Machine learning-based prediction model for postoperative delirium in non-cardiac surgery.

BACKGROUND: Postoperative delirium is a common complication that is distressing. This study aimed to demonstrate a prediction model for delirium. METHODS: Among 203,374undergoing non-cardiac surgery between January 2011 and June 2019 at Samsung Medical Center, 2,865 (1.4%) were diagnosed with postoperative delirium. After comparing performances of machine learning algorithms, we chose variables for a prediction model based on an extreme gradient boosting algorithm. Using the top five variables, we generated a prediction model for delirium and conducted an external validation. The Kaplan-Meier and Cox survival analyses were used to analyse the difference of delirium occurrence in patients classified as a prediction model. RESULTS: The top five variables selected for the postoperative delirium prediction model were age, operation duration, physical status classification, male sex, and surgical risk. An optimal probability threshold in this model was estimated to be 0.02. The area under the receiver operating characteristic (AUROC) curve was 0.870 with a 95% confidence interval of 0.855-0.885, and the sensitivity and specificity of the model were 0.76 and 0.84, respectively. In an external validation, the AUROC was 0.867 (0.845-0.877). In the survival analysis, delirium occurred more frequently in the group of patients predicted as delirium using an internal validation dataset (p < 0.001). CONCLUSION: Based on machine learning techniques, we analyzed a prediction model of delirium in patients who underwent non-cardiac surgery. Screening for delirium based on the prediction model could improve postoperative care. The working model is provided online and is available for further verification among other populations. TRIAL REGISTRATION: KCT 0006363.

Risk factors for femoral-to-radial artery pressure gradient after weaning from cardiopulmonary bypass: a historical cohort study.

PURPOSE: After weaning from cardiopulmonary bypass (CPB), the radial artery pressure is frequently lower than the central pressure as reflected by femoral pressure. This discrepancy may cause improper blood pressure management. In this study, we aimed to evaluate the risk factors related to developing a significant postbypass femoral-to-radial pressure gradient, including the incidence of complications related to femoral pressure monitoring. METHODS: From January 2017 to May 2021, we studied consecutive adult cardiovascular surgical patients undergoing CPB in a historical cohort study. Patients were divided into two groups according to developing a significant femoral-to-radial pressure gradient, which was defined as a difference of ≥ 25 mm Hg for systolic pressure or ≥ 10 mm Hg for mean pressure, lasting ≥ 5 minutes for 30 minutes after CPB weaning. Factors associated with a significant pressure gradient and femoral pressure monitoring-related complications were analyzed. RESULTS: Among 2,019 patients, 677 (34%) showed a significant postbypass femoral-to-radial pressure gradient. Multivariable logistic regression analysis revealed the following factors related to the pressure gradient development: age (adjusted odds ratio [aOR] for an increase in 10 years, 1.09; 95% confidence interval [CI], 1.04 to 1.09; P < 0.001), body surface area (BSA) (aOR for an increase in 1 m2, 0.12; 95% CI, 0.07 to 0.21; P < 0.001), aortic cross-clamping time (aOR for an increase in 30 minutes, 1.05; 95% CI, 1.03 to 1.08; P < 0.001), and intraoperative epinephrine use (aOR, 1.55; 95% CI, 1.23 to 1.95; P < 0.001). The femoral pressure monitoring-related complications were observed in 11/2,019 (0.5%) patients. CONCLUSION: Our study showed that old age, smaller BSA, prolonged aortic cross-clamping time, and intraoperative epinephrine use were associated with developing a significant postbypass femoral-to-radial pressure gradient in cardiovascular surgery. Considering monitoring-related complications occurred very infrequently, it might be helpful to monitor both radial and femoral pressure simultaneously in patients with these risk factors for appropriate blood pressure management. Nevertheless, further studies are needed to confirm our findings because our results are limited by a retrospective design and residual confounding factors.

