In Situ Sprayed Exosome-Cross-Linked Gel as Artificial Lymph Nodes for Postoperative Glioblastoma Immunotherapy.

One key challenge in postoperative glioblastoma immunotherapy is to guarantee a potent and durable T-cell response, which is restricted by the immunosuppressive microenvironment within the lymph nodes (LNs). Here, we develop an in situ sprayed exosome-cross-linked gel that acts as an artificial LN structure to directly activate the tumor-infiltrating T cells for prevention of glioma recurrence. Briefly, this gel is generated by a bio-orthogonal reaction between azide-modified chimeric exosomes and alkyne-modified alginate polymers. Particularly, these chimeric exosomes are generated from dendritic cell (DC)-tumor hybrid cells, allowing for direct and robust T-cell activation. The gel structure with chimeric exosomes as cross-linking points avoids the quick clearance by the immune system and thus prolongs the durability of antitumor T-cell immunity. Importantly, this exosome-containing immunotherapeutic gel provides chances for ameliorating functions of antigen-presenting cells (APCs) through accommodating different intracellular-acting adjuvants, such as stimulator of interferon genes (STING) agonists. This further enhances the antitumor T-cell response, resulting in the almost complete elimination of residual lesions after surgery. Our findings provide a promising strategy for postsurgical glioma immunotherapy that warrants further exploration in the clinical arena.

Chimeric Exosomes Functionalized with STING Activation for Personalized Glioblastoma Immunotherapy.

A critical challenge of existing cancer vaccines is to orchestrate the demands of antigen-enriched furnishment and optimal antigen-presentation functionality within antigen-presenting cells (APCs). Here, a complementary immunotherapeutic strategy is developed using dendritic cell (DC)-tumor hybrid cell-derived chimeric exosomes loaded with stimulator of interferon genes (STING) agonists (DT-Exo-STING) for maximized tumor-specific T-cell immunity. These chimeric carriers are furnished with broad-spectrum antigen complexes to elicit a robust T-cell-mediated inflammatory program through direct self-presentation and indirect DC-to-T immunostimulatory pathway. This chimeric exosome-assisted delivery strategy possesses the merits versus off-the-shelf cyclic dinucleotide (CDN) delivery techniques in both the brilliant tissue-homing capacity, even across the intractable blood-brain barrier (BBB), and the desired cytosolic entry for enhanced STING-activating signaling. The improved antigen-presentation performance with this nanovaccine-driven STING activation further enhances tumor-specific T-cell immunoresponse. Thus, DT-Exo-STING reverses immunosuppressive glioblastoma microenvironments to pro-inflammatory, tumoricidal states, leading to an almost obliteration of intracranial primary lesions. Significantly, an upscaling option that harnesses autologous tumor tissues for personalized DT-Exo-STING vaccines increases sensitivity to immune checkpoint blockade (ICB) therapy and exerts systemic immune memory against post-operative glioma recrudesce. These findings represent an emerging method for glioblastoma immunotherapy, warranting further exploratory development in the clinical realm.

Deep-penetration functionalized cuttlefish ink nanoparticles for combating wound infections with synergetic photothermal-immunologic therapy.

The challenge of wound infections post-surgery and open trauma caused by multidrug-resistant bacteria poses a constant threat to clinical treatment. As a promising antimicrobial treatment, photothermal therapy can effectively resolve the problem of drug resistance in conventional antibiotic antimicrobial therapy. Here, we report a deep-penetration functionalized cuttlefish ink nanoparticle (CINP) for photothermal and immunological therapy of wound infections. CINP is decorated with zwitterionic polymer (ZP, namely sulfobetaine methacrylate-methacrylate copolymer) to form CINP@ZP nanoparticles. Natural CINP is found to not only exhibit photothermal destruction of methicillin-resistant Staphylococcus aureus (MRSA) and Escherichia coli (E. coli), but also trigger macrophages-related innate immunity and enhance their antibacterial functions. The ZP coating on the surface of CINP enables nanoparticles to penetrate into deeply infected wound environment. In addition, CINP@ZP is further integrated into the thermosensitive Pluronic F127 gel (CINP@ZP-F127). After in situ spraying gel, CINP@ZP-F127 is also documented notable antibacterial effects in mice wound models infected with MRSA and E. coli. Collectively, this approach combining of photothermal therapy with immunotherapy can promote delivery efficiency of nanoparticles to the deep foci of infective wounds, and effectively eliminate wound infections.

