Cognitive Training for Reduction of Delirium in Patients Undergoing Cardiac Surgery: A Randomized Clinical Trial.

IMPORTANCE: Postoperative delirium is a common and impactful neuropsychiatric complication in patients undergoing coronary artery bypass grafting surgery. Cognitive training may enhance cognitive reserve, thereby reducing postoperative delirium. OBJECTIVE: To determine whether preoperative cognitive training reduces the incidence of delirium in patients undergoing coronary artery bypass grafting. DESIGN, SETTING, and PARTICIPANTS: This prospective, single-blind, randomized clinical trial was conducted at 3 university teaching hospitals in southeastern China with enrollment between April 2022 and May 2023. Eligible participants included those scheduled for elective coronary artery bypass grafting who consented and enrolled at least 10 days before surgery. INTERVENTIONS: Participating patients were randomly assigned 1:1, stratified by site, to either routine care or cognitive training, which included substantial practice with online tasks designed to enhance cognitive functions including memory, imagination, reasoning, reaction time, attention, and processing speed. MAIN OUTCOMES AND MEASURES: The primary outcome was occurrence of delirium during postoperative days 1 to 7 or until hospital discharge, diagnosed using the Confusion Assessment Method or the Confusion Assessment Method for Intensive Care Units. Secondary outcomes were postoperative cognitive dysfunction, delirium characteristics, and all-cause mortality within 30 days following the operation. RESULTS: A total of 218 patients were randomized and 208 (median [IQR] age, 66 [58-70] years; 64 female [30.8%] and 144 male [69.2%]) were included in final analysis, with 102 randomized to cognitive training and 106 randomized to routine care. Of all participants, 95 (45.7%) had only a primary school education and 54 (26.0%) had finished high school. In the cognitive training group, 28 participants (27.5%) developed delirium compared with 46 participants (43.4%) randomized to routine care. Those receiving cognitive training were 57% less likely to develop delirium compared with those receiving routine care (adjusted odds ratio [aOR] 0.43; 95% CI, 0.23-0.77; P = .007). Significant differences were observed in the incidence of severe delirium (aOR, 0.46; 95% CI, 0.25-0.82; P = .01), median (IQR) duration of delirium (0 [0-1] days for cognitive training vs 0 [0-2] days for routine care; P = .008), and median (IQR) number of delirium-positive days (0 [0-1] days for cognitive training vs 0 [0-2] days for routine care; P = .007). No other secondary outcomes differed significantly. CONCLUSIONS AND RELEVANCE: In this randomized trial of 208 patients undergoing coronary artery bypass grafting, preoperative cognitive training reduced the incidence of postoperative delirium. However, our primary analysis was based on fewer than 75 events and should therefore be considered exploratory and a basis for future larger trials. Trial Registration: Chinese Clinical Trial Registry Identifier: ChiCTR2200058243.

Effect of intraoperative dexmedetomidine on recovery of gastrointestinal function after caesarean section undergoing spinal and epidural anesthesia: A randomized, double blind, placebo-controlled clinical trial.

OBJECTIVE: Gastrointestinal dysfunction after cesarean section negatively affects postoperative recovery. Dexmedetomidine has been shown to improve postoperative gastrointestinal function in patients undergoing lumbar spinal fusion surgery and laparoscopic gastrectomy, but its role in cesarean section has not been fully elucidated. The study aimed to investigate the effect of dexmedetomidine on gastrointestinal function after cesarean section. STUDY DESIGN: 220 pregnant women who underwent elective cesarean section were randomized into group D and group S. Group D patients received a loading dose of 0.5 µg/kg of dexmedetomidine for 10 mins followed by a maintenance dose of 0.5 µg/kg/h intravenously immediately after the umbilical cord was cut intraoperatively, whereas the other group (group S) received an equivalent quantity of normal saline as loading and maintenance dose IV by infusion pump. The primary outcome was time to first flatus after surgery (hours). Secondary outcomes included time to first feces and first bowel sounds (hours), incidence rates of postoperative gastrointestinal complications, and the length of postoperative hospital stay (days). RESULTS: Modified intention-to-treat analysis showed that patients in Group D had a significantly shorter time to first flatus (21 [16 to 28.25] vs. 25 [18 to 32.25] h; P = 0.014), time to first feces (45.5 [35.75 to 55.25] vs. 53 [40 to 60] h; P = 0.019), and time to first bowel sounds (P = 0.010), a lower incidence of abdominal distension (21[20.6 %] vs. 36[34.3 %], P = 0.027), shorter length of postoperative hospital stay (P = 0.010) compared to patients in Group S. CONCLUSION: Intraoperative dexmedetomidine infusion reduces the time to first flatus, the incidence of abdominal distension, and shortens the length of hospital stay, promoting gastrointestinal function after cesarean section.

