This study aimed to evaluate the diagnostic value of telomerase activity (TA) for bladder cancer (BC) by meta-analysis.We conducted a systematic search of studies published on PubMed, Embase, and Web of Science up to June 1, 2019. We used Stata 15 and Review Manager 5.3 for calculations and statistical analysis.To evaluate the diagnostic value of TA for BC, we performed a meta-analysis on 22 studies, with a total of 2,867 individuals, including sensitivity, specificity, positive and negative likelihood ratio , diagnostic odds ratio (DOR), and 95% confidence intervals (CIs). The pooled parameters were calculated from all studies, and we found a sensitivity of 0.79 (95% CI: 0.72–0.84), a specificity of 0.91 (95% CI: 0.87–0.94), a PLR of 8.91 (95% CI: 5.91–13.43), an NLR of 0.24 (95% CI: 0.15–0.37), a DOR of 37.90 (95% CI: 23.32–61.59), and an AUC of 0.92 (95% CI: 0.90–0.94). We also conducted a subgroup analysis based on the different stages and grades of BC. Results from the subgroup analysis showed that there was no significant difference in TA in either high and low stages of BC, but that low-grade tumors had a lower TA than high-grade tumours.TA can be used as a potential biomarker for the diagnosis of bladder cancer with its high specificity. Rigorous and high-quality prospective studies are required to verify our conclusion. Bladder cancer (BC) is a malignant tumor with very high invasiveness and is one of the ten most common cancer types occurring in both males and females , 2. BC cvia cystoscope for pathological diagnosis is the gold standard for the diagnosis of bladder cancer. Its intuitive characteristics are quite reliable for the diagnosis of BC, but this invasive operation will bring great pain to patients, and its expensive charges also affect its clinical frequency of use and late follow-up  is a non-invasive and effective auxiliary test for the diagnosis of BC . TelomerNon-invasive diagnostic methods have become a popular and emerging field. There are many studies reporting the accuracy of TA in the diagnosis of BC. However, these diagnostic capabilities are reported by different research groups and thus have significant differences between them. The limitations of these studies are sampling errors and confounding factors within the experiment. Taking into account the limitations of single studies, we performed a meta-analysis based on several research samples and used statistical calculations to better understand the diagnostic efficiency of TA in patients with BC. Some studies have previously revealed the relationship between telomere length and various cancers . Based oWe systematically retrieved relevant literature from the PubMed, Embase, and Web of Science databases from inception to June 1, 2019. We used TA, BC, and urine as the search terms, and the search language was limited to English. We also searched the relevant references’ directories to avoid missing other relevant documents.Studies that meet the following requirements were included in our research: patients diagnosed with BC using the gold standard cystoscopy, studies with the diagnostic value of TA reflected in the research article, and studies with sufficient data on true positive (TP), false positive (FP), false negative (FN), and true negative (TN). Duplicate articles, insufficient quality, studies focusing on other diseases, letters, comments, case reports, and editorials were excluded from our analysis. The review process was assessed by two authors, independently.Studies that meet the following requirements can be included in our research: (1) A patient must be pathologically confirmed and diagnosed as bladder cancer. (2) The patient does not have other malignant tumors of the urinary system. (3) The patient did not perform any invasive transurethral procedures before taking the patient’s urine sample or bladder wash. (4) The telomerase activity in urine or washing fluid samples of all patients has been verified by scientific reagents. (5) The original study provided the number of samples that scientifically proved the telomerase activity in urine or bladder irrigation fluid samples: the number of patients or healthy people whose telomerase activity was positive/negative. Duplicate studies, low-quality studies, studies that cannot extract complete trial data, focus on other diseases, letters, comments, editorials, and case reports are excluded. This process was independently retrieved by two authors (LP and JZL).We used the Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) to assess the quality of the included studies. We also used a quantitative method to assess the selected studies. The QUADAS-2 included 14 items . Key dom2 to evaluate the heterogeneity of the study, I2>50% improvement was considered as significantly heterogeneous  and Review Manager 5.3 for the statistical analysis. Using a Q test and Iogeneous . We usedogeneous . We calcogeneous . P<0.05 In 2 was greater than 50%, the random effects model was used to combine sensitivity and specificity. The diagnostic value of TA for the detection of BC is shown in Since the value of IWe performed a subgroup analysis of TA based on different stages and grades of the tumors. We specified Tis, Ta, or T1 for a low stage tumor, and T2 and above for a high stage tumor. Similarly, we specified that grade 1 is a low-grade tumor and grades 2–3 is a high-grade tumor. According to the results of the heterogeneity test, we used a fixed model for meta-analysis for both grade and stage, and the results and forest map are shown in The Deeks plot showed there was no publication bias  and specificity (I2 = 83.86%). Due to the obvious heterogeneity among the studies, the random effects model was implemented in the calculation and statistics of the combined results to obtain a relatively conservative confidence interval.According to the results of the forest plot, the heterogeneity of TA was high in both sensitivity , gold standard selection, and description (samemth and reftest), diagnostic test to be evaluated (index), and patient characteristics (subject). It can be seen from the forest plot that in the 22 studies we included, gold standard selection, diagnostic test evaluation, and patient characteristics have statistically significant effects on the heterogeneity of sensitivity and specificity  or between different grades, using meta-analysis. Our results showed that the TA in low-grade tumors was significantly lower than in high-grade tumors (P = 0.001). We believe that this is because the higher the grade, the lower the degree of differentiation, the stronger the invasive ability, and the higher the TA, consistent with results reported by Bravaccini et al . DetectiCystoscopy biopsy, as an invasive examination method, brings pain to patients to a certain extent. For elderly men with enlarged prostate, cystoscopy is more likely to cause prostate bleeding, pain, infection, and other related complications. Anatomically shorter urethra of female patients solves some obstacles for cystoscope access. If the patient has bladder inflammation or tuberculosis infection, the biopsy forceps for the removal of bladder mucosa tissue will make the incidence of bleeding, infection, severe pain, and other complications higher. Whether the clinician’s judgment on the location of the lesion is accurate also affects whether the patient needs to undergo a second cystoscopy to determine the lesion. At present, the diagnosis of malignant tumors is transitioning from invasive to non-invasive. Finding suitable body fluid/blood biomarkers to improve tumor diagnosis is the current research direction. The continuous improvement of the detection technology of telomerase activity in the urine of patients with bladder cancer also indicates that the research of telomerase is becoming more precise and is expected to be widely used in clinical applications in the future , 40.We followed the PRISM guidelines for our meta-analysis . HoweverBased on current evidence, TA can be used as a potential biomarker for the diagnosis of bladder cancer with its high specificity. However, TA performance is not always satisfactory in terms of sensitivity, which may require repeated testing. The maturity of the testing technology will also affect the false negative rate. Further studies in TA is needed, which is more in line with the concept of non-invasive diagnosis of diseases. Rigorous and high-quality prospective studies are required to verify our conclusion.The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found in the article/supplementary material.Conceived and designed the experiments: YL. Analyzed the data: LP, JZL, CM. Contributed reagents/materials/analysis: JML, DT, TW, PX, and FG. Wrote the manuscript: LP and JZL. All authors contributed to the article and approved the submitted version.This study was supported by Sichuan Science and Technology Program under Grant number 2020YFS0320; National Natural Science Foundation of China, grant number: 81900617, application code: H0503, relying unit code: 63700708A0140-0268; Sichuan Provincial Health Committee Program of China, grant Number: 20PJ305.