Inhibition of PI3K/AKT signaling pathway prevents blood-induced heterotopic ossification of the injured tendon.

Objective: It is a common clinical phenomenon that blood infiltrates into the injured tendon caused by sports injuries, accidental injuries, and surgery. However, the role of blood infiltration into the injured tendon has not been investigated. Methods: A blood-induced rat model was established and the impact of blood infiltration on inflammation and HO of the injured tendon was assessed. Cell adhesion, viability, apoptosis, and gene expression were measured to evaluate the effect of blood treatment on tendon stem/progenitor cells (TSPCs). Then RNA-seq was used to assess transcriptomic changes in tendons in a blood infiltration environment. At last, the small molecule drug PI3K inhibitor LY294002 was used for in vivo and in vitro HO treatment. Results: Blood caused acute inflammation in the short term and more severe HO in the long term. Then we found that blood treatment increased cell apoptosis and decreased cell adhesion and tenonic gene expression of TSPCs. Furthermore, blood treatment promoted osteochondrogenic differentiation of TSPCs. Next, we used RNA-seq to find that the PI3K/AKT signaling pathway was activated in blood-treated tendon tissues. By inhibiting PI3K with a small molecule drug LY294002, the expression of osteochondrogenic genes was markedly downregulated while the expression of tenonic genes was significantly upregulated. At last, we also found that LY294002 treatment significantly reduced the tendon HO in the rat blood-induced model. Conclusion: Our findings indicate that the upregulated PI3K/AKT signaling pathway is implicated in the aggravation of tendon HO. Therefore, inhibitors targeting the PI3K/AKT pathway would be a promising approach to treat blood-induced tendon HO.

Lower risks of cirrhosis and hepatocellular carcinoma with GLP-1RAs in type 2 diabetes: A nationwide cohort study using target trial emulation framework.

BACKGROUND: To assess the association of cirrhosis and hepatocellular carcinoma (HCC) with the use of glucagon-like peptide-1 receptor agonists (GLP-1RAs) versus long-acting insulins (LAIs), which are the two commonly prescribed injectable glucose-lowering agents (GLAs) for patients with type 2 diabetes (T2D) after the failure of multiple oral GLAs. METHODS: We emulated a target trial using the nationwide data of a Taiwanese cohort with T2D. Incident new users of GLP-1RAs and LAIs during 2013-2018 were identified, and propensity score (PS) matching was applied to ensure between-group comparability in baseline patient characteristics. The primary outcome was the composite liver disease including cirrhosis or HCC. Each patient was followed until the occurrence of a study outcome, death, or the end of 2019, whichever came first. Subdistribution hazard models were employed to assess the treatment-outcome association. Sensitivity (e.g., stabilized inverse probability of treatment weighting analysis, time-dependent analysis), E-value, and negative control outcome analyses were performed to examine the robustness of study findings. RESULTS: We included 7171 PS-matched pairs of GLP-1RA and LAI users with no significant between-group differences at baseline. Compared with LAIs, the use of GLP-1RAs was associated with significantly reduced risks of composite liver disease (subdistribution hazard ratio [95% confidence interval]: 0.56 [0.42-0.76]), cirrhosis (0.59 [0.43-0.81]), and HCC (0.47 [0.24-0.93]). Results were consistent across sensitivity analyses and among patients with different baseline characteristics. CONCLUSION: Among T2D patients who require injectable GLAs, the use of GLP-1RAs versus LAIs was associated with lower risks of cirrhosis and HCC.

Chronic kidney outcomes associated with GLP-1 receptor agonists versus long-acting insulins among type 2 diabetes patients requiring intensive glycemic control: a nationwide cohort study.