The binding of PKCε and MEG2 to STAT3 regulates IL-6-mediated microglial hyperalgesia during inflammatory pain.

Studies have suggested that microglial IL-6 modulates inflammatory pain; however, the exact mechanism of action remains unclear. We therefore hypothesized that PKCε and MEG2 competitively bind to STAT3 and contribute to IL-6-mediated microglial hyperalgesia during inflammatory pain. Freund's complete adjuvant (FCA) and lipopolysaccharide (LPS) were used to induce hyperalgesia model mice and microglial inflammation. Mechanical allodynia was evaluated using von Frey tests in vivo. The interaction among PKCε, MEG2, and STAT3 was determined using ELISA and immunoprecipitation assay in vitro. The PKCε, MEG2, t-STAT3, pSTAT3Tyr705, pSTAT3Ser727, IL-6, GLUT3, and TREM2 were assessed by Western blot. IL-6 promoter activity and IL-6 concentration were examined using dual luciferase assays and ELISA. Overexpression of PKCε and MEG2 promoted and attenuated inflammatory pain, accompanied by an increase and decrease in IL-6 expression, respectively. PKCε displayed a stronger binding ability to STAT3 when competing with MEG2. STAT3Ser727 phosphorylation increased STAT3 interaction with both PKCε and MEG2. Moreover, LPS increased PKCε, MEG2, pSTAT3Tyr705, pSTAT3Ser727, IL-6, and GLUT3 levels and decreased TREM2 during microglia inflammation. IL-6 promoter activity was enhanced or inhibited by PKCε or MEG2 in the presence of STAT3 and LPS stimulation, respectively. In microglia, overexpression of PKCε and/or MEG2 resulted in the elevation of tSTAT3, pSTAT3Tyr705, pSTAT3Ser727, IL-6, and TREM2, and the reduction of GLUT3. PKCε is more potent than MEG2 when competitively binding to STAT3, displaying dual modulatory effects of IL-6 production, thus regulating the GLUT3 and TREM2 in microglia during inflammatory pain sensation.

Personal versus therapist perioperative music intervention: a randomized controlled trial.

INTRODUCTION: Music interventions can alleviate patient anxiety and improve post-surgical satisfaction. However, it remains uncertain whether music personal preferences affect efficacy. We tested whether personal music intervention with patient-selected songs played ad libitum is more effective than standard therapist-designed treatment with classical music. METHODS: A prospective, parallel-group, single-blinded, randomized controlled trial with 229 participants (aged 18 to 60 y) previously scheduled for elective surgery. Data analyses followed a modified intention-to-treat principle. The patients were randomized into three groups: Standard care without music (Control), therapist-designed classic music treatment (TT), or personal music intervention with patient-selected songs played ad libitum by the patient (PI). All patients received standard post-anesthesia care, and music intervention was started upon arrival at the post-anesthesia care unit. Primary outcomes were anxiety and overall satisfaction at discharge. In contrast, secondary outcomes were systolic blood pressure during music intervention, the sleep quality of the night after surgery, and the occurrence of postoperative nausea and vomiting within the first 24 hours after surgery. RESULTS: Compared with therapist-designed music treatment, personal intervention decreased systolic blood pressure (T 0 : 124.3±13.7, 95%CI:121-127.7; T 20min : 117.6±10.4, 95%CI:115-120.1; T 30min : 116.9±10.6, 95%CI:114.3-119.4), prevented postoperative nausea and vomiting (Control: 55.9%, TT: 64.6%, PI: 77.6%), including severe postoperative nausea (VAS score>4; Control:44.1%; TT:33.8%; PI:20.9%) and severe emesis (Frequency≥3, Control:13.2%; TT:7.7%; PI:4.5%). None of the treatments affected sleep quality at night after surgery (Median, Q1-Q3, Control:3,1-3; TT:3,1-4; PI:3,1-3.5). Personal, but not therapist, music intervention significantly prevented anxiety (Control: 36.4±5.9, 95% CI:35.0-37.9; TT: 36.2±7.1, 95%CI: 34.4-37.9; PI: 33.8±5.6, 95%CI: 32.4-35.2) and emesis (Control:23.9%; TT:23.4%; PI:13.2%) and improved patient satisfaction (Median, Q1-Q3, C:8, 6-8; TT:8,7-9; PI:8,7-9). CONCLUSIONS: Personal music intervention improved postoperative systolic blood pressure, anxiety, nausea, emesis, and overall satisfaction, but not sleep quality, as compared to therapist-designed classic intervention.