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Campbell Biology is divided into eight units and 56 chapters. The organization and size of this book are appropriate and easy for first-year university students and help them to learn and digest the content. Campbell Biology is currently among the best biology books and it is listed with the best shelling textbooks. Campbell Biology is mainly for first-year university students, but it is also an important book for postgraduate medical examinations. Moreover, some high school students may use it as an essential reference book. In its current edition, the latest information in various fields has been added, such as the basal body, which was previously called the 9*3 type microtube arrangement but now has been renamed as the 9 + 0 type in Chapter 6. The updates in molecular biology are closer to the current situation, such as the addition of information on next-generation sequencing and CRISPR/Cas9 in Chapter 20. This content can enable readers to acquire the latest knowledge. Reading this book and understanding the information presented in its pages is very helpful for the future life science professionals. Thus, Campbell Biology is very valuable textbook in the field of biology. Campbell Biology, 11th Lisa Urry, Michael Cain, Steven Wasserman, Peter Minorsky, Jane Reece.Pearson Education, 2017ISBN13: 978-0-134-09341-3Biology is a compulsory course in a university’s biomedicine-related departments. Biology includes cytology, energetics, genetics, molecular biology, botany, evolution, ecology, and taxonomy. Biology is necessary to prepare for detailed study in various fields.Campbell Biology is mainly for first-year university students, but it is also an important book for postgraduate medical examinations. Moreover, some high school students may use it as an essential reference book. Although the content may be difficult for high school students, it is suitable for first-year university students. However, the content may be too basic for candidates appearing for post-baccalaureate Chinese medicine and Western medicine examinations. Because of the fierce competition in these examinations, books with much more advanced content are often preferred. Sometimes, the entrance exam questions for the post-baccalaureate medicine department are taken from more professional books, such as those closely related to biochemistry, molecular biology, genetics, or ecology.Campbell Biology, the latest information in various fields has been added, such as the basal body, which was previously called the 9*3 type microtube arrangement but now has been renamed as the 9 + 0 type in Chapter 6 [In this edition of hapter 6 . The updhapter 6 . This coCampbell Biology is divided into eight units and 56 chapters [Campbell Biology is currently among the best biology books and it is listed with the best shelling textbooks. Of course, some content lack depth compared with more specialized books, but this is understandable given its main target is first-year university students. For more in-depth content, readers may refer to other books, such as Gene 12th, Molecular Cell Biology , Lehninger Principles of Biochemistry 7th, Immunobiology , Principles of Genetics (Snustad and Simmons), Vander’s Human Physiology 15th, Elements of Ecology (Smith and Smith), and Brock Biology of Microorganisms 15th.chapters . The orgStarr Biology [Chapter 6, page 102: The fact that ribosomes are not membrane bounded means that they cannot technically be considered organelles [Campbell Biology as cotransport [Chapter 7, page 138: The term secondary active transport, which is commonly used in other textbooks on physiology  is referGene 12th [Brooker Biology: “Igf 2 is methylated on the maternal allele, where Igf 2 is inactive” [Chapter 15, page 310: On a few genes, methylation has been shown to activate the expression of the allele. One example is the insulin-like growth factor 2 (Igf 2) gene, on which the methylation of particular cytosines on the paternal chromosome leads to the expression of the paternal Igf 2 allele [nactive” .Chapter 20, pages 429–430: Embryonic stem cells (ES cells) are pluripotent, which means that they are capable of differentiating into many different cell types . Note hoPrinciples of genetics [Campbell Biology make it clear that the sex pilus is involved only in cell contact and not in the transmission of DNA.Chapter 27, pages 578: The process of bacterial conjugation by which DNA is transferred has yet to be fully elucidated. In fact, recent evidence suggests that DNA passes directly through the hollow pilus. In Arabidopsis thaliana, where ABCDE genes specify the fate of floral organs by the combinatorial ABCDE model [Campbell biology should change the content of ABC model to ABCDE model.Chapter 35, page 778: The ABC model of flower formation involves formation of the four types of floral organs . The funDE model . In thisDE model : A and EDE model –13. TherChapter 46, page 1032: Animal embryo development process is zygote, cleavage, and blastocyst , 15. ThiCampbell Biology outlines the foundations of life science makes it a must-read for all life science professionals. If you ever expect to apply for a post-baccalaureate position as in a medical department, Campbell Biology should be on your list of essential reading.The fact that


The zero-profile anchored cage (ZP) has been widely used for its lower occurrence of dysphagia. However, it is still controversial whether it has the same stability as the cage-plate construct (CP) and increases the incidence of postoperative subsidence. We compared the rate of subsidence after anterior cervical discectomy and fusion (ACDF) with ZP and CP to determine whether the zero-profile device had a higher subsidence rate.We performed a meta-analysis of studies that compared the subsidence rates of ZP and CP. An extensive and systematic search covered the PubMed and Embase databases according to the PRISMA guidelines and identified ten articles that satisfied our inclusion criteria. Relevant clinical and radiological data were extracted and analyzed by the RevMan 5.3 software.P = 0.0005]. In the subgroup analysis, we found that the definition of subsidence did not affect the higher subsidence rate in the ZP group. Considering the quantity of operative segments, there was no significant difference in the incidence of subsidence between the two groups after single-level fusion . However, the subsidence rate of the ZP group was significantly higher than that of the CP group  after multilevel (≥ 2-level) procedures. There were no significant differences in intraoperative blood loss, JOA score, NDI score, fusion rate, or cervical alignment in the final follow-up between the two groups. In addition, the CP group had a longer operation time and a higher incidence of dysphagia than the ZP group at each follow-up time.Ten trials involving 626 patients were included in this meta-analysis. The incidence of postoperative subsidence in the ZP group was significantly higher than that in the CP group [15.1% (89/588) versus 8.8% (51/581), OR = 1.97 , Based on the limited evidence, we suggest that ZP has a higher risk of postoperative subsidence than CP, although with elevated swallowing discomfort. A high-quality, multicenter randomized controlled trial is required to validate our results in the future. Anterior cervical discectomy and fusion (ACDF) is the standard surgical procedure for cervical degenerative disk disease (CDDD) . The useHowever, some studies have found that these ZPs are prone to subsidence because they do not have a strong fixation ability to maintain the height of the intervertebral space , 11. ThiTherefore, we reviewed the literature and conducted this meta-analysis to compare the postoperative subsidence and other clinical outcomes of ACDF with the ZP and CP; we aimed to determine whether the ZP has a higher postoperative subsidence rate and similar clinical efficacy as the CP.Our research complied with the guidelines of Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) , 22. TheAll systematic reviews and meta-analysis on clinical controlled trials for CDDD were reviewed. The inclusion criteria for studies in this research were as follows: (1) patients had a failure of at least 6 months of non-operative treatments for CDDD; (2) the studies included a comparison of patients who accepted a ZP with those who received a CP; (3) the studies analyzed and compared the radiological outcomes of subsidence; (4) the studies involved an evaluation of an index of clinical effects: Japanese Orthopaedic Association (JOA) score, Neck Disability Index (NDI) score, operative time, intraoperative blood loss, fusion rate, cervical alignment, and complications; and (5) there was a follow-up period of more than 12 months.We excluded studies that were not in line with clinical controlled studies, such as case reports, meta-analysis, conference abstracts, reviews, commentaries, and letters to the editor. In addition, we only included English language articles in