BACKGROUND: Effectiveness of glucagon-like peptide-1 receptor agonists (GLP-1RAs) versus long-acting insulins (LAIs) on preventing progressive chronic kidney outcomes is uncertain for type 2 diabetes (T2D) patients requiring intensive glycemic control. This study aimed to evaluate comparative effectiveness of GLP-1RA versus LAI therapies on progressive chronic kidney outcomes among patients having poor glycemic control and requiring these injectable glucose-lowering agents (GLAs). METHODS: 7279 propensity-score-matched pairs of newly stable GLP-1RA and LAI users in 2013-2018 were identified from Taiwan's National Health Insurance Research Database and followed until death or 12/31/2019 (intention-to-treat). Subdistributional hazard model was utilized to assess the comparative effectiveness on a composite renal outcome (i.e., renal insufficiency [eGFR < 15 mL/min/1.73 m2], dialysis-dependent end-stage renal disease [ESRD], or renal death) and its individual components. Sensitivity analyses with the as-treated scenario, PS weighting, high-dimensional PS techniques, using cardiovascular diseases (CVDs) as positive control outcomes, and interaction testing were performed. RESULTS: In primary analyses, subdistribution hazard ratios (95% CIs) for initiating GLP-1RAs versus LAIs for the composite renal outcome, renal insufficiency, dialysis-dependent ESRD, and renal death were 0.39 (0.30-0.51), 0.43 (0.32-0.57), 0.29 (0.20-0.43), and 0.28 (0.15-0.51), respectively. Sensitivity analysis results were consistent with the primary findings. CVD history and the medication possession ratio of prior oral GLAs possessed modification effects on GLP-1RA-associated kidney outcomes. CONCLUSION: Using GLP-1RAs versus LAIs was associated with kidney benefits in T2D patients requiring intensive glycemic control and potentially at high risk of kidney progression. GLP-1RAs should be prioritized to patients with CVDs or adherence to prior oral GLAs to maximize kidney benefits.

Value of GLP-1 receptor agonists versus long-acting insulins for type 2 diabetes patients with and without established cardiovascular or chronic kidney diseases: A model-based cost-effectiveness analysis using real-world data.

AIMS: To evaluate the cost-effectiveness of glucagon-like peptide-1 receptor agonists (GLP-1RAs) versus long-acting insulins (LAIs) in patients with type 2 diabetes (T2D) using real-world data. METHODS: A Markov model was utilized to estimate healthcare costs (US$) and quality-adjusted life-years (QALYs) of receiving treatments over 10 years from the healthcare sector perspective. Model inputs were derived from the analyses of Taiwan's National Health Insurance Research Database or published literature on Taiwanese T2D populations. Base-case analysis was performed for the overall study cohort and subgroup analyses were stratified by the presence or absence of established cardiovascular diseases (CVDs) or chronic kidney diseases (CKDs). RESULTS: Overall, using GLP-1RAs versus LAIs cost $6,053 per QALY gained. Results were robust across sensitivity and scenario analyses. Among patients with established CVDs and CKDs, GLP-1RA versus LAI therapy saved $673 (cost-saving) and cost $1,675 per QALY gained, respectively. Among patients without established CVDs and CKDs, GLP-1RA versus LAI therapy cost $9,093 and $7,659 per QALY gained, respectively. CONCLUSIONS: Using GLP-1RAs versus LAIs for T2D patients represented good economic value in real-world practice. Pronounced economic benefits of GLP-1RA therapy among those with prior CVDs or CKDs support rational treatment decisions and optimal healthcare resource allocation for these patients.

Effect of Positive End-Expiratory Pressure (PEEP) Titration in Elderly Patients Undergoing Lobectomy.

BACKGROUND Currently, one-lung ventilation in thoracoscopic lobectomy adopts mostly a protective ventilation mode, which includes low tidal volume (a tidal volume of 6 mL/kg predicted body weight), positive end-expiratory pressure (PEEP), and intermittent lung inflation. However, there is no clear conclusion regarding the value of PEEP in elderly patients undergoing lobectomy. MATERIAL AND METHODS Fifty patients who underwent video-assisted thoracoscopic unilateral lobectomy, aged 65 to 78 years, with a body mass index of 18 to 29 kg/m² and ASA grades I to III, were randomly divided into 2 groups (n=25 each): optimal oxygenation titration group (group O) and optimal compliance titration group (group C). Mean arterial pressure (MAP), heart rate (HR), and central venous pressure (CVP) were recorded in both groups at different time points. The radial artery blood samples were collected at 3 time points for blood gas analysis, and the void volume/tidal volume ratio was calculated. The peak airway pressure and PEEP values were recorded at 4 min after the completion of one-lung ventilation titration (T2), and the driving pressure was calculated. RESULTS The best PEEP value of titration in the best compliance group was lower than that of the best oxygenation method, the peak was lower, and the dynamic lung compliance was higher; however, this had no effect on MAP and HR. The CVP was lower than optimal oxygenation at T2. CONCLUSIONS Dynamic lung compliance-guided PEEP titration improved lung function in elderly patients undergoing lobectomy.

The Optimal Second-Line Systemic Treatment Model for Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinoma: A Bayesian Network Meta-Analysis.