RéSUMé: OBJECTIF: Après le sevrage de la circulation extracorporelle (CEC), la pression dans l'artère radiale est souvent inférieure à la pression centrale, comme en témoigne la pression fémorale. Cette divergence peut provoquer une gestion inadaptée de la tension artérielle. Dans cette étude, nous avons cherché à évaluer les facteurs de risque liés au développement d'un gradient de pression significatif fémoro-radial post CEC, y compris l'incidence des complications liées à la surveillance de la pression fémorale. MéTHODES: Nous avons étudié consécutivement, de janvier 2017 à mai 2021, des patients adultes de chirurgie cardiovasculaire subissant une CEC dans une étude de cohorte historique. Les patients ont été séparés en deux groupes en fonction de la survenue d'un gradient de pression fémoro-radial significatif qui était défini ainsi : différence de ≥ 25 mmHg pour la pression systolique ou ≥ 10 mmHg pour la pression moyenne, durant ≥ 5 minutes pendant les 30 minutes suivant le sevrage de la CEC. Les facteurs associés à un gradient de pression significatif et aux complications liées à la surveillance de la pression fémorale ont été analysés. RéSULTATS: Parmi les 2 019 patients, 677 (34 %) ont présenté un gradient de pression fémoro-radial significatif post CEC. Une analyse par régression logistique multifactorielle a révélé que les facteurs suivants étaient liés à la survenue du gradient de pression : l'âge (rapport de cotes ajusté [aOR] pour une augmentation en dix ans, 1,09; intervalle de confiance [IC] à 95 % : 1,04 à 1,09; P < 0,001), la surface corporelle (SC) (aOR pour une augmentation dans 1 m2, 0,12; IC à 95 %, 0,07 à 0,21; P < 0,001), la durée du clampage aortique (aOR pour une augmentation en 30 minutes, 1,05; IC à 95 %, 1,03 à 1,08; P < 0,001) et l'utilisation peropératoire d'épinéphrine (aOR, 1,55; IC à 95 %, 1,23 à 1,95; P < 0,001). Des complications liées à la surveillance de la pression fémorale ont été observées chez 11 patients sur 2019 (0,5 %). CONCLUSION: Notre étude a montré qu'un âge avancé, une petite SC, une durée prolongée de clampage aortique et l'utilisation peropératoire d'épinéphrine étaient associés à la survenue d'un gradient de pression fémoro-radial significatif en chirurgie cardiovasculaire. Considérant que les complications liées à la surveillance ont été très rares, il pourrait être utile de surveiller simultanément la pression radiale et la pression fémorale chez les patients ayant ces facteurs de risque pour une gestion appropriée de la pression artérielle. Néanmoins, d'autres études sont nécessaires pour confirmer nos constatations, car ces résultats sont limités par le plan rétrospectif de l'étude et des facteurs confondants résiduels.

Accuracy of Cloud-Based Speech Recognition Open Application Programming Interface for Medical Terms of Korean.

BACKGROUND: There are limited data on the accuracy of cloud-based speech recognition (SR) open application programming interfaces (APIs) for medical terminology. This study aimed to evaluate the medical term recognition accuracy of current available cloud-based SR open APIs in Korean. METHODS: We analyzed the SR accuracy of currently available cloud-based SR open APIs using real doctor-patient conversation recordings collected from an outpatient clinic at a large tertiary medical center in Korea. For each original and SR transcription, we analyzed the accuracy rate of each cloud-based SR open API (i.e., the number of medical terms in the SR transcription per number of medical terms in the original transcription). RESULTS: A total of 112 doctor-patient conversation recordings were converted with three cloud-based SR open APIs (Naver Clova SR from Naver Corporation; Google Speech-to-Text from Alphabet Inc.; and Amazon Transcribe from Amazon), and each transcription was compared. Naver Clova SR (75.1%) showed the highest accuracy with the recognition of medical terms compared to the other open APIs (Google Speech-to-Text, 50.9%, P < 0.001; Amazon Transcribe, 57.9%, P < 0.001), and Amazon Transcribe demonstrated higher recognition accuracy compared to Google Speech-to-Text (P < 0.001). In the sub-analysis, Naver Clova SR showed the highest accuracy in all areas according to word classes, but the accuracy of words longer than five characters showed no statistical differences (Naver Clova SR, 52.6%; Google Speech-to-Text, 56.3%; Amazon Transcribe, 36.6%). CONCLUSION: Among three current cloud-based SR open APIs, Naver Clova SR which manufactured by Korean company showed highest accuracy of medical terms in Korean, compared to Google Speech-to-Text and Amazon Transcribe. Although limitations are existing in the recognition of medical terminology, there is a lot of rooms for improvement of this promising technology by combining strengths of each SR engines.

Prognosis of Myocardial Injury After Non-Cardiac Surgery in Adults Aged Younger Than 45 Years.

