Active control of terahertz surface plasmonic wave excitation using electromagnetically induced transparency based graphene metasurfaces.

Surface plasmonic waves (SPWs) that propagate at meta-dielectric interface are a good source of information carrier waves for on-chip photonic devices, where SPW excitation is one key procedure. Recently, controlling SPW excitation using metasurface methods has drawn considerable attention owing to their design flexibility, wherein achieving dynamic control is of great importance. However, most studies in the terahertz regime so far are working in a passive way or only dynamically controllable at the propagation process. In this work, an active design for controlling terahertz SPWs at the excitation process is proposed using graphene metasurfaces based on the manipulation of the electromagnetically induced transparency (EIT) effect. Large modulation depth with controllable SPW excitations is demonstrated. Our method is flexible and promising in achieving more controlling degree of freedom, which can find broadband applications in future integrated devices and systems.

The Efficiency of Multipoint Rectus Sheath Block Based on Incision Location in Laparoscopic-Assisted Colorectal Surgery: A Randomized Clinical Trial.

BACKGROUND: Laparoscopic-assisted colorectal surgery is an effective surgery to treat colorectal cancer. During the laparoscopic-assisted colorectal surgery, a midline incision and several trocar insertions are required during the surgery. OBJECTIVE: To observe whether the rectus sheath block based on the locations of the surgical incision and trocars can significantly reduce the pain score on the first day after surgery. DESIGN: This study was a prospective, double-blinded, randomized controlled trial approved by the Ethics Committee of First Affiliated Hospital of Anhui Medical University (registration number: ChiCTR2100044684). SETTINGS: All patients were recruited from 1 hospital. PATIENTS: Forty-six patients aged 18 to 75 years undergoing elective laparoscopic-assisted colorectal surgery were successfully recruited, and 44 patients completed the trial. INTERVENTIONS: Patients in the experimental group received rectus sheath block, with 0.4% ropivacaine 40 to 50 mL, whereas the control group received an equal volume of normal saline. MAIN OUTCOME MEASURES: The primary outcome was pain score on postoperative day 1. Secondary outcomes included patient-controlled analgesia use at 24 and 48 hours after surgery and pain score at 6, 12, and 48 hours after surgery. RESULTS: Pain scores at rest and during activity at 6, 12, 24, and 48 hours after surgery and patient-controlled analgesia consumption of patients on the first day after surgery were significantly lower in the experimental group than those in the control group (all p < 0.05). LIMITATIONS: We did not separate pain into visceral and somatic pain because patients often had difficulty differentiating the source of pain. CONCLUSIONS: Our research indicates that in the context of multimodal analgesia, the rectus sheath block according to the midline incision and the positions of the trocars can reduce the pain scores and consumption of analgesic drugs on the first day after surgery for patients undergoing laparoscopic-assisted colorectal surgery. LA EFICIENCIA DEL BLOQUEO DE LA VAINA DEL RECTO DE VARIOS PUNTOS SEGN LA UBICACIN DE LA INCISIN EN LA CIRUGA COLORRECTAL ASISTIDA POR LAPAROSCOPIA UN ENSAYO CLNICO ALEATORIZADO: ANTECEDENTES:La cirugía colorrectal asistida por laparoscopia es una cirugía eficaz para tratar el cáncer colorrectal. Durante la cirugía colorrectal asistida por laparoscopia, se requiere una incisión en la línea media y varias inserciones de trócaresOBJETIVO:El propósito de nuestro estudio fue observar si el bloqueo de la vaina del recto basado en las ubicaciones de la incisión quirúrgica y los trocares puede reducir significativamente la puntuación del dolor en el primer día después de la cirugía.DISEÑO:Este estudio fue un ensayo controlado aleatorio prospectivo, doble ciego, aprobado por el Comité de Ética del Primer Hospital Afiliado de la Universidad Médica de Anhui (número de registro: ChiCTR2100044684).ESCENARIO:Todos los pacientes fueron reclutados en un hospital.PACIENTES:Cuarenta y seis pacientes de 18 a 75 años de edad que se sometieron a cirugía colorrectal electiva asistida por laparoscopía fueron reclutados con éxito y cuarenta y cuatro pacientes completaron el ensayo.INTERVENCIONES:Los pacientes del grupo experimental recibieron bloqueo de la vaina del recto con 40-50 ml de ropivacaína al 0.4%, mientras que el grupo de control recibió el mismo volumen de solución salina normal.PRINCIPALES MEDIDAS DE RESULTADO:El resultado primario fue la puntuación del dolor en el día 1 postoperatorio. Los resultados secundarios incluyeron el uso de analgesia controlada por el paciente a las 24 y 48 horas después de la cirugía y la puntuación del dolor a las 6, 12, y 48 horas después de la cirugía.RESULTADOS:Las puntuaciones de dolor en reposo y durante la actividad a las 6, 12, 24, y 48 horas después de la cirugía, y el consumo de PCA de los pacientes el primer día después de la cirugía fueron significativamente más bajos en el grupo experimental que en el grupo control (todos p < 0.05).LIMITACIONES:No separamos el dolor en dolor visceral y somático porque los pacientes a menudo tenían dificultades para diferenciar la fuente del dolor.CONCLUSIONES:Nuestra investigación indica que, en el contexto de la analgesia multimodal, el bloqueo de la vaina del recto de acuerdo con la incisión de la línea media y las posiciones de los trócares pueden reducir los puntajes de dolor y el consumo de analgésicos en el primer día después de la cirugía para pacientes sometidos a cirugía colorrectal laparoscópica. (Traducción-Dr. Jorge Silva Velazco ).