In Situ Sprayed Biotherapeutic Gel Containing Stable Microbial Communities for Efficient Anti-Infection Treatment.

Systematic administration of antibiotics to treat infections often leads to the rapid evolution and spread of multidrug-resistant bacteria. Here, an in situ-formed biotherapeutic gel that controls multidrug-resistant bacterial infections and accelerates wound healing is reported. This biotherapeutic gel is constructed by incorporating stable microbial communities (kombucha) capable of producing antimicrobial substances and organic acids into thermosensitive Pluronic F127 (polyethylene-polypropylene glycol) solutions. Furthermore, it is found that the stable microbial communities-based biotherapeutic gel possesses a broad antimicrobial spectrum and strong antibacterial effects in diverse pathogenic bacteria-derived xenograft infection models, as well as in patient-derived multidrug-resistant bacterial xenograft infection models. The biotherapeutic gel system considerably outperforms the commercial broad-spectrum antibacterial gel (0.1% polyaminopropyl biguanide) in pathogen removal and infected wound healing. Collectively, this biotherapeutic strategy of exploiting stable symbiotic consortiums to repel pathogens provides a paradigm for developing efficient antibacterial biomaterials and overcomes the failure of antibiotics to treat multidrug-resistant bacterial infections.

Stemness Subtypes and Scoring System Predict Prognosis and Efficacy of Immunotherapy in Soft Tissue Sarcoma.

Tumor stemness has been reported to play important roles in cancers. However, a comprehensive analysis of tumor stemness remains to be performed to investigate the specific mechanisms and practical values of stemness in soft tissue sarcomas (STS). Here, we applied machine learning to muti-omic data of patients from TCGA-SARC and GSE21050 cohorts to reveal important roles of stemness in STS. We demonstrated limited roles of existing mRNAsi in clinical application. Therefore, based on stemness-related signatures (SRSs), we identified three stemness subtypes with distinct stemness, immune, and metabolic characteristics using consensus clustering. The low-stemness subtype had better prognosis, activated innate and adaptive immunity (e.g., infiltrating B, DC, Th1, CD8+ T, activated NK, gamma delta T cells, and M1 macrophages), more enrichment of metabolic pathways, more sites with higher methylation level, higher gene mutations, CNA burdens, and immunogenicity indicators. Furthermore, the 16 SRS-based stemness prognostic index (SPi) was developed, and we found that low-SPi patients with low stemness had better prognosis and other characteristics similar to those in the low-stemness subtype. Besides, low-stemness subtype and low-SPi patients could benefit from immunotherapy. The predictive value of SPi in immunotherapy was more accurate after the addition of MSI into SPi. MSIlowSPilow patients might be more sensitive to immunotherapy. In conclusion, we highlighted mechanisms and practical values of the stemness in STS. We also recommended the combination of MSI and SPi which is a promising tool to predict prognosis and achieve precise treatments of immunotherapy in STS.

MicroRNA-483-5p inhibits osteogenic differentiation of human bone marrow mesenchymal stem cells by targeting the RPL31-mediated RAS/MEK/ERK signaling pathway.

miR-483-5p has been shown to play a key regulatory role in mediating a variety of biological activities. However, there are only a few studies on how miR-483-5p regulates osteogenic differentiation of human bone marrow mesenchymal stem cells (hBMSCs), hence there is a need to explore the role and mechanism of miR-483-5p in regulating the osteogenic differentiation of hBMSCs. To that end, we used bioinformatics and cell experiments to confirm our hypothesis, a miRNA microarray dataset (GSE74209) and a mRNA dataset (GSE56816) were obtained from the GEO database, and the differentially expressed miRNAs (DE-miRNAs) and mRNAs (DE-mRNAs) were screened. In total, We found that the up-regulated candidate target genes were significantly enriched in the MAPK signaling pathway. Using the MCODE plug-in from Cytoscape, we identified RPL31 as the seed gene in the third major module. And we successfully established a possible miRNA-hub gene regulatory network. More importantly, we confirmed that the expression of miR-483-5p was down-regulated while the expression of RPL31 was up-regulated during osteogenic induction. Overexpression of miR-483-5p significantly inhibited osteogenic differentiation. In addition, western blot was used to measure protein levels of RPL31 and phosphorylated MEK/ERK family members. We demonstrated that miR-483-5p inhibits the RAS/MEK/ERK signaling pathway by targeting RPL31 and inhibiting its expression, thereby playing an inhibitory role in osteogenic differentiation. In light of our findings, RPL31 can be used as a novel therapeutic target for bone defects and osteoporosis, we reveal a newly discovered mechanism of osteogenic differentiation and provide a new strategy for treating osteoporosis and related diseases.