this study.Articles from the literature were thoroughly searched and reviewed from by two reviewers (YJL and YPF) individually and repeatedly. Any discord was resolved through consultation with a third reviewer (XSZ). The data extracted from the article text, tables, and graphs of the qualified studies. The primary radiological data included subsidence, fusion rate, and cervical alignment, and the primary clinical data included JOA, NDI, operative time, blood loss, and the rate of dysphagia. The other basic data included study design, sample size, characteristics of patients, follow-up duration, and type of implants. If partial information from a study was missing, the corresponding author was contacted for the missing data.I2 statistic was used to reflect the degree of heterogeneity. An I2 statistic > 50% identified obvious heterogeneity, and random-effects models were performed in these instances. If the I2 statistic was ≤ 50% (low heterogeneity), fixed-effects models were used. The study also used a funnel plot to evaluate publication bias for subsidence. A P value of 0.05 or less was considered statistically significant.Data analysis was completed by using the Review Manager Software . The continuous variables  were evaluated by weighted mean difference (WMD), while dichotomous variables  were evaluated by odds ratio (OR). Considering the different definitions of subsidence (≥ 2 mm or ≥ 3 mm) and quantity of operative segments (1-level or ≥ 2-level) used in the different studies, we performed corresponding subgroup analysis upon incidence of subsidence. The A total of 221 related records were obtained by searching the databases above. After removing 26 duplicated studies and 22 non-English language articles, 173 studies remained for screening and 163 records were excluded according to the selection criteria. As a result, ten controlled trials , 23–26 wThe 10 studies enrolled a total of 626 patients (315 in the ZP group and 311 in the CP group), which included 380 males and 236 females. The ZPs used in the studies included the Zero-P , ROI-C, ROI-MC+ , PREVAIL , and the Fidji cervical cage . The control group was treated with an anterior plating system and bone graft materials. The mean age, sex, follow-up durations, surgical levels, and other patient information from each study are listed in Table P = 0.04)  noted the operation time , 25, 26.P = 0.08)  reported this variable , 25, 26.08) Fig. .Fig. 3TP = 0.48). In addition, pooled NDI score data at the final follow-up did not reveal a significant difference between the two groups . Figures Data regarding JOA and NDI scores postoperatively were documented in six studies consisting of 436 patients  , 23, 26.P = 0.17) . Nevertheless, the mean difference in cervical alignment between the two groups at the final follow-up was not significant . The corresponding forest plot analysis is shown in Fig. There was a significant difference regarding cervical alignment 3 months postoperatively between the ZP and CP groups . In addition, the ZP group also had a lower incidence of dysphagia at 3 months postoperatively  and at the final follow-up . Forest plots for the postoperative and final follow-up dysphagia evaluations are presented in Fig. The incidence of dysphagia was reported in seven studies , 23, 26,P = 0.0005). The forest plot analysis of subsidence and the funnel plot evaluation of publication bias are presented in Figs. A total of ten studies were included in the comparison of the incidence of subsidence between the ZP and CP groups , 23–26. P = 0.04) and ≥ 3 mm .We performed a subgroup analysis stratified by the definition of subsidence, which included subsidence ≥ 2 mm in five studies , 13, 25 P = 0.41). For the multilevel surgeries, the ZP group had a higher incidence of subsidence . The forest plots for the subgroup analysis of subsidence are described in Figs. A subgroup analysis stratified by the quantity of operative segments was also performed, which included single-level surgery in three studies , 12, 24 ACDF is a classic procedure in treating cervical degenerative diseases that can remove the prominent disk and osteophyte and relieve compressions of the spinal cord and nerve root. It is effective and widely used in the treatment of patients with CDDD . The antP = 0.04). Hofstetter et al. [P = 0.027).However, the application of the anterior plate has a high incidence of postoperative dysphagia –8. In rer et al.  also fouSubsidence is another equally important adverse event after ACDF. It usually refers to an object with a greater elastic modulus  entering another object of relatively lower elastic modulus . The subsidence of the cage causes the loss of intervertebral disk height, which can result in narrowing of the foramen, nerve root compression, and pseudoarthrosis due to cervical instability . EventuaP = 0.025). Kim et al. [P = 0.049), which indicated that the use of a plate could maintain the height of the intervertebral disk and play a pivotal role in reducing postoperative subsidence. However, the incidence of subsidence for ZP compared to CP after reviewing the literature is not clear. Therefore, we conducted this meta-analysis to determine whether there is a statistically high risk of cage subsidence after ACDF with ZP.A systematic review of seventy-one studies reported that the mean incidence of cage subsidence after ACDF was 21% (ranging from 0 to 83%) . Many stm et al.  found thTen trials including 10 cohorts with a total of 626 patients were included in this study. There were no significant differences in blood loss, JOA score, NDI score, fusion rate, or cervical alignment at the final follow-up between the two devices by meta-analysis. Additionally, we found that the incidence of dysphagia in the CP group was significantly higher than that in the ZP group at each follow-up time, which was consistent with previous studies. Xiao et al.  conducteThe results of this study suggested that the ZP group was associated with a high incidence of subsidence, when compared with the CP group. Considering the different definitions of subsidence used in the above ten studies, we conducted subgroup analysis of subsidence defined as ≥ 2 mm and subsidence defined as ≥ 3 mm. However, we found that the incidence of subsidence in the ZP group was still higher than that in the CP group, regardless of definition. Therefore, it could be considered that different definitions of subsidence did not affect the consequences. Then, we performed subgroup analysis according to the quantity of operative segments. There was no significant difference in the rate of subsidence between the ZP group and CP group after single-segment ACDF, while the subsidence rate of the ZP group was significantly higher than that of the CP group after multisegment ACDF. Therefore, we believed that there was no significant difference in the occurrence of cage subsidence after single-level ACDF with ZP or CP. However, considering plate-related complications and the incidence of dysphagia after surgery, we preferred ZP for the treatment of single-level CDDD. For multilevel surgery, due to the high subsidence rate of ZP and with the goal of avoiding subsequent loss of cervical alignment and kyphosis deformity, CP should be preferred without considering the risk of dysphagia.Our meta-analysis was restricted by some limitations. First, retrospective and nonrandom studies were included in this study, which inevitably gave rise to selection bias. Second, only 10 studies were included, the sample sizes were relatively small, and the follow-up times differed. In addition, a variety of zero-profile devices were used, which could affect the accuracy of our conclusions, although the devices had similar fixation mechanisms and structures. Finally, clinical heterogeneity may have resulted from the various surgical approaches and types of implants used in different research centers.To the best of our knowledge, this study was the first meta-analysis to compare the subsidence of ZP to that of CP after ACDF, despite the above shortcomings. Our study showed that ZP had a higher postoperative subsidence than CP, especially in multilevel surgery. Moreover, both devices were safe and effective and achieved similar clinical outcomes. A high-quality, large-sample RCT is required to validate our findings in the future.Currently, there is no consensus on the relationship between subsidence and clinical effectiveness. The research performed by Lee et al.  found thThe ZP, which has been used routinely in recent years, may not reduce the subsidence rate compared to CP. There was no significant difference in subsidence between these two fixed apparatuses after single-level ACDF, while the risk of subsidence in ZP was significantly higher after multilevel fusion. Although there was a high incidence of swallowing discomfort, we would suggest that the anterior plate should be used in multilevel surgery, if possible to reduce subsidence and adverse clinical symptoms in the long term. We conclude that this study provides new opinions for the rational use of ZP.


