Three-year hospital-wide pain management system implementation at a tertiary medical center: Pain prevalence analysis.

We developed a pain management system over a 3-year period. In this project, "Towards a pain-free hospital", we combined evidence-based medicine and medical expertise to develop a series of policies. The intervention mainly included the development of standard procedures for inpatient pain management, the implementation of hospital-wide pain medicine education and training, the establishment of a dashboard system to track pain status, and regular audits and feedback. This study aimed to gain an understanding of the changes in the prevalence of pain in inpatients under the care of the pain management system. The subjects of the survey are inpatients over 20 years old, and who had been hospitalized in the general ward for at least 3 days. The patients would be excluded if they were unable to respond to the questions. We randomly selected eligible patients in the general ward. Our trained interviewers visited inpatients to complete the questionnaires designed by our pain care specialists. A total of 3,094 inpatients completed the survey from 2018 to 2020. During the three-year period, the prevalence of pain was 69.5% (2018) (reference), 63.3% (2019) (OR:0.768, p<0.01), and 60.1% (2020) (OR:0.662, p <0.001). The prevalence rates of pain in patients undergoing surgery during the 3-year period were 81.4% (2018), 74.3% (2019), and 68.8% (2020), respectively. As for care-related causes of pain, injection, change in position/chest percussion, and rehabilitation showed a decreasing trend over the 3-year period of study. Our pain management system provided immediate professional pain management, and achieved a good result in the management of acute moderate to severe pain, especially perioperative pain. Studies on pain prevalence and Pain-Free Hospitals are scarce in Asia. With the aid of the policies based on evidence-based medicine and the dashboard information system, from 2018 to 2020, the prevalence of pain has decreased year by year.

Clinical option of pemetrexed-based versus paclitaxel-based first-line chemotherapeutic regimens in combination with bevacizumab for advanced non-squamous non-small-cell lung cancer and optimal maintenance therapy: evidence from a meta-analysis of randomized control trials.

BACKGROUND: In the era of immunotherapy, it is still unclear which is the best first-line therapy for patients with oncogenic driver negative advanced non-squamous non-small cell lung cancer (NS-NSCLC) who cannot tolerate immunotherapy, or subsequent therapy for patients with oncogenic driver positive NS-NSCLC whose disease progressed on prior targeted therapy. To assess the optimal choice of first-line and maintenance treatment regimens, we performed a meta-analysis of prospective randomized controlled clinical trials (RCTs) of patients with NS-NSCLC on bevacizumab combined with chemotherapy. METHODS: All eligible RCTs comparing pemetrexed-platinum with or without bevacizumab (PP ± B) and paclitaxel-carboplatin with bevacizumab (PC + B) as a first-line therapy, or comparing bevacizumab plus pemetrexed (Pem + B) and bevacizumab alone (B) as a maintenance treatment for advanced NS-NSCLC, were included after systematically searching web databases and meeting abstracts. The main research endpoints were comparisons of overall survival (OS) and progression-free survival (PFS). The other endpoints were objective response rate (ORR), 1-year PFS rate (PFSR1y) and major grade 3/4 treatment-related adverse events. RESULTS: Data of 3139 patients from six RCTs were incorporated into analyses. Three RCTs were included in an analysis that compared PP ± B and PC + B as a first-line therapy for advanced NS-NSCLC. Patients treated with first-line PP ± B showed similar OS and ORR, but significantly improved PFS (hazard ratio [HR], 0.88) and PFSR1y (risk ratio [RR], 0.83), as compared to patients treated with PC + B (all P < 0.05). PP ± B resulted in higher rates of grade 3/4 anemia and thrombocytopenia, but lower rates of neutropenia, febrile neutropenia, and sensory neuropathy than PC + B (all P < 0.001). The other three RCTs were included in an analysis that compared Pem + B and B as a maintenance treatment. Compared with B, Pem + B maintenance treatment resulted in significant improvements in OS (HR, 0.88), PFS (HR, 0.64), and PFSR1y (RR, 0.70), but higher rates of anemia, thrombocytopenia, and neutropenia (all P < 0.001). CONCLUSION: Although the first-line PP + B regimen had longer PFS and PFSR1y than the PC + B regimen, no OS difference was observed. Addition of pemetrexed to bevacizumab as maintenance therapy significantly improved OS compared with bevacizumab maintenance alone, but led to more toxicity.

