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Abstract Background As a popularly used analgesic adjuvant, intravenous (IV) lidocaine could reduce the consumption of propofol in painless gastrointestinal (GI) endoscopy. However, whether IV lidocaine could affect the incidence of oxygen-desaturation episodes (ODE) during painless GI endoscopy is still unknown. Therefore, we tested the hypothesis that IV lidocaine could decrease the incidence of propofol-induced ODE and involuntary movements in patients during GI endoscopy. Methods Three hundred twenty-two patients scheduled for GI endoscopy were randomly divided into lidocaine group and control group. After midazolam and sufentanil injection, a bolus of 1.5 mg/kg lidocaine was given and followed by continuous infusion of 4 mg/kg/h in lidocaine group, whereas the same volumes of saline solution in control group. Then, propofol was titrated to produce unconsciousness. The primary outcome was the incidence of ODE during the procedure. The secondary outcomes were the incidence of different degree of hypoxia and corresponding treatments and the involuntary body movements. Results A total of 300 patients were finally included in the analysis, 147 patients in lidocaine group and 153 in control group. The incidence of ODE was 22% in lidocaine group and 39% in control group (OR:0.052; 95%CI: 0.284–0.889; P = 0.018). IV lidocaine also improved the occurrence of different degree of hypoxia (P = 0.017) and needed few treatments (P = 0.028). The incidence of involuntary body movements (14% vs 26%, P = 0.013) and adverse circulatory events was decreased by IV lidocaine. Conclusions IV lidocaine adjuvant to propofol-based sedation could reduce the incidence of oxygen-desaturation episodes and involuntary body movements, with fewer adverse circulatory events. Trial registration Chinese Clinical Trial Registry ChiCTR2100053818. Registered on 30 November 2021.

Objective At present, due to the lack of early observation methods, the effect of the ‘accordion’ technique on the treatment of nonunion of the docking site varies greatly. In this study, color Doppler ultrasound was used to observe the docking site's local changes and investigate the relationship between local microenvironment changes and bone healing after the accordion technique. Methods 30 patients with tibial bone transport treated at the Department of Orthopedics, Second Hospital of Shanxi Medical University, from May 2018 to June 2022, were analyzed retrospectively. Paired‐sample t‐tests were used for data that conformed to a normal distribution, and paired rank‐sum tests were used for before‐and‐after comparisons that did not conform to a normal distribution. There were 26 males and 4 females, aged 47.3 ± 11.7 years. Before bone transport, the defect gap between tibial bone ends was 6.80 ± 3.61 cm. The steps of the accordion technique were as follows: compression for 7 days, ultrasonic study of the microenvironment at the docking site, distraction for 12 days, latency for 7 days, compression for 14 days, then static fixation and radiological study until complete bone healing. Ultrasound was used to detect the size of the hematoma after 7 days of pressure, and the changes in blood flow before and after the ‘accordion' operation. Results All patients were followed up for 11.9 ± 1.9 months. At the last follow‐up, 22 patients achieved bone healing at the docking site after the treatment of the ‘accordion’ technique. There was a linear negative correlation between the size of the hematoma and the time of bone healing at the docking site (r = −0.639, p

The mind readily learns cue-outcome associations where an object predicts a specific outcome. Previous work suggested that when multiple objects associated with different outcomes were jointly presented , the mind made conjunctive predictions that represented the common property of the associated outcomes. Using attentional tracking measures, we provided more evidence for the weighted summation framework when the conjunctive predictions involved spatial locations (Experiment 1) or conceptual categories (Experiment 2). Then, we examined the reverse of conjunction, where participants were presented with a single object, which is a part of an object pair that was previously associated with an outcome (Experiment 3). Rather than making predictions based on mental operations such as subtraction, we found that participants’ predictions were purely based on previous associations. These results together demonstrated the robust tendency to make conjunctive predictions based on knowledge of cue-outcome associations.