Opioid-sparing effect of modified intercostal nerve block during single-port thoracoscopic lobectomy: Retraction: A randomised controlled trial.

BACKGROUND: Peripheral local anaesthetic blockade has an important role in multimodal postoperative analgesia after video-assisted thoracic surgery. Intercostal nerve block has an opioid-sparing effect after thoracoscopic surgery, but there is little information about an intra-operative opioid-sparing effect. OBJECTIVE: This prospective randomised trial was designed to evaluate the feasibility of a modified intercostal nerve block and its potential opioid-sparing effect during single-port thoracoscopic lobectomy. DESIGN: This was a randomised controlled study. SETTING: The First Affiliated Hospital of Anhui Medical University, Hefei, China, from January 2020 to April 2020. PATIENTS: Fifty patients scheduled for single-port thoracoscopic lobectomy were enrolled. INTERVENTION: Patients were randomised to receive the intercostal nerve block using 10 ml 0.35% ropivacaine (group MINB) or conventional general anaesthesia (group CGA). Following a bolus of 0.5 to 1.0 µg kg-1 remifentanil, it was then infused at 0.2 to 0.5 µg kg-1 min-1 during surgery to keep mean arterial pressure or heart rate values around 20% below baseline values. MAIN OUTCOME MEASURES: The primary outcome was intra-operative remifentanil consumption. RESULTS: Median [IQR] remifentanil consumption was reduced in the MINB group [0 µg (0 to 0 µg)] compared with the CGA group [1650.0 µg (870.0 to 1892.5 µg)]. The median difference was 1650.0 µg (95%CI 1200.0 to 1770.0 µg; P = 0.00). The total number of analgesic demands during the first 24 and 48 h in the MINB group was significantly less than in the CGA group (difference = 1; 95% CI 1 to 3; P = 0.00 and difference = 4; 95% CI 3 to 5; P = 0.00; respectively). The difference in time to first demand for analgesia was significant [difference = 728 min (95% CI 344 to 1381 min), P = 0.00] and also in the number of patients requiring additional tramadol (P = 0.03). CONCLUSION: We have shown intra-operative opioid-sparing with a modified intercostal nerve block during single-port thoracoscopic lobectomy, with opioid-sparing extending 48 h after surgery. However, the opioid-sparing effect was not associated with a reduction in opioid side effects. TRIAL REGISTRATION: http://www.chictr.org.cn, ChiCTR2000029337.

Comparison of Sevoflurane and Propofol on the Incidence of Postoperative Pain and Quality of Life in Patients Undergoing Total Knee Arthroplasty With Chronic Pain Before Surgery.

