Human umbilical cord mesenchymal stem cells to treat spinal cord injury in the early chronic phase: study protocol for a prospective, multicenter, randomized, placebo-controlled, single-blinded clinical trial

Human umbilical cord mesenchymal stem cells(hUC-MSCs)support revascularization,inhibition of inflammation,regulation of apoptosis,and promotion of the release of beneficial factors.Thus,they are regarded as a promising candidate for the treatment of intractable spinal cord injury(SCI).Clinical studies on patients with early chronic SCI(from 2 months to 1 year post-injury),which is clinically common,are rare;therefore,we will conduct a prospective,multicenter,randomized,placebo-controlled,single-blinded clinical trial at the Third Affiliated Hospital of Sun Yat-sen University,West China Hospital of Sichuan University,and Shanghai East Hospital,Tongji University School of Medicine,China.The trial plans to recruit 66 early chronic SCI patients.Eligible patients will undergo randomization at a 2:1 ratio to two arms:the observation group and the control group.Subjects in the observation group will receive four intrathecal transplantations of stem cells,with a dosage of 1×106/kg,at one calendar month intervals.Subjects in the control group will receive intrathecal administrations of 10 mL sterile normal saline in place of the stem cell transplantations.Clinical safety will be assessed by the analysis of adverse events and laboratory tests.The American Spinal Injury Association(ASIA)total score will be the primary efficacy endpoint,and the secondary efficacy outcomes will be the following:ASIA impairment scale,International Association of Neural Restoration-Spinal Cord Injury Functional Rating Scale,muscle tension,electromyogram,cortical motor and cortical sensory evoked potentials,residual urine volume,magnetic resonance imaging–diffusion tensor imaging,T cell subtypes in serum,neurotrophic factors and inflammatory factors in both serum and cerebrospinal fluid.All evaluations will be performed at 1,3,6,and 12 months following the final intrathecal administration.During the entire study procedure,all adverse events will be reported as soon as they are noted.This trial is designed to evaluate the clinical safety and efficacy of subarachnoid transplantation of hUC-MSCs to treat early chronic SCI.Moreover,it will establish whether cytotherapy can ameliorate local hostile microenvironments,promote tracking fiber regeneration,and strengthen spinal conduction ability,thus improving overall motor,sensory,and micturition/defecation function in patients with early chronic SCI.This study was approved by the Stem Cell Research Ethics Committee of the Third Affiliated Hospital of Sun Yat-sen University,China(approval No.[2018]-02)on March 30,2018,and was registered with ClinicalTrials.gov(registration No.NCT03521323)on April 12,2018.The revised trial protocol(protocol version 4.0)was approved by the Stem Cell Research Ethics Committee of the Third Affiliated Hospital of Sun Yat-sen University,China(approval No.[2019]-10)on February 25,2019,and released on ClinicalTrials.gov on April 29,2019.

Early filiform needle acupuncture for poststroke depression: a meta-analysis of 17 randomized controlled clinical trials

OBJECTIVE： To evaluate the effectiveness and safety of filiform needle acupuncture for poststroke depression, and to compare acupuncture with the therapeutic efficacy of antidepressant drugs. DATA RETRIEVAL： We retrieved data from the Chinese National Knowledge Infrastructure （1979-2012）, Wanfang （1980-2012）, VIP （1989-2012）, Chinese Biomedical Literature （1975- 2012）, PubMed （1966-2012）, Ovid Lww （-2012）, and Cochrane Library （-2012） Database using the internet. SELECTION CRITERIA： Randomized controlled trials on filiform needle acupuncture versus antidepressant drugs for treatment of poststroke depression were included. Moreover, the in- cluded articles scored at least 4 points on the Jadad scale. Exclusion criteria： other acupuncture therapies as treatment group, not stroke-induced depression patients, score 〈 4 points, non-ran- domized controlled trials, or animal trials. MAIN OUTCOME MEASURES： These were the Hamilton Depression Scale scores, clinical ef- fective rate, Self-Rating Depression Scale scores, Side Effect Rating Scale scores, and incidence of adverse reaction and events. RESULTS： A total of 17 randomized controlled clinical trials were included. Meta-analysis results displayed that after 4 weeks of treatment, clinical effective rate was better in patients treated with fill- form needle acupuncture than those treated with simple antidepressant drugs [relative risk = 1.11, 95% confidence interval （C/）： 1.03-1.21, P = 0.01]. At 6 weeks, clinical effective rate was similar between filiform needle acupuncture and antidepressant drug groups. At 2 weeks after filiform needle acupuncture, Hamilton Depression Scale （17 items） scores were lower than in the antide- pressant drug group （mean difference = -2.34, 95%CI： -3.46 to -1.22, P 〈 0.000,1）. At 4 weeks, Hamilton Depression Scale （24 items） scores were similar between filiform needle acupuncture and antidepressant drug groups. Self-Rating Depression Scale scores were lower in filiform needle acupuncture group than in the antidepressant drug group. Side Effect Rating Scale was used in only two articles, and no meta-analysis was conducted. Safety evaluation of the 17 arti- cles showed that gastrointestinal tract reactions such as nausea and vomiting were very common in the antidepressant drug group. Incidence of adverse reaction and events was very low in the filiform needle acupuncture group. CONCLUSION： Early filiform needle acupuncture for poststroke depression can perfectly con- trol depression. Filiform needle acupuncture is safe and reliable. Therapeutic effects of filiform needle acupuncture were better than those of antidepressant drugs.