Abstract Background Circulatory and respiratory depression are common problems that occur in propofol alone sedation during gastroscopy. As a widely used analgesic adjuvant, intravenous lidocaine can reduce the consumption of propofol during Endoscopic retrograde cholangiopancreatography (ERCP) or colonoscopy. However, it is still unknown the median effective dose (ED50) of propofol when combined with lidocaine intravenously. This study aimed to compare the ED50 of propofol with or without intravenous lidocaine for inserting gastrointestinal endoscope successfully. Methods Fifty nine patients undergoing gastroscopy or gastrointestinal (GI) endoscopy were randomly divided into control group (Group C, normal saline + propofol) or lidocaine group (Group L, lidocaine + propofol). Patients were initially injected a bolus of 1.5 mg/kg lidocaine in Group L, whereas equivalent volume of 0.9% saline in Group C. Anaesthesia was then induced with a single bolus of propofol in all subjects. The induction dose of propofol was determined by the modified Dixon’s up-and-down method, and the initial dose was 1.5 mg/kg in both groups. The primary outcome was the ED50 of propofol induction dose with or without intravenous lidocaine. The secondary outcomes were the induction time, the first propofol bolus time (FPBT: from MOAA/S score ≤ 1 to first rescue bolus propofol), and adverse events (AEs: hypoxemia, bradycardia, hypotension, and body movements). Results Totally, 59 patients were enrolled and completed this study. The ED50 of propofol combined with lidocaine was 1.68 ± 0.11 mg/kg, significantly reduced compared with the normal saline group, 1.88 ± 0.13 mg/kg (P = 0.002). There was no statistical difference in induction time (P = 0.115) and the FPBT (P = 0.655) between the two groups. There was no significantly difference about the AEs between the two groups. Conclusion The ED50 of propofol combined with intravenous lidocaine for successful endoscope insertion in adult patients, was 1.68 ± 0.11 mg/kg significantly reduced compared with the control group. Trial registration Chinese Clinical Trial Registry, No: ChiCTR2200059450. Registered on 29 April 2022. Prospective registration. http://www.chictr.org.cn .

Until now, acute respiratory distress syndrome (ARDS) has been a difficult clinical condition with a high mortality and morbidity rate, and is characterized by a build-up of alveolar fluid and impaired clearance. The underlying mechanism is not yet fully understood and no effective medications available. Autophagy activation is associated with ARDS caused by different pathogenic factors. It represents a new direction of prevention and treatment of ARDS to restrain autophagy to a reasonable level through pharmacological and molecular genetic methods. Na, K-ATPase is the main gradient driver of pulmonary water clearance in ARDS and could be degraded by the autophagy-lysosome pathway to affect its abundance and enzyme activity. As a normal growth hormone in human body, insulin has been widely used in clinical for a long time. To investigate the association of insulin with Na, K-ATPase, autophagy and inflammatory markers in LPS-treated C57BL/6 mice by survival assessment, proteomic analysis, histologic examination, inflammatory cell counting, myeloperoxidase, TNF-α and IL-1β activity analysis etc. This was also verified on mouse alveolar epithelial type II (AT II) and A549 cells by transmission electron microscopy. We found that insulin restored the expression of Na, K-ATPase, inhibited the activation of autophagy and reduced the release of inflammatory factors caused by alveolar epithelial damage. The regulation mechanism of insulin on Na, K-ATPase by inhibiting autophagy function may provide new drug targets for the treatment of ARDS.