Clinical application of a connection device consisting of a bag valve mask and nebulizer in first aid: Two case reports.

In clinical practice, several emergencies may threaten the life of patients, and these emergencies can be unpredictable and challenging. During the coronavirus disease 2019 pandemic, in January 2023, a patient developed respiratory distress caused by coronavirus, but was unable to access respiratory support due to shortages of medical resources, intensive care unit beds and ventilators. The medical staff quickly created a portable high-flow atomized oxygen therapy apparatus consisting of a simple breathing bag connected to a nebulizer to provide breathing support. In addition, the Ambulatory Surgery Center, The First Affiliated Hospital of Anhui Medical University (Hefei, China) witnessed a case of severe laryngeal spasm after tracheal extubation during the recovery period from general anesthesia. Due to the lack of an anesthesia machine nebulizer, the aforementioned device was used to provide oxygen under pressure and initiate treatment to quickly relieve the symptoms of laryngeal obstruction. The present case report describes how the medical staff quickly applied emergency airway management skills and knowledge to create a portable high-flow atomized oxygen therapy apparatus in a resource-poor setting to save the lives of two patients.

The Association of Preoperative Diabetes With Postoperative Delirium in Older Patients Undergoing Major Orthopedic Surgery: A Prospective Matched Cohort Study.

BACKGROUND: Postoperative delirium (POD) is a common form of postoperative brain dysfunction, especially in the elderly. However, its risk factors remain largely to be determined. This study aimed to investigate whether (1) preoperative diabetes is associated with POD after elective orthopedic surgery and (2) intraoperative frontal alpha power is a mediator of the association between preoperative diabetes and POD. METHODS: This was a prospective matched cohort study of patients aged 60 years or more, with a preoperative diabetes who underwent elective orthopedic surgery. Nondiabetic patients were matched 1:1 to diabetic patients in terms of age, sex, and type of surgery. Primary outcome was occurrence of POD, assessed using the 3-minute Diagnostic Confusion Assessment Method (3D-CAM) once daily from 6 pm to 8 pm during the postoperative days 1-7 or until discharge. Secondary outcome was the severity of POD which was assessed for all participants using the short form of the CAM-Severity. Frontal electroencephalogram (EEG) was recorded starting before induction of anesthesia and lasting until discharge from the operating room. Intraoperative alpha power was calculated using multitaper spectral analyses. Mediation analysis was used to estimate the proportion of the association between preoperative diabetes and POD that could be explained by intraoperative alpha power. RESULTS: A total of 138 pairs of eligible patients successfully matched 1:1. After enrollment, 6 patients in the diabetes group and 4 patients in the nondiabetes group were excluded due to unavailability of raw EEG data. The final analysis included 132 participants with preoperative diabetes and 134 participants without preoperative diabetes, with a median age of 68 years and 72.6% of patients were female. The incidence of POD was 16.7% (22/132) in patients with preoperative diabetes vs 6.0% (8/134) in patients without preoperative diabetes. Preoperative diabetes was associated with increased odds of POD after adjustment of age, sex, body mass index, education level, hypertension, arrhythmia, coronary heart disease, and history of stroke (odds ratio, 3.2; 95% confidence interval [CI], 1.4-8.0; P = .009). The intraoperative alpha power accounted for an estimated 20% (95% CI, 2.6-60%; P = .021) of the association between diabetes and POD. CONCLUSIONS: This study suggests that preoperative diabetes is associated with an increased risk of POD in older patients undergoing major orthopedic surgery, and that low intraoperative alpha power partially mediates such association.

Activating astrocytic α2A adrenoceptors in hippocampus reduces glutamate toxicity to attenuate sepsis-associated encephalopathy in mice.