Background: The optimal second-line systemic treatment model for recurrent and/or metastatic head and neck squamous cell carcinoma (R/M HNSCC) remains controversial. A Bayesian network meta-analysis (NMA) was performed to address this issue with regard to efficacy and toxicity. Methods: By searching MEDLINE (via PubMed), Embase, the Cochrane Central Register of Controlled Trials and Web of Science, we extracted eligible studies. Efficacy, represented as overall survival (OS) and progression-free survival (PFS), and overall toxicity, represented as ≥ grade 3 severe acute events (sAE), were assessed to compare the following 7 treatment models through an NMA: standard-of-care therapy (SoC), single targeted therapy different from SoC (ST), double targeted therapy (DT), targeted therapy combined with chemotherapy (T+C), single immune checkpoint inhibitor therapy (SI), double immune checkpoint inhibitor therapy (DI) and single chemotherapy different from SoC (SC). Rank probabilities according to the values of the surface under the cumulative ranking curve (SUCRA) were separately determined for efficacy and toxicity. Results: In total, 5285 patients from 24 eligible studies were ultimately screened, with 5184, 4532 and 4026 involved in the NMA of OS, PFS and sAE, respectively. All qualifying studies were absent from first-line immune checkpoint inhibitor therapy. In terms of OS, SI was superior to the other treatments, followed by DI, ST, T+C, SoC, DT and SC. Other than SI and SC, all treatments tended to be consistent, with hazard ratios (HRs) close to 1 between groups. For PFS, ST ranked first, while DT ranked last. For the toxicity profiles, compared with the other models, SI resulted in the lowest incidences of sAE, with statistical significance over SoC (odds ratio [OR] 0.31, 95% credible interval [CrI] 0.11 to 0.90), ST (OR 0.23, 95% CrI 0.06 to 0.86) and DT (OR 0.11, 95% CrI 0.02 to 0.53), while DT was the worst. When the SUCRA values of OS and sAE were combined, a cluster plot illustrated the superiority of SI, which demonstrated the best OS and tolerability toward sAE. Conclusion: For R/M HNSCC patients without immune checkpoint inhibitors in the first-line setting, SI may serve as the optimal second-line systemic treatment model, demonstrating the best OS and least sAE.

Longitudinal Relations between Rejection Sensitivity and Adjustment in Chinese Children: Moderating Effect of Emotion Regulation.

The goal of the present study was to examine the moderating effect of emotion regulation in the longitudinal relations between rejection sensitivity and indices of adjustment among Chinese children. Participants were N = 590 children (Mage= 11.25 years, SD = 1.33) attending public elementary and middle schools in Shanghai, P.R. China. Measures of anxious rejection sensitivity and socio-emotional functioning were collected via self-reports and peer nominations. Among the results, rejection sensitivity significantly predicted higher levels of later internalizing problems. Moreover, emotion regulation significantly moderated (i.e. buffering effect) the relations between rejection sensitivity and later peer and emotional difficulties. The current findings suggest that rejection sensitivity poses developmental risk over time, but emotion regulation may serve as a protective factor for Chinese youth. Results are discussed in terms of the implications of rejection sensitivity and emotion regulation in Chinese culture.

Effect of Pressure-Controlled Ventilation-Volume Guaranteed on One-Lung Ventilation in Elderly Patients Undergoing Thoracotomy.

BACKGROUND Volume-controlled ventilation (VCV) in one-lung ventilation (OLV) is most commonly used in thoracotomy, but pressure-controlled ventilation-volume guaranteed (PCV-VG) is used in elderly patients to improve arterial oxygenation, reduce inflammatory factors, and decrease acute lung injury (ALI). The purpose of this study was to investigate the effects of these 2 different ventilation modes - VCV versus PCV-VG - during OLV in elderly patients undergoing thoracoscopic lobectomy. MATERIAL AND METHODS Sixty patients undergoing thoracoscopic lobectomy from September 2018 to February 2019 at Cangzhou Central Hospital, Hebei, China were randomly assigned to a VCV group or a PCV-VG group. Pulmonary dynamic compliance (Cdyn), peak inspiratory pressure (PIP), arterial blood gas, and inflammatory factors were monitored to assess lung function. The Clinical Trial Registration Identifier number is ChiCTR1800017835. RESULTS Compared with the VCV group, PIP in the PCV-VG group was significantly lower (P=0.01) and Cdyn was significantly higher at 30 min after one-lung ventilation (P=0.01). MAP of the PCV-VG group was higher than in the VCV group (P=0.01). MAP of the PCV-VG group was also higher than in the VCV group at 30 min after one-lung ventilation (P=0.01). The concentration of neutrophil elastase (NE) in the PCV-VG group was significantly lower than in the VCV group (P=0.01). CONCLUSIONS Compared with VCV, PCV-VG mode reduced airway pressure in patients undergoing thoracotomy and also decreased the release of NE and reduced inflammatory response and lung injury. We conclude that PCV-VG mode can protect the lung function of elderly patients undergoing thoracotomy.

