Structure of a Pancreatic ATP-Sensitive Potassium Channel.

ATP-sensitive potassium channels (KATP) couple intracellular ATP levels with membrane excitability. These channels play crucial roles in many essential physiological processes and have been implicated extensively in a spectrum of metabolic diseases and disorders. To gain insight into the mechanism of KATP, we elucidated the structure of a hetero-octameric pancreatic KATP channel in complex with a non-competitive inhibitor glibenclamide by single-particle cryoelectron microscopy to 5.6-Å resolution. The structure shows that four SUR1 regulatory subunits locate peripherally and dock onto the central Kir6.2 channel tetramer through the SUR1 TMD0-L0 fragment. Glibenclamide-bound SUR1 uses TMD0-L0 fragment to stabilize Kir6.2 channel in a closed conformation. In another structural population, a putative co-purified phosphatidylinositol 4,5-bisphosphate (PIP2) molecule uncouples Kir6.2 from glibenclamide-bound SUR1. These structural observations suggest a molecular mechanism for KATP regulation by anti-diabetic sulfonylurea drugs, intracellular adenosine nucleotide concentrations, and PIP2 lipid.

Substrate binding and inhibition mechanism of norepinephrine transporter.

Norepinephrine transporter (NET; encoded by SLC6A2) reuptakes the majority of the released noradrenaline back to the presynaptic terminals, thereby affecting the synaptic noradrenaline level1. Genetic mutations and dysregulation of NET are associated with a spectrum of neurological conditions in humans, making NET an important therapeutic target1. However, the structure and mechanism of NET remain unclear. Here we provide cryogenic electron microscopy structures of the human NET (hNET) in three functional states-the apo state, and in states bound to the substrate meta-iodobenzylguanidine (MIBG) or the orthosteric inhibitor radafaxine. These structures were captured in an inward-facing conformation, with a tightly sealed extracellular gate and an open intracellular gate. The substrate MIBG binds at the centre of hNET. Radafaxine also occupies the substrate-binding site and might block the structural transition of hNET for inhibition. These structures provide insights into the mechanism of substrate recognition and orthosteric inhibition of hNET.

Structural insights into the mechanism of human soluble guanylate cyclase.

Soluble guanylate cyclase (sGC) is the primary sensor of nitric oxide. It has a central role in nitric oxide signalling and has been implicated in many essential physiological processes and disease conditions. The binding of nitric oxide boosts the enzymatic activity of sGC. However, the mechanism by which nitric oxide activates the enzyme is unclear. Here we report the cryo-electron microscopy structures of the human sGCα1ß1 heterodimer in different functional states. These structures revealed that the transducer module bridges the nitric oxide sensor module and the catalytic module. Binding of nitric oxide to the ß1 haem-nitric oxide and oxygen binding (H-NOX) domain triggers the structural rearrangement of the sensor module and a conformational switch of the transducer module from bending to straightening. The resulting movement of the N termini of the catalytic domains drives structural changes within the catalytic module, which in turn boost the enzymatic activity of sGC.

Netrin-1 Role in Nociceptive Neuron Sprouting through Activation of DCC Signaling in a Rat Model of Bone Cancer Pain.

BACKGROUND: Bone cancer pain (BCP) is a common primary or metastatic bone cancer complication. Netrin-1 plays an essential role in neurite elongation and pain sensitization. This study aimed to determine the role of netrin-1 from the metastatic bone microenvironment in BCP development and identify the associated signaling pathway for the strategy of BCP management. METHODS: The rat BCP model was established by intratibial implantation of Walker 256 cells. Von Frey filaments measured the mechanical pain threshold. Movement-induced pain was assessed using limb use scores. Expressions of associated molecules in the affected tibias or dorsal root ganglia (DRG) were measured by immunofluorescence, immunohistochemistry, real-time quantitative polymerase chain reaction, or western blotting. Transduction of deleted in colorectal cancer (DCC) signaling was inhibited by intrathecal injection of DCC-siRNA. RESULTS: In BCP rats, the presence of calcitonin gene-related peptide (CGRP)-positive nerve fibers increased in the metastatic bone lesions. The metastatic site showed enrichment of well-differentiated osteoclasts and expressions of netrin-1 and its attractive receptor DCC. Upregulation of DCC and increased phosphorylation levels of focal adhesion kinase (FAK) and Rac family small GTPase 1/Cell division cycle 42 (Rac1/Cdc42) were found in the DRG. Intrathecal administration of DCC-siRNA led to a significant reduction in FAK and Rac1/Cdc42 phosphorylation levels in the DRG, decreased nociceptive nerve innervation, and improved pain behaviors. CONCLUSIONS: Netrin-1 may contribute to the activation of the BCP by inducing nociceptive nerve innervation and improving pain behaviors.

