlight that diverse mechanisms regulate sporulation sigma factor activity in the Firmicutes. [ABSTRACT FROM AUTHOR]

Elderly patients who have an acute illness or who undergo surgery often experience cognitive decline. The pathophysiologic mechanisms that cause neurodegeneration resulting in cognitive decline, including protein deposition and neuroinflammation, also play a role in animal models of surgery-induced cognitive decline. With the aging of the population, surgical candidates of advanced age with underlying neurodegeneration are encountered more often, raising concerns that, in patients with this combination, cognitive function will precipitously decline postoperatively. This special article is based on a symposium that the University of California, San Francisco, convened to explore the contributions of surgery and anesthesia to the development of cognitive decline in the aged patient. A road map to further elucidate the mechanisms, diagnosis, risk factors, mitigation, and treatment of postoperative cognitive decline in the elderly is provided. [ABSTRACT FROM AUTHOR]

Study Objective: To determine whether obesity status is associated with perioperative complications, discharge outcomes and hospital length of stay in older surgical patients.Design: Secondary analysis of five independent study cohorts (N = 1262).Setting: An academic medical center between 2001 and 2017 in the United States.Patients: Patients aged 65 years or older who were scheduled to undergo elective spine, knee, or hip surgery with an expected hospital stay of at least 2 days.Measurements: Body mass index (BMI) was stratified as nonobese (BMI ≤ 30 kg/m2), obesity class 1 (30 kg/m2 ≤ BMI < 35 kg/m2) or obesity class 2-3 (BMI ≥ 35 kg/m2). Primary outcomes included predefined intraoperative and postoperative complications, hospital length of stay (LOS), and discharge location. Univariate and multivariate logistic regression was performed.Main Results: Obesity status was not associated with intraoperative adverse events. However, obesity class 2-3 significantly increased the risk for postoperative complications (IRR 1.43, 95% CI 1.03-1.95, P = 0.03), hospital LOS (IRR 1.13, 95% CI 1.02-1.25, P = 0.02) and non-home discharge destination (OR 1.95, 95% CI 1.35-2.81, P < 0.001) after accounting for patient related factors and surgery type.Conclusions: Obesity class 2-3 status has prognostic value in predicting an increased incidence of postoperative complications, increased hospital LOS, and non-home discharge location. These results have important clinical implications for preoperative informed consent and provide areas to target for care improvement for the older obese individual. [ABSTRACT FROM AUTHOR]

A diverse group of RNA viruses have the ability to gain access to the central nervous system (CNS) and cause severe neurological disease. Current treatment for people with this type of infection is generally limited to supportive care. To address the need for reliable antivirals, we utilized a strategy of lethal mutagenesis to limit virus replication. We evaluated ribavirin (RBV), favipiravir (FAV) and N4-hydroxycytidine (NHC) against La Crosse virus (LACV), which is one of the most common causes of pediatric arboviral encephalitis cases in North America and serves as a model for viral CNS invasion during acute infection. NHC was approximately 3 to 170 times more potent than RBV or FAV in neuronal cells. Oral administration of molnupiravir (MOV), the prodrug of NHC, decreased neurological disease development (assessed as limb paralysis, ataxia and weakness, repeated seizures, or death) by 31% (4 mice survived out of 13) when treatment was started on the day of infection. MOV also reduced disease by 23% when virus was administered intranasally (IN). NHC and MOV produced less fit viruses by incorporating predominantly G to A or C to U mutations. Furthermore, NHC also inhibited virus production of two other orthobunyaviruses, Jamestown Canyon virus and Cache Valley virus. Collectively, these studies indicate that NHC/MOV has therapeutic potential to inhibit viral replication and subsequent neurological disease caused by orthobunyaviruses and potentially as a generalizable strategy for treating acute viral encephalitis., Competing Interests: UNC holds a patent for the use of UMIs in sequencing with R.S. listed as a co-inventor, for which he has received nominal royalties. The remaining authors report no competing interest., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

The prion protein, PrP C , is well known as an essential susceptibility factor for neurodegenerative prion diseases, yet its function in normal, healthy cells remains uncertain. A role in synaptic function has been proposed for PrP C , supported by its cell surface expression in neurons and glia. Here, in mouse retina, we localized PrP C to the junctions between photoreceptors and bipolar cells using synaptic proteins EAAT5, CtBP2, and PSD-95. PrP C localized most densely with bipolar cell dendrites synapsing with cone photoreceptors. In two coisogenic mouse strains, deletion of the gene encoding PrP C , Prnp , significantly altered the scotopic and/or photopic electroretinographic (ERG) responses of photoreceptors and bipolar cells. Cone-dominant pathways showed the most significant ERG changes. Retinal thickness, quantitated by high-resolution optical coherence tomography (OCT), and ribbon synapse morphology were not altered upon deletion of PrP C , suggesting that the ERG changes were driven by functional rather than structural alterations., Competing Interests: The authors declare no competing interests.

Transmission of Yersinia pestis by fleas depends on the formation of condensed bacterial aggregates embedded within a gel-like matrix that localizes to the proventricular valve in the flea foregut and interferes with normal blood feeding. This is essentially a bacterial biofilm phenomenon, which at its end stage requires the production of a Y. pestis exopolysaccharide that bridges the bacteria together in a cohesive, dense biofilm that completely blocks the proventriculus. However, bacterial aggregates are evident within an hour after a flea ingests Y. pestis , and the bacterial exopolysaccharide is not required for this process. In this study, we characterized the biochemical composition of the initial aggregates and demonstrated that the yersinia murine toxin (Ymt), a Y. pestis phospholipase D, greatly enhances rapid aggregation following infected mouse blood meals. The matrix of the bacterial aggregates is complex, containing large amounts of protein and lipid (particularly cholesterol) derived from the flea's blood meal. A similar incidence of proventricular aggregation occurred after fleas ingested whole blood or serum containing Y. pestis , and intact, viable bacteria were not required. The initial aggregation of Y. pestis in the flea gut is likely due to a spontaneous physical process termed depletion aggregation that occurs commonly in environments with high concentrations of polymers or other macromolecules and particles such as bacteria. The initial aggregation sets up subsequent binding aggregation mediated by the bacterially produced exopolysaccharide and mature biofilm that results in proventricular blockage and efficient flea-borne transmission., Importance: Yersinia pestis , the bacterial agent of plague, is maintained in nature in mammal-flea-mammal transmission cycles. After a flea feeds on a mammal with septicemic plague, the bacteria rapidly coalesce in the flea's digestive tract to form dense aggregates enveloped in a viscous matrix that often localizes to the foregut. This represents the initial stage of biofilm development that potentiates transmission of Y. pestis when the flea later bites a new host. The rapid aggregation likely occurs via a depletion-aggregation mechanism, a non-canonical first step of bacterial biofilm development. We found that the biofilm matrix is largely composed of host blood proteins and lipids, particularly cholesterol, and that the enzymatic activity of a Y. pestis phospholipase D (Ymt) enhances the initial aggregation. Y. pestis transmitted by flea bite is likely associated with this host-derived matrix, which may initially shield the bacteria from recognition by the host's intradermal innate immune response., Competing Interests: The authors declare no conflict of interest.