BACKGROUND: Glutamate metabolism disorder is an important mechanism of sepsis-associated encephalopathy (SAE). Astrocytes regulate glutamate metabolism. In septic mice, α2A adrenoceptor (α2A-AR) activation in the central nervous system provides neuroprotection. α2A-ARs are expressed abundantly in hippocampal astrocytes. This study was performed to determine whether hippocampal astrocytic α2A-AR activation confers neuroprotection against SAE and whether this protective effect is astrocyte specific and achieved by the modulation of glutamate metabolism. METHODS: Male C57BL/6 mice with and without α2A-AR knockdown were subjected to cecal ligation and puncture (CLP). They were treated with intrahippocampal guanfacine (an α2A-AR agonist) or intraperitoneal dexmedetomidine in the presence or absence of dihydrokainic acid [DHK; a glutamate transporter 1 (GLT-1) antagonist] and/or UCPH-101 [a glutamate/aspartate transporter (GLAST) antagonist]. Hippocampal tissue was collected for the measurement of astrocyte reactivity, GLT-1 and GLAST expression, and glutamate receptor subunit 2B (GluN2B) phosphorylation. In vivo real-time extracellular glutamate concentrations in the hippocampus were measured by ultra-performance liquid chromatography tandem mass spectrometry combined with microdialysis, and in vivo real-time hippocampal glutamatergic neuron excitability was assessed by calcium imaging. The mice were subjected to the Barnes maze and fear conditioning tests to assess their learning and memory. Golgi staining was performed to assess changes in the hippocampal synaptic structure. In vitro, primary astrocytes with and without α2A-AR knockdown were stimulated with lipopolysaccharide (LPS) and treated with guanfacine or dexmedetomidine in the presence or absence of 8-bromo- cyclic adenosine monophosphate (8-Br-cAMP, a cAMP analog). LPS-treated primary and BV2 microglia were also treated with guanfacine or dexmedetomidine. Astrocyte reactivity, PKA catalytic subunit, GLT-1 an GLAST expression were determined in primary astrocytes. Interleukin-1ß, interleukin-6 and tumor necrosis factor-alpha in the medium of microglia culture were measured. RESULTS: CLP induced synaptic injury, impaired neurocognitive function, increased astrocyte reactivity and reduced GLT-1 and GLAST expression in the hippocampus of mice. The extracellular glutamate concentration, phosphorylation of GluN2B at Tyr-1472 and glutamatergic neuron excitability in the hippocampus were increased in the hippocampus of septic mice. Intraperitoneal dexmedetomidine or intrahippocampal guanfacine administration attenuated these effects. Hippocampal astrocytes expressed abundant α2A-ARs; expression was also detected in neurons but not microglia. Specific knockdown of α2A-ARs in hippocampal astrocytes and simultaneous intrahippocampal DHK and UCPH-101 administration blocked the neuroprotective effects of dexmedetomidine and guanfacine. Intrahippocampal administration of DHK or UCPH-101 alone had no such effect. In vitro, guanfacine or dexmedetomidine inhibited astrocyte reactivity, reduced PKA catalytic subunit expression, and increased GLT-1 and GLAST expression in primary astrocytes but not in primary astrocytes that received α2A-AR knockdown or were treated with 8-Br-cAMP. Guanfacine or dexmedetomidine inhibited microglial reactivity in BV2 but not primary microglia. CONCLUSIONS: Our results suggest that neurocognitive protection against SAE after hippocampal α2A-AR activation is astrocyte specific. This protection may involve the inhibition of astrocyte reactivity and alleviation of glutamate neurotoxicity, thereby reducing synaptic injury. The cAMP/protein kinase A (PKA) signaling pathway is a potential cellular mechanism by which activating α2A-AR modulates astrocytic function.

Intraoperative electroencephalogram features related to frailty in older patients: an exploratory prospective observational study.

Frailty is an independent risk factor for the increased incidence of postoperative delirium (POD). To date, the effect of frailty on intraoperative electroencephalogram (EEG) changes remains unexplored. The present study, an exploratory analysis of a prospective cohort study, aimed to investigate the differences in EEG characteristics between frail and robust patients. This prospective observational study was conducted between December 2020 and November 2021. The preoperative frailty status was assessed using the FRAIL scale. The patients' baseline (before anesthesia) and intraoperative EEG data were collected using a brain function monitor. Finally, 20 robust and 26 frail older patients scheduled for elective spinal surgery or transurethral prostatectomy under propofol-based general anesthesia were included in the final analysis. Baseline and intraoperative EEG spectrogram and power spectra were compared between the frail and robust groups. No differences were observed in baseline EEG between the frail and robust groups. When the intraoperative EEG spectral parameters were compared, the alpha peak frequency (10.56 ± 0.49 vs. 10.14 ± 0.36 Hz, P = 0.002) and alpha peak, delta, theta, alpha, and beta powers were lower in the frail group. After adjusting for age, Charlson Comorbidity Index (CCI), and mini-mental state examination (MMSE) score, the FRAIL score was still negatively associated with total, delta, theta, alpha, and beta powers. Frail patients had reduced EEG (0-30 Hz) power after the induction of propofol-based general anesthesia. After adjusting for age, CCI, and MMSE score, frail patients still showed evidence of reduced δ, θ, α, and ß power.