m6A Modification Patterns With Distinct Immunity, Metabolism, and Stemness Characteristics in Soft Tissue Sarcoma.

N6-methyladenosine (m6A) RNA methylation has been shown to have prognostic value in cancer. Nonetheless, its potential role regarding immunity, metabolism, and stemness in soft tissue sarcoma (STS) remains unknown. We comprehensively estimated the m6A modification patterns and corresponding immunity, metabolism, and stemness characteristics based on 568 STS samples and 21 m6A regulators. The m6Ascore was constructed to quantify m6A modification patterns in individuals using machine learning algorithms. Two distinct m6A modification patterns among the STS patients were identified, which exhibited differences in prognosis, immune cell infiltration, metabolic pathways, stemness, somatic mutation, and copy number variation. Thereafter, immunity-, metabolism-, and stemness phenotype-related genes associated with m6A modification were identified. Furthermore, patients with lower m6Ascores had increased antitumor immune responses, survival benefit under immunotherapy, tumor mutation burden, immunogenicity, and response to anti-PD-1/L1 immunotherapy. Immunotherapy sensitivity was validated using the IMvigor210 dataset. STS patients with lower m6Ascore might be more sensitive to docetaxel and gemcitabine. Finally, pan-cancer analysis illustrated the significant correlations of m6Ascore with clinical outcomes, immune cell infiltration, metabolism, and stemness. This study revealed that m6A modification plays an important role in immunity, metabolism, and stemness in STS. Evaluating the m6A modification pattern and development of m6Ascore may help to guide more effective immunotherapy and chemotherapy strategies.

Molecular Subtypes Based on Cell Differentiation Trajectories in Head and Neck Squamous Cell Carcinoma: Differential Prognosis and Immunotherapeutic Responses.

Objective: Head and neck squamous cell carcinoma (HNSCC) is one of the most common and lethal malignant tumors. We aimed to investigate the HNSCC cell differentiation trajectories and the corresponding clinical relevance. Methods: Based on HNSCC cell differentiation-related genes (HDRGs) identified by single-cell sequencing analysis, the molecular subtypes and corresponding immunity, metabolism, and stemness characteristics of 866 HNSCC cases were comprehensively analyzed. Machine-learning strategies were used to develop a HNSCC cell differentiation score (HCDscore) in order to quantify the unique heterogeneity of individual samples. We also assessed the prognostic value and biological characteristics of HCDscore using the multi-omics data. Results: HNSCCs were stratified into three distinct molecular subtypes based on HDRGs: active stroma (Cluster-A), active metabolism (Cluster-B), and active immune (Cluster-C) types. The three molecular subtypes had different characteristics in terms of biological phenotype, genome and epigenetics, prognosis, immunotherapy and chemotherapy responses. We then demonstrated the correlations between HCDscore and the immune microenvironment, subtypes, carcinogenic biological processes, genetic variation, and prognosis. The low-HCDscore group was characterized by activation of immunity, enhanced response to anti-PD-1/PD-L1 immunotherapy, and better survival compared to the high-HCDscore group. Finally, by integrating the HCDscore with prognostic clinicopathological characteristics, a nomogram with strong predictive performance and high accuracy was constructed. Conclusions: This study revealed that the cell differentiation trajectories in HNSCC played a nonnegligible role in patient prognosis, biological characteristics, and immune responses. Evaluating cancer cell differentiation will help to develop more effective immunotherapy, metabolic therapy, and chemotherapy strategies.

The Potential of Five Immune-Related Prognostic Genes to Predict Survival and Response to Immune Checkpoint Inhibitors for Soft Tissue Sarcomas Based on Multi-Omic Study.