A bite from an infected tick is the primary means of transmission for tick-borne flaviviruses (TBFV). Ticks ingest the virus while feeding on infected blood. The traditional view is that the virus first replicates in and transits the tick midgut prior to dissemination to other organs, including salivary glands. Thus, understanding TBFV infection in the tick midgut is a key first step in identifying potential countermeasures against infection. Ex vivo midgut cultures prepared from unfed adult female Ixodes scapularis ticks were viable and remained morphologically intact for more than 8 days. The midgut consisted of two clearly defined cell layers separated by a basement membrane: an exterior network of smooth muscle cells and an internal epithelium composed of digestive generative cells. The smooth muscle cells were arranged in a stellate circumferential pattern spaced at regular intervals along the long axis of midgut diverticula. When the cultures were infected with the TBFV Langat virus (LGTV), virus production increased by two logs with a peak at 96 hours post-infection. Infected cells were readily identified by immunofluorescence staining for the viral envelope protein, nonstructural protein 3 (NS3) and dsRNA. Microscopy of the stained cultures suggested that generative cells were the primary target for virus infection in the midgut. Infected cells exhibited an expansion of membranes derived from the endoplasmic reticulum; a finding consistent with TBFV infected cell cultures. Electron microscopy of infected cultures revealed virus particles in the basolateral region between epithelial cells. These results demonstrated LGTV replication in midgut generative cells of artificially infected, ex vivo cultures of unfed adult female I. scapularis ticks., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 The Authors. Published by Elsevier GmbH.. All rights reserved.)

The first step in disease pathogenesis for arboviruses is the establishment of infection following vector transmission. For La Crosse virus (LACV), the leading cause of pediatric arboviral encephalitis in North America, and other orthobunyaviruses, the initial course of infection in the skin is not well understood. Using an intradermal (ID) model of LACV infection in mice, we find that the virus infects and replicates nearly exclusively within skin-associated muscle cells of the panniculus carnosus (PC) and not in epidermal or dermal cells like most other arbovirus families. LACV is widely myotropic, infecting distal muscle cells of the peritoneum and heart, with limited infection of draining lymph nodes. Surprisingly, muscle cells are resistant to virus-induced cell death, with long term low levels of virus release progressing through the Golgi apparatus. Thus, skin muscle may be a key cell type for the initial infection and spread of arboviral orthobunyaviruses., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: Postoperative delirium is prevalent in older adults and has been shown to increase the risk of long-term cognitive decline. Plasma biomarkers to identify the risk for postoperative delirium and the risk of Alzheimer's disease and related dementias are needed., Methods: This biomarker discovery case-control study aimed to identify plasma biomarkers associated with postoperative delirium. Patients aged ≥65 years undergoing major elective noncardiac surgery were recruited. The preoperative plasma proteome was interrogated with SOMAmer-based technology targeting 1433 biomarkers., Results: In 40 patients (20 with vs. 20 without postoperative delirium), a preoperative panel of 12 biomarkers discriminated patients with postoperative delirium with an accuracy of 97.5%. The final model of five biomarkers delivered a leave-one-out cross-validation accuracy of 80%. Represented biological pathways included lysosomal and immune response functions., Conclusion: In older patients who have undergone major surgery, plasma SOMAmer proteomics may provide a relatively non-invasive benchmark to identify biomarkers associated with postoperative delirium., (© 2024 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

Background: Infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can lead to post-acute sequelae of SARS-CoV-2 (PASC) that can persist for weeks to years following initial viral infection. Clinical manifestations of PASC are heterogeneous and often involve multiple organs. While many hypotheses have been made on the mechanisms of PASC and its associated symptoms, the acute biological drivers of PASC are still unknown., Methods: We enrolled 494 patients with COVID-19 at their initial presentation to a hospital or clinic and followed them longitudinally to determine their development of PASC. From 341 patients, we conducted multi-omic profiling on peripheral blood samples collected shortly after study enrollment to investigate early immune signatures associated with the development of PASC., Results: During the first week of COVID-19, we observed a large number of differences in the immune profile of individuals who were hospitalized for COVID-19 compared to those individuals with COVID-19 who were not hospitalized. Differences between individuals who did or did not later develop PASC were, in comparison, more limited, but included significant differences in autoantibodies and in epigenetic and transcriptional signatures in double-negative 1 B cells, in particular., Conclusions: We found that early immune indicators of incident PASC were nuanced, with significant molecular signals manifesting predominantly in double-negative B cells, compared with the robust differences associated with hospitalization during acute COVID-19. The emerging acute differences in B cell phenotypes, especially in double-negative 1 B cells, in PASC patients highlight a potentially important role of these cells in the development of PASC., Competing Interests: JL, MW, PK, CC, KD, GT, and CK maintain equity ownership and employment at Verily Life Sciences. NH, JA, CW, CP-K, and IM were employed at Oncimmune Limited. SP reports personal fees from Jazz Pharmaceuticals, Inc., and UpToDate, Inc., and grants from Philips, Inc., Sommetrics, Inc., and Regeneron. CD serves on advisory boards for Abbott Diagnostics, Ortho/Quidel Diagnostics, and Roche Diagnostics. JK receives research funding from Regeneron. JK has also provided consulting for GlaxoSmithKline, AstraZeneca, CereVu Medical, Propeller/ResMed, and BData, Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Leung, Wu, Kheradpour, Chen, Drake, Tong, Ridaura, Zisser, Conrad, Hudson, Allen, Welberry, Parsy-Kowalska, Macdonald, Tapson, Moy, deFilippi, Rosas, Basit, Krishnan, Parthasarathy, Prabhakar, Salvatore and Kim.)