BACKGROUND: This study compared myocardial injury after non-cardiac surgery (MINS) and mortalities between patients under and over the age of 45 years.Methods and Results:From January 2010 and June 2019, patients with cardiac troponin measurement within 30 days after non-cardiac surgery were enrolled and divided into groups according to age: >45 (≥45 years) and <45 (<45 years). Further analyses were conducted only in patients who were diagnosed with MINS. The outcomes were MINS and 30-day mortality. Of the 35,223 patients, 31,161 (88.5%) patients were in the >45-year group and 4,062 (11.5%) were in the <45-year group. After adjustment with inverse probability of weighting, the <45-years group showed a lower incidence of MINS and cardiovascular mortality (16.6% vs. 11.7%; odds ratio, 0.77; 95% confidence interval [CI], 0.69-0.84; P<0.001 and 0.4% vs. 0.2%; hazard ratio [HR], 0.41; 95% CI, 0.19-0.88; P=0.02, respectively). In a comparison of only the <45-years group, MINS was associated with increased 30-day mortality (0.7% vs. 10.3%; HR, 10.48; 95% CI, 6.18-17.78; P<0.001), but the mortalities of patients with MINS did not differ according to age. CONCLUSIONS: MINS has a comparable prognostic impact in patients aged under and over 45 years; therefore, future studies need to also consider patients aged <45 years regarding risk factors of MINS and screening of perioperative troponin elevation.

Association Between High Body Mass Index and Mortality Following Myocardial Injury After Noncardiac Surgery.

BACKGROUND: Despite an association between obesity and increased risks for various diseases, obesity has been paradoxically reported to correlate with improved mortality in patients with established cardiovascular disease. However, its effect has not been evaluated to date in patients with myocardial injury after noncardiac surgery (MINS). METHODS: From January 2010 to June 2019, of a total of 35,269 adult patients with postoperative cardiac troponin level data, 5633 (16.0%) patients had MINS as diagnosed by postoperative cardiac troponin I above the 99th-percentile upper reference of 40 ng·L-1 using the TnI-Ultra immunoassay. Patients with MINS were divided into 3 groups according to body mass index (BMI), with 3246 (57.6%) were in the normal (18.5-25 kg·m-2), 425 (7.5%) in the low BMI (<18.5 kg·m-2), and 1962 (34.8%) in the high BMI (≥25 kg·m-2) groups, respectively. The primary outcome was mortality during the first year after surgery, and the mortality during 30 days was also compared. RESULTS: Following adjustment for confounding with inverse probability of treatment weighting, mortality within the first year appeared to be significantly lower in the high BMI group compared with the normal (14.8% vs 20.9%; hazard ratio [HR], 0.75; 95% confidence interval [CI], 0.66-0.85; P < .001) and the low BMI (14.8% vs 25.6%; HR: 0.56; 95% CI, 0.48-0.66; P < .001) groups. CONCLUSIONS: High BMI may be associated with decreased mortality following MINS. Further investigations are needed to support this finding.

Elevated high-sensitivity C-reactive protein concentrations may be associated with increased postdischarge mortality in patients with myocardial injury after noncardiac surgery: A retrospective observational study.

BACKGROUND: Myocardial injury after noncardiac surgery (MINS) is one of the most common cardiovascular complications associated with mortality and morbidity during the first 2 years after surgery. However, the relevant variables associated with mortality after discharge in patients with MINS have not been fully investigated. OBJECTIVES: This study aimed to evaluate the association between persistent inflammation detected by high-sensitivity C-reactive protein (hsCRP) at discharge and postdischarge mortality after MINS. DESIGN: Retrospective observational analysis of acquired data from Samsung Medical Center Troponin in Noncardiac Operation (SMC-TINCO) registry. SETTING: A tertiary hospital from January 2010 to June 2019. PATIENTS: Patients who were discharged alive after a diagnosis of MINS. MAIN OUTCOME MEASURES: The primary endpoint was postdischarge 1-year mortality, and 30-day mortality and the mortality from 30 days to 1 year was also compared. RESULTS: Data from a total of 4545 adult patients were divided into two groups according to hsCRP concentration at discharge. There were 757 (16.7%) patients in the normal hsCRP group and 3788 (83.3%) patients in the elevated hsCRP group. After inverse probability weighting, 1-year mortality was significantly higher in the elevated group than the normal group (hazard ratio 1.93, 95% CI 1.45 to 2.57, P  < 0.001). Thirty-day mortality and the mortality from 30 days to 1 year were also increased in the elevated group. CONCLUSION: In patients with MINS, an elevated hsCRP concentration at discharge appeared to be associated with increased mortality. Further research is needed to determine whether controlling inflammation can be helpful in reducing mortality.