We aim to generate an artificial neural network (ANN) model to predict early TNF inhibitor users in patients with ankylosing spondylitis. The baseline demographic and laboratory data of patients who visited Samsung Medical Center rheumatology clinic from Dec. 2003 to Sep. 2018 were analyzed. Patients were divided into two groups: early-TNF and non-early-TNF users. Machine learning models were formulated to predict the early-TNF users using the baseline data. Feature importance analysis was performed to delineate significant baseline characteristics. The numbers of early-TNF and non-early-TNF users were 90 and 505, respectively. The performance of the ANN model, based on the area under curve (AUC) for a receiver operating characteristic curve (ROC) of 0.783, was superior to logistic regression, support vector machine, random forest, and XGBoost models  in predicting early-TNF users. Feature importance analysis revealed CRP and ESR as the top significant baseline characteristics for predicting early-TNF users. Our model displayed superior performance in predicting early-TNF users compared with logistic regression and other machine learning models. Machine learning can be a vital tool in predicting treatment response in various rheumatologic diseases. Even though TNF inhibitors are useful for NSAID non-responders, they are not used as a first-line treatment for AS owing to their cost, adverse effects3, and increased chances of infection4. In Korea, medical insurance permits TNF inhibitors for patients with uncontrolled AS who have been treated with at least two kinds of NSAIDs continuously for three months3. However, there is insufficient NSAID treatment response in over 40% of patients5. Thus, NSAID non-responders inevitably suffer for months.Tumor necrosis factor (TNF) inhibitors are important drugs in treating patients with ankylosing spondylitis (AS)6. However, there is no precise predictive model as to who should begin TNF inhibitors earlier than the others.If we can predict the subset of patients who will need TNF inhibitors at an earlier phase, adequate treatment can be provided at an appropriate time and potential damages can be avoided. There have been reports of several factors that affect the start of TNF inhibitor use in AS9. Rheumatologic diseases are no exception. Several machine learning methods have been developed, which can predict survival10, disease activity 12, or drug failure13 in various rheumatologic diseases. These models have shown better predictive abilities compared with conventional methods. Therefore, previous studies have convinced us that machine learning will perform with greater accuracy in generating models in identifying the target population for the early use of TNF inhibitors in AS.As the relationships of clinical variables with phenotypes are not linear but rather complex, newer machine learning methods outperform conventional statistical models in predictions using clinical variables14 model for predicting the target population for the early use of TNF inhibitors in AS using baseline characteristics. The model combines demographic and laboratory data and identifies the subgroup that will require TNF inhibitors within six months of their diagnosis. We compare the performances of our ANN model with conventional statistical methods and other machine learning methods. We perform feature importance analysis with our best performing model to delineate the factors that are important in training the exact model. To our knowledge, this is the first attempt to generate a machine learning model to predict the early use of TNF inhibitors in patients with AS.Herein, we present an artificial neural network (ANN)The number of patients with AS who fulfilled the inclusion criteria was 882. After excluding the ineligible patients, the numbers of patients in the early-TNF and non-early-TNF user groups were 90 and 505, respectively. Figure We trained multiple prediction models using baseline demographics data and laboratory data through various learning methods including a conventional statistical method (logistic regression) and machine learning (support vector machine (SVM), random forest (RF), XGBoost, and ANN). The ANN, XGBoost and RF models were significantly different in terms of their detailed settings. Therefore, we trained them repeatedly by changing the architecture and hyperparameter set to achieve the best predictions. The best ANN model has five layers, except for the output layer. Each layer has 60 hidden nodes Fig. a. The ch. The accuracies of the logistic regression, SVM, RF, XGBoost, and ANN models were 0.846, 0.853, 0.856, 0.838, and 0.878, the AUCs of the ROC curve of sensitivity and specificity were 0.719, 0.699, 0.761, 0.713, and 0.783, the F1 scores were 0.272, 0.272, 0.276, 0.274, and 0.420, and the AUCs of the precision-recall curve were 0.349, 0.366, 0.429, 0.345, and 0.541, respectively  compared with the number of input variables  did not show better performances than simpler models. The number of hidden layers of best performance, i.e., five, implies that the correlation between the input data  and output data (early TNF inhibitor use) is non-linear.18 is relatively older than the other methods but has a suitable performance in simple image discrimination and little computational burdens. RF and XGBoost are newer methods, and are both ensemble models based on decision trees. RF consists of numerous smaller decision trees19, and XGBoost is a gradient boosting method. These approaches have great powers to divide groups and include feature importance analysis. However, ANN shows a better performance than RF or XGBoost in many regards21. In our data, only ANN outperformed the conventional statistical model and logistic regression. This may be due to the complex relationship between clinical inputs and outputs.We tried various machine learning methods including SVM, RF, XGBoost, and ANN. SVM23. However, neural networks have notorious ‘black box’ characteristics; these refer to the difficulty in analyzing feature importance. Several methods that overcome this limitation have recently been announced16. The important variables derived from the ‘risk backpropagation’ method with our ANN model were CRP and ESR. The top two variables were equal to the feature importance analysis in both the RF and XGBoost models. In addition to these two variables, the WBC count, Hb, and platelet count were significantly different between early-TNF users and non-early-TNF users. Thus, we cannot distinguish which variables are more for dividing the two groups when applying a conventional statistical method. As shown in this example, it would be possible to identify relatively more important factors to divide the two groups using the machine learning method that cannot be distinguished through a conventional statistical analysis.Prediction models can also give us insight into baseline clinical variables. Many machine learning tools have distinctive methods to analyze the importance of input variablesOur approach, however, has some limitations. First, we could not add information concerning a review of the system and physical examinations. Due to the limitation of retrospective studies, part of the clinical information and physical examination data were missing for some patients. Therefore, we did not use the frequently missing information. Instead, we showed that it is possible to generate a model with acceptable performances using only laboratory results and demographic data recorded in a regular clinical setting. Second, we only used patient information from one hospital. To reduce the bias as much as possible, we implemented a cross-validation method and repeated it three times. Still, part of our model might be informed about the bias of training the cohort.In conclusion, we made an ANN model that could predict early TNF users in patients with AS using baseline clinical data. It has 5 hidden layers and 60 hidden nodes within each layer. The model has a better performance than a logistic regression model and the other machine learning models . Feature important analysis showed that CRP and ESR were the most important input variables to distinguish early TNF users.This was a retrospective longitudinal study conducted at Samsung Medical Center . Our target cohort population was the patients (1) who fulfilled the modified New York criteria for ankylosing spondylitis (AS) or the assessment of spondyloarthritis international society (ASAS) axial spondyloarthritis (SpA) criteria who started a follow up at the rheumatology department of SMC between Dec 2003, and Sep 2018, and (2) who had followed up more than three months. In order to find this cohort in the electric health database, we included patients who (1) had attended the rheumatology outpatient clinic of the SMC with at least two registered visit that were more than three months apart, (2) had received any ICD9 and/or ICD10 codes for AS by their usual rheumatologist in at least in two consecutive visits, and (3) were diagnosed with AS between Dec 1, 2003, and Sep 1, 2018. We excluded patients who did not have a complete set of baseline laboratory results or baseline demographic data (weight and height); were diagnosed one year or more before their first visit to SMC; had an underlying malignancy, infection, or other rheumatologic diseases; were pregnancy, and who had previous experiences with TNF inhibitors before the index date. The definition of the index date will be explained in the clinical data preparation section.We gathered baseline clinical data including age, sex, height, weight, baseline laboratory results, and HLA-B27. Baseline laboratory results consisted of white blood cell count, hemoglobin, platelet count, blood urea nitrogen (BUN), creatinine, aspartate transaminase (AST), alanine transaminase (ALT), ESR, and CRP. The laboratory results with the closest initial diagnosis date were chosen as baseline laboratory results. We defined the date in which the baseline laboratory tests were performed as the index date. The clinical data was used as machine learning features. The patients were divided into two groups, ‘early-TNF users’ and ‘non-early-TNF users’; those who had used TNF inhibitors within six months and who did not use TNF inhibitors until six months after the baseline laboratory tests, respectively. Non-early-TNF users include patients who used TNF inhibitors six months after their diagnosis.Using a clinical dataset matrix, we trained the prediction models to distinguish between early-TNF users and non-early-TNF users. There is no previous knowledge concerning model architecture and hyperparameter sets that are suitable to predict clinical prognosis using electric health records. Therefore, we tested multiple machine learning models by varying the architecture and hyperparameters. Model architecture for the ANN includes the number of layers and hidden nodes; hyperparameters include learning rate, batch size, and the number of epochs. In the