Background: The understanding of Post-acute sequelae of SARS-CoV-2 infection (PASC) can be improved by longitudinal assessment of symptoms encompassing the acute illness period. To gain insight into the various disease trajectories of PASC, we assessed symptom evolution and clinical factors associated with the development of PASC over 3 months, starting with the acute illness period., Methods: We conducted a prospective cohort study to identify parameters associated with PASC. We performed cluster and case control analyses of clinical data, including symptomatology collected over 3 months following infection., Results: We identified three phenotypic clusters associated with PASC that could be characterized as remittent, persistent, or incident based on the 3-month change in symptom number compared to study entry: remittent (median; min, max: -4; -17, 3), persistent (-2; -14, 7), or incident (4.5; -5, 17) ( p = 0.041 remittent vs. persistent, p < 0.001 remittent vs. incident, p < 0.001 persistent vs. incident). Despite younger age and lower hospitalization rates, the incident phenotype had a greater number of symptoms (15; 8, 24) and a higher proportion of participants with PASC (63.2%) than the persistent (6; 2, 9 and 52.2%) or remittent clusters (1; 0, 6 and 18.7%). Systemic corticosteroid administration during acute infection was also associated with PASC at 3 months [OR (95% CI): 2.23 (1.14, 4.36)]., Conclusion: An incident disease phenotype characterized by symptoms that were absent during acute illness and the observed association with high dose steroids during acute illness have potential critical implications for preventing PASC., Competing Interests: CC, JL, MW, KD, and CK maintain equity ownership and employment at Verily Life Sciences. SP reports personal fees from Jazz Pharmaceuticals, Inc., and UpToDate, Inc., and grants from Philips, Inc., Sommetrics, Inc., and Regeneron. CRd serves on advisory boards for Abbott Diagnostics, Ortho/Quidel Diagnostics, and Roche Diagnostics. JK receives research funding from Regeneron. JK has also provided consulting for GlaxoSmithKline, AstraZeneca, CereVu Medical, Propeller/ResMed, and BData, Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer RP declared a past co-authorship with the author SP to the handling editor., (Copyright © 2023 Chen, Parthasarathy, Leung, Wu, Drake, Ridaura, Zisser, Conrad, Tapson, Moy, deFilippi, Rosas, Prabhakar, Basit, Salvatore, Krishnan and Kim.)

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 β1-42 (Aβ42), 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., (Copyright © 2023 American Society of Anesthesiologists. All Rights Reserved.)

Inflammation in response to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection drives severity of coronavirus disease 2019 (COVID-19) and is influenced by host genetics. To understand mechanisms of inflammation, animal models that reflect genetic diversity and clinical outcomes observed in humans are needed. We report a mouse panel comprising the genetically diverse Collaborative Cross (CC) founder strains crossed to human ACE2 transgenic mice (K18-hACE2) that confers susceptibility to SARS-CoV-2. Infection of CC x K18-hACE2 resulted in a spectrum of survival, viral replication kinetics, and immune profiles. Importantly, in contrast to the K18-hACE2 model, early type I interferon (IFN-I) and regulated proinflammatory responses were required for control of SARS-CoV-2 replication in PWK x K18-hACE2 mice that were highly resistant to disease. Thus, virus dynamics and inflammation observed in COVID-19 can be modeled in diverse mouse strains that provide a genetically tractable platform for understanding anti-coronavirus immunity., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Study Objectives: To describe the association between preoperative sleep disruption and postoperative delirium., Methods: Prospective cohort study with six time points (3 nights pre-hospitalization and 3 nights post-surgery). The sample included 180 English-speaking patients ≥65 years old scheduled for major non-cardiac surgery and anticipated minimum hospital stay of 3 days. Six days of wrist actigraphy recorded continuous movement to estimate wake and sleep minutes during the night from 22:00 to 05:59. Postoperative delirium was measured by a structured interview using the Confusion Assessment Method. Sleep variables for patients with (n = 32) and without (n = 148) postoperative delirium were compared using multivariate logistic regression., Results: Participants had a mean age of 72 ± 5 years (range 65-95 years). The incidence of postoperative delirium during any of the three postoperative days was 17.8%. Postoperative delirium was significantly associated with surgery duration (OR = 1.49, 95% CI 1.24-1.83) and sleep loss >15% on the night before surgery (OR = 2.64, 95% CI 1.10-6.62). Preoperative symptoms of pain, anxiety and depression were unrelated to preoperative sleep loss., Conclusions: In this study of adults ≥65 years of age, short sleep duration was more severe preoperatively in the patients who experienced postoperative delirium as evidenced by sleep loss >15% of their normal night's sleep. However, we were unable to identify potential reasons for this sleep loss. Further investigation should include additional factors that may be associated with preoperative sleep loss to inform potential intervention strategies to mitigate preoperative sleep loss and reduce risk of postoperative delirium., Competing Interests: Declaration of competing interest All authors have seen and approved the manuscript and attest that there are no conflicts of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Introduction: Postoperative delirium is a frequent adverse event following elective non-cardiac surgery. The occurrence of delirium increases the risk of functional impairment, placement to facilities other than home after discharge, cognitive impairment at discharge, as well as in-hospital and possibly long-term mortality. Unfortunately, there is a dearth of effective strategies to minimise the risk from modifiable risk factors, including postoperative pain control and the analgesic regimen. Use of potent opioids, currently the backbone of postoperative pain control, alters cognition and has been associated with an increased risk of postoperative delirium. Literature supports the intraoperative use of lidocaine infusions to decrease postoperative opioid requirements, however, whether the use of postoperative lidocaine infusions is associated with lower opioid requirements and subsequently a reduction in postoperative delirium has not been investigated., Methods and Analysis: The Lidocaine Infusion for the Management of Postoperative Pain and Delirium trial is a randomised, double-blinded study of a postoperative 48-hour infusion of lidocaine at 1.33 mg/kg/hour versus placebo in older patients undergoing major reconstructive spinal surgery at the University of California, San Francisco. Our primary outcome is incident delirium measured daily by the Confusion Assessment Method in the first three postoperative days. Secondary outcomes include delirium severity, changes in cognition, pain scores, opioid use, incidence of opioid related side effects and functional benefits including time to discharge and improved recovery from surgery. Lidocaine safety will be assessed with daily screening questionnaires and lidocaine plasma levels., Ethics and Dissemination: This study protocol has been approved by the ethics board at the University of California, San Francisco. The results of this study will be published in a peer-review journal and presented at national conferences as poster or oral presentations. Participants wishing to know the results of this study will be contacted directly on data publication., Trial Registration Number: NCT05010148., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