BACKGROUND: Propofol and sevoflurane as frequently used general anesthetics can affect postoperative pain. Our study explored whether the incidence of postoperative pain differed among patients with chronic pain undergoing total knee arthroplasty (TKA) anesthetized with sevoflurane or propofol. METHODS: Patients were randomly assigned to groups receiving either sevoflurane (Group S, n = 50) or propofol (Group P, n = 47) for anesthesia maintenance during TKA. The incidences of postoperative pain and quality of life (QoL) were measured using the EuroQol 5-Dimension (EQ-5D) scale at 1, 3, and 7 days post-operation (DPO), and 1 and 3 months post-operation (MPO). RESULTS: At 3 DPO, fewer patients reported moderate pain (P = 0.001) and more patients reported no pain (P = 0.003) in Group S than that in Group P. At 3 MPO, more patients reported no pain (P = 0.04) and fewer patients reported moderate pain (P = 0.04) in Group S than in Group P. No significant differences were found in the incidence of postoperative pain between the 2 groups of patients at the other time points. The EQ-5D scores were higher in Group S than in Group P (P = 0.022), and the difference was 0.15 at most, which was not optimal. The EQ-5D clinical results might be not very significant. CONCLUSIONS: Sevoflurane anesthesia may have potential advantages in reducing postoperative pain in patients undergoing TKA with a preoperative VAS score > 4.

Effects of stage I hypertension on the recovery of early postoperative attention network function in elderly patients undergoing elective hip or knee arthroplasty surgery

Background/aim: Hypertension is an important risk factor for cognitive impairment. This study explored whether elderly patients with stage I hypertension (HPs) and normotensive patients (NPs) showed differences in the recovery of postoperative attention network function according to the attentional network test (ANT) performance. Materials and methods: Of 110 patients screened, 25 HPs and 25 NPs completed this study. The Mini-Mental State Examination (MMSE) was applied to all participants before the operation and the ANT (on days 2 and 7) after the operation. All participants completed 1 day preoperatively and the ANT on postoperative days (PODs) 2 and 7. Results: Compared with NPs, HPs had significantly lower alerting network effect scores and more difficulty resolving conflict on POD 7. However, no significant difference was observed between the groups on POD 2. Orienting network performance was similar between the groups at all time points. Significant differences in alerting and executive control network performances were observed between PODs 2 and 7 in each group. Conclusion: HPs showed selective cognitive impairment at different time points following elective hip or knee arthroplasty. Compared with NPs, during the first postoperative week, HPs were more likely to experience delayed recovery of alerting and executive control network function, but not orienting network function.

Midazolam Enhances Mutant Huntingtin Protein Accumulation via Impairment of Autophagic Degradation In Vitro.

BACKGROUND/AIMS: Autophagy is a well-known pathway to "clean" the misfolded mutant huntingtin protein (mHtt), which plays a considerable role in polyglutamine diseases. To date, there have been few studies of the choice of anesthetic during surgery in patients with polyglutamine diseases and evaluation of the effects and underlying mechanisms of anesthetics in these patients. METHODS: GFP-Htt (Q74)-PC12 cells, which stably express green fluorescent protein-tagged Htt protein containing 74 glutamine repeating units, were used throughout this study. Cells were treated with 15 µM midazolam and 100 mM trehalose (positive control), and the induction of autophagy and autophagic degradation were assessed by detecting changes in autophagy-related proteins and substrates, and cell viability was assessed using the MTT assay. Overexpression of cathepsin D by plasmid transfection was used to restore midazolam-impaired autophagic degradation. RESULTS: Midazolam increased intracellular mHtt levels in a time- and dose-dependent manner. Additionally, enhancing or blocking autophagic flux by trehalose or chloroquine could decrease or increase midazolam-induced mHtt elevation, respectively. Midazolam induced autophagy in the mTOR-dependent signaling pathway, but autophagic degradation was impaired, with a continuous rise in p62 and LC3 II levels and decrease in cathepsin D. However, overexpression of cathepsin D reversed the effects of midazolam. Midazolam led to a 20% decrease in GFP-Htt (Q74)-PC12 cell viability, which could be abrogated by overexpression of cathepsin D. CONCLUSIONS: Midazolam increased mHtt levels and decreased Htt (Q74)-PC12 cell viability via impairment of autophagic degradation, which could be restored by overexpression of cathepsin D.

Sevoflurane Acts on Ubiquitination-Proteasome Pathway to Reduce Postsynaptic Density 95 Protein Levels in Young Mice.