Aggressive intraoperative warming versus routine thermal management during non-cardiac surgery (PROTECT): a multicentre, parallel group, superiority trial.

BACKGROUND: Moderate intraoperative hypothermia promotes myocardial injury, surgical site infections, and blood loss. Whether aggressive warming to a truly normothermic temperature near 37°C improves outcomes remains unknown. We aimed to test the hypothesis that aggressive intraoperative warming reduces major perioperative complications. METHODS: In this multicentre, parallel group, superiority trial, patients at 12 sites in China and at the Cleveland Clinic in the USA were randomly assigned (1:1) to receive either aggressive warming to a target core temperature of 37°C (aggressively warmed group) or routine thermal management to a target of 35·5°C (routine thermal management group) during non-cardiac surgery. Randomisation was stratified by site, with computer-generated, randomly sized blocks. Eligible patients (aged ≥45 years) had at least one cardiovascular risk factor, were scheduled for inpatient non-cardiac surgery expected to last 2-6 h with general anaesthesia, and were expected to have at least half of the anterior skin surface available for warming. Patients requiring dialysis and those with a body-mass index exceeding 30 kg/m2 were excluded. The primary outcome was a composite of myocardial injury (troponin elevation, apparently of ischaemic origin), non-fatal cardiac arrest, and all-cause mortality within 30 days of surgery, as assessed in the modified intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT03111875. FINDINGS: Between March 27, 2017, and March 16, 2021, 5056 participants were enrolled, of whom 5013 were included in the intention-to-treat population (2507 in the aggressively warmed group and 2506 in the routine thermal management group). Patients assigned to aggressive warming had a mean final intraoperative core temperature of 37·1°C (SD 0·3) whereas the routine thermal management group averaged 35·6°C (SD 0·3). At least one of the primary outcome components (myocardial injury after non-cardiac surgery, cardiac arrest, or mortality) occurred in 246 (9·9%) of 2497 patients in the aggressively warmed group and in 239 (9·6%) of 2490 patients in the routine thermal management group. The common effect relative risk of aggressive versus routine thermal management was an estimated 1·04 (95% CI 0·87-1·24, p=0·69). There were 39 adverse events in patients assigned to aggressive warming (17 of which were serious) and 54 in those assigned to routine thermal management (30 of which were serious). One serious adverse event, in an aggressively warmed patient, was deemed to be possibly related to thermal management. INTERPRETATION: The incidence of a 30-day composite of major cardiovascular outcomes did not differ significantly in patients randomised to 35·5°C and to 37°C. At least over a 1·5°C range from very mild hypothermia to full normothermia, there was no evidence that any substantive outcome varied. Keeping core temperature at least 35·5°C in surgical patients appears sufficient. FUNDING: 3M and the Health and Medical Research Fund, Food and Health Bureau, Hong Kong. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Activation of the STING pathway induces peripheral sensitization via neuroinflammation in a rat model of bone cancer pain.

BACKGROUND: Neuroinflammation in the peripheral nervous system has been linked to cancer metastasis-induced bone pain. The stimulator of interferon genes (STING), an innate immune sensor for cytosolic DNA, plays an important role in inflammation and cancer metastasis and is reported to be a critical regulator of nociception. Here, we examined the role of STING in primary nociceptive neurons and chronic pain to determine if it could be a new target for treating bone cancer pain (BCP). METHODS: Walker 256 cancer cells were injected intratibially to induce bone cancer pain in rats. STING and its downstream inflammatory factors in dorsal root ganglia (DRG) were detected using western blotting and immunofluorescent staining. Transmission electron microscopy and the BCL2-associated X (Bax) expression were used to detect the mitochondrial stress in DRG neurons. C-176, a specific inhibitor of STING, was used to block STING activation and to test the pain behavior. RESULTS: Mechanical hyperalgesia and spontaneous pain were observed in BCP rats, accompanied by the upregulation of the STING expression in the ipsilateral L4-5 DRG neurons which showed significant mitochondrion stress. The STING/TANK-binding kinase 1 (TBK1)/nuclear factor-kappa B (NF-κB) pathway activation was observed in the DRGs of BCP rats as well as increased IL-1ß, IL-6, and TNF-α expression. C-176 alleviated bone cancer pain and reduced the STING and its downstream inflammatory pathway. CONCLUSION: We provide evidence that STING pathway activation leads to neuroinflammation and peripheral sensitization. Pharmacological blockade of STING may be a promising novel strategy for preventing BCP.

The Emerging Structural Pharmacology of ATP-Sensitive Potassium Channels.

