Lack of S1PR2 in Macrophage Ameliorates Sepsis-associated Lung Injury through Inducing IL-33-mediated Type 2 Immunity.

The function of type 2 immunity and mechanisms underlying the initiation of type 2 immunity after sepsis-induced lung injury remain unclear. Sphingosine-1-phosphate receptor 2 (S1PR2) has been demonstrated to modulate type 2 immunity in the context of asthma and pulmonary fibrosis. Thus, this study aims to investigate the role of type 2 immunity and whether and how S1PR2 regulates type 2 immunity in sepsis. Peripheral type 2 immune responses in patients with sepsis and healthy control subjects were assessed. The impact of S1PR2 on type 2 immunity in patients with sepsis and in a murine model of sepsis was further investigated. The type 2 innate immune responses were significantly increased in the circulation of patients 24 hours after sepsis, which was positively related to clinical complications and negatively correlated with S1PR2 mRNA expression. Animal studies showed that genetic deletion or pharmacological inhibition of S1PR2 induced type 2 innate immunity accumulation in the post-septic lungs. Mechanistically, S1PR2 deficiency promoted macrophage-derived interleukin (IL)-33 increase and the associated type 2 response in the lung. Furthermore, S1PR2-regulated IL-33 from macrophages mitigated lung injury after sepsis in mice. In conclusion, a lack of S1PR2 modulates the type 2 immune response by upregulating IL-33 release from macrophages and alleviates sepsis-induced lung injury. Targeting S1PR2 may have potential therapeutic value for sepsis treatment.

High intraoperative fluid load associated with prolonged length of hospital stay and complications after non-cardiac surgery in neonates.

Inappropriate perioperative fluid load can lead to postoperative complications and death. This retrospective study was designed to investigate the association between intraoperative fluid load and outcomes in neonates undergoing non-cardiac surgery. From April 2020 to September 2022, 940 neonates who underwent non-cardiac surgery were retrospectively enrolled and their perioperative data were harvested for further analysis. According to recorded intraoperative fluid volumes defined as ml.kg-1 h-1, patients were mandatorily divided into quintile with fluid load as restrictive (quintile 1, Q1), moderately restrictive (Q2), moderate (Q3), moderately liberal (Q4), and liberal (Q5). The primary outcomes were defined as prolonged length of hospital stay (LOS) (postoperative LOS ≥ 14 days), complications beyond prolonged LOS, and 30-day mortality. Secondary outcomes included postoperative complications within 14 days of hospital stay. The intraoperative fluid load was in Q1 of 6.5 (5.3-7.3) (median and IQR); Q2: 9.2 (8.7-9.9); Q3: 12.2 (11.4-13.2); Q4: 16.5 (15.4-18.0); and Q5: 26.5 (22.3-32.2) ml.kg-1 h-1. The odd of prolonged LOS was positively correlated with an increase fluid volume (Q5 quintile: OR 2.602 [95% CI 1.444-4.690], P = 0.001), as well as complications beyond prolonged LOS (Q5: OR 3.322 [95% CI 1.656-6.275], P = 0.001). The overall 30-day mortality rate was increased with high intraoperative fluid load but did not reach to a statistical significance after adjusted with confounders. Furthermore, the highest quintile of fluid load (26.5 ml.kg-1 h-1, IQR [22.3-32.2]) (Q5 quintile) was significantly associated with longer postoperative mechanical ventilation time compared with Q1 (Q5: OR 2.212 [95% CI 1.101-4.445], P = 0.026).    Conclusion: Restrictive intraoperative fluid load had overall better outcomes, whilst high fluid load was significantly associated with prolonged LOS and complications after non-cardiac surgery in neonates.    Trial registration:  Chictr.org.cn Identifier: ChiCTR2200066823 (December 19, 2022). What is Known: • Inappropriate perioperative fluid load can lead to postoperative complications and even death. What is New: • High perioperative fluid load was significantly associated with an increased length of stay after non-cardiac surgery in neonates, whilst low fluid load was consistently related to better postoperative outcomes.

Inflammation Disrupts the Brain Network of Executive Function after Cardiac Surgery.