Short-term outcomes and safety of radiotherapy for immediate breast reconstruction with autologous flap transfer following breast-conserving surgery.

BACKGROUND: The outcomes of immediate autologous breast reconstruction (IABR) after partial mastectomy followed by postoperative radiotherapy (RT) in terms of aesthetics, treatment-related complications, and local control are unclear. In this study, we evaluated the efficacy of IABR after partial mastectomy with or without breast RT, and thus the impact of radiation on autologous flap transfer. METHOD: A retrospective cohort study involving consecutive breast cancer patients who underwent IABR after partial mastectomy between July 2011 and December 2017 at Shengjing Hospital was performed. Patients were divided into two groups based on whether or not they received RT after IABR. We compared aesthetic outcomes and changes in the flap size over the three-dimensional coordinates at various timepoints (pre-RT, 1, 6, and 12 months post-RT), as well as postoperative complications, survival, and recurrence rates between the two groups. RESULTS: In total, 84 breast cancer patients were enrolled, with 32 patients in the RT group and 52 in the non-RT group. At a median follow-up time of 33.3 months, no significant difference was found in the rate of regional recurrence between the two groups (3.13% vs. 3.85%, P = 1.00), and no local recurrences occurred in either group. At the timepoints pre-RT, 1, and 6 months post-RT (approximately 4, 7, and 12 months after IABR, respectively), 77 (91.7%), 70 (83.3%), and 83 (98.8%) patients, respectively, had achieved very good or good cosmetic outcomes, and only changes in breast skin color at 1 month after RT significantly differed between the RT and non-RT groups, with very good or good cosmetic result rates of 62.5% vs. 96.2%, respectively (P < 0.001). No significant difference in the reduction of flap size was observed at any timepoint between the two groups. There were no significant differences between the two groups in the rates of postoperative complications including necrosis of the flap, infection, hematoma, or seroma (all P > 0.05). Additionally, no grade 3 or greater RT-associated adverse events occurred during or after RT. CONCLUSION: RT following IABR provides aesthetically satisfactory results without intolerable adverse complications and may safely be performed in patients who underwent IABR after partial mastectomy.

Pain prevalence in hospitalized patients at a tertiary academic medical center: Exploring severe persistent pain.

OBJECTIVE: The pain prevalence of inpatients is not a well-studied medical issue in Asia. We have aimed to evaluate pain prevalence and characterize those patients who have suffered from severe, persistent pain. METHODS: We investigated pain prevalence using a quota sampling from 19 general wards during the year 2018. Using a structured questionnaire, eight interviewers visited patients at an age ≥ 20 years, and who had been staying in general wards for ≥ 3 days. Those patients were excluded if they were unable to respond to the interview questions. If they reported pain during hospitalization, the maximum pain level and the duration of pain suffered in the past 24 hours were assessed. Care-related pain was also surveyed. RESULTS: A total of 1,034 patients (M/F, 537/497) completed the survey. Amongst them, 719 patients (69.5%) experienced pain, with moderate and severe pain levels being 27.3% and 43%, respectively. Surgery was considered as it related to pain, including significantly severe pain. The top 3 care-related pain causes were needle pain, wound dressing, and change in position/chest percussion. Change in position/chest percussion and rehabilitation were associated with severe, persistent pain. CONCLUSIONS: Pain is common in approximately 70% of inpatients, with surgery being associated with severe pain. Mobilization and rehabilitation may lead to severe, persistent pain. The periodic study of pain prevalence is essential in order to provide precise pain management.

MicroRNA-195 prevents hippocampal microglial/macrophage polarization towards the M1 phenotype induced by chronic brain hypoperfusion through regulating CX3CL1/CX3CR1 signaling.

