Different digestion enzymes used for human pancreatic islet isolation: A mixed treatment comparison (MTC) meta-analysis

Collagenases are critical reagents determining yield and quality of isolated human pancreatic islets and may affect islet transplantation outcome. Some islet transplantation centers have compared 2 or more collagenase blends; however, the results regarding differences in quantity and quality of islets are conflicting. Thus, for the first time, a mixed treatment comparison (MTC) meta-analysis was carried out to compile data about the effect of different collagenases used for human pancreas digestion on islet yield, purity, viability and stimulation index (SI). Pubmed, Embase and Cochrane libraries were searched. Of 755 articles retrieved, a total of 15 articles fulfilled the eligibility criteria and were included in the MTC meta-analysis. Our results revealed that Vitacyte and Liberase MTF were associated with a small increase in islet yield (islet equivalent number/g pancreas) when compared with Sevac enzyme [standardized mean difference (95% credible interval – CrI) = −2.19 (−4.25 to −0.21) and −2.28 (−4.49 to −0.23), respectively]. However, all other enzyme comparisons did not show any significant difference regarding islet yield. Purity and viability percentages were not significantly different among any of the analyzed digestion enzymes. Interestingly, Vitacyte and Serva NB1 were associated with increased SI when compared with Liberase MTF enzyme [unstandardized weighted mean difference (95% CrI) = −1.69 (−2.87 to −0.51) and −1.07 (−1.79 to −0.39), respectively]. In conclusion, our MTC meta-analysis suggests that the digestion enzymes currently being used for islet isolation works with similar efficiency regarding islet yield, purity and viability; however, Vitacyte and Serva NB1 enzymes seem to be associated with an improved SI as compared with Liberase MTF.     

Improvement of collagenase distribution with the ductal preservation for human islet isolation

A delivery of collagenase at the islet-exocrine interface is crucial for successful human islet isolation. In this study, we investigated how the ductal preservation method at the procurement site affected collagenase distribution. At first, we analyzed human islet isolation data among groups using Serva collagenase with or without ductal injection (DI) or using new Liberase MTF with DI. Then, to assess the distribution of collagenase, human pancreata were classified into two groups: without DI (no DI, n = 5) and with DI at the procurement site (DI, n = 5). Collagenase with 1% marking dye was perfused in the same manner as in our clinical isolation. The distension of the pancreas and the microscopic distribution of the dyed collagenase in pancreas sections were examined. For microscopic analysis, islets were counted and classified into three criteria: unreached, dye didn't reach the islet surface; surface, dye resided on the surface of the islet but not inside; and inside, dye was found inside the islet. As a result, DI groups substantially improved islet yields. In addition, Liberase MTF with DI significantly improved efficacy of pancreas digestion. All pancreata were well distended macroscopically. However, microscopically, the majority of islets in the no DI group were untouched by the dyed collagenase. Ductal preservation substantially improved dyed collagenase delivery on the surface of islets. In conclusion, delivery of collagenase on the surface of islets was unexpectedly insufficient without DI, which was substantially improved by DI. Thus, ductal preservation is a potent method to improve collagenase delivery and islet yields.     

Improvement of collagenase distribution with the ductal preservation for human islet isolation

A delivery of collagenase at the islet-exocrine interface is crucial for successful human islet isolation. In this study, we investigated how the ductal preservation method at the procurement site affected collagenase distribution. At first, we analyzed human islet isolation data among groups using Serva collagenase with or without ductal injection (DI) or using new Liberase MTF with DI. Then, to assess the distribution of collagenase, human pancreata were classified into two groups: without DI (no DI, n = 5) and with DI at the procurement site (DI, n = 5). Collagenase with 1% marking dye was perfused in the same manner as in our clinical isolation. The distension of the pancreas and the microscopic distribution of the dyed collagenase in pancreas sections were examined. For microscopic analysis, islets were counted and classified into three criteria: unreached, dye didn’t reach the islet surface; surface, dye resided on the surface of the islet but not inside; and inside, dye was found inside the islet. As a result, DI groups substantially improved islet yields. In addition, Liberase MTF with DI significantly improved efficacy of pancreas digestion. All pancreata were well distended macroscopically. However, microscopically, the majority of islets in the no DI group were untouched by the dyed collagenase. Ductal preservation substantially improved dyed collagenase delivery on the surface of islets. In conclusion, delivery of collagenase on the surface of islets was unexpectedly insufficient without DI, which was substantially improved by DI. Thus, ductal preservation is a potent method to improve collagenase delivery and islet yields.     