Pre-operative anaemia and myocardial injury after noncardiac surgery: A retrospective study.

BACKGROUND: Pre-operative anaemia is associated with adverse outcomes of noncardiac surgery, but its association with myocardial injury after noncardiac surgery (MINS) has not been fully investigated. OBJECTIVE: The association between pre-operative anaemia and MINS. DESIGN: A single-centre retrospective cohort study. SETTING: Tertiary care referral centre. PATIENTS: Patients with measured cardiac troponin (cTn) I levels after noncardiac surgery. INTERVENTIONS: Patients were separated according to pre-operative anaemia (haemoglobin <13 g dl-1 in men and <12 g dl-1 in women). Anaemia was further stratified into mild and moderate-to-severe at a haemoglobin level threshold of 11 g dl-1. MAIN OUTCOME MEASURES: The primary outcome was MINS, defined as a peak cTn I level more than 99th percentile of the upper reference limit within 30 postoperative days. RESULTS: Data from a total of 35 170 patients were collected, including 22 062 (62.7%) patients in the normal group and 13 108 (37.3%) in the anaemia group. After propensity score matching, 11919 sets of patients were generated, and the incidence of MINS was significantly associated with anaemia [14.5 vs. 21.0%, odds ratio (OR) 1.57, 95% confidence interval (CI) 1.47 to 1.68, P < 0.001]. For the entire population, multivariable analysis showed a graded association between anaemia severity and MINS (OR 1.32, 95% CI 1.22 to 1.43, P < 0.001 for mild anaemia and OR 1.80, 95% CI 1.66 to 1.94, P < 0.001 for moderate-to-severe anaemia compared with the normal group) and a significantly higher incidence of MINS for moderate-to-severe anaemia than mild anaemia (18.6 vs. 28.6%, OR 1.37, 95% CI 1.25 to 1.50, P < 0.001). The estimated threshold for pre-operative haemoglobin associated with MINS was 12.2 g dl-1, with an area under the curve of 0.622. CONCLUSIONS: Pre-operative anaemia was independently associated with MINS, suggesting that MINS may be related to the association between anaemia and postoperative mortality. TRIAL REGISTRATION: SMC 2019-08-048.

Sumoylation of a small isoform of NFATc1 is promoted by PIAS proteins and inhibits transactivation activity.

The NFAT family of transcription factors plays an important role in immune system development and function. NFATc1 and NFATc2 are highly expressed in peripheral T cells, and several isoforms are produced via the use of different promoters and polyadenylation sites. The specific isoforms with relatively long C-termini, NFATc1/C and NFATc2/A, have been shown to be modified by SUMO within their specific C-terminal regions, which regulates NFAT protein localization and transactivation activity. Here, we demonstrate that an isoform NFATc1/A, which has a short C-terminus and does not contain the sumoylation sites found in the long isoforms, is also modified by SUMO. NFATc1/A sumoylation increased with low level expression of SUMO E3 ligases, specifically PIAS1, PIAS3, and PIASy, in co-transfected cells. PIAS3 interacted with NFATc1/A and an active site mutant failed to promote NFATc1/A sumoylation, indicating a role for PIAS3 as a SUMO E3 ligase. A lysine residue at 351 within the central regulatory domain was identified as the major SUMO attachment site in both co-transfection and in vitro assays. Sumoylation of NFATc1/A did not affect nuclear translocation upon ionomycin and phorbol 12-myristate 13-acetate treatment. However, although sumoylation of NFATc1/A slightly increased protein stability, it inhibited transactivation activity for reporter genes driven by promoters containing NFAT sites. Our results indicate that the transactivation activity of NFATc1/A is negatively regulated by PIAS protein-mediated sumoylation, and that SUMO is a general regulator of NFAT family members with either long or short C-termini.

A therapeutic human antibody against the domain 4 of the Bacillus anthracis protective antigen shows protective efficacy in a mouse model.