BACKGROUND: Microglial polarization is a dynamic response to acute brain hypoxia induced by stroke and traumatic brain injury (TBI). However, studies on the polarization of microglia in chronic cerebral circulation insufficiency (CCCI) are limited. Our objective was to investigate the effect of CCCI on microglial polarization after chronic brain hypoperfusion (CBH) and explore the underlying molecular mechanisms. METHODS: CBH model was established by bilateral common carotid artery occlusion (2-vessel occlusion, 2VO) in rats. Using the stereotaxic injection technique, lenti-pre-miR-195 and anti-miR-195 oligonucleotide fragments (lenti-pre-AMO-miR-195) were injeted into the CA1 region of the hippocampus to construct animal models with high or low expression of miR-195. Immunofluorescence staining and flow cytometry were conducted to examine the status of microglial polarization. In vitro, Transwell co-culture system was taken to investigate the role of miR-195 on neuronal-microglial communication through CX3CL1-CX3CR1 signaling. Quantitative real-time PCR was used to detect the level of miR-195 and inflammatory factors. The protein levels of CX3CL1 and CX3CR1 were evaluated by both western blot and immunofluorescence staining. RESULTS: CBH induced by 2VO initiated microglial/macrophage activation in the rat hippocampus from 1 week to 8 weeks, as evaluated by increased ratio of (CD68+ and CD206+)/Iba-1 immunofluorescence. And the microglial/macrophage polarization was shifted towards the M1 phenotype at 8 weeks following CBH. The expression of CX3CL1 and CX3CR1 was increased in the hippocampus of 2VO rats at 8 weeks. An in vitro study in a Transwell co-culture system demonstrated that transfection of either primary-cultured neonatal rat neurons (NRNs) or microglial BV2 cells with AMO-195-induced M1 polarization of BV2 cells and increased CX3CL1 and CX3CR1 expression and that these effects were reversed by miR-195 mimics. Furthermore, the upregulation of miR-195 induced by lenti-pre-miR-195 injection prevented microglial/macrophage polarization to M1 phenotype triggered by hippocampal injection of lenti-pre-AMO-miR-195 and 2VO surgery. CONCLUSIONS: Our findings conclude that downregulation of miR-195 in the hippocampus is involved in CBH-induced microglial/macrophage polarization towards M1 phenotype by governing communication between neurons and microglia through the regulation of CX3CL1 and CX3CR1 signaling. This indicates that miR-195 may provide a new strategy for clinical prevention and treatment of CBH.

Neoadjuvant EGFR-TKI Therapy for EGFR-Mutant NSCLC: A Systematic Review and Pooled Analysis of Five Prospective Clinical Trials.

PURPOSE: The role of neoadjuvant epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) targeted therapy for patients with EGFR-mutant non-small cell lung cancer (NSCLC) has not been clarified. A pooled analysis of prospective clinical trials was conducted to evaluate the efficacy and safety of neoadjuvant EGFR-TKI therapy. METHODS: The PubMed, Embase, Web of Science, and Cochrane Library databases, as well as meeting abstracts were searched for prospective clinical trials evaluating the efficacy and safety of neoadjuvant EGFR-TKI for treatment of EGFR-mutant NSCLC. The main outcomes included the objective response rate (ORR), downstaging rate, surgical resection rate (SRR), pathologic complete response (pCR) rate, progression-free survival (PFS), and adverse events. RESULTS: A total of five, phase II, prospective, clinical trials involving 124 patients with resectable or potentially resectable EGFR-mutant NSCLC treated with neoadjuvant erlotinib or gefitinib treatment were included in this pooled analysis. The median neoadjuvant medication time was 42 (range, 21-56) days and the median time of response evaluation was 45 (range, 42-56) days. The pooled ORR was 58.5% [95% confidence interval (CI), 45.5%-71.8%] and the surgical resection and complete resection (R0) rates were 79.9% (95% CI, 65.3%-94.5%) and 64.3% (95% CI, 43.8%-84.8%), respectively. In the stage IIIA subgroup (n = 68), the pooled ORR, SRR, and R0 rate were 51.4%, 72.9%, and 57.0%, respectively, while the downstaging and pCR rates were 14.0% and 0.0%, respectively. The pooled median PFS and overall survival were 13.2 and 41.9 months, respectively. Of the most common grade 3/4 adverse events in the overall group, the incidences of hepatotoxicity and skin rash were 5.3% and 14.7%, respectively. The most commonly reported postoperative complications were lung infection, arrhythmia, and pneumothorax. CONCLUSION: Neoadjuvant EGFR-TKI therapy provides a feasible treatment modality for patients with resectable or potentially resectable EGFR-mutant NSCLC, with satisfactory surgical outcomes and low toxicity. Although further phase III clinical trials are needed to confirm these findings, it is necessary to explore the feasibility of a more effective EGFR-TKI combination neoadjuvant therapy given the modest downgrade and pCR rates for EGFR-TKI alone.