La Crosse virus (LACV) is a mosquito-borne orthobunyavirus that causes approximately 60 to 80 hospitalized pediatric encephalitis cases in the United States yearly. The primary treatment for most viral encephalitis, including LACV, is palliative care, and specific antiviral therapeutics are needed. We screened the National Center for Advancing Translational Sciences library of 3,833 FDA-approved and bioactive small molecules for the ability to inhibit LACV-induced death in SH-SY5Y neuronal cells. The top three hits from the initial screen were validated by examining their ability to inhibit virus-induced cell death in multiple neuronal cell lines. Rottlerin consistently reduced LACV-induced death by 50% in multiple human and mouse neuronal cell lines with an effective concentration of 0.16-0.69 µg ml -1 depending on cell line. Rottlerin was effective up to 12 hours post-infection in vitro and inhibited virus particle trafficking from the Golgi apparatus to trans-Golgi vesicles. In human inducible pluripotent stem cell-derived cerebral organoids, rottlerin reduced virus production by one log and cell death by 35% compared with dimethyl sulfoxide-treated controls. Administration of rottlerin in mice by intraperitoneal or intracranial routes starting at 3 days post-infection decreased disease development by 30-50%. Furthermore, rottlerin also inhibited virus replication of other pathogenic California serogroup orthobunyaviruses (Jamestown Canyon and Tahyna virus) in neuronal cell lines., (© 2021. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

Staphylococcus aureus is an important human pathogen that can cause a variety of diseases ranging from mild superficial skin infections to life-threatening conditions like necrotizing pneumonia, endocarditis, and septicemia. Polymorphonuclear leukocytes (PMNs; neutrophils in particular herein) are essential for host defense against S. aureus infections, and the microbe is phagocytosed readily. Most ingested bacteria are killed, but some S. aureus strains-such as the epidemic USA300 strain-have an enhanced ability to cause PMN lysis after phagocytosis. Although progress has been made, the mechanism for lysis after phagocytosis of S. aureus remains incompletely determined. Here, we tested the hypothesis that disruption of phagosome integrity and escape of S. aureus from the PMN phagosome into the cytoplasm precedes PMN lysis. We used USA300 wild-type and isogenic deletion strains to evaluate and/or verify the role of selected S. aureus molecules in this cytolytic process. Compared to the wild-type USA300 strain, Δ agr , Δ hla , Δ lukGH , and Δ psm strains each caused significantly less lysis of human PMNs 3 h and/or 6 h after phagocytosis, consistent with previous studies. Most notably, confocal microscopy coupled with selective permeabilization assays demonstrated that phagosome membrane integrity is largely maintained prior to PMN lysis after S. aureus phagocytosis. We conclude that PMN lysis does not require escape of S. aureus from the phagosome to the cytoplasm and that these are independent phenomena. The findings are consistent with the ability of S. aureus (via selected molecules) to trigger lysis of human PMNs by an undetermined signaling mechanism. IMPORTANCE S. aureus strain USA300 has the ability to cause rapid lysis of human neutrophils after phagocytosis. Although this phenomenon likely contributes to the success of USA300 as a human pathogen, our knowledge of the mechanism remains incomplete. Here, we used a selective permeabilization assay coupled with confocal microscopy to demonstrate that USA300 is contained within human neutrophil phagosomes until the point of host cell lysis. Thus, consistent with a process in macrophages, S. aureus fails to escape into the neutrophil cytoplasm prior to cytolysis.

Objectives/background: Sleep disruption is prevalent in older patients. No previous studies have considered the impact of surgery duration or surgery end time of day on postoperative sleep disruption. Accordingly, we examined the duration of surgery and surgery end times for associations with postoperative sleep disruption., Methods: Inclusion criteria were patients ≥ 65 years of age undergoing major, non-cardiac surgery. Sleep disruption was measured by wrist actigraphy and defined as wake after sleep onset (WASO) during the night, or inactivity/sleep time during the day. The sleep opportunity window was set from 22:00 to 06:00 which coincided with "lights off and on" in the hospital. WASO during this 8-hour period on the first postoperative day was categorized into one of three groups: ≤ 15%, 15-25%, and > 25%. Daytime sleep (inactivity) during the first postoperative day was categorized as ≤ 20%, 20-40%, and > 40%. Statistical analyses were conducted to test for associations between surgery duration, surgery end time and sleep disruption on the first postoperative day and following night., Results: For this sample of 156 patients, surgery duration ≥ 6 hours and surgery end time after 19:00 were not associated with WASO groups (p = 0.17, p = 0.94, respectively). Furthermore, daytime sleep was also not affected by surgery duration or surgery end time (p = 0.07, p = 0.06 respectively)., Conclusion: Our hypothesis that patients with longer duration or later-ending operations have increased postoperative sleep disruption was not supported. Our results suggest the pathophysiology of postoperative sleep disruption needs further investigation., Competing Interests: Conflict of Interest The authors do not have any conflicts of interest.

Studies of controlled lab animals and natural populations represent two insightful extremes of microbiota research. We bridged these two approaches by transferring lab-bred female C57BL/6 mice from a conventional mouse facility to an acclimation room and then to an outdoor enclosure, to investigate how the gut microbiota changes with environment. Mice residing under constant conditions served as controls. Using 16S rRNA sequencing of fecal samples, we found that the shift in temperature and humidity, as well as exposure to a natural environment, increased microbiota diversity and altered community composition. Community composition in mice exposed to high temperatures and humidity diverged as much from the microbiota of mice housed outdoors as from the microbiota of control mice. Additionally, infection with the nematode Trichuris muris modulated how the microbiota responded to environmental transitions: The dynamics of several families were buffered by the nematodes, while invasion rates of two taxa acquired outdoors were magnified. These findings suggest that gut bacterial communities respond dynamically and simultaneously to changes within the host's body (e.g. the presence of nematodes) and to changes in the wider environment of the host., (© FEMS 2020.)