ATP-sensitive potassium channels (KATP) are energy sensors that participate in a range of physiologic processes. These channels are also clinically validated drug targets. For decades, KATP inhibitors have been prescribed for diabetes and KATP activators have been used for the treatment of hypoglycemia, hypertension, and hair loss. In this Emerging Concepts article, we highlight our current knowledge about the drug binding modes observed using cryogenic electron microscopy techniques. The inhibitors and activators bind to two distinct sites in the transmembrane domain of the sulfonylurea receptor (SUR) subunit. We also discuss the possible mechanism of how these drugs allosterically modulate the dimerization of SUR nucleotide-binding domains (NBDs) and thus KATP channel activity. SIGNIFICANCE STATEMENT: ATP-sensitive potassium channels (KATP) are fundamental to energy homeostasis, and they participate in many vital physiological processes. KATP channels are important drug targets. Both KATP inhibitors (insulin secretagogues) and KATP activators are broadly used clinically for the treatment of related diseases. Recent cryogenic electron microscopy studies allow us to understand the emerging concept of KATP structural pharmacology.

Causes, Risk Factors and Outcomes of Patients Readmitted to the Intensive Care Unit After Esophageal Cancer Surgery: A Retrospective Cohort Study.

BACKGROUND: Readmission to intensive care unit (ICU) after esophageal cancer surgery is a major concern and can be associated with increased adverse outcomes. This study aims to explore causes, risk factors and early outcomes. METHODS: We performed a monocentric retrospective analysis in 1140 patients who received esophageal cancer surgery in a higher volume surgeon group between January 2016 and December 2019, at Shanghai Chest Hospital. Univariate and multivariate analysis were performed to identify risk factors, and 1:4 propensity score matching (PSM) analysis was conducted to compare early outcomes. RESULTS: The incidence of ICU readmission was about 3.8% (43 of 1140). The most common cause was respiratory failure, found in 30 patients (70%). ICU readmission mainly occurred within 3 days after surgery, accounting for 46.5% (20 of 43), with the median length of stay was 3 days. Multivariate analysis identified heavy smoking (odds ratio[OR] = 2.445, 95% CI = 1.128 to 5.301, P = 0.024), intraoperative hypoxemia (OR = 2.461, 95% CI = 1.078 to 5.621, P = 0.033), mechanical ventilation during initial ICU stay (OR = 16.036, 95% CI = 7.332 to 35.074, P < 0.001), postoperative anemia (OR = 3.993, 95% CI = 1.893 to 8.420, P < 0.001) and unplanned reoperation (OR = 45.378, 95% CI = 13.023 to 158.122, P < 0.001) as independent risk factors for ICU readmission. Compared with no-readmitted patients, patients readmitted to ICU were associated with increased postoperative pulmonary complications (44.2% vs 97.7%, P < 0.001), prolonged median length of hospital stay (9[7-11] vs 19[13-30], P < 0.001) and ICU stay (1[1-3] vs 7[4-11], P < 0.001), higher hospitalization expenses (14,916 ± 3483 vs 19,850 ± 7595 dollars, P < 0.001) and 30-day readmission rates (1.8% vs 9.3%, P = 0.011). After 1:4 PSM, the baseline characteristics were comparable and the matched results were similar. CONCLUSIONS: This study identified five independent risk factors for ICU readmission, which were associated with adverse early outcomes. Preemptive attention given to pulmonary complications within three days after surgery may be important to prevent patients from ICU readmission.

Target blood pressure management during cardiopulmonary bypass improves lactate levels after cardiac surgery: a randomized controlled trial.

BACKGROUND: Hyperlactatemia is associated with a poor prognosis in cardiac surgery patients. This study explored the impact of target blood pressure management during cardiopulmonary bypass (CPB) on blood lactate levels after cardiac surgery. METHODS: Adult patients undergoing cardiac valve surgery between 20/1/2020 and 30/6/2020 at Shanghai Chest Hospital were enrolled. The patients were randomized into a low mean arterial pressure (L-MAP) group (target MAP between 50 and 60 mmHg) or a high mean arterial pressure (H-MAP) group (target MAP between 70 and 80 mmHg), n = 20 for each. Norepinephrine was titrated only during CPB to maintain MAP at the target level. Blood lactate levels in the two groups were detected before the operation (T0), at the end of CPB (T1), at the end of the operation (T2), 1 h after the operation (T3), 6 h after the operation (T4) and 24 h after the operation (T5). The primary outcome was the blood lactate level at the end of the operation (T2). The secondary outcomes included the blood lactate level at T1, T3, T4, and T5 and the dose of epinephrine and dopamine within 24 h after the operation, time to extubation, length of stay in the ICU, incidence of readmission within 30 days, and mortality within 1 year. RESULTS: Forty patents were enrolled and analyzed in the study. The lactate level in the H-MAP group was significantly lower than that in the L-MAP group at the end of the operation (3.1 [IQR 2.1, 5.0] vs. 2.1 [IQR 1.7, 2.9], P = 0.008) and at the end of CPB and 1 hour after surgery. The dose of epinephrine within 24 h after the operation, time to extubation and length of stay in the ICU in the L-MAP group were significantly higher than those in the H-MAP group. CONCLUSIONS: Maintaining a relatively higher MAP during CPB deceased the blood lactate level at the end of surgery, reduced epinephrine consumption, and shortened the time to extubation and length of stay in the ICU after surgery. TRIAL REGISTRATION: This single-center, prospective, RCT has completed the registration of the Chinese Clinical Trial Center at 8/1/2020 with the registration number ChiCTR2000028941 . It was conducted from 20/1/2020 to 30/6/2020 as a single, blinded trial in Shanghai Chest Hospital.