Since Bacillus anthracis is a high-risk pathogen and a potential tool for bioterrorism, numerous therapeutic methods including passive immunization have been actively developed. Using a human monoclonal antibody phage display library, we screened new therapeutic antibodies for anthrax infection against protective antigen (PA) of B. anthracis. Among 5 selected clones of antibodies based on enzyme-linked immunosorbent assay (ELISA) results, 7B1 showed neutralizing activity to anthrax lethal toxin (LT) by inhibiting binding of the domain 4 of PA (PD4) to its cellular receptors. Through light chain shuffling process, we improved the productivity of 7B1 up to 25 folds. The light chain shuffled 7B1 antibody showed protective activity against LT both in vitro and in vivo. Furthermore, the antibody also conferred protection of mice from 3 × LD50 challenges of fully virulent anthrax spores. Our result expands the possibility of developing a new therapeutic antibody for anthrax cure.

One-Year Recipient Morbidity of Liver Transplantation Using Pure Laparoscopic Versus Open Living Donor Right Hepatectomy: Propensity Score Analysis.

Donor safety and graft results of pure laparoscopic living donor right hepatectomy (LLDRH) have previously been compared with those of open living donor right hepatectomy (OLDRH). However, the clinical outcomes of recipients at 1-year follow-up have never been accurately compared. We aimed to compare 1-year outcomes of recipients of living donor right liver transplantation (LRLT) using pure LLDRH and OLDRH. From May 2013 to May 2017, 197 consecutive recipients underwent LRLT. Donor hepatectomies were performed either by OLDRH (n = 127) or pure LLDRH (n = 70). After propensity score matching, 53 recipients were included in each group for analysis. The clinical outcomes at 1-year follow-up were compared between the 2 groups. The primary outcome was recipient death or graft failure during the 1-year follow-up period. In the propensity-matched analysis, the incidence of death or graft failure during the 1-year follow-up period was not different between the 2 groups (3.8% versus 5.7%; odds ratio [OR], 1.45; 95% confidence interval [CI], 0.24-8.95; P = 0.69). However, the composite of Clavien-Dindo 3b-5 complications was more frequent in the pure LLDRH group (OR, 2.62; 95% CI, 1.15-5.96; P = 0.02). In conclusion, although pure LLDRH affords a comparable incidence of fatal complications in recipients, operative complications may increase at the beginning of the program. The safety of the recipients should be confirmed to accept pure LLDRH as a feasible option.

A retrospective analysis of re-exploration after living donor right lobe liver transplantation: incidence, causes, outcomes, and risk factors.

Despite technical difficulties, right lobe liver grafting is preferred in living donor liver transplantation because of the graft size. Re-exploration after living donor right lobe liver transplantation (LRLT) has never been separately analyzed. We aimed to analyze the incidence, causes, outcomes, and risk factors of re-exploration after LRLT. We reviewed medical records of 1016 LRLT recipients from October 2003 to July 2017 and identified recipients who underwent re-exploration within hospital stay. Separate analyses were also performed according to cause of re-exploration. The overall incidence of re-exploration was 17.0% (173/1016). The most common cause of re-exploration was bleeding (50%). Overall re-exploration was associated with clinical outcome, but different results were shown on analyses according to cause of re-exploration. Risk factors of re-exploration were underlying hepatocellular carcinoma and operative duration [Odds ratio (OR), 1.49; 95% confidence interval (CI), 1.05-2.12; P = 0.03, and OR, 1.002; 95% CI, 1.001-1.004; P = 0.0023, respectively]. Re-exploration after LRLT is relatively common, and is strongly associated with mortality and graft failure.

The angle range of leg abduction with external hip rotation which can minimize femoral artery and vein overlap in pediatric patients.