An effective purification method using large bottles for human pancreatic islet isolation

The purification process is one of the most difficult procedures in pancreatic islet isolation. It was demonstrated that the standard purification method using a COBE 2991 cell processor with Ficoll density gradient solution harmed islets mechanically by high shear force. We reported that purification using large bottles with a lower viscosity gradient solution could improve the efficacy of porcine islet purification. In this study, we examined whether the new bottle purification method could improve the purification of human islets. Nine human pancreata from brain-dead donors were used. After pancreas digestion, the digested tissue was divided into three groups. Each group was purified by continuous density gradient using ET-Kyoto and iodixanol gradient solution with either the standard COBE method (COBE group) or the top loading (top group) or bottom loading (bottom group) bottle purification methods. Islet yield, purity, recovery rate after purification, and in vitro and in vivo viability were compared. Islet yield per pancreas weight (IE/g) and the recovery rate in the top group were significantly higher than in the COBE and bottom groups. Furthermore, the average size of purified islets in the top group was significantly larger than in the COBE group, which indicated that the bottle method could reduce the shear force to the islets. In vivo viability was also significantly higher in the top group compared with the COBE group. In conclusion, the top-loading bottle method could improve the quality and quantity of human islets after purification.     

An effective purification method using large bottles for human pancreatic islet isolation

The purification process is one of the most difficult procedures in pancreatic islet isolation. It was demonstrated that the standard purification method using a COBE 2991 cell processor with Ficoll density gradient solution harmed islets mechanically by high shear force. We reported that purification using large bottles with a lower viscosity gradient solution could improve the efficacy of porcine islet purification. In this study, we examined whether the new bottle purification method could improve the purification of human islets. Nine human pancreata from brain-dead donors were used. After pancreas digestion, the digested tissue was divided into three groups. Each group was purified by continuous density gradient using ET-Kyoto and iodixanol gradient solution with either the standard COBE method (COBE group) or the top loading (top group) or bottom loading (bottom group) bottle purification methods. Islet yield, purity, recovery rate after purification, and in vitro and in vivo viability were compared. Islet yield per pancreas weight (IE/g) and the recovery rate in the top group were significantly higher than in the COBE and bottom groups. Furthermore, the average size of purified islets in the top group was significantly larger than in the COBE group, which indicated that the bottle method could reduce the shear force to the islets. In vivo viability was also significantly higher in the top group compared with the COBE group. In conclusion, the top-loading bottle method could improve the quality and quantity of human islets after purification.     

Use of additives,scaffolds and extracellular matrix components for improvement of human pancreatic islet outcomes in vitro: A systematic review

Pancreatic islet transplantation is an established treatment to restore insulin independence in type 1 diabetic patients. Its success rates have increased lately based on improvements in immunosuppressive therapies and on islet isolation and culture. It is known that the quality and quantity of viable transplanted islets are crucial for the achievement of insulin independence and some studies have shown that a significant number of islets are lost during culture time. Thus, in an effort to improve islet yield during culture period, researchers have tested a variety of additives in culture media as well as alternative culture devices, such as scaffolds. However, due to the use of different categories of additives or devices, it is difficult to draw a conclusion on the benefits of these strategies. Therefore, the aim of this systematic review was to summarize the results of studies that described the use of medium additives, scaffolds or extracellular matrix (ECM) components during human pancreatic islets culture. PubMed and Embase repositories were searched. Of 5083 articles retrieved, a total of 37 articles fulfilled the eligibility criteria and were included in the review. After data extraction, articles were grouped as follows: 1) “antiapoptotic/anti-inflammatory/antioxidant,” 2) “hormone,” 3) “sulphonylureas,” 4) “serum supplements,” and 5) “scaffolds or ECM components.” The effects of the reviewed additives, ECM or scaffolds on islet viability, apoptosis and function (glucose-stimulated insulin secretion - GSIS) were heterogeneous, making any major conclusion hard to sustain. Overall, some “antiapoptotic/anti-inflammatory/antioxidant” additives decreased apoptosis and improved GSIS. Moreover, islet culture with ECM components or scaffolds increased GSIS. More studies are needed to define the real impact of these strategies in improving islet transplantation outcomes.     

Human pancreatic tissue dissociation enzymes for islet isolation: Advances and clinical perspectives

Background and aimsSuccessful clinical human allo or auto-islet transplantation requires the recovery of a sufficient number of functional islets from either brain-dead or chronic pancreatitis pancreases respectively.MethodsIn the last two decades (2000–2019), significant progress has been made in improving the human islet isolation procedures and in standardizing the use of different tissue dissociation enzyme (TDE; a mixture of collagenase and protease enzymes) blends to recover higher islet yields.Results and ConclusionsThis review presents information focusing on properties and role of TDE blends during the islet isolation process, particularly emphasizing on the current developments, associated challenges and future perspectives within the field.     