OBJECTIVE: To investigate postoperative functional connectivity (FC) alterations across impaired cognitive domains and their causal relationships with systemic inflammation. BACKGROUND: Postoperative cognitive dysfunction commonly occurs after cardiac surgery, and both systemic and neuroinflammation may trigger its development. Whether FC alterations underlying deficits in specific cognitive domains after cardiac surgery are affected by inflammation remains unclear. METHODS: Seventeen patients, who underwent cardiac valve replacement, completed a neuropsychological test battery and brain MRI scan before surgery and on days 7 and 30 after surgery compared to age-matched healthy controls. Blood samples were taken for tumor necrosis factor-a and interleukin-6 measurements. Seed-to-voxel FC of the left dorsolateral prefrontal cortex (DLPFC) was examined. Bivariate correlation and linear regression models were used to determine the relationships among cognitive function, FC alterations, and cytokines. RESULTS: Executive function was significantly impaired after cardiac surgery. At day 7 follow-up, the surgical patients, compared to the controls, demonstrated significantly decreased DLPFC FC with the superior parietal lobe and attenuated negative connectivity in the default mode network, including the angular gyrus and posterior cingulate cortex. The left DLPFC enhanced the connectivity in the right DLPFC and posterior cingulate cortex, all of which were related to the increased tumor necrosis factor-a and decreased executive function up to day 7 after cardiac surgery. CONCLUSIONS: The decreased FC of executive control network and its anticorrelation with the default mode network may contribute to executive function deficits after cardiac surgery. Systemic inflammation may trigger these transient FC changes and executive function impairments.

Advances in photobiomodulation for cognitive improvement by near-infrared derived multiple strategies.

Cognitive function is an important ability of the brain, but cognitive dysfunction can easily develop once the brain is injured in various neuropathological conditions or diseases. Photobiomodulation therapy is a type of noninvasive physical therapy that is gradually emerging in the field of neuroscience. Transcranial photobiomodulation has been commonly used to regulate neural activity in the superficial cortex. To stimulate deeper brain activity, advanced photobiomodulation techniques in conjunction with photosensitive nanoparticles have been developed. This review addresses the mechanisms of photobiomodulation on neurons and neural networks and discusses the advantages, disadvantages and potential applications of photobiomodulation alone or in combination with photosensitive nanoparticles. Photobiomodulation and its associated strategies may provide new breakthrough treatments for cognitive improvement.

TAK1 Reduces Surgery-induced Overactivation of RIPK1 to Relieve Neuroinflammation and Cognitive Dysfunction in Aged Rats.

BACKGROUND: Postoperative cognitive dysfunction (POCD) is a common clinical complication in elderly patients, but its underlying mechanism remains unclear. Receptor-interacting protein kinase 1 (RIPK1), a key molecule mediating necroptosis and regulated by transforming growth factor ß-activated kinase 1 (TAK1), was reported to be associated with cognitive impairment in several neurodegenerative diseases. This study was conducted to investigate the possible role of TAK1/RIPK1 signalling in POCD development following surgery in rats. METHODS: Young (2-month-old) and old (24-month-old) Sprague-Dawley rats were subjected to splenectomy under isoflurane anaesthesia. The young rats were treated with the TAK1 inhibitor takinib or the RIPK1 inhibitor necrostatin-1 (Nec-1) before surgery, and old rats received adeno-associated virus (AAV)-TAK1 before surgery. The open field test and contextual fear conditioning test were conducted on postoperative day 3. The changes in TNF-α, pro-IL-1ß, AP-1, NF-κB p65, pRIPK1, pTAK1 and TAK1 expression and astrocyte and microglia activation in the hippocampus were assessed. RESULTS: Old rats had low TAK1 expression and were more susceptible to surgery-induced POCD and neuroinflammation than young rats. TAK1 inhibition exacerbated surgery-induced pRIPK1 expression, neuroinflammation and cognitive dysfunction in young rats, and this effect was reversed by a RIPK1 inhibitor. Conversely, genetic TAK1 overexpression attenuated surgery-induced pRIPK1 expression, neuroinflammation and cognitive dysfunction in old rats. CONCLUSION: Ageing-related decreases in TAK1 expression may contribute to surgery-induced RIPK1 overactivation, resulting in neuroinflammation and cognitive impairment in old rats.

Diagnostic power of vertebral hydroxyapatite concentration measurements in spectral CT for osteoporosis-associated fractures and impact of intravenous contrast administration.