Low response rates to immunotherapy have been reported in soft tissue sarcoma (STS). There are few predictive biomarkers of response, and the tumor immune microenvironment associated with progression and prognosis remains unclear in STS. Gene expression data from the Cancer Genome Atlas were used to identify the immune-related prognostic genes (IRPGs) and construct the immune gene-related prognostic model (IGRPM). The tumor immune microenvironment was characterized to reveal differences between patients with different prognoses. Furthermore, somatic mutation data and DNA methylation data were analyzed to understand the underlying mechanism leading to different prognoses. The IGRPM was constructed using five IRPGs (IFIH1, CTSG, STC2, SECTM1, and BIRC5). Two groups (high- and low-risk patients) were identified based on the risk score. Low-risk patients with higher overall survival time had higher immune scores, more immune cell infiltration (e.g., CD8 T cell and activated natural killer cells), higher expression of immune-stimulating molecules, higher stimulating cytokines and corresponding receptors, higher innate immunity molecules, and stronger antigen-presenting capacity. However, inhibition of immunity was observed in low-risk patients owing to the higher expression of immune checkpoint molecules and inhibiting cytokines. High-risk patients had high tumor mutation burden, which did not significantly influence survival. Gene set enrichment analysis further revealed that pathways of cell cycle and cancers were activated in high-risk patients. DNA methylation analysis indicated that relative high methylation was associated with better overall survival. Finally, the age, mitotic counts, and risk scores were independent prognostic factors for STS. Five IRPGs performed well in risk stratification of patients and are candidate biomarkers for predicting response to immunotherapy. Differences observed through the multi-omic study of patients with different prognoses may reveal the underlying mechanism of the development and progression of STS, and thereby improve treatment.

Comparative Efficacy and Acceptability of Pharmaceutical Management for Adults With Post-Traumatic Stress Disorder: A Systematic Review and Meta-Analysis.

The current clinical guidelines on post-traumatic stress disorder (PTSD) recommend selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs) of drugs. However, there is uncertainty about the efficacy of other drugs and selecting which treatments work best for which patients. This meta-analysis evaluated efficacy and acceptability of pharmaceutical management for adults with PTSD. Randomized-controlled trials, which reported active comparators and placebo-controlled trials of pharmaceutical management for adults with PTSD, from the Ovid Medline, EMBase, CENTRAL, PsycINFO, Ovid Health and Psychosocial Instruments, and ISIWeb of Science, were searched until June 21, 2019. In terms of efficacy, all active drugs demonstrated superior effect than placebo (SMD = -0.33; 95% CI, -0.43 to -0.23). The medications were superior to placebo in reducing the symptom of re-experiencing, avoidance, hyperarousal, depression, and anxiety. For acceptability, medicine interventions for PTSD showed no increase in all-cause discontinuation compared with placebo. Nevertheless, in terms of safety, medicine interventions indicated a higher risk of adverse effect compared with placebo (RR = 1.47, 95% CI: 1.24 to 1.75). Compared with placebo, the SSRIs and atypical antipsychotics drugs had significant efficacy whether in patients with severe or extremely severe PTSD status. However, only atypical antipsychotics (SMD = -0.29, 95% CI: -0.48 to -0.10) showed superior efficacy than placebo in veterans. Medication management could be effective in intervention of PTSD, which demonstrated a sufficient improvement in the core symptoms. This meta-analysis supports the status of SSRIs and SNRIs as recommended pharmacotherapy. However, patients with different clinical characteristics of PTSD should consider individualized drug management.

Risk score based on expression of five novel genes predicts survival in soft tissue sarcoma.

In this study, The Cancer Genome Atlas and Genotype-Tissue Expression databases were used to identify potential biomarkers of soft tissue sarcoma (STS) and construct a prognostic model. The model was used to calculate risk scores based on the expression of five key genes, among which MYBL2 and FBN2 were upregulated and TSPAN7, GCSH, and DDX39B were downregulated in STS patients. We also examined gene signatures associated with the key genes and evaluated the model's clinical utility. The key genes were found to be involved in the cell cycle, DNA replication, and various cancer pathways, and gene alterations were associated with a poor prognosis. According to the prognostic model, risk scores negatively correlated with infiltration of six types of immune cells. Furthermore, age, margin status, presence of metastasis, and risk score were independent prognostic factors for STS patients. A nomogram that incorporated the risk score and other independent prognostic factors accurately predicted survival in STS patients. These findings may help to improve prognostic prediction and aid in the identification of effective treatments for STS patients.