BACKGROUND: Since the femoral artery frequently overlaps the femoral vein, femoral central venous catheterization carries the risk of arterial puncture in pediatric patients. AIMS: We evaluated the angle range of leg abduction with external hip rotation to minimize the overlap between the femoral artery and vein in pediatric patients undergoing general anesthesia. METHODS: Eighty-two pediatric patients who underwent elective surgery with general anesthesia were enrolled in this study. Using ultrasonography, patients were divided into groups N (patients with non-overlap) and O (patients with continuing overlap) based on the presence of non-overlap range between the femoral artery and vein. The range minimizing the overlap was defined as the range without overlap in group N and as the range presenting the overlap that was less-than-half of the radius of the femoral vein in group O. By increasing the angle of leg abduction with external hip rotation, the starting and ending angles minimizing the overlap were found using ultrasonographic images. RESULTS: The angle range of leg abduction with external hip rotation minimizing the overlap between the femoral artery and vein was defined as the range from the maximum 99% confidence interval of starting angles to the minimum 99% confidence interval of ending angles, which was between 45° and 65° in group N and between 48° and 58° in group O, respectively. CONCLUSION: Positioning patients in a range of 48° and 58° leg abduction with external hip rotation can minimize the overlap between the femoral artery and vein. However, the clinical usefulness of this positioning for femoral venous catheterization remains to be seen.

Predictive Value of Intraoperative Pulmonary Vascular Resistance in Liver Transplantation.

We aimed to evaluate the association between intraoperative pulmonary vascular resistance (PVR) and clinical outcome of liver transplantation (LT). Cardiovascular involvement of end-stage liver disease is relatively common, and hemodynamic instability during LT can be fatal to recipients. However, the clinical impact of intraoperative PVR in LT remains undetermined. A total of 363 adult recipients with intraoperative right heart catheterization from January 2011 to May 2016 were analyzed. Patients were divided into 2 groups according to PVR. Two separate analyses were performed according to the time point of measurement: at the beginning and at the end of LT. The primary outcome was all-cause death or graft failure during the follow-up period. Increased PVR was observed in 11.8% (43/363) of recipients at the beginning and 12.7% (46/363) of recipients at the end of LT. PVR at the beginning of LT had no significant effect on the rate of death or graft failure in the multivariate analysis (hazard ratio [HR], 1.24; 95% confidence interval [CI], 0.64-2.38; P = 0.52). In contrast, PVR at the end of LT was significantly associated with death or graft failure during the overall follow-up period (HR, 2.00; 95% CI, 1.13-3.54; P = 0.02). In conclusion, PVR at the end of LT, rather than the beginning, is associated with clinical outcome. Larger trials are needed to support this finding.

Muramyl dipeptide potentiates a Bacillus anthracis poly-γ-d-glutamic acid capsule surrogate that induces maturation and activation of mouse dendritic cells.

Poly-γ-d-glutamic acid (PGA) of anthrax is an important pathogenic factor due to its anti-phagocytic activity. Additionally, PGA has the ability to activate mouse macrophages for the secretion of cytokines through Toll-like receptor (TLR) 2. Peptidoglycan (PGN), a major bacterial cell-wall component, induces inflammatory responses in the host. We assessed whether PGA can induce maturation and cytokine expression in immature mouse dendritic cells (DCs) in the existence of muramyl dipeptide (MDP), the minimum motif of PGN with immunostimulatory activity. Stimulation of immature DCs with PGA or MDP alone augmented expression of costimulatory molecules and MHC class II proteins, which are all cell surface markers indicative of maturation. The observed effects were further enhanced by costimulation of PGA and MDP. PGA alone was sufficient to induce expression of TNF-α, IL-6, MCP-1, and MIP1-α, whereas MDP alone did not under the same conditions. Treatment with MDP enhanced PGA-induced expression of the tested inflammatory mediators; however, the synergistic effect found for PGA and MDP was not observed in TLR2- or nucleotide-binding oligomerization domain (NOD) 2-knockout DCs. Additionally, MDP augmented PGA-induced MAP kinases and NF-κB activation, which is crucial for expression of cytokines. Furthermore, MAP kinase and NF-κB inhibitors attenuated MDP enhancement of PGA-induced cytokine production. In addition, co-culture of splenocytes and PGA/MDP-matured DCs induced higher expression of IL-2 and IFN-γ compared to that of splenocytes and PGA-matured DCs. Collectively, our results suggest that PGA and MDP cooperatively induce inflammatory responses in mouse DCs through TLR2 and NOD2 via MAP kinase and NF-κB pathways, subsequently leading to lymphocyte activation.

The Poly-γ-d-Glutamic Acid Capsule Surrogate of the Bacillus anthracis Capsule Is a Novel Toll-Like Receptor 2 Agonist.