Chemotherapy for patients with gastric cancer after complete resection: A network meta-analysis

AIM:To conduct a network meta-analysis to evaluate the effectiveness of different chemotherapy regimens for patients with gastric cancer.METHODS:PubMed(1966-2011.12),the Cochrane Library(2011 Issue 2)and EMBASE(1974-2011.12)were searched with the terms"gastric cancer"and"chemotherapy",as well as the medical subject headings.References from relevant articles and conferences were also included.Patients who had previous gastric surgery,radiation before or after surgery or chemotherapy before surgery were excluded.In this study,only randomized controlled trials(RCTs)were considered,and the end-point was the overall mortality.Direct comparisons were performed using traditional meta-analysis whereas indirect comparisons were performed using network meta-analysis.RESULTS:In total,31 RCTs with 7120 patients were included.Five chemotherapy regimens,fluorouracil(FU)+BCNU,FU+methyl-CCNU(mCCNU),FU+cisplatin,FU+anthracyclines and FU+mitomycin c(MMC)+cytarabine(Ara-c),were found to be less beneficial in terms of overall mortality.In contrast,four chemotherapy regimens were effective for the patients after surgery,including FU+MMC+adriamycin(FMA),FU+MMC(FM),Tegafur and MMC,There was no significant difference in terms of overall mortality among these regimens.The evidence for the FM regimen and MMC regimen was poor.Additionally,the FMA regimen,which includes a variety of chemotherapy drugs and causes many side effects,was not better than the Tegafur regimen.CONCLUSION:Although the four chemotherapy regimens were effective in patients with gastric cancer after surgery and the overall mortality revealed no significant difference among them in the network metaanalysis,thorough analysis of the results recommends Tegafur as the first-line adjuvant chemotherapy regimen for patients after complete resection.     

Binocular treatment for individual with amblyopia: A systematic review and meta-analysis

Objective:To assess the efficacy of binocular treatment for individual with amblyopia.Methods:In this meta-analysis, a comprehensive search of literatures was performed from PubMed, Embase, Cochrane Library and Web of Science databases up to December 21, 2020. Sensitivity analysis was performed for all outcomes. The Begg’s test was used to assess the publication bias. Heterogeneity test was conducted for each effect indicator. Indicators were analyzed by random-effects model when the heterogeneity statistic I2 ≥ 50%, on the contrary, indicators were analyzed by fixed-effect model. Standard mean difference (SMD) or weighted mean difference (WMD) was adopted as effect indicators, and the effect amount was expressed as 95% confidence intervals (CIs).Results:A total of 13 literatures including 1146 participants were finally enrolled, with 595 in the intervention group and 551 in the control group. The results indicated that the improvement of amblyopic eye visual acuity [SMD: 0.882, 95%CI: (0.152, 1.613), P = 0.018] in binocular treatment group was better than that in control group. And binocular treatment could improve stereo acuity in individual with amblyopia [WMD: 0.138, 95%CI: (0.068, 0.208), P < 0.001].Conclusion:Binocular treatment may be beneficial to visual acuity, stereo acuity and binocular function improvement for individual with amblyopia. In clinical practice, binocular treatment can be used as one of the treatments for individual with amblyopia.     

A comparison of the efficacy and safety of traditional Chinese medicine external treatment for the knee osteoarthritis: A protocol for systematic review and network meta-analysis

Background:Knee osteoarthritis (KOA), also known as degenerative osteoarthritis, is a common and frequently occurring disease in orthopedics with cartilage degeneration as the pathogenic cause and articular bone hyperplasia as the sign. Many studies have confirmed that KOA can be effectively treated by traditional Chinese medicine (TCM) external treatment. So we take advantage of the method of network meta-analysis to systematically compare the efficacy and safety of different types of TCM external treatment for the KOA.Methods:We will research on external treatment of KOA by traditional Chinese medicine using randomized controlled trials (RCTs) in search database (EMBASE, PubMed, Web of Science, Chinese National Knowledge Infrastructure [CNKI], Weipu database [VIP], Wanfang, and China BioMedical Literature [CBM]). The data and evidence obtained will be processed using Stata 15.0 and WinBUGS 1.4.3.Results:We will evaluate the efficacy and safety of traditional Chinese medicine external treatment for the knee osteoarthritis in this study.Conclusion:This study will provide a new regimen for KOA treatment. It has extremely high reference value.INPLASY registration number:INPLASY2020120001.DOI number: 10.37766/inplasy2020.12.0001.     