Aging aggravates liver fibrosis through downregulated hepatocyte SIRT1-induced liver sinusoidal endothelial cell dysfunction.

BACKGROUND: Aging increases the susceptibility to chronic liver diseases and hastens liver fibrosis deterioration, but the underlying mechanisms remain partially understood. The aim of this study was to investigate the effect of aging and chronic liver diseases on hepatocyte Sirtuin 1 (SIRT1) and LSECs and their contribution to liver fibrosis pathogeneses. METHODS: Young (8-12 wk) and aged (18-20 mo) mice were subjected to carbon tetrachloride-induced liver fibrosis. Primary HSCs and LSECs were isolated and cocultured for in vitro experiments. Liver tissues and blood samples from healthy controls and patients with liver fibrosis were analyzed. RESULTS: Downregulated hepatocytes SIRT1 in aged mice increased high mobility group box 1 acetylation, cytoplasmic translocation, and extracellular secretion, causing LSECs dysfunction by means of the toll-like receptor 4/AK strain transforming (AKT)/endothelial nitric oxide synthase pathway, ultimately activating HSCs and increasing susceptibility to liver injury and fibrosis. Adeno-associated virus-mediated overexpression of SIRT1 in hepatocytes suppressed the abovementioned alterations and attenuated carbon tetrachloride-induced liver injury and fibrosis in liver fibrosis mice, and there were no significant differences in liver injury and fibrosis indicators between young and aged mice after SIRT1 overexpression treatment. In vitro experiments demonstrated that SIRT1 overexpression and endothelial nitric oxide synthase agonist YC-1 improved LSECs function and inhibited HSCs activation, mediated by nitric oxide. Similarly, downregulated hepatocytes SIRT1 and LSECs dysfunction were observed in the livers of aged individuals compared to young individuals and were more pronounced in aged patients with liver fibrosis. CONCLUSIONS: Aging aggravates liver fibrosis through downregulated hepatocytes SIRT1-induced LSECs dysfunction, providing a prospective curative approach for preventing and treating liver fibrosis.

Donor and recipient age matching in lung transplantation: A retrospective study.

Purpose: This study aimed to clarify the effect of donor and recipient age combinations on the short-term survival rates of patients undergoing lung transplantation. Patients and methods: We retrospectively reviewed the 2017-2020 data of the Affiliated Wuxi People's Hospital of Nanjing Medical University database for all adults (≥18 years), lung transplant recipients, and their associated donors. The impact of donor and recipient ages on survival was analyzed using a multivariable Cox proportional hazards regression model. Subgroup analysis was also performed based on recipient and donor ages. Results: Different donor and recipient age combinations affected the short-term postoperative survival rates. When recipients were ≤55 years, the survival rates of the younger donor age group were significantly higher than the older donor age group at 30 days after surgery (P = 0.040); when the donors were ≤40 years, the postoperative survival rates of the younger recipient age group were significantly higher than the older recipient age group (P = 0.031, P = 0.026, P = 0.034, and P = 0.018 for 30 days, 90 days, 180 days, and 1 year after surgery, respectively). Conclusion: Younger recipients had a higher survival rate after transplantation than older recipients, and this benefit could be compromised by older donors. Furthermore, the influence of donor age on patient survival rate was limited and more pronounced in younger recipients and shortly after surgery.

Ropivacaine-loaded hydrogels for prolonged relief of chemotherapy-induced peripheral neuropathic pain and potentiated chemotherapy.

Chemotherapy can cause severe pain for patients, but there are currently no satisfactory methods of pain relief. Enhancing the efficacy of chemotherapy to reduce the side effects of high-dose chemotherapeutic drugs remains a major challenge. Moreover, the treatment of chemotherapy-induced peripheral neuropathic pain (CIPNP) is separate from chemotherapy in the clinical setting, causing inconvenience to cancer patients. In view of the many obstacles mentioned above, we developed a strategy to incorporate local anesthetic (LA) into a cisplatin-loaded PF127 hydrogel for painless potentiated chemotherapy. We found that multiple administrations of cisplatin-loaded PF127 hydrogels (PFC) evoked severe CIPNP, which correlated with increased pERK-positive neurons in the dorsal root ganglion (DRG). However, incorporating ropivacaine into the PFC relieved PFC-induced CIPNP for more than ten hours and decreased the number of pERK-positive neurons in the DRG. Moreover, incorporating ropivacaine into the PFC for chemotherapy is found to upregulate major histocompatibility complex class I (MHC-I) expression in tumor cells and promote the infiltration of cytotoxic T lymphocytes (CD8+ T cells) in tumors, thereby potentiating chemotherapy efficacy. This study proposes that LA can be used as an immunemodulator to enhance the effectiveness of chemotherapy, providing new ideas for painless cancer treatment.