BACKGROUND: Children with multiple exposures to anesthesia and surgery may have an increased risk of developing cognitive impairment. Sevoflurane, a commonly used anesthetic in children, has been reported to decrease levels of postsynaptic density 95 protein. However, the upstream mechanisms and downstream consequences of the sevoflurane-induced reduction in postsynaptic density 95 protein levels remains largely unknown. We therefore set out to assess whether sevoflurane acts on ubiquitination-proteasome pathway to facilitate postsynaptic density 95 protein degradation. METHODS: Six-day-old wild-type mice received anesthesia with 3% sevoflurane 2 h daily for 3 days starting on postnatal day 6. We determined the effects of the sevoflurane anesthesia on mRNA, protein and ubiquitinated levels of postsynaptic density 95 protein in neurons, and synaptosomes and hippocampus of young mice. Cognitive function in the mice was determined at postnatal day 31 by using a Morris water maze. Proteasome inhibitor MG132 and E3 ligase mouse double mutant 2 homolog inhibitor Nutlin-3 were used for the interaction studies. RESULTS: The sevoflurane anesthesia decreased protein, but not mRNA, levels of postsynaptic density 95, and reduced ubiquitinated postsynaptic density 95 protein levels in neurons, synaptosomes, and hippocampus of young mice. Both MG132 and Nutlin-3 blocked these sevoflurane-induced effects. Sevoflurane promoted the interaction of mouse double mutant 2 homolog and postsynaptic density 95 protein in neurons. Finally, MG132 and Nutlin-3 ameliorated the sevoflurane-induced cognitive impairment in the mice. CONCLUSIONS: These data suggest that sevoflurane acts on the ubiquitination-proteasome pathway to facilitate postsynaptic density 95 protein degradation, which then decreases postsynaptic density 95 protein levels, leading to cognitive impairment in young mice. These studies would further promote the mechanistic investigation of anesthesia neurotoxicity in the developing brain.

Opioid receptor A118G polymorphism does not affect the consumption of sufentanil and ropivacaine by patient-controlled epidural analgesia after cesarean section.

BACKGROUND: Previous reports have suggested that polymorphism of the opioid receptor A118G affects the efficacy of opioid analgesia. The aim of this study was to investigate whether such polymorphism contributed to variability in epidural mixture (sufentanil plus ropivacaine) requirements through patient-controlled epidural analgesia (PCEA) after cesarean section. METHODS: One hundred eighty consenting women undergoing elective cesarean delivery were enrolled in the study. Patients received sufentanil and ropivacaine for pain control after surgery. Sufentanil (50 mcg) diluted with 0.2% ropivacaine in a total volume of 100 mL was administered by PCEA with a background infusion rate of 2 mL/h and a pump program set to deliver 0.5-mL boluses with a lockout time of 15 minutes. The analgesic effect and adverse effects were measured with rating scales. The total consumption of the epidural mixture in the first 24 hours postoperatively was recorded. Blood samples were genotyped to classify patients into 3 groups according to A118G polymorphism. RESULTS: Of 161 patients included in the analysis, 63 were homozygous (AA), 81 were heterozygous (AG), and 17 were homozygous (GG) for the A118G polymorphism. No difference was observed among groups in the consumption of the epidural mixture within the first 24 hours postoperatively (P = 0.3). Satisfaction with analgesia, pain scores, and adverse effects were similar among the groups. CONCLUSIONS: The analgesic requirements of patients receiving sufentanil and ropivacaine through PCEA after caesarean section were not associated with A118G polymorphism.

Involvement of GSK3ß/ß-catenin signaling in the impairment effect of ketamine on spatial memory consolidation in rats.

The cellular mechanisms underlying amnesia produced by the analgesic ketamine are not clear. The current study examined the effects of ketamine on memory consolidation in rats trained in a Morris water maze task, and further tested whether the glycogen synthase kinase (GSK)3ß/ß-catenin signaling pathway was involved in mediating the effects of posttraining ketamine on retention. Adult male Sprague-Dawley rats were injected with ketamine (0, 25, 50, or 100mg/kg) immediately after an eight-trial water maze training session. A probe trial was carried out 24 h later to examine the effects of ketamine on memory. Rats hippocampi were subjected to western blot assays to measure levels of native versus phosphorylated (p) GSK3ß and ß-catenin protein. Memory performance was significantly impaired in rats injected with ketamine (100 mg/kg) after training. Western blots showed that p-GSK-3ß(Ser9) levels were reduced and p-ß-catenin(Ser33/37/Thr41) levels were elevated in ketamine treated rats during consolidation. These posttraining changes in hippocampal p-GSK-3ß and p-ß-catenin were blocked by injection of 100mg/kg ketamine immediately after training, indicating that the 100mg/kg dose of ketamine altered activation of GSK3ß/ß-catenin signaling pathway in the hippocampus. Acute injection of the GSK3ß specific inhibitor SB216763 (1 ng/0.5 µl/side) into area CA1 of the hippocampus after water maze training prevented ketamine-induced impairment of memory and blocked ketamine-induced effects on the GSK3ß/ß-catenin signaling pathway in the hippocampus. Our results suggest that an anesthetic dose of ketamine injected immediately after Morris water maze training impaired memory consolidation and support the hypothesis that GSK3ß/ß-catenin signaling may play a role in ketamine-induced retrograde amnesia.