Abstract Finely tuned mitogen-activated protein kinase (MAPK) signaling is important for cancer cell survival. Perturbations that push cells out of the MAPK fitness zone result in cell death. Previously, in a screen of the North China Pharmaceutical Group Corporation’s pure compound library of microbial origin, we identified elaiophylin as an autophagy inhibitor. Here, we demonstrated a new role for elaiophylin in inducing excessive endoplasmic reticulum (ER) stress, ER-derived cytoplasmic vacuolization, and consequent paraptosis by hyperactivating the MAPK pathway in multiple cancer cells. Genome-wide CRISPR/Cas9 knockout library screening identified SHP2, an upstream intermediary of the MAPK pathway, as a critical target in elaiophylin-induced paraptosis. The cellular thermal shift assay (CETSA) and surface plasmon resonance (SPR) assay further confirmed the direct binding between the SHP2 and elaiophylin. Inhibition of the SHP2/SOS1/MAPK pathway through SHP2 knockdown or pharmacological inhibitors distinctly attenuated elaiophylin-induced paraptosis and autophagy inhibition. Interestingly, elaiophylin markedly increased the already-elevated MAPK levels and preferentially killed drug-resistant cells with enhanced basal MAPK levels. Elaiophylin overcame drug resistance by triggering paraptosis in multiple tumor-bearing mouse models resistant to platinum, taxane, or PARPi, suggesting that elaiophylin might offer a reasonable therapeutic strategy for refractory ovarian cancer.

Abstract Background Oxygen-desaturation episodes, blood pressure drops, and involuntary body movement are common problems that occur in propofol-based sedation in the procedure of painless gastrointestinal (GI) endoscopy. As a widely used analgesic adjuvant, intravenous lidocaine can reduce the consumption of propofol during ERCP or colonoscopy. However, it is still unknown how lidocaine affects the incidence of oxygen-desaturation episodes and cardiovascular events, and involuntary movement during painless GI endoscopy. Therefore, we aimed to assess the effectiveness and safety of intravenous lidocaine in propofol-based sedation for GI endoscopy. Methods We will conduct a single-center, prospective, randomized, double-blind, saline-controlled trial. A total number of 300 patients undergoing painless GI procedures will be enrolled and randomly divided into the lidocaine group (Group L) and the control group (Group C). After midazolam and sufentanil intravenous injection, a bolus of 1.5 mg/kg lidocaine was immediately injected and followed by a continuous infusion of 4 mg/kg/h in the lidocaine group, whereas the same volumes of saline solution in the control group. Then, propofol was titrated to produce unconsciousness during the procedure. The primary outcome will be the incidence of oxygen-desaturation episodes. Secondary outcomes will be the incidence of involuntary body movement, discomfort symptoms, propofol consumption, endoscopist, and patient satisfaction. Discussion Propofol-based deep sedation without intubation is widely used in painless GI endoscopy. However, adverse events such as hypoxemia often occur clinically. We expect to assess the effect of lidocaine on reducing the incidence of oxygen-desaturation episodes, cardiovascular events, and involuntary body movement. We believe that the results of this trial will provide an effective and safe method for painless GI endoscopy. Trial registration Chinese Clinical Trial Registry ChiCTR2100053818. Registered on 30 November 2021.

Dipeptidyl peptidase 4 (DPP4) is a serine protease widely distributed in membrane-bound and soluble forms in various tissues and organs throughout the body. DPP4 plays a role in inflammation, immune regulation, cell growth, migration and differentiation. The role of DPP4 in tumors has garnered increasing attention. Previous research has demonstrated that DPP4 contributes to the promotion of cancer in most cancers, and it may play a specific biological function through the variation in tumor cell types and expression forms. However, the expression of DDP4 in different tumor types and its specific mechanism remains unclear. In this review, we describe the structure of DPP4, summarize the recent research progress of its expression and potential mechanisms in common tumors, and discuss the development prospects of DPP4 inhibitors in tumor therapy. Although current research emphasizes the potential of DPP4 as a drug target, the incomplete understanding of its regulatory mechanisms impedes the discovery and development of new therapies against it. Further research on DPP4-related tumors is anticipated to promote its clinical application as a potential therapeutic target. [ABSTRACT FROM AUTHOR]

The cognitive system readily detects statistical relationshipswhere the presence of an object predicts a specific outcome.What is less known is how the mind generates predictionswhen multiple objects predicting different outcomes arepresent simultaneously. Here we examine the rules with whichpredictions are made in the presence of two objects that areassociated with two distinct outcomes. In three experiments,participants first implicitly learned that an object predicted aspecific target location in a visual search task. When twoobjects predicting two different target locations were presentsimultaneously, participants were reliably faster to find thetarget when it appeared in the conjunctive location than indisjunctive locations. This was true even if participants werenot consciously aware of the association between the objectsand target locations. The results suggest that in the presence ofmultiple predictors, statistical learning generates implicitexpectations about the outcomes in a conjunctive fashion.