Effect of general anaesthesia with remimazolam versus propofol on postoperative quality of recovery in patients undergoing ambulatory arthroscopic meniscus repair: a randomised clinical trial.

Background: The type of anaesthesia and choice of anaesthetic drugs may affect the quality of recovery after surgery. Remimazolam is a new benzodiazepine with rapid onset and offset, specifically antagonised by flumazenil. This study aimed to compare remimazolam with propofol on the quality of recovery in patients undergoing ambulatory arthroscopic surgery. Methods: Patients aged 18-65 yr and scheduled for ambulatory arthroscopic meniscus repair were recruited and randomly assigned to receive either continuous i.v. infusion of remimazolam or plasma target-controlled infusion of propofol. The quality of recovery-15 (QoR-15) scale was administered on postoperative day 1 (POD1) as the primary outcome. Secondary outcomes included the Athens Insomnia Scale (AIS) scores and cardiovascular variables. Results: In total, 120 patients were randomly assigned to the remimazolam or propofol groups and 114 patients were included in the analysis. The remimazolam group had higher total QoR-15 scores on POD1 (125 [120-127.5] vs 121.5 [119-124], with a median difference of 3 (95% confidence interval: 1-5; P=0.002). Physical independence and psychological support were higher in the remimazolam group (8.5 [8-10] vs 8 [7-9], P=0.043; 17 [13-17] vs 12.5 [12-14], P<0.001). Remimazolam lowered the number of awakenings during the first postoperative night (P=0.042) and the incidence of hypotension (P=0.04). Conclusions: Remimazolam-based total i.v. anaesthesia was associated with small improvements in the quality of recovery; however, the improvement was less than the minimally clinically important difference. Clinical trial registration: ChiCTR2100053014.

Anti-Proteolytic Peptide R7I Protects the Intestinal Barrier and Alleviates Fatty Acid Malabsorption in Salmonella typhimurium-Infected Mice.

With a wide range of hosts, environmental adaptation, and antibiotic resistance, Salmonella typhimurium is one of the most common causes of food poisoning in the world. Infection with Salmonella typhimurium not only results in intestinal inflammation but also damages the intestinal barrier and interferes with the host's ability to absorb nutrients. It is imperative to find alternatives to antibiotics for eradicating bacteria, reducing intestinal damage, and reestablishing nutrient absorption, especially given that antibiotics are currently prohibited. This research aims to understand the protective role of anti-proteolytic peptide R7I on the gut in the setting of Salmonella typhimurium infection and its impact on nutritional absorption, maybe offering an alternative to antibiotics for bacterial killing. The findings demonstrated that R7I reduced the production of inflammatory factors, including IL-6, TNF-α, and L-1ß in the jejunum and decreased the expression of genes like TLR4 and NF-κB in the jejunum (p < 0.05). R7I enhanced antioxidant capacity and preserved the antioxidant/pro-oxidant balance in the jejunum (p < 0.05). R7I also normalized intestinal shape and restored tight junction protein expression. Fatty acid binding protein 2 (FABP2) and fatty acid transport protein 4 (FATP4) expression in the jejunum was restored by R7I. In addition, serum-free fatty acids and lipid metabolites were significantly higher in the R7I group than in the control group (p < 0.05). Overall, the anti-enzyme peptide R7I maintained the healthy state of the intestine and alleviated the abnormal fatty acid absorption caused by bacterial infection.

MANF Alleviates Sevoflurane-Induced Cognitive Impairment in Neonatal Mice by Modulating Microglial Activation and Polarization.

The precise mechanism underlying sevoflurane-induced neurotoxicity and cognitive impairment remains largely unknown. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a neuroprotective factor that has shown promise in various neurological disorders. However, its impact on sevoflurane-induced alterations has not been investigated. Thus, the objective of this study was to examine the effect of MANF in mitigating sevoflurane-induced neurotoxicity in young mice. Anesthesia with 3% sevoflurane 2 h daily was administered to young mice on postnatal day (P) 3, 6 and 9. We also constructed mono-macrophage-specific MANF knockout (MKO) mice in the mechanistic studies. Finally, the recombinant human MANF (rhMANF, 20 µg) protein was intraperitoneally administrated to neonatal mice before the sevoflurane anesthesia and the cognitive function, levels of pro-inflammatory cytokine and synapse-associated protein PSD95, the status of neural apoptosis, microglia activation and oxidative stress in hippocampus of the mice were investigated. The sevoflurane anesthesia increased the expression of endogenous MANF in the hippocampus, especially in microglia. MKO upregulated the expression of tumor necrosis factor-α (TNF-α), accelerated the neural apoptosis and the activation of microglia in hippocampus in young mice. MANF reversed the sevoflurane-induced cognitive impairment and inhibited the upregulation of TNF-α, the neural apoptosis and the reduction of the postsynaptic density protein-95 (PSD95) induced by sevoflurane anesthesia. Also, pretreatment with MANF alleviated the sevoflurane-induced activation of microglia and oxidative stress. Our current results demonstrated that MANF ameliorated neurotoxicity induced by the sevoflurane anesthesia in young mice, and such protective effect was associated with inhibition of microglia activation and neuroinflammation.