OBJECTIVES: To evaluate the diagnostic power of using vertebral hydroxyapatite concentration measurements in unenhanced and contrast-enhanced spectral CT for detecting and predicting the risk of osteoporosis-associated fractures. METHODS: L1 of 210 patients (105 men, 105 women; mean age, 64 years, range, 19-103 years) who had undergone spectral CT examinations from January 1, 2018, to March 1, 2019, were retrospectively analyzed. Patient data for 3 years after spectral CT were retrieved from electronic medical record information systems to obtain the incidence of osteoporotic fractures. Baseline vertebral cancellous hydroxyapatite concentration from unenhanced and contrast-enhanced late-arterial-phase images was measured. The receiver operating characteristic curves were used to evaluate the diagnostic power for detecting and predicting the 3-year risk of osteoporosis-associated fractures using hydroxyapatite concentrations in both phases. RESULTS: The hydroxyapatite concentrations in both phases had good diagnostic power to detect fractures at baseline. The sensitivity and specificity for predicting one or more osteoporosis-associated fractures within 3 years after spectral CT were 76.80% and 93.10%, respectively, using the cutoff of 74.79 mg/cm3 in vertebral hydroxyapatite concentration in the unenhanced CT phase, and 82.87% and 82.76%, respectively, using the cutoff of 84.65 mg/cm3 in the late-arterial phase. Furthermore, there was no significant difference in the diagnosis between unenhanced and enhanced CT-derived hydroxyapatite concentrations (p = 0.360). CONCLUSIONS: Both unenhanced and enhanced spectral CT-derived hydroxyapatite concentrations can accurately detect and predict future risk of osteoporosis-associated fractures. The hydroxyapatite concentration assessed in the late-arterial phase may have a similar diagnostic efficacy to that in the unenhanced phase. KEY POINTS: • A cutoff of 74.79 mg/cm3 of vertebral hydroxyapatite concentration in the unenhanced CT scans had 76.80% sensitivity and 93.10% specificity to predict one or more osteoporosis-associated fractures within 3 years after spectral CT examinations. • A cutoff of 84.65 mg/cm3 of vertebral hydroxyapatite concentration in the late-arterial-enhanced CT scans had 82.87% sensitivity and 82.76% specificity to predict one or more osteoporosis-associated fractures within 3 years after spectral CT examinations. • The hydroxyapatite concentration assessed in the late-arterial phase may have a similar diagnostic efficacy to that in the unenhanced phase.

Sevoflurane but not propofol enhances ovarian cancer cell biology through regulating cellular metabolic and signaling mechanisms.

Perioperative risk factors, including the choice of anesthetics, may influence ovarian cancer recurrence after surgery. Inhalational anesthetic sevoflurane and intravenous agent propofol might affect cancer cell metabolism and signaling, which, in turn, may influence the malignancy of ovarian cancer cells. The different effects between sevoflurane and propofol on ovarian cancer cell biology and underlying mechanisms were studied. Cultured ovarian cancer cells were exposed to 2.5% sevoflurane, 4 µg/mL propofol, or sham condition as the control for 2 h followed by 24-h recovery. Glucose transporter 1 (GLUT1), mitochondrial pyruvate carrier 1 (MPC1), glutamate dehydrogenase 1 (GLUD1), pigment epithelium-derived factor (PEDF), p-Erk1/2, and hypoxia-inducible factor 1-alpha (HIF-1α) expressions were determined with immunostaining and/or Western blot. Cultured media were collected for 1H-NMR spectroscopy-based metabolomics analysis. Principal component analysis (PCA) and orthogonal projections to latent structures discriminant analysis (OPLS-DA) were used to analyze metabolomics data. Sevoflurane increased the GLUT1, MPC1, GLUD1, p-Erk1/2, and HIF-1α expressions but decreased the PEDF expression relative to the controls. In contrast to sevoflurane, propofol decreased GLUT1, MPC1, GLUD1, p-Erk1/2, and HIF-1α but increased PEDF expression. Sevoflurane increased metabolite isopropanol and decreased glucose and glutamine energy substrates in the media, but the opposite changes were found after propofol treatment. Our data indicated that, unlike the pro-tumor property of sevoflurane, propofol negatively modulated PEDF/Erk/HIF-1α cellular signaling pathway and inhibited ovarian cancer metabolic efficiency and survival, and hence decreased malignancy. The translational value of this work warrants further study. • Sevoflurane promoted but propofol inhibited ovarian cancer cell biology. • Sevoflurane upregulated but propofol downregulated the GLUT1, MPC1, and GLUD1 expressions of ovarian cancer cells. • Sevoflurane enhanced but propofol inhibited ovarian cancer cellular glucose. metabolism and glutaminolysis. • Sevoflurane downregulated PEDF but upregulated the Erk pathway and HIF-1α, while propofol had the adverse effects on ovarian cancer cells.

The differential cancer growth associated with anaesthetics in a cancer xenograft model of mice: mechanisms and implications of postoperative cancer recurrence.