Durable Clinical Response to Pyrotinib After Resistance to Prior Anti-HER2 Therapy for HER2-Positive Advanced Gastric Cancer: A Case Report.

Background: Patients with advanced gastric cancer, especially the HER2-positive type, have a poor prognosis; there is a paucity of effective anti-HER2 drug therapies in patients who develop resistance to trastuzumab. Case presentation: We report the case of a 36-year-old male with HER2-positive gastric cancer with lung and liver metastases. The patient responded after treatment with trastuzumab combined with chemotherapy and attained a progression-free survival (PFS) of 17 months. Subsequently, the patient received apatinib that selectively inhibits the VEGFR2 and obtained an evident tumor response and a PFS of 8 months. When the disease progressed again, the regimen containing lapatinib failed. Then, the patient received treatment with nivolumab. However, he presented with hyper-progressive disease (HPD). Finally, he received a combination of capecitabine and pyrotinib, an irreversible dual TKI, acting on HER2 and EGFR. The tumor shrank markedly with this combination therapy. The mechanism of both HPD due to immunotherapy and the resistance to trastuzumab and lapatinib were investigated in this case. Loss of phosphatase and tensin homolog (PTEN) and new mutations of BRCA1 and KRAS were detected after resistance to trastuzumab and lapatinib. Conclusions: For patients with HER2-positive advanced gastric cancer who have developed resistance to trastuzumab, pyrotinib is a promising new agent, which can be used as salvage therapy.

TRIM65 is a potential oncogenic protein via ERK1/2 on Jurkat and Raji cells: A therapeutic target in human lymphoma malignancies.

In human lung cancer, Tripartite motif 65 (TRIM65) is documented as an important regulator in carcinogenesis. Knockdown of TRIM65 prevents the tumorigenesis of lung cancer cells, while TRIM65 overexpression presents the opposite effect. However, the roles of TRIM65 in human lymphocyte malignancies have reported little. Herein, we found that Jurkat (T-lymphocyte) and Raji (B-lymphocyte) expressed TRIM65. We aimed to investigate whether TRIM65 was a potential oncogenic protein that regulated the tumorigenesis of Jurkat and Raji cells. In our present study, cells were transfected with siRNA-TRIM65 or TRIM65 overexpression vector, Cell counting kit-8 (CCK-8), Flow cytometry and Annexin V-FITC/propidium iodide (PI) staining was carried out to detect cell viability, cell cycle profile and cell apoptosis, respectively. Extracellular signal-regulated kinases 1/2 (ERK1/2) pathway-associated proteins, such as Bcl2, cleaved-caspase 3, vascular endothelial growth factor (VEGF), and phosphorylated ERK1/2 (p-ERK1/2) were assessed. Our data indicated that knockdown of TRIM65 prevented the tumorigenesis of Jurkat and Raji cells. TRIM65 silencing inhibited cell proliferation, promoted cell apoptosis and arrested cell cycle, highly like through blocking ERK1/2 pathway. However, TRIM65 overexpression enhanced cell viability, increased the protein levels of Bcl2, VEGF, p-ERK1/2 while decreased cleaved-caspase 3 expression, suggesting the promoted effect of TRIM65 overexpression in the tumorigenesis of those two lymphoma cells. To validate the involvement of ERK1/2 pathway, ERK1/2 inhibitor AZD8330 (1 µmol/L) was introduced. We found that AZD8330 significantly prevented TRIM65 overexpression-induced tumorigenesis. We concluded that TRIM65 served as a potential oncogenic protein on Jurkat and Raji cells, and ERK1/2 pathway was the underlying mechanism. Approaches targeting TRIM65 provided a novel strategy for the treatment of lymphoma.