Anesthesia/surgery activate MMP9 leading to blood-brain barrier disruption, triggering neuroinflammation and POD-like behavior in aged mice.

Anesthesia and surgery activate matrix metalloproteinase 9 (MMP9), leading to blood-brain barrier (BBB) disruption and postoperative delirium (POD)-like behavior, especially in the elderly. Aged mice received intraperitoneal injections of either the MMP9 inhibitor SB-3CT, melatonin, or solvent, and underwent laparotomy under 3 % sevoflurane anesthesia(anesthesia/surgery). Behavioral tests were performed 24 h pre- and post-operatively. Serum and cortical tissue levels of interleukin (IL)-1ß, IL-6, and tumor necrosis factor-α (TNF-α) were measured using ELISA. Levels of PDGFRß, MMP9, tight junction, Mfsd2a, caveolin-1, synaptophysin, and postsynaptic densin (PSD)-95 proteins in the prefrontal cortex were assayed using Western blotting. BBB permeability was assessed by detecting IgG in the prefrontal cortex and serum S100ß levels. Anesthesia/surgery-induced peripheral inflammation activated MMP9, which in turn injured pericytes and tight junctions and increased transcytosis, thereby disrupting the BBB. Impaired BBB allowed the migration of peripheral inflammation into the central nervous system (CNS), thereby inducing neuroinflammation, synaptic dysfunction, and POD-like behaviors. However, MMP9 inhibition reduced pericyte and tight junction injury and transcytosis, thereby preserving BBB function and preventing the migration of peripheral inflammation into the CNS, thus attenuating synaptic dysfunction and POD-like behavior. In addition, to further validate the above findings, we showed that melatonin exerted similar effects through inhibition of MMP9. The present study shows that after anesthesia/surgery, inflammatory cytokines upregulation is involved in regulating BBB permeability in aged mice through activation of MMP9, suggesting that MMP9 may be a potential target for the prevention of POD.

Discovery of Biphenyl Derivatives to Target Hsp70-Bim Protein-Protein Interaction in Chronic Myeloid Leukemia by Scaffold Hopping Strategy.

Hsp70-Bim protein-protein interaction (PPI) is the most recently identified specific target in chronic myeloid leukemia (CML) therapy. Herein, we developed a new class of Hsp70-Bim PPI inhibitors via scaffold hopping of S1g-10, the most potent Hsp70-Bim PPI inhibitor thus far. Through structure-activity relationship (SAR) study, we obtained a biphenyl scaffold compound JL-15 with a 5.6-fold improvement in Hsp70-Bim PPI suppression (Kd = 123 vs 688 nM) and a 4-fold improvement in water solubility (29.42 vs 7.19 µg/mL) compared to S1g-10. It maintains comparable apoptosis induction capability with S1g-10 against both TKI-sensitive and TKI-resistant CML cell lines in an Hsp70-Bim-dependent manner. Additionally, through SAR, 1H-15N TRSOY-NMR, and molecular docking, we revealed that Lys319 is a "hot spot" in the Hsp70-Bim PPI interface. Collectively, these results provide a novel chemical scaffold and structural insights for the rational design of Hsp70-Bim PPI inhibitors.

A Novel Opioid-Sparing Analgesia Following Thoracoscopic Surgery: A Non-Inferiority Trial.