The application of enhanced recovery after surgery for upper gastrointestinal surgery: Meta-analysis.

BACKGROUND: Although enhanced recovery after surgery (ERAS) has made great progress in the field of surgery, the guidelines point to the lack of high-quality evidence in upper gastrointestinal surgery. METHODS: Randomized controlled trials in four electronic databases that involved ERAS protocols for upper gastrointestinal surgery were searched through December 12, 2018. The primary endpoints were lung infection, urinary tract infection, surgical site infection, postoperative anastomotic leakage and ileus. The secondary endpoints were postoperative length of stay, the time from end of surgery to first flatus and defecation, and readmission rates. Subgroup analysis was performed based on the type of surgery. RESULTS: A total of 17 studies were included. The results of the meta-analysis indicate that there was a decrease in rates of lung infection (RR = 0.50, 95%CI: 0.33 to 0.75), postoperative length of stay (MD = -2.53, 95%CI: - 3.42 to - 1.65), time until first postoperative flatus (MD = -0.64, 95%CI: - 0.84 to - 0.45) and time until first postoperative defecation (MD = -1.10, 95%CI: - 1.74 to - 0.47) in patients who received ERAS, compared to conventional care. However, other outcomes were not significant difference. There was no significant difference between ERAS and conventional care in rates of urinary tract infection (P = 0.10), surgical site infection (P = 0.42), postoperative anastomotic leakage (P = 0.45), readmissions (P = 0.31) and ileus (P = 0.25). CONCLUSIONS: ERAS protocols can reduce the risk of postoperative lung infection and accelerating patient recovery time. Nevertheless, we should also consider further research ERAS should be performed undergoing gastrectomy and esophagectomy.

Key Clinical Interest Outcomes of Pharmaceutical Administration for Veterans With Post-Traumatic Stress Disorder Based on Pooled Evidences of 36 Randomised Controlled Trials With 2,331 Adults.

Background: The effects of drug treatment on veterans, who have a high risk of post-traumatic stress disorder (PTSD), are not clear, and the guidelines are different from the recommendations of the recent meta-analysis. Our goal was to find the efficacy and frequencies of complications of drugs that can treat PTSD in veterans. Method: We searched Ovid MEDLINE, Ovid Embase, The Cochrane Library and Web of Science until January 1, 2020. The outcomes were designed as the change of PTSD total scale, subsymptom score, response rate, frequencies of complications outcomes, and acceptability. Results: We included a total of 36 randomised controlled trials with a total of 2,331 adults. In terms of overall effect, drug treatment is more effective than placebo in change in total PTSD symptoms scale (SMD = -0.24, 95% CI [-0.42, -0.06]) and response (RR = 1.66, 95% CI [1.01, 2.72]). However, in terms of frequencies of complications, drugs generally had a higher withdrawal rate (RR = 1.02, 95% CI [0.86, 1.20]) and a higher frequencies of complications (RR = 1.72, 95% CI [1.20, 2.47]) than placebo. Risperidone showed a good curative effect in change in total PTSD symptoms scale (SMD = -0.22, 95% CI [-0.43, 0.00]) and acceptability (RR = 1.31, 95% CI [0.82, 2.59]). The drugs acting on 5-HT receptors, our results showed that symptoms of hyper-arousal (SMD = -0.54, 95% CI [-0.86, -0.21]), symptoms of re-experiencing (SMD = -0.62, 95% CI [-0.86, -0.39]) and symptoms of avoidance (SMD = -0.53, 95% CI [- 0.77,-0.3]), The drugs acting on dopamine receptors, our results showed that symptoms of re-experiencing (SMD = -0.35, 95% CI [-0.55, -0.16]) and the drugs acting on α2 receptor has a significant effect on reducing total PTSD symptoms scale (SMD = -0.34, 95% CI [-0.62, -0.06]). Conclusion: Drug therapy can effectively treat PTSD, but its frequencies of complications should be considered. Different from the guidelines for adult PTSD, this study supports atypical antipsychotics, selective serotonin reuptake inhibitors and receptors that act on 5-HT and dopamine for the treatment of PTSD in veterans. Based on evidence among these drugs, the risperidone is the most effective for veterans, otherwise, sertraline is used as an alternative.