Glaucoma is a common blinding eye disease characterized by progressive loss of retinal ganglion cells (RGCs) and their axons, progressive loss of visual field, and optic nerve atrophy. Autophagy plays a pivotal role in the pathophysiology of glaucoma and is closely related to its pathogenesis. Targeting autophagy and blocking the apoptosis of RGCs provides emerging guidance for the treatment of glaucoma. Here, we provide a systematic review of the mechanisms and targets of interventions related to autophagy in glaucoma and discuss the outlook of emerging ideas, techniques, and multidisciplinary combinations to provide a new basis for further research and the prevention of glaucomatous visual impairment.

Ingenane-type diterpenoids (ITDs) are distinct components of plants belonging to the genus Euphorbia. These compounds have significant cytotoxic effects on non-small cell lung cancer (NSCLC) cells. However, the underlying molecular mechanism has yet to be reported. To explore the mechanism of the anticancer effect of ITDs, we carried out a network pharmacology prediction study. PPI network suggested that SRC and PI3K had high levels of interaction. In addition, KEGG analysis revealed that these common targets were significantly enriched in the PI3K/Akt signalling pathway. 13-oxyingenol-dodecanoate (13OD) was used for validation after the biological evaluation of some ITDs against NSCLC cells. It demonstrated that 13OD could significantly inhibit the growth of NSCLC cells by inducing apoptosis. The results from molecular docking and Western blotting showed that 13OD interacted with SRC and PI3K and down-regulated the SRC/PI3K/Akt signalling pathway in NSCLC cells. This study provided the underlying mechanism of ITDs against NSCLC. [ABSTRACT FROM AUTHOR]

Objective To explore the clinical characteristics and treatment outcome of testicular cancer. Methods To review retrospectly the clinical data of 49 patients who were diagnosed with testicular cancer and treated with operation in the Urology Department of Peking University Cancer Hospital. Results Among the 49 patients, 11 had elevated preoperative alpha fetal protein(AFP) levels, all have the age as≤ 44 years; 21 had elevated β-human chorionic gonadotropin(β-hCG) level, including 19 cases with age as ≤ 44 years; 20 had elevated lactate dehydrogenase(LDH), including 18 cases with the age as ≤ 44 years. Two weeks after operation, there were 2 cases of abnormal AFP, both ≤ 44 years old; 6 cases of abnormal β-hCG, including 5 cases ≤ 44 years old; LDH were all normal. All patients underwent radical resection of testicular cancer, including 6 patients with retroperitoneal lymph node dissection(RLND), and 23 patients with postoperative radiotherapy/chemotherapy followed. Conclusions The significance of AFP, β-hCG and LDH is greater for the diagnosis and evaluation of patients < 45 years old. Markers with higher sensitivity and specificity are needed for evaluation. RLND can be an option for initial treatment.

Binary information is prevalent in the environment. In thisstudy, we examined how people process repetition andalternation in binary sequences. Across four paradigmsinvolving estimation, working memory, change detection, andvisual search, we found that the number of alternations isunder-estimated compared to repetitions (Experiment 1).Moreover, recall for binary sequences deteriorates as thesequence alternates more (Experiment 2). Changes in bits arealso harder to detect as the sequence alternates more(Experiment 3). Finally, visual targets superimposed on bitsof a binary sequence take longer to process as alternationincreases (Experiment 4). Overall, our results indicate thatcompared to repetition, alternation in a binary sequence isless salient in the sense of requiring more attention forsuccessful encoding. The current study thus reveals thecognitive constraints in the representation of alternation andprovides a new explanation for the over-alternation bias inrandomness perception.