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.

Purpose of Review: This review aims to explore how circadian rhythms influence disease susceptibility and potentially modify the effect of environmental exposures. We aimed to identify biomarkers commonly used in environmental health research that have also been the subject of chronobiology studies, in order to review circadian rhythms of relevance to environmental health and determine if time-of-day is an important factor to consider in environmental health studies. Moreover, we discuss opportunities for studying how environmental exposures may interact with circadian rhythms to structure disease pathology and etiology., Recent Findings: In recent years, the study of circadian rhythms in mammals has flourished. Animal models revealed that all body tissues have circadian rhythms. In humans, circadian rhythms were also shown to exist at multiple levels of organization: molecular, cellular, and physiological processes, including responding to oxidative stress, cell trafficking, and sex hormone production, respectively. Together, these rhythms are an essential component of human physiology and can shape an individual's susceptibility and response to disease. Circadian rhythms are relatively unexplored in environmental health research. However, circadian clocks control many physiological and behavioral processes that impact exposure pathways and disease systems. We believe this review will motivate new studies of (i) the impact of exposures on circadian rhythms, (ii) how circadian rhythms modify the effect of environmental exposures, and (iii) how time-of-day impacts our ability to observe the body's response to exposure.

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.

Background: TgDCX is a doublecortin-domain protein associated with the conoid fibers, a set of strongly curved non-tubular tubulin-polymers in Toxoplasma. TgDCX deletion impairs conoid structure and parasite invasion. TgDCX contains two tubulin-binding domains: a partial P25α and the DCX/doublecortin domain. Orthologues are found in apicomplexans and their free-living relatives Chromera and Vitrella., Results: We report that isolated TgDCX-containing conoid fibers retain their pronounced curvature, but loss of TgDCX destabilizes the fibers. We crystallized and determined the 3D-structure of the DCX-domain, which is similar to those of human doublecortin and well-conserved among TgDCX orthologues. However, the orthologues vary widely in targeting to the conoid in Toxoplasma and in modulating microtubule organization in Xenopus cells. Several orthologues bind to microtubules in Xenopus cells, but only TgDCX generates short, strongly curved microtubule arcs. EM analysis shows microtubules decorated with TgDCX bundled into rafts, often bordered on one edge by a "C"-shaped incomplete tube. A Chromera orthologue closely mimics TgDCX targeting in Toxoplasma and binds to microtubules in Xenopus cells, but does not generate arcs or "C"-shaped tubes, and fails to rescue the defects of the TgDCX-knockout parasite., Conclusions: These observations suggest that species-specific features of TgDCX enable it to generate strongly curved tubulin-polymers to support efficient host-cell invasion.

Background: Postoperative pain and opioid use are associated with postoperative delirium. We designed a single-center, randomized, placebo-controlled, parallel-arm, double-blinded trial to determine whether perioperative administration of gabapentin reduced postoperative delirium after noncardiac surgery., Methods: Patients were randomly assigned to receive placebo (N = 347) or gabapentin 900 mg (N = 350) administered preoperatively and for the first 3 postoperative days. The primary outcome was postoperative delirium as measured by the Confusion Assessment Method. Secondary outcomes were postoperative pain, opioid use, and length of hospital stay., Results: Data for 697 patients were included, with a mean ± SD age of 72 ± 6 yr. The overall incidence of postoperative delirium in any of the first 3 days was 22.4% (24.0% in the gabapentin and 20.8% in the placebo groups; the difference was 3.20%; 95% CI, 3.22% to 9.72%; P = 0.30). The incidence of delirium did not differ between the two groups when stratified by surgery type, anesthesia type, or preoperative risk status. Gabapentin was shown to be opioid sparing, with lower doses for the intervention group versus the control group. For example, the morphine equivalents for the gabapentin-treated group, median 6.7 mg (25th, 75th quartiles: 1.3, 20.0 mg), versus control group, median 6.7 mg (25th, 75th quartiles: 2.7, 24.8 mg), differed on the first postoperative day (P = 0.04)., Conclusions: Although postoperative opioid use was reduced, perioperative administration of gabapentin did not result in a reduction of postoperative delirium or hospital length of stay.

Background: Inflammatory bowel diseases (IBD) are believed to be driven by dysregulated interactions between the host and the gut microbiota. Our goal is to characterize and infer relationships between mucosal T cells, the host tissue environment, and microbial communities in patients with IBD who will serve as basis for mechanistic studies on human IBD., Methods: We characterized mucosal CD4 T cells using flow cytometry, along with matching mucosal global gene expression and microbial communities data from 35 pinch biopsy samples from patients with IBD. We analyzed these data sets using an integrated framework to identify predictors of inflammatory states and then reproduced some of the putative relationships formed among these predictors by analyzing data from the pediatric RISK cohort., Results: We identified 26 predictors from our combined data set that were effective in distinguishing between regions of the intestine undergoing active inflammation and regions that were normal. Network analysis on these 26 predictors revealed SAA1 as the most connected node linking the abundance of the genus Bacteroides with the production of IL17 and IL22 by CD4 T cells. These SAA1-linked microbial and transcriptome interactions were further reproduced with data from the pediatric IBD RISK cohort., Conclusions: This study identifies expression of SAA1 as an important link between mucosal T cells, microbial communities, and their tissue environment in patients with IBD. A combination of T cell effector function data, gene expression and microbial profiling can distinguish between intestinal inflammatory states in IBD regardless of disease types.