Impact and Beneficial Critical Points of Clinical Outcome in Corticosteroid Management of Adult Patients With Sepsis: Meta-Analysis and GRADE Assessment.

Background: With new randomised pieces of evidence and the latest clinical practice guideline from the BMJ emerging in 2018, an updated analysis of best available evidence on the controversial effects of corticosteroids in sepsis is warranted. Objectives: To comprehensively evaluate whether corticosteroids are beneficial in reducing mortality and what cumulative dosage, daily dosage, and duration of corticosteroid treatment would enable adult patients with sepsis to reach the critical point of benefits. Methods: Ovid MEDLINE, Ovid EMbase, Cochrane Library, and LILACS database were searched until March 22, 2019. Results: Thirty RCTs with 8,836 participants were identified. Long course low-dose corticosteroid therapy could improve 28-day mortality (RR = 0.90, 95% CI = 0.84-0.97; high quality), intensive care unit mortality (RR = 0.87; 95% CI = 0.79-0.95; moderate quality), and in-hospital mortality (RR = 0.88, 95% CI = 0.79-0.997; high quality). However, we found no benefits for 90-day, 180-day, and 1-year mortality. Subgroup results of long course corticosteroid treatment in a population with septic shock and vasopressor-dependent septic shock, corticosteroid regimen with hydrocortisone plus fludrocortisone, corticosteroid dosing strategies including bolus dosing and infusion dosing, the strategies of abrupt discontinuation, timing of randomisation ≤24 h, impact factor of ≥10, and sample size ≥500 were associated with a marginally reduction in 28-day mortality. Conclusions: This meta-analysis found that the long course low-dose and not short course high-dose corticosteroid treatment could marginally improve short-term 28-day mortality with high quality, especially septic shock and vasopressor-dependent septic shock, and it is recommended that long course (about 7 days) low-dose (about 200-300mg per day) hydrocortisone (or equivalent) with cumulative dose (at least about 1,000mg) may be a viable management option for overall patients with sepsis, and it can be also adapted to patient with septic shock alone. Early hydrocortisone plus fludrocortisone administration, via continuous infusion or bolus dosing, is also particularly important for the prognosis. Abrupt discontinuation of corticosteroids, as opposed to the conventional tapered discontinuation, may be considered as a desirable option in 28-day mortality. The safety profile of long course low-dose corticosteroid treatment, including adverse hyperglycaemia and hypernatraemia events, remains a concern, although these events could be easily treated. Clinical Trial Registration: PROSPERO, identifier CRD 42018092849.

Identification of Hub Genes and Key Pathways Associated With Bipolar Disorder Based on Weighted Gene Co-expression Network Analysis.

Bipolar disorder (BD) is a complex mental disorder with high mortality and disability rates worldwide; however, research on its pathogenesis and diagnostic methods remains limited. This study aimed to elucidate potential candidate hub genes and key pathways related to BD in a pre-frontal cortex sample. Raw gene expression profile files of GSE53987, including 36 samples, were obtained from the gene expression omnibus (GEO) database. After data pre-processing, 10,094 genes were selected for weighted gene co-expression network analysis (WGCNA). After dividing highly related genes into 19 modules, we found that the pink, midnight blue, and brown modules were highly correlated with BD. Functional annotation and pathway enrichment analysis for modules, which indicated some key pathways, were conducted based on the Enrichr database. One of the most remarkable significant pathways is the Hippo signaling pathway and its positive transcriptional regulation. Finally, 30 hub genes were identified in three modules. Hub genes with a high degree of connectivity in the PPI network are significantly enriched in positive regulation of transcription. In addition, the hub genes were validated based on another dataset (GSE12649). Taken together, the identification of these 30 hub genes and enrichment pathways might have important clinical implications for BD treatment and diagnosis.

Impact of Enhanced Recovery After Surgery on Postoperative Recovery for Pancreaticoduodenectomy: Pooled Analysis of Observational Study.