External treatment of traditional Chinese medicine for radiation enteritis: A protocol for systematic review and meta-analysis

Background:Radiation enteritis (RE) is a common complication that often occurs after radiotherapy for abdominal and pelvic malignancies. RE could influence patients’ quality of life seriously and it is difficult to cure by conventional treatments. A lot of studies have revealed that the external treatment of traditional Chinese medicine (TCM) for RE is a safe and economical approach, but there is no relevant systematic review. The present study performed a systematic review and meta-analysis to compare TCM external treatment and conventional treatment for RE to evaluate the effectiveness and safety of external treatment of traditional Chinese medicine in the treatment of RE.Methods:Cochrane Library, PubMed, Embase, China National Knowledge Infrastructure (CNKI), Wan-Fang database, VIP Chinese Science and Technique Journals Database, and the Chinese Biomedical Literature Database (CBM) were searched. The time of publication was limited from inception to April, 2021. Two reviewers independently searched for the selected articles and extract the data. The RevMan V.5.3 statistical software (Cochrane Collaboration) and Stata V.16.0 software were used to conduct the meta-analysis.Results:We will show the results of this study in a peer-reviewed journal.Conclusion:This meta-analysis will provide reliable evidence for external treatment of TCM in the treatment of RE.INPLASY registration number:INPLASY202140120     

Use of traditional Chinese medicine as an adjunctive treatment for COVID-19: A systematic review and meta-analysis

Background:This review aims to evaluate the supportive effects of frequently used traditional Chinese medicine (TCM) for the treatment of coronavirus disease 2019 (COVID-19).Methods:Five databases were searched through July 7, 2020. Randomized controlled trials investigating the efficacy of TCM for use in the treatment of COVID-19 were included. Newcastle–Ottawa Scale (NOS) and modified Jadad score were used for the evaluation of the methodological quality of the included studies. Weighted mean difference, odds ratio (OR), and 95% confidence interval (95% CI) were calculated for pooling out results. Data were extracted for conducting a meta-analysis using STATA version 12.0.Results:Eight studies with a total of 750 patients were included in this meta-analysis. All included trial groups involved treatment with TCM and Western medicine, while the control groups were treated only with Western medicine. The intervention therapy significantly improved the overall effective rate (n = 346, OR = 2.5, 95% CIs = 1.46–4.29), fever symptom disappearance rate (n = 436; OR = 3.6; 95% CIs = 2.13–6.08), fatigue symptom disappearance rate (n = 436; OR = 3.04; 95% CIs = 1.76–5.26), cough symptom disappearance rate (n = 436; OR = 2.91; 95% CIs = 1.36–6.19), and sputum production reduction (n = 436; OR = 5.51; 95% CIs = 1.94–15.64). Based on the Newcastle–Ottawa Scale assessment, 6 studies received a score of 4, and 1 study achieved a score of 5. One study was assessed using the modified Jadad score, achieving a score of 6.Conclusions:The integration of TCM with Western medicine has significantly improved the treatment for COVID-19 patients compared to Western medicine treatment alone. Combined therapy using TCM and Western medicine revealed the potential adjunctive role of TCM in treating COVID-19. However, high-quality clinical studies are still required to further evaluate the efficacy and safety of TCM in the treatment of COVID-19.     

Acupuncture for postoperative delirium (POD): A systematic review and meta-analysis protocol

Background:Postoperative delirium (POD) is a form of delirium that is newly diagnosed after a surgical procedure. This study aims to examine the effectiveness and safety of acupuncture treatment for POD in patients who underwent surgery.Methods:Randomized controlled trials for patients diagnosed with POD using validated delirium assessment scales will be included in this review. Electronic databases, such as MEDLINE, EMBASE, CENTRAL, CINAHL (English DB), CNKI, Wanfang, VIP (Chinese database), KoreaMed, RISS, KISS, DBpia, OASIS (Korean DB), and J-STAGE (Japanese DB) will be searched without language limitation from their inception to October 2020. The intervention group will include patients who have received any type of acupuncture treatment for POD. The control group will include individuals with no treatment, sham acupuncture treatment, and conventional treatment. The primary outcome is the incidence of POD in each study. Quality assessment will be performed using the Cochrane risk of bias tool. A meta-analysis will be performed to pool the estimated effect.Conclusion:This study will provide evidence for acupuncture as a potential treatment for POD, in researchers, patients, and policy makers.Dissemination:The result of the study will be disseminated through posters, press releases, conference presentations, and peer-reviewed papers.Trial registration number:OSF 2020: (https://osf.io/usvdg)     