Background: Sleep disruption in critically ill adults can result in acute decrements in cognitive function, including delirium, but it is underdiagnosed in the setting of the intensive care unit (ICU). Although sleep stages can be assessed by polysomnography (PSG), acquisition and interpretation of PSG is costly, is labor intensive, is difficult to do over an extended period of time with critically ill patients (multiple days of continuous recording), and may interfere with patient care. In this pilot study, we investigated the feasibility and utility of monitoring sleep in the ICU setting using a portable electroencephalography (EEG) monitor, the SedLine brain monitor., Methods: We first performed a baseline comparison study of the SedLine brain monitor by comparing its recordings to PSG recorded in a sleep laboratory (n = 3). In a separate patient cohort, we enrolled patients in the ICU who were monitored continuously with the SedLine monitor for sleep disruption (n = 23). In all enrolled patients, we continuously monitored their EEG. The raw EEG was retrieved and sleep stages and arousals were analyzed by a board-certified technologist. Delirium was measured by a trained research nurse using the Confusion Assessment Method developed for the ICU., Results: For all enrolled patients, we continuously monitored their EEGs and were able to retrieve the raw EEGs for analysis of sleep stages. Overall, the SedLine brain monitor was able to differentiate sleep stages, as well as capture arousals and transitions between sleep stages compared with the PSG performed in the sleep laboratory. The percentage agreement was 67% for the wake stage, 77% for the non-rapid eye movement (REM) stage (N1 = 29%, N2 = 88%, and N3 = 6%), and 89% for the REM stage. The overall agreement was measured with the use of weighted kappa, which was 0.61, 95% confidence interval, 0.58 to 0.64. In the ICU study, the mean recording time for the 23 enrolled patients was 19.10 hours. There were several signs indicative of poor-quality sleep, where sleep was distributed throughout the day, with reduced time spent in REM (1.38% ± 2.74% of total sleep time), and stage N3 (2.17% ± 5.53% of total sleep time) coupled with a high arousal index (34.63 ± 19.04 arousals per hour). The occurrence of ICU delirium was not significantly different between patients with and without sleep disruption., Conclusions: Our results suggest the utility of a portable EEG monitor to measure different sleep stages, transitions, and arousals; however, the accuracy in measuring different sleep stages by the SedLine monitor varies compared with PSG. Our results also support previous findings that sleep is fragmented in critically ill patients. Further research is necessary to develop portable EEG monitors that have higher agreement with PSG.

Study Objectives: To describe preoperative and postoperative sleep disruption and its relationship to postoperative delirium., Design: Prospective cohort study with 6 time points (3 nights pre-hospitalization and 3 nights post-surgery)., Setting: University medical center., Patients: The sample consisted of 50 English-speaking patients ≥ 40 years of age scheduled for major non-cardiac surgery, with an anticipated hospital stay ≥ 3 days., Interventions: None., Measurements and Results: Sleep was measured before and after surgery for a total of 6 days using a wrist actigraph to quantify movement in a continuous fashion. Postoperative delirium was measured by a structured interview using the Confusion Assessment Method. Sleep variables for patients with (n = 7) and without (n = 43) postoperative delirium were compared using the unpaired Student t-tests or χ(2) tests. Repeated measures analysis of variance for the 6 days was used to examine within-subject changes over time and between group differences. The mean age of the patients was 66 ± 11 years (range 43-91 years), and it was not associated with sleep variables or postoperative delirium. The incidence of postoperative delirium observed during any of the 3 postoperative days was 14%. For the 7 patients who subsequently developed postoperative delirium, wake after sleep onset (WASO) as a percentage of total sleep time was significantly higher (44% ± 22%) during the night before surgery compared to the patients who did not subsequently developed delirium (21% ± 20%, p = 0.012). This sleep disruption continued postoperatively, and to a greater extent, for the first 2 nights after surgery. Patients with WASO < 10% did not experience postoperative delirium. Self-reported sleep disturbance did not differ between patients with vs. without postoperative delirium., Conclusions: In this pilot study of adults over 40 years of age, sleep disruption was more severe before surgery in the patients who experienced postoperative delirium. A future larger study is necessary to confirm our results and determine if poor sleep is associated with delirium in larger samples and what specific sleep problems best predict postoperative delirium in older surgical patients., (© 2015 American Academy of Sleep Medicine.)

Background: Preoperative cognitive impairment is a major risk factor for postoperative delirium. We therefore investigated the prognostic significance and feasibility of administering a brief cognitive screen before surgery., Methods: Patients > 65 yr of age undergoing hip, knee, or spine surgery were enrolled. A 60-sec cognitive screen, the animal fluency test (AFT), was administered preoperatively. Postoperative delirium was measured using a chart-based tool previously validated using criteria from the Confusion Assessment Method., Results: Of the 362 patients satisfying the inclusion/exclusion criteria, 199 (55%) underwent the AFT. Among them, 57 patients (29%) had an AFT score < 15, and 38 patients (19%, 95% confidence interval [CI]: 14 to 25%) developed postoperative delirium as measured by chart review. Patients with scores of < 15 were more likely to develop postoperative delirium than those who scored ≥ 15 (54% vs 5%, P < 0.01). A multiple logistic regression, with postoperative delirium as the dependent variable, identified an AFT score of < 15 (odds ratio 20.1, 95% CI: 7.9 to 51.4) and high American Society of Anesthesiologists classification (odds ratio 3.5, 95% CI: 1.3 to 9.2) as independent predictors., Conclusions: The AFT is a potentially useful brief cognitive screen for identifying patients at risk of developing postoperative delirium. Limited participation by eligible participants in this study, however, raises questions about how useful and feasible systematic administration of the test is. Large studies using prospective measurement of postoperative delirium are indicated to validate our results.

Background: There are a variety of techniques to handle missing data, such as removing observations with missing data from the analyses or estimating the missing values using various imputation algorithms. Dropping subjects from standard regression models and analyzing only completers, however, may bias results from the true value of reality. Likewise, 'last-observation-carried-forward' may not be an appropriate technique for studies measuring a particular variable over time., Methods: This dataset was part of a larger prospective cohort study that examined postoperative cognitive decline (POCD) after surgery in older adults. Data collectors had provided the reasons for data being missing using adjectives including 'confused', 'incapable', 'stuporous', 'comatose', and 'intubated'. Data having these qualitative notations were re-coded as 'incapable' and trial scores of zero were recorded. This value of '0' indicated that the patient was cognitively incapable of performing the neuropsychological test., Results: Missing data varied by cognitive test and postoperative day. Re-coding word list scores from missing to zero when a patient was too cognitively impaired to complete the tests improved sample size by 13.5% of postoperative day (POD) 1 and 12.8% on POD 2. Recoding missing data to zero for the digit symbol test resulted in 29.3% larger sample size on POD 1 and 22.7% on POD 2. Verbal fluency gained 15.7% sample size with re-coding for POD 1 and 13.7% for POD 2. Re-coding of each cognitive test reduced missing data sample size to 20-32% in all cognitive tests for each day., Discussion: Our data suggest that using a scoring system that enters a value of '0' when patients are unable to perform cognitive testing did significantly increase the number of patients that met the diagnosis of postoperative cognitive decline using the criteria that were determined a priori and may lessen chances of type II error (failure to detect a difference)., (Copyright © 2013 Elsevier Inc. All rights reserved.)