Triple Puncture for Primary Trigeminal Neuralgia:A Randomized Clinical Trial

To evaluate the effect of triple puncture on primary trigeminal neuralgia (pTN),64 patients with pTN were randomly assigned to two groups:treatment group and control group.The participants in the treatment group received triple puncture treatment of 6 times per week for 4 weeks,and those in control group were given carbamazepine (300-600 mg per day) for at least 1 month.Before and after treatment,the primary outcomes including the total efficiency rate and the VAS pain scores,and the secondary outcomes including the frequency of pain attack and adverse events were observed.Sixty-two participants finished the study (33 in treatment group and 29 in control group individually).After treatment,the symptoms (mainly pain) of the two groups were alleviated.The total efficiency rate in the treatment group and control group was 90.9% and 75.9% respectively.The VAS pain scores and frequency of pain attack were significantly reduced in the treatment group as compared with the control group (P<0.05).The incidence of adverse events in the treatment group and control group was 9.1% and 24.1% respectively.It can be inferred that triple puncture can effectively improve the quality of life of patients with pTN and has less side effects.

Probiotics supplementation for management of type Ⅱ diabetes risk factors in adults with polycystic ovarian syndrome: a meta-analysis of randomized clinical trial

This meta-analysis of randomized controlled trials aimed to evaluate the effects of probiotic supplementation on glucose homeostasis in patients with polycystic ovary syndrome(PCOS).The meta-analysis was performed in accordance with the Cochrane Handbook guidelines and relevant the preferred reporting items for systematic reviews and meta-analyses(PRISMA)statement criteria.Of 825 identified reports,11 randomized clinical trials were included in the meta-analysis.An analysis of pooled extracted data revealed that supplementation with probiotics significantly decreased fasting blood glucose(FBG,n=7;standardized mean difference(SMD)=−0.40;95%confidence interval(CI):−2.02,−0.02;P=0.04)and insulin levels(n=6;SMD=−0.57;95%CI:−0.89,−0.25;P=0.0004)and the homeostatic model assessment of insulin resistance(n=7;SMD=−0.64;95%CI:−0.96,−0.31;P=0.0001)while increasing the quantitative insulin sensitivity check index(QUICKI,n=5;SMD=0.58;95%CI:0.08,1.09;P=0.02)in patients with PCOS.The FBG-reducing effect decreased as the baseline body mass index(BMI)and mean age of the participants increased.Indeed,a greater number of bacterial species and a higher bacterial dose were shown to reduce QUICKI effectively.The systematic review indicated that probiotic supplementation may help to control glucose homeostasis in adults with polycystic ovarian syndrome.

Lavender aromatherapy on anxiety and depression in patients with Acute Coronary Syndrome: a single-blind randomized clinical trial

Objective:In cardiovascular disease,a patient’s anxiety and depression can increase cardiac rehabilitation duration and recovery.Lavender aromatherapy as a non-pharmacological intervention effective in other contexts may be an efficient intervention to alleviating anxiety and depression in patients with Acute Coronary Syndrome(ACS).Methods:In this study,110 ACS patients were randomly assigned to two intervention and control groups.Inhalation of the lavender fragrance was prescribed for the intervention group and the drop of aromatic almond for the control group for 3 days.Results:The first-day anxiety and depression were significantly different in the two groups at 1 h and 9 h after the intervention.The’morning’s difference before the intervention was not significant,but it was substantial 1 h after the intervention.On the third morning of the intervention,this difference was confirmed.Conclusions:This study confirmed the effectiveness of lavender aromatherapy in reducing anxiety and depression in ACS patients.This’study’s results enable intensive care nurses to use aromatherapy with lavender oil as a non-pharmacological and cost-effective intervention to reduce their psychological tensions and increase patient satisfaction during hospitalization in the cardiac care units(CCU).