case of XGBoost, the hyperparameters include the learning rate, maximum depth of a tree, and the gamma value. For the RF model, the hyperparameters include the maximum depth of a tree, total number of trees, minimum sample split, and minimum leaf samples. The learning rate is the number of changes newly acquired information undergoes in overriding old information, batch size refers to the number of training examples utilized in a single iteration, epochs refer to one forward pass and one backward pass of all the training datasets, gamma refers to minimum loss reduction required to make a further partition on a leaf node of the tree, the minimum sample split refers to the minimum number of samples required to split an internal node, and the minimum leaf samples refers to the minimum number of samples required to be at a leaf node. Detailed learning methods and background mathematics are covered in Supplementary Information.24. As the early TNF users are not equally distributed in the dataset, we used stratified cross-validation to divide the dataset. In each round, an entire dataset was randomly and equally divided into three, with stratified probability. Two of these parts were used as the training dataset, and the final part was used as the test dataset. The process was repeated three times. A model was trained using the training dataset and scored on the other; this process was repeated after swapping the test datasets. Three rounds of the three-fold cross-validation gave a total of 9 scores, the average of which became the estimated performance of the model. The performances were compared by the AUC of the ROC curve, accuracy, F1 score, and AUC of the precision-recall curve. For sensitivity analysis, we tried various methods for dividing the test dataset. First, we simply divided the dataset into three groups: training, validation, and test dataset rather using cross-validation. A model was trained using the training and validation datasets, and the AUC of the ROC curve was assessed using the test dataset. Second, we divided the independent test dataset before generating the model and the prediction model using the rest of the data. We evaluated the performance of the model using the independent test dataset again to compensate for the lack of independent cohort data. Additional information for performance evaluation is included in the Supplementary Information.The prediction models were evaluated in three rounds of three-fold cross-validationWe compared our ANN model with other models trained by other machine learning methods and a conventional statistical method. We chose SVM, RF, and XGBoost as comparing machine learning methods because they are not only popular but are representative of supervised learning methods other than neural networks. A logistic regression model was chosen as representative of the conventional statistical method. We performed three rounds of three-fold cross-validation on these models identical to that of our ANN model. The logistic regression model was trained and scored by three-fold cross-validation to evaluate its performance but it did not need a three-rounds learning procedure because of its lack of hyperparameters.16. We used the differential value of the prediction score in changing each input variable for feature importance. In previous research, this method is called ‘risk backpropagation’16.ith variable).One of the disadvantages of ANN model is its ‘black box’ characteristics, which are indicative of the difficulty in identifying the importance of each feature used in the model’s training. There are several methods to evaluate feature importance despite this limitationThe more important the role an input variable plays in model training, the more the output value  will be changed as the input changes; i.e., when the output value is differentiated into a specific input variable, the larger the value of the differential, the more important the variable is in training the prediction model. We calculated the differential value of each input variable to reveal the feature importance. In addition, we performed feature importance analysis by XGBoost and RF to verify the robustness of the results. The method used to find feature importance by XGBoost and RF is explained in Supplementary Information.25 were used for statistical analysis. We used Keras (ver. 2.2.4)26 and TensorFlow (ver. 1.14)27 to construct ANN models. ‘Scikit-learn’ module28 was used for the logistic regression, SVM, RF, and XGBoost models, and for calculating the performances. A ROC graph was depicted by the ‘matplotlib’ module29 in Python. Figures were depicted using ‘ggplot2 2.2.1’ package30.Python (ver. 3.7.3) and R (ver. 3.6.3)Data was extracted from the Clinical Data Warehouse Darwin-C of Samsung Medical Center for this study. This study was approved by the Institutional Review Board of the Samsung Medical Center, Seoul, South Korea (IRB No.: 2019-04-079) and the informed consent requirement was waived by the IRB, because the study information was de-identified. All methods were carried out in accordance with relevant guideline and regulations.Supplementary Information


We describe a mixed qualitative and quantitative research study in a military facility regarding the role of nature in well-being. Study intervention included two 20-minute walks. One walk was in an intentionally designed woodland environment (Green Road) and the other was on a busy campus road in a medical treatment facility (Urban Road). Twelve volunteers from a military facility participated in both walks in a cross-over experimental design. The two walking sessions were randomly ordered and preceded by pre-walk instructions appropriate to each road’s characteristics and incorporated focused attention and present moment orientation. A semi-structured post-walk interview, the primary outcome, was conducted after the conclusion of each walk. Qualitative data analyses consisted of sentiments and themes by using NVivo 12 software. The Green Road was unanimously rated as positive (100%). Responses to Urban Road were evenly distributed among positive (33.3%), negative (33.3%), and neutral/mixed (33.3%) sentiments. The Green Road yielded predominantly positive themes such as enjoyment of nature, relaxation, and feelings of privacy and safety. Urban Road produced significantly more negative themes such as concerns for safety, dislike of noise and other noxious experiences. Quantitative assessment of distress and mindfulness with Distress Thermometer (DT) and Mindful Attention Awareness Scale-state version (MAAS) demonstrated that a walk on the Green Road significantly decreased distress and increased mindfulness compared to a walk on the Urban Road. We also observed that pre-walk instructions could direct attention to both obvious and subtle elements of experience and enhance awareness. Results support the notion that an intentional nature-based environment may produce significantly more positive experiences and result in health-promoting benefits in a military health-care setting compared to an urban environment. Future studies with clinical populations could advance our understanding of the healing value of nature-based interventions. The impact of intentional green environments may be enhanced by well-designed instructions for both recreational and therapeutic use. Military service members spend an inordinate amount of their lives on military installations. As a result, in the US Department of Defense at large, there is an overall commitment to use installations’ existing environments to optimize service member health and wellbeing throughout the readiness cycle . DomestiComplementary and ancillary interventions may enhance the success of efforts to promote better physical and mental health, and quality of life for military service members . Among aCity living impacts mental health negatively and contributes to increased amygdala activity, negative affect, stress, mood and anxiety disorders  whereas Enhancing the impact of intentional green spaces is clearly desirable. Mindfulness, which is the capacity to engage awareness in the present moment , has beeEven though green spaces clearly have the potential to reduce stress and improve health and wellbeing, little research has been conducted to examine their effects in military installations.The purpose of our research on the Green Road at the NSA/B was to assess participants’ subjective experience of spending time in nature by walking in an intentionally designed nature environment (Green Road), in comparison to the subjective experience of walking through a busy campus street (Urban Road) . Our priThis is a single site, randomized, multiple methods, and cross-over design. We are reporting on qualitative findings as part of our phase one study. Self-report secondary outcomes for Distress Thermometer and Mindful Attention Awareness Scale are also reported. The study was supported by the Consortium for Health Performance (CHAMP) at Uniformed Services University (USU) and a grant awarded from TKF Foundation/Nature Sacred  in collaTwelve (12) volunteer personnel participated in the study. They were included if they were a service member , military retiree, military family member, caregiver, student, or employee at the NSA/B/Walter Reed. Other inclusion criteria included being ambulatory; 18–60 years of age; able to speak and read English; able to complete study questionnaires; willing to abstain from food, alcohol and tobacco one hour prior to the experiment; have no overt heart disease, and/or any diagnosis that would limit ability to understand procedures or make informed consent such as severe Traumatic Brain Injury (TBI) or active psychosis; and for women not be pregnant or lactating. The average age was 35 years, with nine women and three men. No other gender identification was made. Green Road  was completed in September, 2017. It is intended to provide healing and stress relief to the 12,000 military personnel at Naval Support Activity, Bethesda (NSA/B), home of the Walter Reed National Military Medical Center (WRNMMC) , especially for those with traumatic brain injury and post-traumatic stress disorder. The two-acre garden sits in an eight-acre woodland ravine, surrounding an existing natural stream. The site connects with a 1. The A walk through the Green Road takes an average of 20 min, which is an acceptable span of time to reduce stress .Urban Road consists of campus sidewalks and crosswalks along relatively busy campus streets surrounded by buildings, parking garages, wayfinding signage, small grassy areas, and occasional trees. The Urban Road borders on a memorial plaza featuring a Navy anchor in the form of a large, upright cement plaque, a tall bust statute with a dedication plaque to honor Walter Reed for his contributions, and several low walls with plaques listing Medical Honor Recipients. Compared to the Green Road, the Urban Road would be considered man-made with limited touches of nature. 