External treatment of traditional Chinese medicine for constipation after thoracolumbar compression fractures: A protocol for systematic review and meta-analysis

Background:Constipation is one of the common complications of thoracolumbar compression fractures, which seriously affects the quality of life and increases pain of patients. External treatment of traditional Chinese medicine (TCM) has been widely used clinically for constipation after thoracolumbar compression fractures, but there are no systematic review and meta-analysis of its efficacy. Therefore, we will conduct this study to systematically evaluate the clinical effects of external treatment of TCM for patients with constipation after thoracolumbar compression fractures.Methods:We will search the following electronic databases: PubMed, Embase, Cochrane Library, Web of Science, China National Knowledge Infastructure, Chinese Biomedical Literatures Database, Chinese Scientific Journal Database, and Wanfang Database. Randomized controlled trials on the treatment of constipation after thoracolumbar compression fractures with external treatment of TCM published from inception to May 2021 will be included in the search scope. The observation group was treated with Simple external treatment of TCM (such as external application of Chinese medicine, Chinese drugs at the acupoint, acupuncture, moxibustion, etc) or external treatment of TCM combined with conventional treatment/nursing of Western medicine, while the control group only was treated by conventional treatment/nursing of Western medicine. After screening literatures, extracting data, and assessing the risk of bias in the included studies, meta-analysis will be performed by Revman 5.3 software.Results:This study is expected to provide an evidence of the efficacy of external treatment of TCM for constipation after thoracolumbar compression fractures.Conclusion:The results of this meta-analysis may help provide evidence to determine whether external treatment of TCM can be effective interventions for thoracolumbar compression fractures patients with constipation.Trial registration number:INPLASY202150005     

Different acupuncture therapies combined with rehabilitation in the treatment of scapulohumeral periarthritis: A protocol for systematic review and network meta-analysis

Background:Scapulohumeral periarthritis is a disease that seriously affects human daily work and life, and greatly reduces peoples quality of life and affects human health all over the world. Now, many studies have shown that acupuncture and rehabilitation have a significant effect on scapulohumeral periarthritis. In this study, network meta-analysis was used to analyze and compare the clinical efficacy and difference of different acupuncture treatments on scapulohumeral periarthritis.Methods:All patients were diagnosed as scapulohumeral periarthritis by randomized controlled trial. Computer searches will be conducted on CNKI, Wan-Fang databases, VIP, CBM, Pubmed, Cochrane library, Embase, Web of Science. The retrieval period is from the date of database establishment to September 8, 2020. To avoid omissions, we will manually retrieve relevant references and conference papers. Finally, the risk of bias included in the study will be assessed according to the guidelines of the Cochrane Handbook for systematic review of interventions. All data analysis will be performed by Revman 5.3, WinBUGS1.4.3 and Stata14.2.Results:The effectiveness of each intervention was quantified. The main results included cure rate, total effective rate, VAS score and shoulder function score.Conclusion:Objective to provide evidence-based medicine basis for clinicians to choose more effective acupuncture therapy for scapulohumeral periarthritis.INPLASY Registration number:202090035.     

Fusion proteins of biologic agents in the treatment of rheumatoid arthritis (RA): A network meta-analysis

Background:To evaluate the efficacy of fusion proteins biologics (Etanercept (ETN), Anakinra (ANA), and Abatacept) combinations in the treatment of rheumatoid arthritis (RA) using network meta-analysis to rank those according to their performance medicines. The performance of these processes is ranked according to the results of the analysis and an explanatory study of the possible results is carried out.Methods:Multiple databases including PubMed, EMBASE, and Cochrane Library were used to identify applicable articles and collect relevant data to analyze using STATA (14.0) software. The literature included in this study was divided into a combination of a placebo, methotrexate (MTX), and an observation group (1 of the 3 drugs). The last search date was December 12, 2019.Results:A total of 19 eligible randomized controlled trials of fusion proteins biologics were identified, a total of 1109 papers were included, and the results showed that the ETN + MTX had the highest probability of being the most clinically efficacious intervention, with a surface under the cumulative ranking curve of 91.6, was significantly superior (P < .05). Patients who had received ETN or ETN + MTX or ANA had effective compared with patients who had received placebo (95% CI 1.28%–8.47%; 1.92%–19.18%; 1.06%–10.45%).Conclusions:1. The combination of ETN and MTX had the highest probability of optimal treatment compared to other drugs and 2. ENT, ENT + MTX, and ANA were effective in the treatment of RA compared to placebo.