Influence of low-dose esketamine on postoperative depressive symptoms in patients with breast cancer (EASE): study protocol for a randomised controlled trial.

INTRODUCTION: Depressive symptoms have surfaced as the principal mental health concern among patients with breast cancer, with surgical interventions potentially exacerbating these symptoms and adversely influencing clinical outcomes. This study protocol is designed to investigate the efficacy of low-dose esketamine administered perioperatively on depressive symptoms in patients with breast cancer. It also aims to illuminate the potential neurobiological underpinnings of this effect. METHODS AND ANALYSIS: This research represents a single-centre, prospective, randomised, double-blind, placebo-controlled study. The trial anticipates enrolling 108 female patients exhibiting mild-to-severe depressive symptoms who are slated for radical mastectomy. Through stratified randomisation, eligible patients will be systematically assigned to either the esketamine group (0.25 mg/kg) or placebo group (0.9% saline) in a 1:1 ratio. The primary outcome is the response rate at the third postoperative day. Secondary outcomes encompass the remission rate, depression-related scores, depression severity and safety-related endpoints. Tertiary (exploratory) outcomes involve alterations in brain-derived neurotrophic factor and resting-state functional brain connectivity. ETHICS AND DISSEMINATION: The Clinical Trial Ethics Committee at The First Affiliated Hospital of Anhui Medical University has conferred ethical approvals for this trial (approval number: PJ2023-05-25). Results from this trial will be disseminated in peer-reviewed journals and presented at professional symposiums. TRIAL REGISTRATION NUMBER: Chinese Clinical Trials Registry (ChiCTR2300071062).

Analgesic and potentiated photothermal therapy with ropivacaine-loaded hydrogels.

Rationale: Tumor ablation can cause severe pain to patients, but there is no satisfactory means of analgesia available. In addition, recurrence of residual tumors due to incomplete ablation threatens patient safety. Photothermal therapy (PTT), a promising approach for tumor ablation, also faces the aforementioned problems. Therefore, developing novel photothermal agents that can efficiently relieve PTT-associated pain and potentiate the PTT efficacy are urgently needed. Methods: The Pluronic F127 hydrogel doped with indocyanine green (ICG) was served as photothermal agent for PTT. Mouse model that inoculation of tumor near the sciatic nerve was constructed to assess the PTT-evoked pain. Subcutaneous and sciatic nerve vicinal tumor-bearing mice were used to test the efficacy of PTT. Results: PTT-evoked pain depends on an increase in tumor temperature and is accompanied by the activation of TRPV1. A simple introduction of local anesthetic (LA) ropivacaine into ICG-loaded hydrogels relieves PTT-induced pain and exerts long-lasting analgesia compared with opioid analgesia. More interestingly, ropivacaine upregulates major histocompatibility complex class I (MHC-I) in tumor cells by impairing autophagy. Therefore, a hydrogel co-doped with ropivacaine, TLR7 agonist imiquimod and ICG was rationally designed. In the hydrogel system, imiquimod primes tumor-specific CD8+ T cells through promoting DCs maturation, and ropivacaine facilitates tumor cells recognition by primed CD8+ T cells through upregulating MHC-I. Consequently, the hydrogel maximumly increases CD8+ T cells infiltration into tumor and potentiates PTT efficacy. Conclusion: This study for the first time provides an LA-dopped photothermal agents for painless PTT and innovatively proposes that a LA can be used as an immunomodulator to potentiate the PTT efficacy.

Cardiac sirtuin1 deficiency exacerbates ferroptosis in doxorubicin-induced cardiac injury through the Nrf2/Keap1 pathway.