[Study on anti-inflammation and immunoloregulation effect of Guizhi Fuling capsule ingredients using high content screening].

The present study sought to investigate the anti-inflammation and immunoloregulation effect of 17 Guizhi Fuling capsule ingredients. The anti-inflammatory ingredients on LPS-induced RAW264. 7 cell injury were assessed with ELISA and immunofluorescence. The release of IL-1ß, TNF-α, PGE2 were detected with ELISA and the expression of COX-2 was detected with immunofluorescence. The effects of them on promoting splenic lymphocyte proliferation were assessed with MTT and Hoechst 33342 staining method. The results showed that 15 ingredients had obviously anti-inflammatory activity on LPS- induced injury and play the immunoloregulation roles. This study suggested that the 15 ingredients may be the active ingredients on pelvic infection.

Genetic variants at 6p21.1 and 7p15.3 Identified by GWASs of multiple cancers and ovarian cancer risk: a case-control study in Han Chinese women.

A recent study summarized several published genome-wide association studies (GWASs) of cancer and reported two pleiotropic loci at 6p21.1 and 7p15.3 contributing to multiple cancers including lung cancer, noncardia gastric cancer (NCGC), and esophageal squamous-cell carcinoma (ESCC) in Han Chinese. However, it is not known whether such genetic variants have similar effects on the risk of gynecologic cancers, such as ovarian cancer. Hence, we explored associations between genetic variants in 6p21.1 and 7p15.3 and ovarian cancer risk in Han Chinese women. We performed an independent case-control study by genotyping the two loci (rs2494938 A > G at 6p21.1 and rs2285947 A > G at 7p15.3) in a total of 377 ovarian cancer cases and 1,034 cancer-free controls using TaqMan allelic discrimination assay. We found that rs2285947 at 7p15.3 was significantly associated with risk of ovarian cancer with per allele odds ratio (OR) of 1.33 [95% confidence interval (CI): 1.08-1.64, P=0.008]. However, no significant association was observed between rs2494938 and ovarian cancer risk. Our results showed that rs2285947 at 7p15.3 may also contribute to the development of ovarian cancer in Han Chinese women, further suggesting pleiotropy of 7p15.3 in multiple cancers.

Effect of ozone on aflatoxins detoxification and nutritional quality of peanuts.

Aflatoxins are a group of secondary metabolites produced by Aspergillus flavus and Aspergillus parasiticus with carcinogenicity, teratogenicity, and mutagenicity. Aflatoxins may be found in a wide range of agri-products, especially in grains, oilseeds, corns, and peanuts. In this study, the conditions for detoxifying peanuts by ozonation were optimised. Aflatoxins in peanuts at moisture content of 5% (w/w) were sensitive to ozone and easily degraded when reacted with 6.0mg/l of ozone for 30min at room temperature. The detoxification rates of the total aflatoxins and aflatoxin B1 (AFB1) were 65.8% and 65.9%, respectively. The quality of peanut samples was also evaluated in this research. No significant differences (P>0.05) were found in the polyphenols, resveratrol, acid value (AV), and peroxide value (PV) between treated and untreated samples. The results suggested that ozonation was a promising method for aflatoxin detoxification in peanuts.

Cathepsin L plays a role in quinolinic acid-induced NF-Κb activation and excitotoxicity in rat striatal neurons.