Bacillus anthracis is a pathogenic Gram-positive bacterium that causes a highly lethal infectious disease, anthrax. The poly-γ-d-glutamic acid (PGA) capsule is one of the major virulence factors of B. anthracis, along with exotoxins. PGA enables B. anthracis to escape phagocytosis and immune surveillance. Our previous study showed that PGA activates the human macrophage cell line THP-1 and human dendritic cells, resulting in the production of the proinflammatory cytokine interleukin-1ß (IL-1ß) (M. H. Cho et al., Infect Immun 78:387-392, 2010, http://dx.doi.org/10.1128/IAI.00956-09). Here, we investigated PGA-induced cytokine responses and related signaling pathways in mouse bone marrow-derived macrophages (BMDMs) using Bacillus licheniformis PGA as a surrogate for B. anthracis PGA. Upon exposure to PGA, BMDMs produced proinflammatory mediators, including tumor necrosis factor alpha (TNF-α), IL-6, IL-12p40, and monocyte chemoattractant protein 1 (MCP-1), in a concentration-dependent manner. PGA stimulated Toll-like receptor 2 (TLR2) but not TLR4 in Chinese hamster ovary cells expressing either TLR2 or TLR4. The ability of PGA to induce TNF-α and IL-6 was retained in TLR4(-/-) but not TLR2(-/-) BMDMs. Blocking experiments with specific neutralizing antibodies for TLR1, TLR6, and CD14 showed that TLR6 and CD14 also were necessary for PGA-induced inflammatory responses. Furthermore, PGA enhanced activation of mitogen-activated protein (MAP) kinases and nuclear factor-kappa B (NF-κB), which are responsible for expression of proinflammatory cytokines. Additionally, PGA-induced TNF-α production was abrogated not only in MyD88(-/-) BMDMs but also in BMDMs pretreated with inhibitors of MAP kinases and NF-κB. These results suggest that immune responses induced by PGA occur via TLR2, TLR6, CD14, and MyD88 through activation of MAP kinase and NF-κB pathways.

Monoclonal antibody against the poly-gamma-D-glutamic acid capsule of Bacillus anthracis protects mice from enhanced lethal toxin activity due to capsule and anthrax spore challenge.

BACKGROUND: The poly-gamma-D-glutamic acid (PGA) capsule, a major virulence factor of Bacillus anthracis, protects bacilli from immune surveillance and allows its unimpeded growth in the host. Recently, the importance of the PGA in the pathogenesis of anthrax infection has been reported. The PGA capsule is associated with lethal toxin (LT) in the blood of experimentally infected animals and enhances the cytotoxicity of LT. METHODS: To investigate the role of anti-PGA Abs on progression of anthrax infection, two mouse anti-PGA mAbs with K(d) values of 0.8 microM and 2.6 microM respectively were produced and in silico three dimensional (3D) models of mAbs with their cognitive PGA antigen complex were analyzed. RESULTS: Anti-PGA mAbs specifically bound encapsulated B. anthracis H9401 and showed opsonophagocytosis activity against the bacteria with complement. The enhancement effect of PGA on LT-mediated cytotoxicity was confirmed ex vivo using mouse bone marrow-derived macrophages and was effectively inhibited by anti-PGA mAb. Passive immunization of mAb completely protected mice from PGA-enhanced LT toxicity and partially rescued mice from anthrax spore challenges. 3D structure models of these mAbs and PGA complex support specific interactions between CDR and cognitive PGA. These results indicate that mouse mAb against PGA capsule prevents the progress of anthrax disease not only by eliminating the vegetative form of encapsulated B. anthracis but also by inhibiting the enhanced cytotoxic activity of LT by PGA through specific binding with PGA capsule antigen. GENERAL SIGNIFICANCE: Our results suggest a potential role for PGA antibodies in preventing and treating anthrax infection.

WITHDRAWN: Response to letter.

Ahead of Print article withdrawn by Editorial Board.

Association of preoperative blood glucose level with delirium after non-cardiac surgery in diabetic patients.