Acute pain after serratus anterior plane or thoracic paravertebral blocks for video-assisted thoracoscopic surgery: A noninferiority randomised trial.

BACKGROUND: Serratus anterior plane blocks (SAPBs) and thoracic paravertebral blocks (TPVBs) can both be used for video-assisted thoracic surgery. However, it remains unknown whether the analgesic efficacy of a SAPB is comparable to that of a TPVB. OBJECTIVE: We tested the primary hypothesis that SAPBs provide noninferior analgesia compared with TPVBs for video-assisted thoracic surgery. DESIGN: A noninferiority randomised trial. SETTING: Shanghai Chest Hospital, between August 2018 and November 2018. PATIENTS: Ninety patients scheduled for video-assisted thoracic lobectomy or segmentectomy were randomised. Patients were excluded if they were unable to perform the visual analogue pain scale, or surgery was converted to thoracotomy. INTERVENTIONS: Blocks were performed after induction of general anaesthesia. The three groups were paravertebral blocks (n = 30); serratus anterior plane blocks (n = 29); and general anaesthesia alone (n = 30). PRIMARY OUTCOME MEASURES: Visual analogue pain scores (0 to 10 cm) at rest and while coughing, and Prince-Henry pain scores (0 to 4 points) were used to assess postoperative analgesia at 2, 24 and 48 h after surgery. We assessed the noninferiority of SAPBs with TPVBs on all three primary pain outcomes using a delta of 1 cm or one point as appropriate. RESULTS: The mean difference (95% confidence intervals) in visual analogue scores between the SAPBs and TPVBs was -0.04 (-0.10 to 0.03) cm at rest, -0.22 (-0.43 to -0.01) cm during coughing and -0.10 (-0.25 to 0.05) for Prince-Henry pain scores. As the upper limit of the confidence intervals were less than 1 (all P < 0.001), noninferiority was claimed for all three primary outcomes. Compared with general anaesthesia alone, the VAS scores at rest and while coughing, and the Prince-Henry pain scores for the two blocks were significantly lower during the initial 2 h after surgery. CONCLUSIONS: Serratus anterior plane blocks are quicker and easier to perform than paravertebral blocks and provide comparable analgesia in patients having video-assisted thoracic surgery. Both blocks provided analgesia that was superior to general anaesthesia alone during the initial 2 h after surgery. TRIAL REGISTRATION: Chinese Clinical Trial Registry, identifier: ChiCTR1800017671.

Structural Insights into the Inhibitory Mechanism of Insulin Secretagogues on the Pancreatic ATP-Sensitive Potassium Channel.

Sulfonylureas and glinides are commonly used oral insulin secretagogues (ISs) that act on the pancreatic ATP-sensitive potassium (KATP) channel to promote insulin secretion in order to lower the blood glucose level. Physiologically, KATP channels are inhibited by intracellular ATP and activated by Mg-ADP. Therefore, they sense the cellular energy status to regulate the permeability of potassium ions across the plasma membrane. The pancreatic KATP channel is composed of the pore-forming Kir6.2 subunits and the regulatory SUR1 subunits. Previous electrophysiological studies have established that ISs bind to the SUR1 subunit and inhibit the channel activity primarily by two mechanisms. First, ISs prevent Mg-ADP activation. Second, ISs inhibit the channel activity of Kir6.2 directly. Several cryo-EM structures of the pancreatic KATP channel determined recently have provided remarkable structural insights into these two mechanisms.

The Prevalence and Impact of Undiagnosed Mild Cognitive Impairment in Elderly Patients Undergoing Thoracic Surgery: A Prospective Cohort Study.