Doxorubicin (DOX), a broad-spectrum chemotherapeutic agent for various cancers, has limited clinical application because of its serious cardiotoxicity, which is due to different mechanisms, including cardiac ferroptosis and oxidative stress. Some drugs, such as berberine or dioscin, show efficacy in impeding DOX-induced cardiotoxicity by activating Sirtuin 1 (Sirt1). However, there is no direct evidence to clarify the role of Sirt1 in DOX-induced cardiomyopathy and its underlying role in cardiac ferroptosis. In this study, C57BL/6 and cardiac-specific Sirt1-/- knockout mice were used as a DOX-induced cardiotoxicity model. We found that cardiac Sirt1 was downregulated, oxidative stress was increased and ferroptosis were obviously enhanced, as reflected by decreased Glutathione peroxidase 4 (GPX4) and increased Heme oxygenase 1 (Hmox-1), exposure to DOX treatment in mice and H9c2 cells compared with the control. And Sirt1 activation was resistant to cardiac injury induced by DOX, as observed the improvement of cardiac dysfunction, and the reduction of cardiac fibrosis. However, cardiac Sirt1 deficiency aggravated Dox-induced cardiac dysfunction and cardiac remodeling, further downregulated GPX4, upregulated Hmox-1 expression and increased ROS level. In addition, Sirt1-siRNA exacerbated DOX-induced cardiotoxicity in H9c2 cells, which is similar to the results obtained in vivo. Furthermore, DOX decrease Nrf2 translocation from the cytosol to the nucleus, and Sirt1 deficiency further restrain the process, as well as the downstream Keap1 pathways, in DOX-induced cardiotoxicity. This study provides direct evidence that Sirt1 plays a protective role in DOX-induced cardiotoxicity by mediating ferroptosis reduction via the Nrf2/Keap1 pathway.

Mannose-coated superparamagnetic iron oxide nanozyme for preventing postoperative cognitive dysfunction.

Postoperative cognitive dysfunction (POCD) is associated with increased postoperative morbidity and mortality in patients. Excessive production of reactive oxygen species (ROS) and the consequent inflammatory response in the postoperative brain play crucial roles in the development of POCD. However, effective ways to prevent POCD have yet to be developed. Moreover, effective penetration of the blood-brain barrier (BBB) and maintaining viability in vivo are major challenges for preventing POCD using traditional ROS scavengers. Herein, mannose-coated superparamagnetic iron oxide nanoparticles (mSPIONs) were synthesized by co-precipitation method. The BBB penetration of mSPIONs was verified through fluorescent imaging and ICP-MS quantification. The ROS scavenging and anti-inflammatory of mSPIONs were evaluated in H2O2-treated J774A.1 â€‹cells and in tibial fracture mice model. The novel object recognition (NOR) and trace-fear conditioning (TFC) were used to test the cognitive function of postoperative mice. The average diameter of mSPIONs was approximately 11 â€‹nm. mSPIONs significantly reduced ROS levels in H2O2-treated cells and in hippocampus of surgical mice. mSPIONs administration reduced the levels of IL-1ß and TNF-α in the hippocampus and inhibited surgery-upregulated HIF1-α/NF-κB signaling pathway. Moreover, mSPIONs significantly improved the cognitive function of postoperative mice. This study provides a new approach for preventing POCD using a nanozyme.

Long-lasting postoperative analgesia with local anesthetic-loaded hydrogels prevent tumor recurrence via enhancing CD8+T cell infiltration.

Postoperative pain (POP) can promote tumor recurrence and reduce the cancer patient's quality of life. However, POP management has always been separated from tumor treatment in clinical practice, and traditional postoperative analgesia using opioids is still unsatisfactory for patients, which is not conducive to tumor treatment. Here, ropivacaine, a popular amide-type LA, was introduced into a Pluronic F127 hydrogel. Postoperative analgesia with ropivacaine-loaded hydrogels reduced the incidence of high-dose ropivacaine-induced convulsions and prolonged pain relief for more than 16 h. More interestingly, ropivacaine-loaded hydrogel was found to upregulate major histocompatibility complex class I (MHC-I) in tumor cells by impairing autophagy. Therefore, a hydrogel co-dopped with ropivacaine and TLR7 agonist imiquimod (PFRM) was rationally synthesized. After postoperative analgesia with PFRM, imiquimod primes tumor-specific CD8+T cells through promoting DCs maturation, and ropivacaine facilitates tumor cells recognition by primed CD8+T cells through upregulating MHC-I. Consequently, postoperative analgesia with PFRM maximumly increases CD8+T cells infiltration into residual tumor tissue and prevents tumor recurrence. Overall, this study for the first time provides an LA-based approach for simultaneous long-lasting postoperative analgesia and prevention of tumor recurrence.