Purpose: To assess the impact of enhanced recovery after surgery (ERAS) protocols in pancreaticoduodenectomy. Methods: Four databases were searched for studies describing ERAS program in patients undergoing pancreatic surgery published up to May 01, 2018. Primary outcomes were mortality, readmission, reoperation and postoperative complications. Secondary outcomes were the length of stay and cost. Results: A total of 19 studies met inclusion and exclusion criteria and included 3,387 patients. Meta-analysis showed a decrease in pancreatic fistula (OR = 0.79, 95% CI: 0.67 to 0.95; I 2 = 0%), infection (OR = 0.63, 95% CI: 0.50 to 0.78; I 2 = 0%), especially incision infection (OR = 0.62, 95% CI: 0.42 to 0.91; I 2 = 0%), and pulmonary infection (OR = 0.28, 95% CI: 0.12 to 0.66; I 2 = 0%). Length-of-stay (MD: -3.89 days, 95% CI: -4.98 to -2.81; I 2 = 78%) and cost were also significantly reduced. There was no significant increase in mortality, readmission, reoperation, or delayed gastric emptying. Conclusion: This analysis revealed that using ERAS protocols in pancreatic resections may help decrease the incidence of pancreatic fistula and infections. Furthermore, ERAS also reduces length of stay and cost of care. This study provides evidence for the benefit of ERAS protocols.

Are Corticosteroids Beneficial for Sepsis and Septic Shock? Based on Pooling Analysis of 16 Studies.

Background: A host of systematic reviews and meta-analyses were carried out to estimate the role of corticosteroids in sepsis and septic shock. Discordant opinions were investigated to determine whether patients who experienced sepsis and septic shock could benefit from corticosteroids treatment. Our purpose is to perform a systematic review of overlapping meta-analyses, to explore the role of corticosteroids in the treatment of sepsis and septic shock. Method: Ovid MEDLINE, EMBase, Cochrane Database of Systematic Reviews, and LILACS were searched for eligible studies. Two authors individually extracted the relevant data and evaluated the quality of the meta-analysis using A MeaSurement Tool to Assess systematic Reviews 2 (AMSTAR 2) and ROBIS. The Jadad decision algorithm was implemented to identify the meta-analyses that offered the optimal level of evidence. Result: Sixteen meta-analyses met the eligibility criteria. None of the studies that reported mortality illustrated a significant improvement on mortality (14-day and 90-day), but a 28-day mortality on a long course of a low dose corticosteroids was described. Only four studies stated that a long course of low-dose corticosteroids had advantageous effect on 28-day mortality. A meta-analysis by Fang et al. was regarded as the highest level of evidence in the Jadad decision algorithm among the meta-analyses that were investigated in this systematic review. Conclusion: The 28-day mortality was reduced, as well as the mortality in the ICU and hospital and the length of stay in the ICU, using a long course of low-dose corticosteroids. This was demonstrated by a meta-analysis of the current optimal available evidence. Additionally, significant improvements on the adverse events of hyperglycemia and hypernatraemia have been made.

The Clinical Benefit of Device Therapy for Meniere's Disease in Adults: Systematic Review and Meta-Analysis.

OBJECTIVES: This study aimed to assess the clinical benefit of device therapy on controlling the symptoms of Meniere's disease (MD). MATERIALS AND METHODS: We searched PubMed, Embase, the Cochrane Library, China National Knowledge Internet, and Wanfang Data before January 13, 2018. We selected randomized controlled clinical trials, case-controlled studies, and cohort studies that dealt with outcomes of device therapy for the treatment of MD. RESULTS: Sixteen trials met our inclusion criteria. The use of device therapy resulted in improved vertigo control, which was described as a reduction in the number of vertigo days by month (weighted mean difference [WMD]: 3.15, 95% confidence interval [CI]: 2.00-4.31), in the number of vertigo episodes by month (WMD: 7.37, 95% CI: 2.40-12.35), and in the vertigo visual analog score (WMD: 41.51, 95% CI: 34.68-48.34). In addition, the overall complete vertigo control (class A) rate was 50% (95% CI: 37%-64%). The device therapy also reduced the number of sick days by month (WMD: 4.56, 95% CI: 2.15-6.97), and the functional level improved (WMD: 2.66, 95% CI: 2.15-3.17). The electrocochleographic parameters decreased. The device therapy proved beneficial for hearing changes (WMD: 3.19, 95% CI: 0.66-5.71). No publication bias was found in the funnel plot and the results of Egger's test. CONCLUSION: This study showed that the device therapy might reduce vertigo attacks and sick days in patients with MD. Additionally, the function level and hearing level may improve after the device therapy. In addition, the decrease in electrocochleographic parameters showed that inner ear electrophysiology improved after device therapy.