OBJECTIVES: The objective of this study was to explore the prevalence of undiagnosed mild cognitive impairment (MCI) and its association with adverse outcomes in elderly patients undergoing thoracic surgery. DESIGN: A prospective cohort study. SETTING: Large tertiary medical center. PARTICIPANTS: The authors enrolled 170 patients aged 65 years or older who were scheduled for thoracic surgery between November 7, 2018, and April 1, 2019, at the Shanghai Chest Hospital. Patients with a history of schizophrenia or dementia disease, uncorrected vision or hearing impairment, and refusal to participate were excluded. INTERVENTIONS: A total of 154 elderly patients completed the Chinese version of the Montreal Cognitive Assessment (MoCA) test preoperatively and were included in the final analysis. They were categorized into a normal group (MoCA ≥ 26 scores, group N) and an abnormal group (MoCA < 26 scores, group AN) based on test results. Delirium was assessed with the Confusion Assessment Method twice daily during the first 3 postoperative days. MEASUREMENTS AND MAIN RESULTS: The primary outcome was the incidence of postoperative delirium (POD). Secondary outcomes included the incidence of postoperative pulmonary complications (PPCs), cardiovascular complications, other complications, intensive care unit (ICU) stay, and the hospital length of stay (LOS). The incidence of MCI before thoracic surgery in elderly patients was 49.4% (76 of 154). Compared with group N, MCI could increase the incidence of POD (14.1% v 30.3%, p = 0.016) and median LOS (4 d v 5 d, p = 0.016). However, the differences in pulmonary complications, cardiovascular and other complications, and ICU stay were not significant. Multivariable logistic regression analysis showed preoperative MCI (OR = 2.573, 95% CI =1.092 to 6.060, p = 0.031) as an independent risk factor of POD. Compared with the elderly patients without POD, POD could increase the risk of PPCs (17.5% v 35.3%, p = 0.026) and median LOS (4 d v 5 d, p < 0.001). CONCLUSIONS: The incidence of MCI before thoracic surgery in elderly patients was higher and associated with a higher rate of adverse postoperative outcomes. The findings may be important for preoperative patient counseling, operative planning, and eventually reducing potential risk exposure and related outcomes.

Acute pain after serratus anterior plane or thoracic paravertebral blocks for video-assisted thoracoscopic surgery: A randomised trial.

BACKGROUND: Serratus anterior and paravertebral blocks can both be used for video-assisted thoracic surgery. However, serratus anterior blocks are easier to perform, and possibly safer. We therefore tested the primary hypothesis that serratus anterior plane blocks and thoracic paravertebral blocks provide comparable analgesia for video-assisted thoracic surgery. Secondarily, we tested the hypothesis that both blocks lengthen the time to onset of surgical pain and reduce the need for rescue tramadol. METHODS: Patients having video-assisted thoracic lobectomy or segmentectomy were randomly allocated to ultrasound-guided thoracic paravertebral blocks, n = 30; ultrasound-guided serratus anterior plane blocks, n = 30; or, general anaesthesia alone, n = 30. Visual analogue pain scores analogue pain scores at rest, during coughing and Prince-Henry pain scores were used to assess postoperative analgesia. Our primary analysis was noninferiority of serratus anterior blocks compared with paravertebral blocks. RESULTS: Baseline characteristics were comparable among the three groups. Two hours after surgery, the mean difference in visual analogue pain scores between the serratus anterior and paravertebral blocks was 0.0 (96.8% CI -0.4 to 0.3) cm at rest, -0.2 (-0.8 to 0.4) cm during coughing and -0.1(-0.5 to 0.3) for Prince-Henry pain scores. After 24 h, the mean difference was 0.0 (-0.7 to 0.8) cm at rest, 0.1 (-0.8 to 0.9) cm during coughing and 0.1(-0.4 to 0.6) for Prince-Henry pain scores. All differences were significantly noninferior. Time to onset of pain after surgery was 19 ±â€Š5 (SD) hours with serratus anterior blocks, 16 ±â€Š5 h with paravertebral blocks and 12 ±â€Š5 h with general anaesthesia. Anaesthesia with either block was associated with significantly less intra-operative propofol and sufentanil, reduced postoperative rescue analgesia (tramadol) and less postoperative nausea and vomiting compared with general anaesthesia alone. Patients with serratus anterior block had a significantly lower incidence of intra-operative hypotension and requirement for intra-operative vasopressor (3.4%), compared with general anaesthesia alone. Serratus anterior block took less time to perform than paravertebral block (5.1 ±â€Š1.1 min versus 10.1 ±â€Š2.9 min). CONCLUSION: Serratus anterior plane blocks, which are easier and quicker than paravertebral blocks, provide comparable analgesia in patients having video-assisted thoracic surgery. CLINICAL TRIAL NUMBER AND REGISTRY URL: ChiCTR1800017671; http://www.chictr.org.cn/hvshowproject.aspx?id=13510.