Anaesthetics may modify colorectal cancer cell biology which potentially affects long-term survival. This study aims to compare propofol and sevoflurane regarding with the direct anaesthetic effects on cancer malignancy and the indirect effects on host immunity in a cancer xenograft mode of mice. Cultured colon cancer cell (Caco-2) was injected subcutaneously to nude mice (day 1). Mice were exposed to either 1.5% sevoflurane for 1.5 h or propofol (20 µg g-1; ip injection) with or without 4 µg g-1 lipopolysaccharide (LPS; ip) from days 15 to 17, compared with those without anaesthetic exposure as controls. The clinical endpoints including tumour volumes over 70 mm3 were closely monitored up to day 28. Tumour samples from the other cohorts were collected on day 18 for PCR array, qRT-PCR, western blotting and immunofluorescent assessment. Propofol treatment reduced tumour size (mean ± SD; 23.0 ± 6.2mm3) when compared to sevoflurane (36.0 ± 0.3mm3) (p = 0.008) or control (23.6 ± 4.7mm3). Propofol decreased hypoxia inducible factor 1α (HIF1α), interleukin 1ß (IL1ß), and hepatocyte growth factor (HGF) gene expressions and increased tissue inhibitor of metalloproteinases 2 (TIMP-2) gene and protein expression in comparison to sevoflurane in the tumour tissue. LPS suppressed tumour growth in any conditions whilst increased TIMP-2 and anti-cancer neutrophil marker expressions and decreased macrophage marker expressions compared to those in the LPS-untreated groups. Our data indicated that sevoflurane increased cancer development when compared with propofol in vivo under non-surgical condition. Anaesthetics tested in this study did not alter the effects of LPS as an immune modulator in changing immunocyte phenotype and suppressing cancer development.

Tumour excisional surgery, anaesthetic-analgesic techniques, and oncologic outcomes: a narrative review.

Cancer is a growing global burden; there were an estimated 18 million new cancer diagnoses worldwide in 2020. Excisional surgery remains one of the main treatments for solid organ tumours in cancer patients and is potentially curative. Cancer- and surgery-induced inflammatory processes can facilitate residual tumour cell survival, growth, and subsequent recurrence. However, it has been hypothesised that anaesthetic and analgesic techniques during surgery might influence the risk of cancer recurrence. This narrative review aims to provide an updated summary of recent observational studies and new randomised controlled clinical trials on whether certain specific anaesthetic and analgesic techniques or perioperative interventions during tumour resection surgery of curative intent materially affect long-term oncologic outcomes.

Reducing complement activation during sleep deprivation yields cognitive improvement by dexmedetomidine.

BACKGROUND: Sleep loss and its associated conditions (e.g. cognitive deficits) represent a large societal burden, but the underlying mechanisms of these cognitive deficits remain unknown. This study assessed the effect of dexmedetomidine (DEX) on cognitive decline induced by sleep loss. METHODS: C57BL/6 mice were subjected to chronic sleep restriction (CSR) for 20 h (5 pm-1 pm the next day) daily for 7 days, and cognitive tests were subsequently carried out. The neuromolecular and cellular changes that occurred in the presence and absence of DEX (100 µg kg-1, i.v., at 1 pm and 3 pm every day) were also investigated. RESULTS: CSR mice displayed a decline in learning and memory by 12% (P<0.05) in the Y-maze and by 18% (P<0.01) in the novel object recognition test; these changes were associated with increases in microglial activation, CD68+ microglial phagosome counts, astrocyte-derived complement C3 secretion, and microglial C3a receptor expression (all P<0.05). Synapse elimination, as indicated by a 66% decrease in synaptophysin expression (P=0.0004) and a 45% decrease in postsynaptic density protein-95 expression (P=0.0003), was associated with the occurrence of cognitive deficits. DEX activated astrocytic α2A adrenoceptors and inhibited astrocytic complement C3 release to attenuate synapse elimination through microglial phagocytosis. DEX restored synaptic connections and reversed cognitive deficits induced by CSR. CONCLUSIONS: The results demonstrate that complement pathway activation associated with synapse elimination contributes to sleep loss-related cognitive deficits and that dexmedetomidine protects against sleep deprivation-induced complement activation. Dexmedetomidine holds potential for preventing cognitive deficits associated with sleep loss, which warrants further study.

Effects of propofol and sevoflurane on social and anxiety-related behaviours in sleep-deprived rats.