Purpose: This randomized, non-inferiority study aimed to observe the feasibility of opioid-sparing analgesia based on modified intercostal nerve block (MINB) following thoracoscopic surgery. Patients and Methods: 60 patients scheduled for single-port thoracoscopic lobectomy were randomized to the intervention group or control group. After MINB was performed in both groups at the end of the surgery, the intervention group received patient controlled-intravenous analgesia (PCIA) of dexmedetomidine 0.05 µg/kg/h for 72 h after surgery, and the control group received conventional PCIA of sufentanil 3 µg/kg for 72 h. The primary outcome was a visual analog scale (VAS) on coughing 24 h after surgery. Secondary outcomes included the time to first analgesic request, pressing times of PCIA, time to first flatus, and hospital stay. Results: There was no difference in the cough-VAS at 24 h (median [interquartile range]) between the intervention group [3 (2-4)] and control group [3 (2-4), P = 0.36]. The median difference (95% CI) in the cough-VAS at 24 h was [0 (0 to 1), P = 0.36]. There was no significant difference in the time to first analgesic request, pressing times of PCIA, and hospital stay between groups (P > 0.05). A significant decrease in time to first flatus was observed in the intervention group (P < 0.01). Conclusion: Opioid-sparing analgesia provided safe and analogous postoperative analgesia with a shortened time to first flatus, compared with sufentanil-based analgesia in thoracoscopic surgery. This might be a novel method recommended for thoracoscopic surgery.

Opioid-Sparing Effect of Multi-Point Incision-Based Rectus Sheath Block in Laparoscopic-Assisted Radical Gastrectomy: A Randomized Clinical Trial.

BACKGROUND: Profound trauma from laparoscopic-assisted gastrectomy (LAG) requires medication with a large number of opioids. The purpose of our study was to observe whether an incision-based rectus sheath block (IBRSB) based on the locations of the surgical incision could significantly reduce the consumption of remifentanil during LAG. METHODS: A total of 76 patients were included. The patients were prospectively randomized into two groups. Patients in group IBRSB (n = 38) received ultrasound-guided IBRSB, and the patients received 0.4% ropivacaine 40-50 mL. Patients in group C (n = 38) received the same IBRSB with 40-50 mL normal saline. The following were recorded: the consumption of remifentanil and sufentanil during surgery, pain scores at rest and during conscious activity in the post-anesthesia care unit (PACU) and at 6, 12, 24, and 48 h after surgery, and use of the patient-controlled analgesia (PCA) at 24 and 48 h after surgery. RESULTS: A total of 60 participants completed the trial. The consumption of remifentanil and sufentanil in group IBRSB were significantly lower than that in group C (p < 0.001). Pain scores at rest and during conscious activity in the PACU and at 6, 12, 24, and 48 h after surgery and patients' PCA consumption within 48 h of surgery were significantly lower in group IBRSB than in group C (all p < 0.05). CONCLUSIONS: IBRSB based on incision multimodal anesthesia can effectively reduce the consumption of opioids during LAG, improving the postoperative analgesic effect and increasing patients' satisfaction.

Analgesic Effects of Different Local Infiltration Anesthesia Techniques Combined with Femoral Nerve Block in Patients Undergoing Total Knee Arthroplasty: A Randomized Controlled Clinical Trial.

Objective: Pain after total knee arthroplasty (TKA) remains an unresolved problem. Femoral nerve block (FNB) could relieve pain; however, it alone is insufficient. The local infiltration anesthesia technique (LIA) has been suggested as a supplement to FNB. This study aimed to evaluate the analgesic effects of different LIA combined with FNB in TKA patients. Methods: The femoral nerve was blocked with 0.375% ropivacaine 20mL, and all patients routinely received general anesthesia. The primary indicator was the proportion of patients who did not receive post-operative remedial analgesia. Seventy-eight patients were randomly assigned to PAI (periarticular injection combined with FNB), IAI (intra-articular injection combined with FNB), or control (FNB alone) groups. All patients underwent FNB under general anesthesia. The primary outcome was the proportion of patients who did not receive additional postoperative analgesia within the first 48 h after surgery. Results: Compared with the PAI and control groups, the IAI group had a higher proportion (69.23%) of patients who did not receive remedial analgesia within 48 hours after surgery (P = 0.009; P = 0.009), a lower consumption of diclofenac sodium lidocaine (P = 0.021; P < 0.001), and an earlier time of walking with a walker (P < 0.001; P < 0.001). The time of first need for remedial analgesia postoperatively in IAI group was longer than the PAI group (P = 0.008) and IAI group has a shorter hospital stay than the control group (P = 0.008). The maximum NRS during the first 48 hours postoperatively and NRS 24 hours after surgery in the IAI group were lower than those in the control and PAI groups. The incidences of POD and PONV were similar among the three groups (P = 0.610; P = 0.264). Conclusion: When combined with FNB, intra-articular injection offers a superior analgesic effect and favorable recovery compared to periarticular injection and separate application of FNB.