The present study seeks to investigate the role of cathepsin L in glutamate receptor-induced transcription factor nuclear factor-kappa B (NF-κB) activation and excitotoxicity in rats striatal neurons. Stereotaxic administration of the N-methyl-d-aspartate (NMDA) receptor agonist Quinolinic acid (QA) into the unilateral striatum was used to produce the in vivo excitotoxic model. Co-administration of QA and the cathepsin L inhibitor Z-FF-FMK or 1-Naphthalenesulfonyl-IW-CHO (NaphthaCHO) was used to assess the contribution of cathepsin L to QA-induced striatal neuron death. Western blot analysis and cathepsin L activity assay were used to assess the changes in the levels of cathepsin L after QA treatment. Western blot analysis was used to assess the changes in the protein levels of inhibitor of NF-κB alpha isoform (IκB-α) and phospho-IκB alpha (p-IκBα) after QA treatment. Immunohistochemical analysis was used to detect the effects of Z-FF-FMK or NaphthaCHO on QA-induced NF-κB. Western blot analysis was used to detect the effects of Z-FF-FMK or NaphthaCHO on QA-induced IκB-α phosphorylation and degradation, changes in the levels of IKKα, p-IKKα, TP53, caspase-3, beclin1, p62, and LC3II/LC3I. The results show that QA-induced loss of striatal neurons were strongly inhibited by Z-FF-FMK or NaphthaCHO. QA-induced degradation of IκB-α, NF-κB nuclear translocation, up-regulation of NF-κB responsive gene TP53, and activation of caspase-3 was strongly inhibited by Z-FF-FMK or NaphthaCHO. QA-induced increases in beclin 1, LC3II/LC3I, and down-regulation of p62 were reduced by Z-FF-FMK or NaphthaCHO. These results suggest that cathepsin L is involved in glutamate receptor-induced NF-κB activation. Cathepsin L inhibitors have neuroprotective effects by inhibiting glutamate receptor-induced IκB-α degradation and NF-κB activation.

[Inhibitory and lethal effects of human-mouse chimeric antibody against CD80 on the growth of B lymphoma cell lines Raji and Daudi].

AIM: To study the inhibitory and lethal effects of human-mouse chimeric antibody against CD80 (named ch-4E5) on the growth of B lymphoma cell lines Daudi and Raji. METHODS: Immunofluorescence and flow cytometry were used to analyze the detection of membrane CD80 in Raji and Daudi by ch-4E5. After the co-culture of ch-4E5 with Raji and Daudi, respectively, at the final concentration of 10 mg/L, the expression of Fas and FasL was observated to be at the 0 h, 4 h, 10 h, 16 h, 24 h and 48 h by direct immunofluorescence and flow cytometry, and the blocking effect on cell growth of ch-4E5 was determined at 72 h by MTT assay. MTT assay was also used to study the ADCC effect with PBMC as effector cells and Raji and Daudi as target cells. The efficiency target ratio was 20:1. RESULTS: The combination rate between ch-4E5 and Raji and Daudi was 98.6% and 96.4%, respectively. After the co-culture of ch-4E5 with Raji and Daudi cells for 4 hs, the expression of FasL in Raji began to up-regulate. It reached the peak at 16 h and its positive rate was 16.8%. Compared with human IgG1 control group, it was increased obviously (P<0.01). The expression of Fas increased at 10 h, and then reached the top at 24 h. The combination rate was 15.6%. There was significant deviation compared with human IgG1 control group (P<0.01). Moreover, the expression of FasL and Fas on Daudi was also altered. The trend was similar to these on Raji, and the highest expression was 15.9% and 13.7%, respectively. The inhibitory rate was 34.60% and 32.64% respectively when ch-4E5 with Raji and Daudi had been co-cultured for 72 h (P<0.01). Furthermore, ch-4E5 could mediate the ADCC effect and the maximum killing rate was 55.61% and 54.42%, respectively(P<0.01). CONCLUSION: The human-mouse chimeric antibody against CD80 can inhibit the proliferation of B lymphoma cell lines Daudi and Raji cells through Fab and Fc sections in vitro.