BACKGROUND: Sleep disorders can profoundly affect neurological function. We investigated changes in social and anxiety-related brain functional connectivity induced by sleep deprivation, and the potential therapeutic effects of the general anaesthetics propofol and sevoflurane in rats. METHODS: Twelve-week-old male Sprague-Dawley rats were subjected to sleep deprivation for 20 h per day (from 14:00 to 10:00 the next day) for 4 consecutive weeks. They were free from sleep deprivation for the remaining 4 h during which they received propofol (40 mg kg-1 i.p.) or sevoflurane (2% for 2 h) per day or no treatment. These cohorts were instrumented for EEG/EMG recordings on days 2, 14, and 28. Different cohorts were used for open field and three-chambered social behavioural tests, functional MRI, nuclear magnetic resonance spectroscopy, and positron emission tomography imaging 48 h after 4 weeks of sleep deprivation. RESULTS: Propofol protected against sleep deprivation-induced anxiety behaviours with more time (44.7 [8.9] s vs 24.2 [4.1] s for the sleep-deprivation controls; P<0.001) spent in the central area of the open field test and improved social preference index by 30% (all P<0.01). Compared with the sleep-deprived rats, propofol treatment enhanced overall functional connectivity by 74% (P<0.05) and overall glucose metabolism by 30% (P<0.01), and improved glutamate kinetics by 20% (P<0.05). In contrast, these effects were not found after sevoflurane treatment. CONCLUSIONS: Unlike sevoflurane, propofol reduced sleep deprivation-induced social and anxiety-related behaviours. Propofol might be superior to sevoflurane for patients with sleep disorders who receive anaesthesia, which should be studied in clinical studies.

Delirium in older patients given propofol or sevoflurane anaesthesia for major cancer surgery: a multicentre randomised trial.

BACKGROUND: Delirium is a common and disturbing postoperative complication that might be ameliorated by propofol-based anaesthesia. We therefore tested the primary hypothesis that there is less delirium after propofol-based than after sevoflurane-based anaesthesia within 7 days of major cancer surgery. METHODS: This multicentre randomised trial was conducted in 14 tertiary care hospitals in China. Patients aged 65-90 yr undergoing major cancer surgery were randomised to either propofol-based anaesthesia or to sevoflurane-based anaesthesia. The primary endpoint was the incidence of delirium within 7 postoperative days. RESULTS: A total of 1228 subjects were enrolled and randomised, with 1195 subjects included in the modified intention-to-treat analysis (mean age 71 yr; 422 [35%] women); one subject died before delirium assessment. Delirium occurred in 8.4% (50/597) of subjects given propofol-based anaesthesia vs 12.4% (74/597) of subjects given sevoflurane-based anaesthesia (relative risk 0.68 [95% confidence interval {CI}: 0.48-0.95]; P=0.023; adjusted relative risk 0.59 [95% CI: 0.39-0.90]; P=0.014). Delirium reduction mainly occurred on the first day after surgery, with a prevalence of 5.4% (32/597) with propofol anaesthesia vs 10.7% (64/597) with sevoflurane anaesthesia (relative risk 0.50 [95% CI: 0.33-0.75]; P=0.001). Secondary endpoints, including ICU admission, postoperative duration of hospitalisation, major complications within 30 days, cognitive function at 30 days and 3 yr, and safety outcomes, did not differ significantly between groups. CONCLUSIONS: Delirium was a third less common after propofol than sevoflurane anaesthesia in older patients having major cancer surgery. Clinicians might therefore reasonably select propofol-based anaesthesia in patients at high risk of postoperative delirium. CLINICAL TRIAL REGISTRATION: Chinese Clinical Trial Registry (ChiCTR-IPR-15006209) and ClinicalTrials.gov (NCT02662257).

Long-term survival in older patients given propofol or sevoflurane anaesthesia for major cancer surgery: follow-up of a multicentre randomised trial.