2. The Guidance and instructions appropriate to the characteristics of each road were developed . These sThe primary qualitative outcome measure was a semi-structured interview conducted soon after the completion of the walk on each road. It was designed to elicit participants’ sentiments and themes of their experience for both walks. Participants were not required to answer every question. The interview was preceded by written reminders to the interviewer as well as verbal instructions to the participant . After aSecondary outcome measures included the Distress Thermometer and Mindful Awareness Attention Scale.1. Distress Thermometer (DT)    is a one2. Mindful Attention Awareness Scale (MAAS), state version, .Statistical analysis included qualitative (QDA) and quantitative approaches. QDA was performed using NVivo 12 software package . In addition to NVivo 12, two members of the research team independently assessed, classified, and categorized responses that were ambiguous. If there were disagreements, a third team member, without knowledge of the first two raters’ categorizations, broke the tie. There were few such disagreements.r, which is the Wilcoxon z-value divided by the square root of the number of observations.Quantitative analyses of self-report measures used the nonparametric Wilcoxon Signed Rank test to examine differences in DT ratings and MAAS scores across the two study conditions. Analyses included three comparisons: post-walk Green Road versus post-walk Urban Road ratings; pre-post changes before and after walking on the Green Road; and pre-post changes before and after walking on the Urban Road. Effects sizes for the Wilcoxon Signed Rank test were quantified using Qualitative data were analyzed in terms of sentiments and themes. Sentiments classified participants’ experiences into positive, negative, or neutral/mixed categories . Themes Experiences after each of the two walks were categorized as positive, negative, or neutral/mixed . SentimeA variety of themes emerged during the semi-structured post-walk interviews for both the Green and Urban Roads which, in alphabetical order, included appreciation and gratitude, enjoyment, God or higher power, landscape and architecture, nature, noxious experiences, physical experiences, present moment orientation, privacy, relaxation, rush, safety, stress, and unprompted mention of topics unique to pre-walk scripts. Green Road produced more positive and Urban Road more negative Themes. z = 0.59, p = 0.55; distress: z = 0.65, p = 0.52).After walking on the Green Road, levels of distress were lower and mindfulness was higher compared to the Urban Road. For both of these outcomes, the effect size could be categorized as strong (based on r) . With reThis study reports the results of a mixed methods research study in a military medical facility that examined responses to intentional natural surroundings compared to a city/urban medical environment. Qualitative analyses of semi-structured interviews  demonstrA large number of prior studies have compared nature and urban experiences and the near universal finding among these studies is that natural green environments promote health and well-being . This neOur study was different from most prior studies in that we provided pre-walk scripts  that incIndeed, present moment orientation—ability to let go, become present, enjoy the unique qualities of the Green Road—emerged as a theme contributing to feeling relaxed and rejuvenated after the walk. In addition, our self-report data show that a walk on the Green Road, supported by instructions to mindfully stay present, resulted in increases in mindfulness and decreases in stress levels compared to walking on the Urban Road corroborating qualitative findings. Present moment orientation is a key component of mindfulness, and the benefits of mindfulness and its impact on stress reduction have been strongly supported by the literature . We beliLimitations of the current report include a sample size that is sufficient for qualitative data analysis but small for broader inferences. In addition, the generalizability of our data to other populations, age groups, or institutional environments requires caution. The participants of the study were self-selected and social desirability bias should be considered. In addition, our secondary outcome measures were limited in their scope and included only two short self-report measures. Furthermore, pre-walk scripts were likely impactful and it is possible that they could have biased the participants differentially towards one of the roads. Future studies should design such instructions with special care and with additional scrutiny, vigilance, and attention to details.In conclusion, the results of the present study support the notion that intentional nature-based environments compared to urban environments may enhance positive experiences and result in health promoting benefits in military health-care settings. We also observed that pre-walk instructions can direct attention to both obvious and subtle elements of experiences and can enhance awareness. We encourage future studies to pay special attention to the details, purpose, and message of such instructions. Future studies with clinical populations could advance our understanding of the healing value of nature-based interventions. The positive impact of intentional nature-based environments may be enhanced by well-designed instructions for both recreational and therapeutic use. In addition, inclusion of clinical groups, such as those exposed to trauma and stress, in studies that combine various therapeutic interventions with nature interventions to produce positive psychological change is needed.The opinions and assertions expressed herein are those of the author(s) and do not necessarily reflect the official policy or position of the Uniformed Services University or the Department of Defense.The contents of this publication are the sole responsibility of the author(s) and do not necessarily reflect the views, opinions or policies of The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. Mention of trade names, commercial products, or organizations does not imply endorsement by the US Government.10.7717/peerj.10519/supp-1Supplemental Information 1Imagery ©2019 Google, Map data ©2019 Google.Click here for additional data file.10.7717/peerj.10519/supp-2Supplemental Information 2Click here for additional data file.10.7717/peerj.10519/supp-3Supplemental Information 3Click here for additional data file.10.7717/peerj.10519/supp-4Supplemental Information 4Click here for additional data file.10.7717/peerj.10519/supp-5Supplemental Information 5Click here for additional data file.


Gouty arthritis (GA) is a chronic disease caused by monosodium urate crystal deposition. Repeated attacks of arthritis may lead to the deposition of urate to form gout stone, resulting in joint deformity and joint damage. Although GA is not fatal, it causes low work productivity and low quality of life. Western drug, such as febuxostat, colchicine, allopurinol, often cannot get satisfying curative effect, and may even lead to serious side effects, such as exfoliative dermatitis or uremia. However, the therapeutic effect of Traditional Chinese medicine is very satisfactory. The treatment effect of simiao powder, a Chinese patent medicine, combined with acupuncture was widely used on treatment of GA. Although it has been widely used in clinical practice, its relative effectiveness and safety have not been confirmed. Therefore, this study will use meta-analysis to verify the efficacy and safety of simiao powder combined with acupuncture in the treatment of GA.All randomized controlled trial of simiao powder combined with acupuncture for the treatment of RA from their inception 29 October, 2020 will be searched form the China National Knowledge Infrastructure, Wanfang Database, Chinese Science and Technology Periodical Database, Chinese Biomedical Literature Database, Pubmed, Embase, Web of Science, and the Cochrane library. Two authors will independently select studies, extract data based on pre-designed inclusion and exclusion criteria. Methodological quality assessment and risk of bias will be assessed using Cochrane bias risk tool. All data analysis will be conducted using Revman5.3, WinBUGS 1.4.3, and Stata14.2 software.We will compare the different outcome indicators of various studies to provide a synthesis of the efficacy and safety of Simiao powder combined with acupuncture for GA patients. The main outcome measures included efficacy, remission rate (no drug symptoms), recurrence rate, clinical absolute score and relative score. Secondary outcome measures included related adverse reactions and uric acid concentration.The findings of the study will provide helpful evidence for the efficacy and safety of simiao powder combined with acupuncture in the treatment of GA.This study protocol have been funded through a protocol registry. The registry number is INPLASY2020110028 The frequent attack of GA has seriously affected the life of patients and brought heavy burden to social medical treatment. The pathogenesis of GA is complex and it is not yet clear. It has been found that environment, genetics, immunity, diet, internal environment, trauma and stimulation are involved in the pathogenesis in varying degrees. Currently, western medicine treatment of GA include febuxostat, colchicine, allopurinol and so on. It can be divided into two categories: analgesics, uric acid lowering drugs. These drugs can temporarily reduce joint pain and uric acid level, but their side effects should not been ignored. For example, allopurinol may cause severe allergic reactions and fatal exfoliative dermatitis, especially in Asian population. Benzbromarone may cause severe renal damage, especially in patients with kidney stones. Therefore, we need to further explore new treatments methods for GA, with good efficacy and small side effects.Gouty arthritisc (GA) is a chronic disease of deposition of monosodium urate crystals, which form in the presence of increased urate concentrations.,7 Simiao powder is composed of cortex phellodendri, atractylodes lancea, achyranthes bidentata and coix seed. It can clear away heat and damp, relax tendons and strengthen bones. Shi x et al. found that simiao powder can significantly improve the symptoms of acute arthritis in gout patients, its curative effect is not lower than colchicine, and the side effects are small. Another meta analysis reported that simiao powder are effective in the treatment of GA through anti-inflammation and lowering urate. Liu et al found that through acupuncture, the treatment of GA are invigorating spleen, tonifying kidney, dissipating dampness, resolving blood stasis, clearing away heat, removing toxic substances, soothing Liver, regulating qi, dredging collaterals and relieving pain. At present, simiao powder and acupuncture has been widely used due to low price, convenience, high efficacy, and