BACKGROUND: Hyperglycemia has shown a negative association with cognitive dysfunction. We analyzed patients with high preoperative blood glucose level and hemoglobin A1c (HbA1c) level to determine the prevalence of postoperative delirium. METHODS: We reviewed a database of 23,532 patients with diabetes who underwent non-cardiac surgery. Acute hyperglycemia was defined as fasting blood glucose > 140 mg/dl or random glucose > 180 mg/dl within 24 h before surgery. Chronic hyperglycemia was defined as HbA1c level above 6.5% within three months before surgery. The incidence of delirium was compared according to the presence of acute and chronic hyperglycemia. RESULTS: Of the 23,532 diabetic patients, 21,585 had available preoperative blood glucose level within 24 h before surgery, and 18,452 patients reported levels indicating acute hyperglycemia. Of the 8,927 patients with available HbA1c level within three months before surgery, 5,522 had levels indicating chronic hyperglycemia. After adjustment with inverse probability weighting, acute hyperglycemia was related to higher incidence of delirium (hazard ratio: 1.33, 95% CI [1.10,1.62], P = 0.004 for delirium) compared with controls without acute hyperglycemia. On the other hand, chronic hyperglycemia did not correlate with postoperative delirium. CONCLUSIONS: Preoperative acute hyperglycemia was associated with postoperative delirium, whereas chronic hyperglycemia was not significantly associated with postoperative delirium. Irrespective of chronic hyperglycemia, acute glycemic control in surgical patients could be crucial for preventing postoperative delirium.

Does coronavirus disease 2019 history alone increase the risk of postoperative pulmonary complications after surgery? Prospective observational study using serology assessment.

BACKGROUND: Concern exists about the increasing risk of postoperative pulmonary complications in patients with a history of coronavirus disease 2019 (COVID-19). OBJECTIVE: We conducted a prospective observational study that compared the incidence of postoperative pulmonary complications in patients with and without a history of COVID-19. METHODS: From August 2022 to November 2022, 244 adult patients undergoing major non-cardiac surgery were enrolled and allocated either to history or no history of COVID-19 groups. For patients without a history of confirming COVID-19 diagnosis, we tested immunoglobulin G to nucleocapsid antigen of SARS-CoV-2 for serology assessment to identify undetected infection. We compared the incidence of postoperative pulmonary complications, defined as a composite of atelectasis, pleural effusion, pulmonary edema, pneumonia, aspiration pneumonitis, and the need for additional oxygen therapy according to a COVID-19 history. RESULTS: After excluding 44 patients without a COVID-19 history who were detected as seropositive, 200 patients were finally enrolled in this study, 100 in each group. All subjects with a COVID-19 history experienced no or mild symptoms during infection. The risk of postoperative pulmonary complications was not significantly different between the groups according to the history of COVID-19 (24.0% vs. 26.0%; odds ratio, 0.99; 95% confidence interval, 0.71-1.37; P-value, 0.92). The incidence of postoperative pulmonary complications was also similar (27.3%) in excluded patients owing to being seropositive. CONCLUSION: Our study showed patients with a history of no or mild symptomatic COVID-19 did not show an increased risk of PPCs compared to those without a COVID-19 history. Additional precautions may not be needed to prevent PPCs in those patients.

Association between Preoperative Glucose Dysregulation and Delirium after Non-Cardiac Surgery.

This study aimed to investigate the association between glucose dysregulation and delirium after non-cardiac surgery. Among a total of 203,787 patients who underwent non-cardiac surgery between January 2011 and June 2019 at our institution, we selected 61,805 with available preoperative blood glucose levels within 24 h before surgery. Patients experiencing glucose dysregulation were divided into three groups: hyperglycemia, hypoglycemia, and both. We compared the incidence of postoperative delirium within 30 days after surgery between exposed and unexposed patients according to the type of glucose dysregulation. The overall incidence of hyperglycemia, hypoglycemia, and both was 5851 (9.5%), 1452 (2.3%), and 145 (0.2%), respectively. The rate of delirium per 100 person-months of the exposed group was higher than that of the unexposed group in all types of glucose dysregulation. After adjustment, the hazard ratios of glucose dysregulation in the development of delirium were 1.35 (95% CI, 1.18-1.56) in hyperglycemia, 1.36 (95% CI, 1.06-1.75) in hypoglycemia, and 3.14 (95% CI, 1.27-7.77) in both. The subgroup analysis showed that exposure to hypoglycemia or both to hypo- and hyperglycemia was not associated with delirium in diabetic patients, but hyperglycemia was consistently associated with postoperative delirium regardless of the presence of diabetes. Preoperative glucose dysregulation was associated with increased risk of delirium after non-cardiac surgery. Our findings may be helpful for preventing postoperative delirium, and further investigations are required to verify the association and mechanisms for the effect we observed.