Ropivacaine relieves pain and prevents chondrocyte degradation probably through Calcineurin/NFAT1 signaling pathway in osteoarthritis rats.

Calcineurin/NFAT1 signaling pathway plays critical roles in maintaining the homeostasis of articular chondrocytes and in regulating the pathogenesis of osteoarthritis (OA). A few studies demonstrate therapeutic values of ropivacaine (Rop) in OA, but the underlying mechanisms have not been defined. Here, we determined whether Calcineurin/NFAT1 signaling pathway mediates the benefits of Rop to OA. OA rat models were established by a single intra-articular injection of monosodium iodoacetate. The pathophysiology of OA was evaluated by measuring hyperalgesia behavior and the expression of NFAT1, calcineurin, catabolic enzymes in chondrocytes, and chondrogenic markers in affected articular cartilage and primary chondrocyte cultures treated with IL-1ß. ROP was applied both in vivo and in vitro to examine its effects on the pathophysiology of OA. Hyperalgesia in OA rats was improved by intra-articular injection of Rop. Moreover, Rop suppressed the overexpression of NFAT1, calcineurin, TNF-α, IL-6, MMP1 and MMP3, and reversed the diminution of collagen II and aggrecan, in affected cartilage of OA rats. Similar effects of Rop were also observed in mouse chondrocyte cultures treated with IL-1ß. In in vitro preparations, either activation (by increasing extracellular Ca2+) or inhibition (by cyclosporin A) of calcineurin blocked the effects of Rop. These results suggest that Rop may have therapeutic potential for OA in three aspects: analgesia, anti-inflammation, and anti-degradation of articular cartilage, probably via down-regulating calcineurin/NFAT1 signaling pathway.

[Effects of dexmedetomidine preconditioning attenuating remote lung injury of lower limb ischemia-reperfusion].

OBJECTIVE: To investigate the effects of dexmedetomidine preconditioning attenuating remote lung injury of lower limb ischemia-reperfusion. METHODS: Sixty patients form Central Hospital of Cangzhou scheduled for lower limb operation with tourniquet from January 2014 to June 2014. Lumbar plexus combined with sciatic nerve block was performed guided by a nerve stimulator in both groups. All patients were randomly assigned to two groups, conventional general anesthesia group (R group, n = 30) and dexmedetomidine preconditioning group (Pre-Dex group, n = 30). In the group Pre-Dex, a dexmedetomidine intravenous infusion was started at a dose of 0.125 ml/kg (4 µg/ml) for 10 minutes before using tourniquet, whereas group R received an equivalent volume of normal saline. Blood samples were taken in femoral vein for 4 ml. Monocytes TLR4 expression and interleukin-6(IL-6), interleukin-8(IL-8), tumor necrosis factor-α(TNF-α) level were determinated 15 minute before tourniquet inflation(T(1)), 15 minute (T(2)), 2 h(T(3)), 6 h(T(4))and 24 h(T(5)) after tourniquet release. Artery blood gas analysis, respiratory index and oxygenation index were measured by drawing off femoral artery for 2 ml. RESULTS: Compare with T(1), RI in group R was higher at T(4) and OI was lower at T(3-5) (P < 0.01), and there were no significant differences in group Pre-Dex at T(2)-T(5) about RI and OI (P > 0.05); IL-8,IL-6 level at T(3)-T(5) and TNF-α level at T(2)-T(5) in group R were significantly higher. IL-8,IL-6 level at T(3)-T(4) and TNF-α level at T(2)-T(4) in group Pre-Dex were higher. Monocytes TLR4 expression was higher in group R at T(3)-T(4) (P < 0.05). Compare with group R, RI in group Pre-Dex was lower and OI was higher at T(4) (P < 0.05); IL-8, IL-6 level at T(3)-T(5) and TNF-α level at T(2)-T(4) in group Pre-Dex was significantly lower (P < 0.05). Monocytes TLR4 expression was lower in group Pre-Dex at T(3)-T(5) (P < 0.05). IL-6, IL-8 level had positive correlation with TLR4 and RI ((r = 0.673, 0.647, 0.521, 0.457, P < 0.01 ), but had negative correlation with OI in group R (r = -0.613, -0.578, P < 0.01). CONCLUSION: Dexmedetomidine preconditioning attenuate remote lung injury of lower limb ischemia-reperfusion, and the mechanism may be related to down-regulation of monocytes TLR4 expression and degradation of IL-6, IL-8 and TNF-α level.