An adaptive function of the visual system is that it flexibly updates existing representations of objects upon changes.Such updating can also alter the representations of associated objects that are not directly observable. What mechanism supportsthis process? We propose that statistical learning provides a channel through which changes in one object are automaticallytransferred to related objects. Observers viewed a temporal sequence of paired circles. One circle in each pair then changed insize, and observers recalled the size of the other circle. When the first circle enlarged (or shrank), the second circle was judgedto be larger (or smaller), suggesting that the change was automatically transferred to the predicted object (Experiment 1). Thesame, however, was not true if the second circle changed in size (Experiment 2). No observer was explicitly aware of the circlepairs. Thus, statistical learning enables the implicit updating of representations through predictive associations.

Objective: At present, due to the lack of early observation methods, the effect of the 'accordion' technique on the treatment of nonunion of the docking site varies greatly. In this study, color Doppler ultrasound was used to observe the docking site's local changes and investigate the relationship between local microenvironment changes and bone healing after the accordion technique. Methods: 30 patients with tibial bone transport treated at the Department of Orthopedics, Second Hospital of Shanxi Medical University, from May 2018 to June 2022, were analyzed retrospectively. Paired‐sample t‐tests were used for data that conformed to a normal distribution, and paired rank‐sum tests were used for before‐and‐after comparisons that did not conform to a normal distribution. There were 26 males and 4 females, aged 47.3 ± 11.7 years. Before bone transport, the defect gap between tibial bone ends was 6.80 ± 3.61 cm. The steps of the accordion technique were as follows: compression for 7 days, ultrasonic study of the microenvironment at the docking site, distraction for 12 days, latency for 7 days, compression for 14 days, then static fixation and radiological study until complete bone healing. Ultrasound was used to detect the size of the hematoma after 7 days of pressure, and the changes in blood flow before and after the 'accordion' operation. Results: All patients were followed up for 11.9 ± 1.9 months. At the last follow‐up, 22 patients achieved bone healing at the docking site after the treatment of the 'accordion' technique. There was a linear negative correlation between the size of the hematoma and the time of bone healing at the docking site (r = −0.639, p < 0.01). According to the Paley healing criteria, 18 of the 22 patients were excellent, and 4 patients were good. Conclusion: Hematoma is necessary for the 'accordion' technique's success in the treatment of nonunion. The size of the hematoma is negatively related to the time of bone healing. The 'accordion' technique can increase the blood flow of tissue around the docking site. Ultrasound can be used to monitor the changes in the microenvironment at the docking site during the 'accordion' technique and guide the exact plan and prognosis of the 'accordion' technique. [ABSTRACT FROM AUTHOR]

Abstract Background Copy number variation (CNV) is a complex genomic rearrangement that has been linked to a large number of human diseases. Chromosome 15q13 microduplication is a rare form of CNV, which has been proved to be associated with multiple human disorders; however, the association between chromosome 15q13 microduplication and cardiac disorders has not been fully understood. Case presentation A fetus with fetal cardiac developmental defects was detected by Color Doppler ultrasound imaging; however, further chromosomal G-banding revealed no abnormal karyotype. Then, chromosomal microarray analysis (CMA) was performed and revealed a 1.8 Mb-duplication of the chromosome 15q13.2q13.3 region containing 7 genes (TRPM1, KLF13, OTUD7A, CHRNA7, FAN1, MIR211 and RAHGAP11A). Cardiac ultrasound follow-up displayed significant enlargement of the space-occupying lesion in the fetal heart with extension of the gestational age, and the space-occupying lesion was finally pathologically diagnosed as cardiac rhabdomyoma. Next-generation sequencing revealed no mutations in the TSC1 or TSC2 gene in the fetus, the mother or the father. Conclusions This is the first report to demonstrate the potential association between chromosome 15q13 microduplication and fetal cardiac rhabdomyoma. It is recommended that CMA be employed in fetuses with abnormal cardiac development diagnosed by routine cardiac color Doppler ultrasound imaging for early detection of congenital genetic abnormality, which may provide valuable information for prenatal diagnostic consultation and the decision on pregnancy termination.

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