Identification of the Biomarkers and Pathological Process of Osteoarthritis: Weighted Gene Co-expression Network Analysis.

Osteoarthritis (OA) is a joint disease resulting in high rates of disability and low quality of life. The initial site of OA (bone or cartilage) is uncertain. The aim of the current study was to explore biomarkers and pathological processes in subchondral bone samples. The gene expression profile GSE51588 was downloaded from the Gene Expression Omnibus database. Fifty subchondral bone [knee lateral tibial (LT) and medial tibial (MT)] samples from 40 OA and 10 non-OA subjects were analyzed. After data preprocessing, 5439 genes were obtained for weighted gene co-expression network analysis. Highly correlated genes were divided into 19 modules. The yellow module was found to be highly correlated with OA (r = 0.71, p = 1e-08) and the brown module was most associated with the differences between the LT and MT regions (r = 0.77, p = 1e-10). Gene ontology functional annotation and Kyoto Encyclopedia of Genes and Genomes pathway enrichment indicated that the yellow module was enriched in a variety of components including proteinaceous extracellular matrix and collagen trimers, involved in protein digestion and absorption, axon guidance, ECM-receptor interaction, and the PI3K-Akt signaling pathway. In addition, the brown module suggests that the differences between the early (LT) and end (MT) stage of OA are associated with extracellular processes and lipid metabolism. Finally, 45 hub genes in the yellow module (COL24A1, COL5A2, COL3A1, MMP2, COL6A1, etc.) and 72 hub genes in the brown module (LIPE, LPL, LEP, SLC2A4, FABP4, ADH1B, ALDH4A1, ADIPOQ, etc.) were identified. Hub genes were validated using samples from cartilage (GSE57218). In summary, 45 hub genes and 72 hub genes in two modules are associated with OA. These hub genes could provide new biomarkers and drug targets in OA. Further studies focusing on subchondral bone are required to validate these hub genes and better understand the pathological process of OA.

Increasing Nonsteroidal Anti-inflammatory Drugs and Reducing Opioids or Paracetamol in the Management of Acute Renal Colic: Based on Three-Stage Study Design of Network Meta-Analysis of Randomized Controlled Trials.

Background: Currently, although non-steroidal anti-inflammatory drugs (NSAIDs) were recommended for acute renal colic in the 2018 European Association of Urology guidelines, there are no specific NSAIDs and no specific routes of administration in this guideline. The clinical practice of advocating intravenous opioids as the initial analgesia is still common out of the fear of adverse events from NSAIDs. Objectives: To comprehensively assess the efficacy and safety of NSAIDs, opioids, paracetamol, and combination therapy for acute renal colic. Methods: Ovid MEDLINE, Ovid EMbase, the Cochrane Library, Clinical Trials Registry Platform for Clinicaltrials.gov, and WHO International Clinical Trials Registry Platform were searched through February 2, 2018. Two reviewers selected all randomized controlled trails (RCTs) regarding NSAIDs, opioids, paracetamol, combination therapy, and placebo were identified for analysis. We designed a three-stage strategy based on classification and pharmacological mechanisms in the first stage, routes of administration in the second stage, and specific drug branches with different routes in the third stage using network meta-analysis. The pain variance at 30 min was seen as the primary outcome. Results: 65 RCTs with 8633 participants were involved. Comparing different classification and pharmacological mechanisms, combination therapy with more adverse events was more efficient than NSAIDs for the primary outcomes. Opioids gave rise to more nonspecific adverse events and vomiting events. NSAIDs were superior to opioids, paracetamol, and combination therapy after a full consideration of all outcomes. Comparing different routes of administration, NSAIDs with IV or IM route ranked first from efficacy and safety perspective. Comparing different specific drug branches with different routes, ibuprofen via IV route, ketorolac via IV route and diclofenac via IM route were superior for the management of acute renal colic. The results from diclofenac using IM route were more than those from ibuprofen used with IV route and ketorolac with IV route. Conclusions: In patients with adequate renal function, diclofenac via the IM route is recommended for patients without risks of cardiovascular events. Ibuprofen and ketorolac with IV route potentially superior to diclofenac via IM route remain to be investigated. Combination therapy is an alternative choice for uncontrolled pain after the use of NSAIDs.