few adverse reactions. The treatment of combined with internal and external treatment of TCM has also received good feedback from GA patients. Simiao powder combined with acupuncture is welcomed by patients in clinic.Traditional Chinese medicine (TCM) is an advanced experience that Chinese people have summed up in the struggle against diseases for thousands of years. Experienced doctors of Chinese medicine make choice of treatment drugs based on syndrome differentiation and a variety of clinical symptoms of patients. In TCM, GA is classified as “Bi zheng,” “Bai hu li feng jie,” and “Li jie bing.” The etiology of GA is summarized as abnormal of wind cold, dampness and phlegm stagnation. Among these, damp heat accumulation are regarded as the key factors of GA. TCM treatment includes oral Chinese herbal medicine, acupuncture, moxibustion, cupping, external application of Chinese medicine and other forms. In view of the cause of disease, TCM mostly adopts external treatment and internal treatment. Among them, the most widely used is acupuncture and Chinese herbal medicine simiao powder. Acupuncture is based on the theory of meridians, which stimulates characteristic acupuncture points to clear meridians and smooth the body's qi and blood.Nonetheless, no systematic review or meta-analysis is available to assess the effect of simiao powder combined with acupuncture on treating GA. Therefore, the aim of this meta-analysis of randomized controlled trails is to evaluate the efficacy of simiao powder combined with acupuncture for GA, results in this study might prove to be more reliable for clinical practice and decision-making.22.1 If there is any information adjustment during the entire study period, we will promptly correct and update it in the final report.This study protocol has been funded through a protocol registry on the INPLASY website (registration number is INPLASY2020110028). We will strictly abide by the requirements of the “the Preferred Reporting Items for Systematic Review and Meta-analysis Protocols” to report the meta-analysis.2.22.2.1Randomized controlled trials including simiao powder combined with acupuncture for the treatment of GA will be included. Exclude non- randomized controlled trial (RCT), animal experiments, unclear results indicators such as images and other nonquantitative indicators. For the articles published repeatedly in Chinese and English journals, take the latest 1 published.2.2.2Patients diagnosed with GA by ACR (1997), not restricted in age, gender, ethnicity, race, and disease stage. Reluctant to accept TCM treatment, patients with severe cardiovascular diseases, mental illnesses, Pregnant women, breast stage and cancer will be excluded.2.2.32.2.3.1The intervention measures of the experimental group were simiao powder combined with acupuncture. It can be monotherapy or combination. RCT comparing the above 2 therapies can also be included, and those who combine Western medicine will be excluded.2.2.3.2The control group received conventional treatment of western medicine, including the use of febuxostat, colchicine, allopurinol.2.3The main outcome indicators include effectiveness , effective including basic recovery, marked effect, improvement; remission rate (no drug symptoms), relapse rate, clinical absolute score, and relative score. Secondary outcome indicators: including any related adverse reactions,uric acid concentration.2.4We will search the following databases: the China National Knowledge Infrastructure, Wanfang Database, Chinese Science and Technology Periodical Database, Chinese Biomedical Literature Database, Pubmed, Embase, Web of Science, and the Cochrane library. Collect all the RCT on the treatment of GA with simiao powder combined with acupuncture. And manually search for references in related literature. The retrieval time is from the inception of the database to 29 October, 2020. The language is limited to Chinese and English. The search strategy is to combine search terms with subject words and free words. The primary selection process are shown in PubMed search strategy Table .2.5Two authors independently complete the following process: according to the above search strategy to complete the process of document retrieval, import documents into EndNote X7 for centralized management. Then, according to the inclusion and exclusion criteria, filter the literature by reading the title and abstract. If it is not possible to determine whether the article meets the requirements based on the inclusion and exclusion criteria, then read the full text to select. In the entire literature screening process, if the 2 authors have different opinions, the third author joins the discussion to get a common opinion. The process of research selection is shown in Figure 2.6After the literature search process was completed, the 2 authors independently extracted the following information from the selected study: author, article title, year of publication, contact information, country/region, sample size, participants, diagnostic criteria, baseline characteristics, study design, random methods, blind methods, results, adverse events, and so on, and fill the extracted information into a pre-built Excel table. If necessary, we will contact the trial author for further information.2.7If there is data loss in the included study, we will contact the original author of the article to obtain the original information. If the missing data is still not available, the existing data will be analyzed and a sensitivity analysis will be performed to address the potential impact of the missing data.2.8 Including 7 items: random sequence generation, allocation concealment, blind participants and personnel, blind assessment of results, incomplete result data, selective reports, and other biases. The results in each field will be divided into 3 levels: low bias risk, high bias risk, and unclear bias risk. The 2 authors will exchange assessment results and check whether the assessment results are consistent. If there is a disagreement, the third author will participate in the discussion and determine the final result.The 2 authors will independently assess the risk of bias  of the included studies based on the bias risk assessment tool recommended in the Cochrane “Risk of bias” assessment tool.2.9 Categorical data will be calculated with the risk ratio and 95% confidence intervals (95% CIs), continuous variables will be reported as mean differences or standardized mean differences with 95% CI. Heterogeneity will be evaluated by Chi-squared test and Higgins I2 test; If there is no obvious heterogeneity (I2 ≤50% and P > .10), the fixed effect model will be used; otherwise, the random effect model will be applied. Use WinBUGS 1.4.3 and Stata14.2 for network meta-analysis. In WinBUGS 1.4.3 software, Bayesian framework is implemented by the Markov chain Monte Carlo method, which is simulated by 4 chains, the number of iterations is set to 50000, and the step size is set to 10. At the same time, the Potential Scale Reduced Factor is used to evaluate the convergence of the results. When the PRSF value is approximately equal to 1.00, it indicates that the results are well converged, and the obtained results are highly reliable. If the PRSF is not within this interval, then continue to manually increase the number of iterations 50,000 times until the FRSF is within this range. In the case of many interventions involved, in the evidence network of each outcome indicator, the closed loop formed by the research with direct and indirect evidence needs to be tested for inconsistency. Calculate the inconsistency factor (IF), and judge whether there is inconsistency by the IF value and the P-value. If the IF is close to 0, the 95% CI starts at 0, and P > .05, it is considered that the direct comparison and the indirect comparison are consistent. At the same time, the node-split model is used to determine whether each node has local inconsistency. If P > .05, there is no obvious inconsistency. If there is no obvious inconsistency between the 2, the consistency model is adopted, otherwise, the inconsistency model is adopted. For the results obtained by the analysis of the consistency model, the stability of the results can be checked by the inconsistency model.,17 Make evidence network diagram, correct-compare funnel diagram, and conduct inconsistency test in Stata14.2 software. Simultaneously calculate the value of surface under the cumulative ranking curves and the area under the surface under the cumulative ranking curves curve in order to rank the efficacy of various interventions. The value range is 0 to 100. The larger the value, the larger the area under the curve indicates the intervention and the greater the likelihood of being the best intervention.Pairwise meta-analyses is conducted by RevMan5.3,2.10I2 test detect obvious heterogeneity between studies, we will conduct a subgroup analysis from the following aspects: treatment time, GA classification, stage of disease, and so on. In order to ensure the Credibility of the research results, we will conduct a sensitivity analysis of the included literature and will eliminate low-quality literature.If the Chi-squared test and Higgins 2.11 the funnel plot will be used to assess the publication bias of the literature. If the funnel chart has poor symmetry, it indicates publication bias.If the included studies are sufficient (n≥10),2.12The evaluation of the strength of the evidence will be based on the grading of recommendations assessment, development, and evaluation system, there are 4 levels of evidence strength: high, medium, low, or very low.3 Another research found that acupuncture on 5 Shu in Spleen Meridian appeared to be safe and efficacious for decreasing serum uric acid in a Chinese HUA patient population. The mechanism might be associated with the decrease level of enzyme URAT-1. The findings of Lin suggested that simiao decoction was an effective therapeutic drug for GA and the gut ecosystem might act as a potential anti-inflammatory target of Simiao powder. Qiu found that simiao powder can significantly improve the symptoms and signs of GA and decrease the levels of UA and CRP. However, no reports of comparisons simiao powder and acupuncture on GA has been found. Therefore, this is the first meta-analysis to directly or indirectly compare the treatment of simiao powder and acupuncture in treating GA. It will provide the best evidence for clinical practice.In recent years, a large number of simiao powder or acupuncture in the treatment of GA have emerged. Wang indicate that the effects of needling the Shu, Yuan, and Mu acupoints can significantly reduce serum uric acid and xanthine oxidase levels compared with the western drug, possibly suggesting reduced renal damage.Conceptualization: Li-ming Liu.Methodology: Li-jun Ren.Project administration: Yong-li Li.Software: Yan Xie.Supervision: Yan Xie.Writing – original draft: Meng-jun Pu.Writing – review & editing: Cheng-jiao Yao.