The Effect of Dezocine on the Median Effective Dose of Sufentanil-Induced Respiratory Depression in Patients Undergoing Spinal Anesthesia Combined with Low-Dose Dexmedetomidine.

Purpose: The application of sedation and analgesia in spinal anesthesia has many benefits, but the risk of respiratory depression (RD) caused by opioids cannot be ignored. We aimed to observe the effect of dezocine, a partial agonist of µ-receptor, on the median effective dose (ED50) of sufentanil-induced RD in patients undergoing spinal anesthesia combined with low-dose dexmedetomidine. Patients and Methods: Sixty-two patients were randomly assigned to dezocine group (DS) and control group (MS). After spinal anesthesia, mask oxygen (5 L/min) and dexmedetomidine (0.1 ug/kg) were given. Five minutes later, patients in the DS group received an Intravenous (IV) bolus of sufentanil and 0.05mg/kg dezocine, while patients in the MS group only received an IV bolus of sufentanil. Results: ED50 of DS group was 0.342 ug/kg, 95% confidence interval (CI) was (0.269, 0.623) ug/kg, and the ED50 of MS group was 0.291 ug/kg, 95% CI was (0.257, 0.346) ug/kg. There was no difference in the type and treatment measures of RD and hemodynamic changes between the two groups, and no serious adverse reactions occurred in either group. Conclusion: Dezocine can improve RD induced by sufentanil in patients with spinal anesthesia combined with low-dose dexmedetomidine, and increase the safety window of sufentanil use.

Exploiting the "Hot-Spots" of Hsp70-Bim Protein-Protein Interaction to Optimize the 1-Oxo-1H-phenalene-2,3-dicarbonitrile Analogues as Specific Hsp70-Bim Inhibitors.

Selectively targeting the cancer-specific protein-protein interaction (PPI) between Hsp70 and Bim has been discovered as a promising strategy for treating chronic myeloid leukemia (CML). The first Hsp70-Bim PPI inhibitor, S1g-2, has been identified to overcome the on-target toxicity of known Hsp70 inhibitors when it induces apoptosis of CML cells. Herein, we carried out a hit-to-lead optimization of S1g-2, yielding S1g-10, which exhibited a 10-fold increase in Hsp70/Bim suppressing potency. Furthermore, S1g-10 not only exhibited a 5- to 10-fold stronger antitumor activity in the sub-µM range against CML cells than S1g-2 in vitro, but it also overcame BCR-ABL-independent tyrosine kinase inhibitor resistance in CML in vivo depending on the Hsp70-Bim signaling pathway. Moreover, through structure-activity relationship analysis, TROSY-HSQC NMR, molecular dynamics simulation, and point mutation validation, two hydrophobic pockets composed of eight key residues were demonstrated to produce predominant interactions with either Bim or S1g-10, regarded as the "hot-spots" in the Hsp70-Bim PPI interface.

Propofol Versus Sevoflurane General Anaesthesia for Selective Impairment of Attention Networks After Gynaecological Surgery in Middle-Aged Women: A Randomised Controlled Trial.

Purpose: Attention is an essential component of cognitive function that may be impaired after surgery with anaesthesia. Propofol intravenous anaesthesia and sevoflurane inhalational anaesthesia are frequently used in gynaecological surgery. However, which type of anaesthetic has fewer cognitive effects postoperatively remains unclear. We compared the differences in attention network impairment after surgery in women receiving propofol versus sevoflurane general anaesthesia. Patients and Methods: Eighty-three patients with gynaecological diseases who were 40-60 years of age were involved in the study. All patients underwent elective gynaecological surgery under either total intravenous anaesthesia or sevoflurane inhalational anaesthesia, depending on randomisation. The efficiencies of the three attention networks were captured using the attention network test preoperatively and on the 1st and 5th postoperative days. Results: Both groups of patients showed differences in impairments on the 1st and 5th postoperative days. Pairwise comparisons indicated that the alerting and orienting networks of patients in the propofol group were impaired to a greater extent than those of patients in the sevoflurane group on the 1st postoperative day, while the executive control network was impaired to a lesser extent. On the 5th postoperative day, the alerting networks of both groups recovered to the baseline level. Patients in the propofol group still showed impairment of the orienting network, while patients in the sevoflurane group recovered to baseline. For the executive control network, patients in the sevoflurane group still exhibited more severe impairment than those in the propofol group. Conclusion: In middle-aged women, propofol impaired orienting and alerting networks more than sevoflurane, while sevoflurane showed more residual impairment of the executive control network.