BACKGROUND: Experimental evidence indicates that i.v. anaesthesia might reduce cancer recurrence compared with volatile anaesthesia, but clinical information is observational only. We therefore tested the primary hypothesis that propofol-based anaesthesia improves survival over 3 or more years after potentially curative major cancer surgery. METHODS: This was a long-term follow-up of a multicentre randomised trial in 14 tertiary hospitals in China. We enrolled 1228 patients aged 65-90 yr who were scheduled for major cancer surgery. They were randomised to either propofol-based i.v. anaesthesia or to sevoflurane-based inhalational anaesthesia. The primary endpoint was overall survival after surgery. Secondary endpoints included recurrence-free and event-free survival. RESULTS: Amongst subjects randomised, 1195 (mean age 72 yr; 773 [65%] male) were included in the modified intention-to-treat analysis. At the end of follow-up (median 43 months), there were 188 deaths amongst 598 patients (31%) assigned to propofol-based anaesthesia compared with 175 deaths amongst 597 patients (29%) assigned to sevoflurane-based anaesthesia; adjusted hazard ratio 1.02; 95% confidence interval (CI): 0.83-1.26; P=0.834. Recurrence-free survival was 223/598 (37%) in patients given propofol anaesthesia vs 206/597 (35%) given sevoflurane anaesthesia; adjusted hazard ratio 1.07; 95% CI: 0.89-1.30; P=0.465. Event-free survival was 294/598 (49%) in patients given propofol anaesthesia vs 274/597 (46%) given sevoflurane anaesthesia; adjusted hazard ratio 1.09; 95% CI 0.93 to 1.29; P=0.298. CONCLUSIONS: Long-term survival after major cancer surgery was similar with i.v. and volatile anaesthesia. Propofol-based iv. anaesthesia should not be used for cancer surgery with the expectation that it will improve overall or cancer-specific survival. CLINICAL TRIAL REGISTRATIONS: ChiCTR-IPR-15006209; NCT02660411.

Prediction of postoperative infection in elderly using deep learning-based analysis: an observational cohort study.

Elderly patients are susceptible to postoperative infections with increased mortality. Analyzing with a deep learning model, the perioperative factors that could predict and/or contribute to postoperative infections may improve the outcome in elderly. This was an observational cohort study with 2014 elderly patients who had elective surgery from 28 hospitals in China from April to June 2014. We aimed to develop and validate deep learning-based predictive models for postoperative infections in the elderly. 1510 patients were randomly assigned to be training dataset for establishing deep learning-based models, and 504 patients were used to validate the effectiveness of these models. The conventional model predicted postoperative infections was 0.728 (95% CI 0.688-0.768) with the sensitivity of 66.2% (95% CI 58.2-73.6) and specificity of 66.8% (95% CI 64.6-68.9). The deep learning model including risk factors relevant to baseline clinical characteristics predicted postoperative infections was 0.641 (95% CI 0.545-0.737), and sensitivity and specificity were 34.2% (95% CI 19.6-51.4) and 88.8% (95% CI 85.6-91.6), respectively. Including risk factors relevant to baseline variables and surgery, the deep learning model predicted postoperative infections was 0.763 (95% CI 0.681-0.844) with the sensitivity of 63.2% (95% CI 46-78.2) and specificity of 80.5% (95% CI 76.6-84). Our feasibility study indicated that a deep learning model including risk factors for the prediction of postoperative infections can be achieved in elderly. Further study is needed to assess whether this model can be used to guide clinical practice to improve surgical outcomes in elderly.

Orthopedic Surgery Causes Gut Microbiome Dysbiosis and Intestinal Barrier Dysfunction in Prodromal Alzheimer Disease Patients: A Prospective Observational Cohort Study.

OBJECTIVE: To investigate gut microbiota and intestinal barrier function changes after orthopedic surgery in elderly patients with either normal cognition (NC) or a prodromal Alzheimer disease phenotype (pAD) comprising either subjective cognitive decline (SCD) or amnestic mild cognitive impairment (aMCI). BACKGROUND: Homeostatic disturbances induced by surgical trauma and/or stress can potentially alter the gut microbiota and intestinal barrier function in elderly patients before and after orthopedic surgery. METHODS: In this prospective cohort study, 135 patients were subject to preoperative neuropsychological assessment and then classified into: NC (n=40), SCD (n=58), or aMCI (n=37). Their gut microbiota, bacterial endotoxin (lipopolysaccharide), tight junction (TJ) protein, and inflammatory cytokines in blood were measured before surgery and on postsurgical day 1, 3, and 7 (or before discharge). RESULTS: The short-chain fatty acid (SCFA)-producing bacteria were lower while the gram-negative bacteria, lipopolysaccharide and TJ were higher preoperatively in both the SCD and aMCI (pAD) groups compared with the NC group. After surgery, a decrease in SCFA-producing bacteria, and an increase in both gram-negative bacteria and plasma claudin were significant in the pAD groups relative to the NC group. SCFA-producing bacteria were negatively correlated with TJ and cytokines in pAD patients on postsurgical day 7. Furthermore, surgery-induced perioperative metabolic stress and inflammatory responses were associated with gut microbiota alterations. CONCLUSIONS: Surgery exacerbates both preexisting microbiota dysbiosis and intestinal barrier dysfunction in pAD patients, all of which may be associated with systemic inflammation and, in turn, may lead to further cognitive deterioration.