A novel nomogram to predict the risk of anastomotic leakage in patients after oesophagectomy.

BACKGROUND: Anastomotic leakage is a dangerous postoperative complication of oesophageal surgery. The present study aimed to develop a simple and practical scoring system to predict the risk of anastomotic leakage after oesophageal resection. METHODS: A consecutive series of 330 patients who underwent oesophageal cancer surgery from January 2016 to January 2018 at the Shanghai Chest Hospital were included to develop a prediction model. Anastomotic leakage was evaluated using oesophagography, computed tomography, or flexible endoscopy. Least absolute shrinkage and selection operator regression based on a generalized linear model was used to select variables for the anastomotic leakage risk model while avoiding overfitting. Multivariable logistic regression analysis was applied to build forest plots and a prediction model. The concordance index or the area under the curve was used to judge the discrimination, and calibration plots verified the consistency. Internal validation of the model was conducted, and the clinical usefulness and threshold screening of the model were evaluated by decision curve analysis. RESULTS: The factors included in the predictive nomogram included Sex, diabetes history, anastomotic type, reconstruction route, smoking history, CRP level and presence of cardiac arrhythmia. The model displayed a discrimination performance with a concordance index of 0.690 (95% confidence interval: 0.620-0.760) and good calibration. A concordance index value of 0.664 was maintained during the internal validation. The calibration curve showed good agreement between the actual observations and the predicted results. CONCLUSION: The present prediction model, which requires only seven variables and includes Sex, diabetes history, anastomotic type, reconstruction route, smoking history, CRP level and presence of cardiac arrhythmia, may be useful for predicting anastomotic leakage in patients after oesophagectomy.

Upregulation of bone morphogenetic protein 2 ( Bmp2) in dorsal root ganglion in a rat model of bone cancer pain.

Bone cancer pain is one of the most severe and intractable complications in patients suffering from primary or metastatic bone cancer and profoundly compromises the quality of life. Emerging evidence indicates that the dorsal root ganglion play an integral role in the modulation of pain hypersensitivity. However, the underlying molecular mechanisms during dorsal root ganglion-mediated bone cancer pain remain elusive. In this study, RNA-sequencing was used to detect the differentially expressed genes in dorsal root ganglion neurons of a rat bone cancer pain model established by intratibial inoculation of Walker 256 breast cancer cells. Gene ontology and Kyoto Encyclopedia of Genes and Genomes analysis showed that the differentially expressed genes (fold change > 1.5; false discovery rate < 0.05) were enriched in the bone morphogenetic protein (BMP) signaling pathway, transforming growth factor-ß signaling pathway, and positive regulation of cartilage development. Importantly, serum deprivation-response protein ( Sdpr), hephaestin ( Heph), transthyretin ( Ttr), insulin receptor substrate 1 ( Irs1), connective tissue growth factor ( Ctgf ), and Bmp2 genes were associated with bone pain and degeneration. Of note, Bmp2, a pleiotropic and secreted molecule mediating pain and inflammation, was one of the most significantly upregulated genes in dorsal root ganglion neurons in this bone cancer pain model. Consistent with these data, upregulation of Bmp2 in the bone cancer pain model was validated by immunohistochemistry, real-time quantitative polymerase chain reaction, and western blotting. Importantly, intrathecal administration of siRNA significantly reduced Bmp2 transcription and ameliorated bone cancer pain in rat as shown by paw withdrawal mechanical threshold and spontaneous and movement-evoked pain-like behaviors. In conclusion, we have characterized the comprehensive gene expression profile of dorsal root ganglion from a bone cancer pain rat model by RNA-sequencing and identified Bmp2 as a potential therapeutic target for bone cancer pain treatment.

Variational Thermal Quantum Simulation via Thermofield Double States.

We present a variational approach for quantum simulators to realize finite temperature Gibbs states by preparing thermofield double (TFD) states. Our protocol is motivated by the quantum approximate optimization algorithm and involves alternating time evolution between the Hamiltonian of interest and interactions which entangle the system and its auxiliary counterpart. As a simple example, we demonstrate that thermal states of the 1D classical Ising model at any temperature can be prepared with perfect fidelity using L/2 iterations, where L is system size. We also show that a free fermion TFD can be prepared with nearly optimal efficiency. Given the simplicity and efficiency of the protocol, our approach enables near-term quantum platforms to access finite temperature phenomena via preparation of thermofield double states.

Postoperative Myocardial Injury in Middle-Aged and Elderly Patients Following Curative Resection of Esophageal Cancer With Aggressive or Standard Body Temperature Management: A Randomized Controlled Trial.