God is in the rain: The impact of rainfall-induced early social distancing on COVID-19 outbreaks.

We measure the benefit to society created by preventing COVID-19 deaths through a marginal increase in early social distancing. We exploit county-level rainfall on the last weekend before statewide lockdown in the early phase of the pandemic. After controlling for historical rainfall, temperature, and state fixed-effects, current rainfall is a plausibly exogenous instrument for social distancing. A one percent decrease in the population leaving home on the weekend before lockdown creates an average of 132 dollars of benefit per county resident within 2 weeks. The impacts of earlier distancing compound over time and mainly arise from lowering the risk of a major outbreak, yielding large but unevenly distributed social benefit.

Dexmedetomidine Combined with Femoral Nerve Block Provides Effective Analgesia Similar to Femoral Nerve Combined with Sciatic Nerve Block in Patients Undergoing Total Knee Arthroplasty: A Randomized Controlled Study.

BACKGROUND: Total knee arthroplasty (TKA) is a severe traumatic procedure, and femoral nerve block (FNB) combined with a sciatic nerve block (SNB) is widely used in TKA. However, injury of the sciatic nerve is clinically reported. Dexmedetomidine (DEX) could reduce stress and inflammation, as well as improve pain in TKA. This study aims to observe the analgesic impact of DEX combined with FNB in TKA. METHODS: Eighty-eight patients undergoing TKA were included and randomly divided into two groups: DF group (FNB combined with DEX 0.6µg/kg before surgery, followed by DEX 0.2-0.4µg/kg/h until articular closure) and SF group (FNB combined with SNB). Each nerve was blocked with 0.375% ropivacaine 20mL, and all patients received general anesthesia routinely. The primary endpoint was the pain visual analog scale (VAS) score during activities at postoperative 24 hours. RESULTS: There was no statistical difference in the pain VAS scores at any time point. The mean duration of analgesia for patients with rescue analgesic requests was comparable between the two groups: 25.4 ± 6.3 hours in the DF group vs 24.8 ± 6.4 hours in the SF group (two-sample t-test, p=0.738). The total dose of sufentanil was similar between groups (P=0.355). The maintenance dose of propofol and dose of rescue analgesics were comparable (all P>0.05). There were no statistical differences in the incidence of adverse events. However, the time to extubate in the DF group was significantly longer than those in the SF group (P<0.001). CONCLUSION: DEX combined with FNB could provide effective analgesia similar to SNB combined with FNB in TKA. CLINICAL TRIAL REGISTRATION: The trial was registered at the Chinese Clinical Trial Registry on November 17, 2019 (identifier: ChiCTR1900027552).

Caloric Restriction Alleviates CFA-Induced Inflammatory Pain via Elevating ß-Hydroxybutyric Acid Expression and Restoring Autophagic Flux in the Spinal Cord.

Inflammatory pain is the most common type of pain encountered in clinical practice; however, the currently available treatments are limited by insufficient efficacy and side effects. Therefore, new methods to relieve inflammatory pain targeting new mechanisms are urgently needed. Preclinical investigations have shown that CR (calorie restriction) exerts analgesic effects in neuropathic and cancer pain; however, the effect of CR on chronic inflammatory pain remains unknown. During calorie restriction, autophagy, a lysosome-dependent degradation process, can be activated to support cell survival. In the present study, we investigated the analgesic effects of CR on complete Freund's adjuvant (CFA)-induced inflammatory pain. The accumulation of LC3-II and p62 showed impaired autophagic flux in the ipsilateral spinal cord of mice with CFA-induced inflammatory pain. CR alleviated mechanical allodynia and thermal hyperalgesia and reduced paw edema and pro-inflammatory factors following CFA administration. CR exerted an analgesic effect by restoring autophagic flux in the spinal cord. Regarding the mechanisms underlying the analgesic effects of CR, ß-hydroxybutyric acid (BHB) was studied. CR increased BHB levels in the ipsilateral spinal cord. Furthermore, exogenous BHB administration exerted an analgesic effect by restoring autophagic flux in the spinal cords of CFA-induced inflammatory pain mice. Taken together, these results illustrated that CR relieved inflammatory pain by restoring autophagic flux in the spinal cord, while BHB controlled the benefits of CR, suggesting that CR or BHB might be a promising treatment for inflammatory pain.