Circular RNAs in organ injury: recent development.

Circular ribonucleic acids (circRNAs) are a class of long non-coding RNA that were once regarded as non-functional transcription byproducts. However, recent studies suggested that circRNAs may exhibit important regulatory roles in many critical biological pathways and disease pathologies. These studies have identified significantly differential expression profiles of circRNAs upon changes in physiological and pathological conditions of eukaryotic cells. Importantly, a substantial number of studies have suggested that circRNAs may play critical roles in organ injuries. This review aims to provide a summary of recent studies on circRNAs in organ injuries with respect to (1) changes in circRNAs expression patterns, (2) main mechanism axi(e)s, (3) therapeutic implications and (4) future study prospective. With the increasing attention to this research area and the advancement in high-throughput nucleic acid sequencing techniques, our knowledge of circRNAs may bring fruitful outcomes from basic and clinical research.

Prognosis and antibody profiles in survivors of critical illness from COVID-19: a prospective multicentre cohort study.

BACKGROUND: There is a need to assess the long-term outcomes of survivors of critical illness from COVID-19. METHODS: Ninety-two survivors of critical illness from COVID-19 from four hospitals in Hubei Province, China participated in this prospective cohort study. Multiple characteristics, including lung function (lung volumes, diffusing capacity for carbon monoxide, chest computed tomography scores, and walking capacity); immune status (SARS-CoV-2-neutralising antibody and all subtypes of immunoglobulin (Ig) G against SARS-CoV-2, immune cells in response to ex vivo antigen peptide stimuli, and lymphocyte count and its subtypes); liver, coagulation, and kidney functions; quality of life; cognitive function; and mental status, were assessed after 3, 6, and 12 months of follow-up. RESULTS: Amongst the 92 enrolled survivors, 72 (78%) patients required mechanical ventilation. At 12 months, the predicted percentage diffusing capacity of lung for carbon monoxide was 82% (inter-quartile range [IQR]: 76-97%) with a residual volume of 77 (64-88)%. Other lung function parameters and the 6-min walk test improved gradually over time and were almost back to normal by 12 months. The titres of IgG and neutralising antibody to COVID-19 remained high at 12 months compared with those of controls who were not infected with COVID-19, although IgG titres decreased significantly from 34.0 (IQR: 23.8-74.3) to 15.0 (5.8-24.3) AU ml-1 (P<0.001), whereas neutralising antibodies decreased from 29.99 (IQR: 19.43-53.93) AU ml-1 at 6 months to 19.75 (13.1-29.8) AU ml-1 (P<0.001) at 12 months. In general, liver, kidney, physical, and mental functions also improved over time. CONCLUSIONS: Survivors of critical illness from COVID-19 show some persistent long-term impairments in lung function. However, a majority of these tests were normal by 12 months. These patients still had detectable levels of neutralising antibodies against SARS-CoV-2 and all types of IgG at 12 months, but the levels had declined over this time period. CLINICAL TRIAL REGISTRATION: None.

Comparison between dexmedetomidine and propofol on outcomes after coronary artery bypass graft surgery: a retrospective study.

BACKGROUND: Dexmedetomidine (DEX) has a pharmacological profile that should allow rapid recovery and prevent undesirable outcomes such as pulmonary complications. METHODS: This large retrospective study compared the beneficial effects of perioperative infusion of DEX with propofol on the postoperative outcome after coronary artery bypass graft surgery. We reviewed patients' medical notes at Luoyang Central Hospital from 1st January 2012 to 31st December 2019. All continuous variables, if normally distributed, were presented as mean ± SD; Otherwise, the non-normally distributed data and categorical data were presented as median (25-75 IQR) or number (percentage). The Mann-Whitney U test and Chi-square test were used to evaluate the difference of variables between the DEX and propofol groups. Multivariate logistic regression analysis was performed on the main related and differential factors in the perioperative period. RESULTS: A total of 1388 patients were included in the study; of those, 557 patients received propofol infusion, and 831 patients received dexmedetomidine. DEX significantly reduced postoperative pulmonary complications compared with propofol, 7.82% vs 13.29%; P < 0.01, respectively. When compared with propofol, DEX significantly shortened the duration of mechanical lung ventilation, 18 (13,25) hours vs 21 (16,37) hours; P < 0.001, the length of stay in the intensive care unit, 51 (42,90) vs 59 (46,94.5) hours; P = 0.001 and hospital stay, 20 (17,24) vs 22 (17,28) days; P < 0.001, respectively. The incidences of postoperative wound dehiscence and infection were significantly reduced with DEX compared with propofol groups, 2.53% vs 6.64%; P < 0.001, respectively. Interestingly, patients receiving DEX had significantly shorter surgical time compared to propofol; 275 (240,310) vs 280 (250,320) minutes respectively (P = 0.005) and less estimated blood loss (P = 0.001). CONCLUSION: Perioperative infusion of dexmedetomidine improved the desirable outcomes in patients who had coronary artery bypass graft surgery compared with propofol.