BACKGROUND: Risk of intraoperative hypothermia is relatively high in middle-aged and elderly patients undergoing curative resection of esophageal cancer, which may cause myocardial ischemia during the early postoperative period. The objective of this study was to compare aggressive or standard body temperature management for lowering the incidence of postoperative myocardial injury that was assessed by troponin levels collected at a priori defined set times in these patients. METHODS: Seventy patients undergoing elective curative resection of esophageal cancer were randomly assigned to undergo aggressive body temperature management (nasopharyngeal temperature ≥36°C) or standard body temperature management (n = 35 in each arm). The primary outcome was myocardial injury, defined as the occurrence of elevated troponin I (>0.06 µg/L) or elevated high-sensitivity troponin T (≥0.065, or 0.02 µg/L≤ high-sensitivity troponin T <0.065 µg/L, but with an absolute change of at least 0.005 µg/L) or both during 2 days after surgery. Secondary outcomes included (1) severe arrhythmia, including atrial fibrillation, supraventricular tachycardia, frequent premature ventricular contractions intraoperatively or during 3 days postoperatively; (2) hypoxemia or metabolic acidosis during the first 12 h postoperatively; and (3) deep vein thrombosis or pulmonary embolism during 3 days postoperatively. RESULTS: Incidence of postoperative 2-day myocardial injury was 8.6% (3/35) among patients receiving aggressive body temperature management and 31.4% (11/35) among patients receiving standard body temperature management (P = .017, χ). Relative risk of myocardial injury in the aggressive body temperature management group was 0.27 (95% CI, 0.08-0.89). Incidence of intra- and postoperative 3-day severe cardiac arrhythmia was 2.9% (1/35) among patients receiving aggressive body temperature management and 28.6% (10/35) among patients receiving standard body temperature management. Incidence of postoperative 12-h hypoxia was 17.1% (6/35) with aggressive body temperature management and 40.0% (14/35) with standard body temperature management. Incidence of postoperative 12-h metabolic acidosis was 20% (7/35) among patients receiving aggressive body temperature management and 48.6% (17/35) among patients receiving standard body temperature management. Incidence of postoperative 3-day deep vein thrombosis or pulmonary embolism was 0% (0/35) with aggressive body temperature management and 2.9% (1/35) with standard body temperature management. CONCLUSIONS: Aggressive body temperature management may be associated with a lower incidence of postoperative myocardial injury.

Comparison of the effect of different degrees of passive leg raising on the internal jugular vein cross-sectional area in patients before thoracic surgery.

BACKGROUND: This study investigated the effect of different degrees of passive leg raising (PLR) on the internal jugular vein (IJV) cross-sectional area (CSA) and on the success rate of IJV cannulation in patients waiting for thoracic surgery, to analyze whether body mass index (BMI), gender, age, fasting time and preoperative rehydration have any impact on changes in the IJV CSA. METHODS: Eighty-two patients scheduled for selective thoracic surgery were enrolled in this study. Patients were randomly assigned based on a computer-generated randomization sequence into 3 groups: 0, 30, and 50 degrees (n = 32, 25, and 25 patients, respectively). The right IJV CSA in the sequence of 0-degree (supine position), 30-degree and 50-degree PLR positions was recorded in all patients using an ultrasound probe. The relationship of BMI, gender, age, fasting time and preoperative rehydration to the IJV CSA was analyzed. Then, each patient was returned to a supine position. After waiting for at least 5 min, patients were placed in a PLR position at 0, 30, or 50 degrees, and then IJV cannulation was performed without ultrasound guidance. The success rate of IJV catheterization at different PLR angles was compared. RESULTS: The average CSA of the right IJV in the supine position, 30-degree PLR position and 50-degree PLR position was 1.39 ± 0.63 cm2, 1.65 ± 0.73 cm2, and 1.68 ± 0.71 cm2, respectively. These results showed gradual increases in the IJV CSA of 18.5% (30-degree PLR) and 20.2% (50-degree PLR) when compared to that in the supine position (P = 0.045 and 0.025, respectively). However, only fasting time had a significant impact on the increase in the right IJV CSA at different PLR angles (P = 0.026). Other factors, such as BMI, gender, age and preoperative rehydration, had no significant effects. The success rates of IJV catheterization at angles of 0, 30 and 50 degrees were 84.3, 88 and 92%, respectively; however, there were no significant differences among the three groups (P = 0.674). CONCLUSIONS: PLR increases the CSA of the right IJV, especially for patients with long fasting times before thoracic surgery. The effect of the 30-degree PLR position is similar to that of the 50-degree PLR position. However, the success rate of right IJV catheterization was not enhanced in this study using landmark-guided puncture, even though the CSA of the right IJV was increased. TRIAL REGISTRATION: Clinical trial registration number: ChiCTR1800015051 . Date of registration: March 2018.