This study used local resources- community members, photographer and speech therapists to develop a new test for screening receptive language skills and sought to determine its feasibility for use with a larger population in KwaZulu-Natal province, South Africa.The aim of this study was to develop a one-word receptive vocabulary test appropriate for screening and diagnosis of isiZulu-speaking preschool-aged children. The objectives were (1) to determine sensitivity and specificity of the Ingwavuma Receptive Vocabulary Test (IRVT) and (2) to determine the relationship of IRVT scores with age, gender, time and the confounding variables of stunting and school.The study was quantitative, cross-sectional and descriptive in nature. The IRVT was piloted before being administered to 51 children (4–6 years old). Statistical analysis of test item prevalence, correlations to confounding variables and validity measurements were conducted using Statistical Package for Social Scientists version 25 (SPSS 25).p < 0.05) with a high effect size (Cohen’s d = 0. 949), gender  with a medium effect size (Cohen’s d = 0.521) and school  with a small effect size (Cohen’s d = 0.353). The sensitivity and specificity values were 66.7% and 33%, respectively. The test reliability  was 0.739, with a good test–retest reliability.The IRVT was able to profile the receptive skills for the preschool children in Ingwavuma. The mean raw score for boys was 35, and 32 for girls. There was a significant Pearson correlation between test scores and age (0.028, The IRVT has potential as a screening test for isiZulu receptive vocabulary skills amongst preschool children. This study contributes to a development of clinical and research resources for assessing language abilities. Language is a combination of expressive and receptive communication skills, including the ability to speak, listen, read and write. Language development informs many aspects of child development, including emotional wellness, cognitive abilities and literacy. Information on language development can be sensitive in determining the effects of various medical conditions, such as meningitis, cerebral malaria and human immunodeficiency virus (HIV) , providing the scaffolding for independence and literacy in grade 1  during development but also in temporal variations  on language development  centres located in the traditional rural areas of Ndumo, Makwakwa, Manyiseni and Skhemelele within Ingwavuma  grade R and grade 1 life skills student book, whilst pictures were collected from public inventory on the Internet , a visual inspection of the histograms, normal Q-Q plots and box plots showed that the test scores were approximately normally distributed for both males and females, with a skewness of -0.401 (standard error [SE] = 0.464) and a kurtosis of −0.288 (SE = 0.902) for girls and a skewness of 0.107 (SE = 0.464) and a kurtosis of 0.514 (SE = 0.902) for boys. The mean for the total raw score was 34 (SD = 5.13) and the range was 26. The majority of the children fell within the 5-year-old group . There was less representation of children in the 4-year-old group and above 6.0 years of age. A Shapiro–Wilk’s test , which is interesting since gender was equally represented in the sample. The males had a higher mean than females, with a correlation to gender was supported by a moderate Cohen’s d (0.521). The results show that children between 4.0 and 5.0 were able to achieve a minimum raw score of 20. The results indicate significant differences in performance by gender , which was supported by a high effect size as Cohen’s d = 0.949. The mean time taken to complete the test (TTT) was 23.14 min, with no correlation of TTT to gender or age.The results indicate significant differences in performance by age with Pearson’s correlation of r = -0.262  and showed a small effect as Cohen’s d = 0.353. There was no correlation between school to age and TTT.The prevalence of stunting was 26% in our sample and the results showed no significant correlation of test scores to stunting. Bivariate correlation measurement of school attended to test scores was significant as Reliability across items was measured through two tests of internal consistency, namely, the Cronbach’s alpha and split half correlation  was ensured though qualitative observations by local people (Johnstone, Altman, Thurlow, & Thompson, For the analysis of reliability, test items that carried a variance of 1% or 100% score were automatically excluded by the software which negatively influenced the Cronbach’s alpha but the average was still adequate, suggesting that all remaining items measured the same construct. Since there was only one tester, the inter-rater reliability could not be measured; to compensate for this limitation, rigorous analysis of internal consistency and validity were done, which showed satisfactory reliability and sensitivity for language scores.The TTT mean of 23 min was much higher than the reported mean of 8 min with similar standardised tests (Prado et al., The prevalence of stunting in our study matched trends in other African countries and similar to other studies conducted in other rural areas of KwaZulu-Natal, where there was a need for additional school resources, poor infrastructure, overcrowded classrooms, a need for inservice training for teachers and a need for more meaningful parental involvement (Hannaway, Govender, Marais, & Meier, Similarly, the school factor introduced no variation in the performance of children on the IRVT. This similarity does not reduce the significance of considering the children’s context and bio-psycho-social factors when assessing language. Factors such as teacher experience, level of skills, play behaviour and learning resources have been proven to directly impact learning outcomes, whilst factors like water source and sanitation contribute to cultural variations within societies Feza, . The perThe IRVT needs to be evaluated with a larger sample size for evaluation of the adjusted word list, illustrations and for generalisability of the results. Although the IRVT achieved moderate sensitivity, there is an indication from the PPV and NPV that adjustments to the vocabulary choice, grading and presentation order of items should provide better results. Furthermore, the test item selection was based on the opinions of experienced adult language users and CAPS books. We acknowledge the subjectivity associated with the process and the technical exclusion of the 4-year-old group that was not the target for the books. Another limitation of the study was a small sample size and a lack of an in-depth individualised socio-economic questionnaire which could have contextually ascertained the level of risk for speech and language delays Hoff, . The strReceptive language lays the foundation for expressive language development and allows for scaffolding of literacy skills, such as reading and writing. A test of receptive vocabulary in isiZulu is a valuable tool in baseline school readiness assessment of isiZulu-speaking preschool children to achieve early intervention. The children in this study took an average of 23 min to complete the one-word receptive vocabulary test in isiZulu and obtained an average score of 35, with boys performing statistically better than girls, whilst a significant variation in scores depended on age and school attended. The IRVT is a promising screening tool appropriate for preschool children from low SES communities. However, there is a need to adjust the test structure, evaluate it using a larger sample size, develop a complimentary intervention programme and align it with educational goals.