Phosphorylation at Ser 727 Increases STAT3 Interaction with PKCε Regulating Neuron-Glia Crosstalk via IL-6-Mediated Hyperalgesia In Vivo and In Vitro.

METHODS: A rat hyperalgesia model was induced using an intraplantar injection of Freund's complete adjuvant (FCA) or an intrathecal injection of IL-6. Mechanical allodynia was evaluated using von Frey filament tests after intrathecal injections of T-5224 (c-Fos/AP-1 inhibitor), minocycline (Mino, a specific microglia inhibitor), L-2-aminoadipic acid (LAA, an astroglial toxin), PKCε inhibitor peptide, APTSTAT3-9R (STAT3 inhibitor), or anti-IL-6 antibody. The c-Fos, GFAP, Iba-1, PKCε, STAT3, pSTAT3Tyr705 and pSTAT3Ser727, and IL-6 expression at the spinal cord level was assessed by Western blot analysis. The interactive effects of PKCε and STAT3 were determined using immunofluorescence staining and immunoprecipitation in vivo and in vitro. Interleukin-6 promoter activity was examined using luciferase assays. RESULTS: T-5224, Mino, and LAA attenuated FCA- or IL-6-mediated inflammatory pain, with a decrease in c-Fos, GFAP, Iba-1, PKCε, and IL-6 expression. PKCε inhibitor peptide and APTSTAT3-9R reversed FCA-induced nociceptive behavior, while decreasing pSTAT3Ser727, IL-6, c-Fos, GFAP, and Iba-1 expression and PKCε and STAT3 coexpression. Interleukin-6 promoter activity increased in the presence of PKCε and STAT3. The interaction with PKCε increased on phosphorylating STAT3 at Ser727 but not at Tyr705. CONCLUSION: STAT3 phosphorylation at Ser 727 and the interaction with PKCε contribute to hyperalgesia via the IL-6-mediated signaling pathway, thus regulating neuron-glia crosstalk during inflammatory pain.

Pretreatment with valproic acid alleviates pulmonary fibrosis through epithelial-mesenchymal transition inhibition in vitro and in vivo.

Epithelial-mesenchymal transition (EMT) plays a crucial role in the development of pulmonary fibrosis. This study aims to investigate the effects of valproic acid (VPA) on EMT in vitro and in vivo. In vitro, EMT was induced by the administration of transforming growth factor-ß1 (TGF-ß1) in a human alveolar epithelial cell line (A549). The dose effects of VPA (0.1-3 mM) on EMT were subsequently evaluated at different timepoints. VPA (1 mM) was applied prior to the administration of TGF-ß1 and the expression of E-cadherin, vimentin, p-Smad2/3 and p-Akt was assessed. In addition, the effects of a TGF-ß type I receptor inhibitor (A8301) and PI3K-Akt inhibitor (LY294002) on EMT were evaluated. In vivo, the effects of VPA on bleomycin-induced lung fibrosis were evaluated by assessing variables such as survival rate, body weight and histopathological changes, whilst the expression of E-cadherin and vimentin in lung tissue was also evaluated. A8301 and LY294002 were used to ascertain the cellular signaling pathways involved in this model. The administration of VPA prior to TGF-ß1 in A549 cells prevented EMT in both a time- and concentration-dependent manner. Pretreatment with VPA downregulated the expression of both p-Smad2/3 and p-Akt. A8301 administration increased the expression of E-cadherin and reduced the expression of vimentin. LY294002 inhibited Akt phosphorylation induced by TGF-ß1 but failed to prevent EMT. Pretreatment with VPA both increased the survival rate and prevented the loss of body weight in mice with pulmonary fibrosis. Interestingly, both VPA and A8301 prevented EMT and facilitated an improvement in lung structure. Overall, pretreatment with VPA attenuated the development of pulmonary fibrosis by inhibiting EMT in mice, which was associated with Smad2/3 deactivation but without Akt cellular signal involvement.