The intestinal tract is home to nematodes as well as commensal bacteria (microbiota), which have coevolved with the mammalian host. The mucosal immune system must balance between an appropriate response to dangerous pathogens and an inappropriate response to commensal microbiota that may breach the epithelial barrier, in order to maintain intestinal homeostasis. IL-22 has been shown to play a critical role in maintaining barrier homeostasis against intestinal pathogens and commensal bacteria. Here we review the advances in our understanding of the role of IL-22 in helminth infections, as well as in response to commensal and pathogenic bacteria of the intestinal tract. We then consider the relationship between intestinal helminths and gut microbiota and hypothesize that this relationship may explain how helminths may improve symptoms of inflammatory bowel diseases. We propose that by inducing an immune response that includes IL-22, intestinal helminths may enhance the mucosal barrier function of the intestinal epithelium. This may restore the mucosal microbiota populations from dysbiosis associated with colitis and improve intestinal homeostasis., (Copyright © 2012 Australian Society for Parasitology Inc. Published by Elsevier Ltd. All rights reserved.)

Purpose: Preoperative cognitive impairment is associated with the development of postoperative delirium, a common and consequential complication of major surgery in older patients. Screening for cognitive impairment should become a routine part of the preoperative evaluation of older patients; however, its implementation is hampered by limited clinical time and resources. The objective of this review was to identify cognitive screening tools that could be easily incorporated into the evaluation of older patients before major surgery., Search Strategy: Using strict inclusion and exclusion criteria, we searched PubMed over a 15-year period for short and simple cognitive screening tools. In addition, we reviewed studies that examined these cognitive screening tools in a perioperative environment. SEARCH RESULTS: We identified six cognitive screening tools that could each be administered in 2.5 min or less. Among the tools, sensitivity for cognitive impairment ranged from 79-99%, while specificity ranged from 70-98%. Only one (Mini-Cog) of the six tools we identified had been tested in a perioperative environment., Conclusions: Incorporating a cognitive screening assessment into the preoperative evaluation of older patients is feasible. More research is needed to validate cognitive screening tools in the perioperative setting.

Background: The effect of peripheral nerve blocks on postoperative delirium in older patients has not been studied. Peripheral nerve blocks may reduce the incidence of postoperative opioid use and its side effects such as delirium via opioid-sparing effect., Methods: A prospective cohort study was conducted in patients who underwent total knee replacement. Baseline cognitive function was assessed using the Telephone Interview for Cognitive Status. Postoperative delirium was measured using the Confusion Assessment Method postoperatively. Incidence of postoperative delirium was compared in two postoperative management groups: femoral nerve block ± patient-controlled analgesia and patient-controlled analgesia only. In addition, pain levels (using numeric rating scales) and opioid use were compared in two groups., Results: 85 patients were studied. The overall incidence of postoperative delirium either on postoperative day one or day two was 48.1%. Incidence of postoperative delirium in the femoral nerve block group was lower than patient controlled analgesia only group (25% vs. 61%, P = 0.002). However, there was no significant difference between the groups with respect to postoperative pain level or the amount of intravenous opioid use., Conclusions: Femoral nerve block reduces the incidence of postoperative delirium. These results suggest that a larger randomized control trial is necessary to confirm these preliminary findings.

Purpose: Effective postoperative pain management is important for older surgical patients because pain affects perioperative outcomes. A prospective cohort study was conducted to describe the direct and indirect effects of patient risk factors and pain treatment in explaining levels of postoperative pain in older surgical patients., Methods: We studied patients who were 65 years of age or older and were scheduled for major noncardiac surgery with a postoperative hospital stay of at least 2 days. The numeric rating scale (0 = no pain, 10 = worst possible pain) was used to measure pain levels before surgery and once daily for 2 days after surgery. Path analysis was performed to examine the association between predictive variables and postoperative pain levels., Results: Three hundred fifty patients were studied. We found that preoperative pain level, use of preoperative opioids, female gender, higher ASA physical status, and postoperative pain control methods were the strongest predictors of postoperative pain as measured on the first day after surgery. Younger age, greater preoperative symptoms of depression, and lower cognitive function also contributed to higher postoperative pain levels. Pain levels on the second day after surgery were strongly predicted by preoperative pain level, use of preoperative opioids, surgical risk, and pain and opioid dose on postoperative day 1. However, younger age, female gender, higher ASA physical status, greater preoperative symptoms of depression, lower cognitive function, and postoperative pain control methods indirectly contributed to pain levels on the second day after surgery., Conclusion: Although preoperative pain and use of preoperative opioids have the strongest effects on postoperative pain, clinicians should be aware that other factors such as age, gender, surgical risk, preoperative cognitive impairment, and depression also contribute to reported postoperative pain. Based on significant statistical correlations, these study results can contribute to more effective postoperative care for those patients having the risk factors studied here. Preoperative treatment/intervention based in part on factors such as preoperative pain, use of preoperative opioids, and depression may improve postoperative pain management.

We investigated whether preoperative frailty among older noncardiac surgical patients provides information about the development of postoperative delirium that is in addition to traditional geriatric risk factors. One-third of patients had a frailty score ≥3, which is considered "frail" in others' research. Twenty-five percent of patients developed postoperative delirium, which was measured using the confusion assessment method. Multivariable logistic regression showed that age, activities of daily living dependence, instrumental activities of daily living dependence, and cognitive functioning did not contribute significantly to the prediction of postoperative delirium. Only preoperative symptoms of depression (odds ratio=1.42; 95% confidence interval=1.06-1.91; P=0.018) and the frailty score (odds ratio=1.84; 95% confidence interval=1.07-3.1; P=0.028) were independently associated with the development of postoperative delirium., (© 2011 International Anesthesia Research Society)