Comparison of deep or moderate neuromuscular blockade for thoracoscopic lobectomy: a randomized controlled trial.

BACKGROUND: Laparoscopic surgery typically requires deep neuromuscular blockade (NMB), but whether deep or moderate NMB is superior for thoracoscopic surgery remains controversial. METHODS: Patients scheduled for thoracoscopic lobectomy under intravenous anesthesia were randomly assigned to receive moderate [train of four (TOF) 1-2] or deep NMB [TOF 0, post-tetanic count (PTC) 1-5]. Depth of anesthesia was controlled at a Narcotrend rating of 30 ± 5 in both groups. The primary outcome was the need to use an additional muscle relaxant (cisatracurium) during surgery. Secondary outcomes included surgeon satisfaction, recovery time of each stage after drug withdrawal [time from withdrawal until TOF recovery to 20% (antagonists administration), 25, 75, 90, 100%], blood gas data, VAS pain grade after extubation, the time it takes for patients to begin walking after surgery, postoperative complications and hospitalization time. Results were analyzed on an intention-to-treat basis. RESULTS: Thirty patients were enrolled per arm, and all but one patient in each arm was included in the final analysis. Among patients undergoing moderate NMB, surgeons applied additional cisatracurium in 8 patients because of body movement and 5 because of coughing (13/29, 44.8%). Additional cisatracurium was not applied to any of the patients undergoing deep NMB (p < 0.001). Surgeons reported significantly higher satisfaction for patients undergoing deep NMB (p < 0.001, Wilcoxon rank sum test). The mean difference between the two groups in the time from withdrawal until TOF recovery of 25% or 90% was 10 min (p < 0.001). The two groups were similar in other recovery data, blood gas analysis, VAS pain grade, days for beginning to walk and mean hospitalization time. CONCLUSIONS: Deep NMB can reduce the use of additional muscle relaxant and increase surgeon satisfaction during thoracoscopic lobectomy. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR-IOR-15007117 , 22 September 2015.

Two-minute disconnection technique with a double-lumen tube to speed the collapse of the non-ventilated lung for one-lung ventilation in thoracoscopic surgery.

BACKGROUND: Thoracic surgery requires the effective collapse of the non-ventilated lung. In the majority of cases, we accomplished, accelerated lung collapse using a double-lumen tube (DLT). We hypothesized that using the two-minute disconnection technique with a DLT would improve lung collapse during subsequent one-lung ventilation. METHODS: Fifty patients undergoing thoracoscopic surgery with physical classification I or II according to the American Society of Anesthesiologists were randomly divided into two groups for respiratory management of one-lung ventilation (OLV). In group N, OLV was initiated after the DLT was disconnected for 2 min; the initiation time began when the surgeon made the skin incision. In group C, OLV was initiated when the surgeon commenced the skin incision and scored the quality of lung collapse (using a four-point ordinal scale). The surgeon's satisfaction or comfort with the surgical conditions was assessed using a visual analogue scale. rSO2 level, mean arterial pressure, pulse oxygen saturation, arterial blood gas analysis, intraoperative hypoxaemia, intraoperative use of CPAP during OLV, and awakening time were determined in patients at the following time points: while inhaling air (T0), after anaesthesia induction andinhaling 100% oxygen in the supine position under double lung ventilation for five mins (T1), at two mins after skin incision (T2), at ten mins after skin incision (T3), and after the lung recruitment manoeuvres and inhaling 50% oxygen for five mins (T4). RESULTS: The two-minute disconnection technique was associated with a significantly shorter time to total lung collapse compared to that of the conventional OLV ventilation method (15 mins vs 22 mins, respectively; P < 0.001), and the overall surgeon's satisfaction was higher (9 vs 7, respectively; P < 0.001). At T2, the PaCO2, left rSO2 and right rSO2 were higher in group N than in group C. There were no statistically significant differences between the incidence of intraoperative hypoxaemia and intraoperative use of CPAP during OLV (10% vs 5%, respectively; P = 1.000), duration of awakening (18 mins vs 19 mins, respectively; P = 0.616). CONCLUSIONS: A two-minute disconnection technique using a double-lumen tube was used to speed the collapse of the non-ventilated lung during one-lung ventilation for thoracoscopic surgery. The surgeon was satisfied with the surgical conditions. TRIAL REGISTRATION: Chinese Clinical Trial Registry number, ChiCTR-IPR-17010352 . Registered on Jan, 7, 2017.