Ulcerative colitis, a type of inflammatory bowel disease, is less common in countries endemic for helminth infections, suggesting that helminth colonization may have the potential to regulate intestinal inflammation in inflammatory bowel diseases. Indeed, therapeutic effects of experimental helminth infection have been reported in both animal models and clinical trials. Here, we provide a comprehensive cellular and molecular portrait of dynamic changes in the intestinal mucosa of an individual who infected himself with Trichuris trichiura to treat his symptoms of ulcerative colitis. Tissue with active colitis had a prominent population of mucosal T helper (T(H)) cells that produced the inflammatory cytokine interleukin-17 (IL-17) but not IL-22, a cytokine involved in mucosal healing. After helminth exposure, the disease went into remission, and IL-22-producing T(H) cells accumulated in the mucosa. Genes involved in carbohydrate and lipid metabolism were up-regulated in helminth-colonized tissue, whereas tissues with active colitis showed up-regulation of proinflammatory genes such as IL-17, IL-13RA2, and CHI3L1. Therefore, T. trichiura colonization of the intestine may reduce symptomatic colitis by promoting goblet cell hyperplasia and mucus production through T(H)2 cytokines and IL-22. Improved understanding of the physiological effects of helminth infection may lead to new therapies for inflammatory bowel diseases.

To determine risks for postoperative cognitive dysfunction (POCD), the authors conducted a prospective cohort study of 225 patients > or = 65 years of age undergoing noncardiac surgery. Cognitive testing using the Word List, Verbal Fluency, and Digit Symbol tests was conducted for each patient preoperatively and 1 and 2 days postoperatively in patients without postoperative delirium. POCD was defined as meeting statistical criteria for decline from the patient's preoperative performance levels on at least two of the three cognitive tests. Multivariate logistic regression analysis determined the association between pain and postoperative analgesia with POCD after controlling for demographics, comorbidities, preoperative level of cognitive and daily functioning, preoperative medications, duration and type of anesthesia, and adverse events. Patients were on average 72 years old and 13% of patients experienced POCD on day 1, 7% on day 2, and 15% had POCD on either day 1 or day 2 after the surgery. Multivariate regression analyses revealed that only postoperative analgesia was associated with the development of POCD. Compared with those receiving postoperative analgesia through a patient-controlled analgesia device that administered opioids intravenously, those who received postoperative analgesia orally were at significantly lower risk for the development of POCD (odds ratio: 0.22; 95% confidence interval: 0.06-0.80; Wald chi-square = 5.36, df = 1, p = 0.02). Older patients undergoing noncardiac surgery who are not delirious can experience significant declines in cognitive functioning postoperatively. Those at least risk of experiencing POCD were those who received postoperative analgesia orally.

Beta-lactamases, which evolved from bacterial penicillin-binding proteins (PBPs) involved in peptidoglycan (PG) synthesis, confer resistance to beta-lactam antibiotics. While investigating the genetic basis of biofilm development by Pseudomonas aeruginosa, we noted that plasmid vectors encoding the common beta-lactamase marker TEM-1 caused defects in twitching motility (mediated by type IV pili), adherence and biofilm formation without affecting growth rates. Similarly, strains of Escherichia coli carrying TEM-1-encoding vectors grew normally but showed reduced adherence and biofilm formation, showing this effect was not species-specific. Introduction of otherwise identical plasmid vectors carrying tetracycline or gentamicin resistance markers had no effect on biofilm formation or twitching motility. The effect is restricted to class A and D enzymes, because expression of the class D Oxa-3 beta-lactamase, but not class B or C beta-lactamases, impaired biofilm formation by E. coli and P. aeruginosa. Site-directed mutagenesis of the catalytic Ser of TEM-1, but not Oxa-3, abolished the biofilm defect, while disruption of either TEM-1 or Oxa-3 expression restored wild-type levels of biofilm formation. We hypothesized that the A and D classes of beta-lactamases, which are related to low molecular weight (LMW) PBPs, may sequester or alter the PG substrates of such enzymes and interfere with normal cell wall turnover. In support of this hypothesis, deletion of the E. coli LMW PBPs 4, 5 and 7 or combinations thereof, resulted in cumulative defects in biofilm formation, similar to those seen in beta-lactamase-expressing transformants. Our results imply that horizontal acquisition of beta-lactamase resistance enzymes can have a phenotypic cost to bacteria by reducing their ability to form biofilms. Beta-lactamases likely affect PG remodelling, manifesting as perturbation of structures involved in bacterial adhesion that are required to initiate biofilm formation.

Background: Atrial fibrillation (AF) is a common complication after coronary artery bypass graft (CABG) surgery. The purpose of this study was to determine whether pre-existing left atrial dysfunction is a predictor of postoperative AF compared with other clinical predictors., Methods: Ninety-three patients undergoing CABG were prospectively studied. Intraoperatively, transesophageal echocardiography was performed to measure left atrial size, transmitral flow velocity, and other routine parameters. Left atrial function was estimated by the following formula: Atrial index = Transmitral VTI total x LAEF/Left atrial maximal area (where VTI = velocity time integral of E and A waves, LAEF = left atrial ejection fraction). The association of potential clinical predictors with the occurrence of postoperative AF was evaluated by chi2 or Fisher exact tests, followed by stepwise multivariate logistic regression model. P values and odds ratios (OR) with 95% CIs were reported. Significance was set at P <.05., Results: Postoperative AF occurred in 28 of 93 patients (30.1%). Patients with postoperative AF were older (67.0 +/- 8.3 vs 61.5 +/- 9.6 years, P =.0075), had larger left atrial maximal area (14.3 +/- 4.6 cm(2) vs 10.9 +/- 4.3 cm2, P <.001), lower atrial index (0.54 +/- 0.56 vs 0.82 +/- 0.64, P =.008), larger body surface area (BSA) (OR 57, 95% CI 3.97-827), longer aortic cross-clamp time (OR 1.03, 95% CI 1.00-1.05), and more likely to have a postoperative myocardial infarction (OR 3.28, 95% CI 0.99-10.87) compared with those without AF. By multivariate analysis, only age (OR 1.11, 95% CI 1.04-1.19, P =.002) and atrial dimension (OR 1.75, 95% CI 1.03-2.96, P =.038) were significant independent predictors of postoperative AF. Body surface area also increased the odds of postoperative AF, but the CI was wide (OR 114, 95% CI 4.65-2810, P =.004)., Conclusions: Our results demonstrate that age and atrial enlargement, rather than atrial function, were independent predictors of postoperative AF.