Immunomodulatory Activities of a Concentrated Fruit and Vegetable Juice Tested in a Randomized,Placebo-Controlled,Double-Blind Clinical Trial in Healthy Volunteers

22 healthy volunteers were included in a randomized, placebo-controlled pilot study in order to investigate immunomodulatory effects of a concentrated juice, containing the ingredients of a total of 80 different fruits, vegetables, herbs, mushrooms, oils, and others (Cellagon aurum?, “CA”). 11 subjects received the concentrated juice while 11 were allocated to the placebo group. Stimulated whole-blood cultures were used to assess any treatment-related changes in the response of leukocytes towards experimental immune cell activation. For each of the individuals, 5 cultures were performed either immediately before, during, or 3 days after termination of the 7 weeks treatment. Leukocyte activities were determined by measuring cytokine levels in the supernatants at the end of the 48 h of stimulation (induced by the addition of LPS + SE-B + anti-CD28 antibodies). Despite the relatively small number of volunteers, multiplexed cytokine assays revealed a typical T-cell signature of cytokines that were increased significantly in the course of CA treatment compared to placebo (GM-CSF, IFNγ, IL-4, IL-10, IL-17, TNFβ, all p 0.05). These preliminary results suggest that CA is able to support leukocyte activation, in particular that of T-lymphocytes.

Bias-Variation Dilemma Challenges Clinical Trials: Inherent Limitations of Randomized Controlled Trials and Meta-Analyses Comparing Hernia Therapies

Purpose:Evaluation of hernia therapies according to the current rules of Evidence Based Medicine is widely reduced to results of RCTs or meta-analyses. RCTs have been accepted as a most important tool to confirm a superior effect of an intervention. Unfortunately, in hernia surgery, comparisons of RCTs and correspondingly their use in meta-analyses, are not, surprisingly often, able to confirm any significant impact of a specific procedure due to intrinsic restrictions in a multi-causal setting with its web of influences. Methods:Based on our own experiences of clinical studies in surgery, the present article outlines several situations, with their respective reasons, which argue the severe limitations of RCTs and meta-analysis to define an optimum treatment. Results:Meta-analyses accumulate the variations of each trial, which then may cover any clear causal relationship. RCTs usually are dealing with subgroups of standard patients thus excluding the majority of our patients. Low statistical power of current cohort sizes restricts the analysis of subgroups or of effects with low incidences. Simple comparisons of means frequently are hampered by nonlinear relationships to outcome. The relevance of a specific variable is difficult to separate from other influences. The limited surveillance period of studies ignores a delayed change in outcome. Randomization cannot guarantee a standardized patient’s condition. All the arguments have to be considered as a crucial and fundamental consequence of the bias-variance dilemma or principle of uncertainty in medicine, and underline the many limitations of RCTs to evaluate any specific impact of hernia therapies on e.g. infection, pain or recurrence. Conclusions: Many surgical issues cannot be and should not be investigated by RCTs, in particular, if a marked patients’ heterogeneity has to be considered or the low incidences of the outcome readout cannot be addressed with sufficient statistical power without getting lost in the variation mire. Registries with their non-restricted data-acquisition should be regarded as reliable alternatives for postoperative outcome quality surveillance studies.

Design flaws in randomized, placebo controlled, double blind clinical trials

The hypothesis in drug clinical trials is that the drug is better than a placebo in patients suffering from a disease. The unstated assumption is that the drug cures the disease or is a powerful treatment for the disease. This is an incorrect assumption. Drugs do not cure or treat diseases. The body heals itself; drugs promote this ability of the body to heal itself. Placebos are assumed to be inactive; however, placebos can also promote the ability of the body to heal itself. Placebos are actually treatments that can stimulate endogenous healing mechanisms. The possible place of placebos in health management is controversial. Clinical trial design should be altered. The hypothesis of clinical trials should be that the drug speeds up or improves the healing of the patient, putting patient healing as the first objective. Placebos should not be used as controls but could be tested as drugs in their own right. The control in clinical trials should be no treatment. Alternatively, new drugs could be compared to existing drugs in clinical trials.

Primary Question and Hypothesis Testing in Randomized Controlled Clinical Trials

本文中我们简要地回顾并提供了医疗和公共研究设计中使用的一些基本概念的有关注意事项,特别是主要问题、假设检验、和样本量。此外,我们还讨论了最近几年的一些扩展和发展。

Safety and efficacy of intraperitoneal perfusion with tumor vesicle-encapsulated methotrexate for the treatment of cancerous ascites - an open, randomized and controlled clinical trial

Background:Cancerous ascites is a common and severe complication that occurs in patients with late-stage malignant tumors.The prognosis of cancerous ascites is poor,clinical treatment is difficult and therapeutic outcome is disappointing.In the present study,tumor cell-derived vesicles were used as drug delivery vehicles that encapsulated a chemotherapeutic agent and were perfused into a patients’abdominal cavity to effectively kill the cancer cells in cancerous ascites.Pre-clinical data has demonstrated that tumor vesicles that carry low-dose chemotherapeutics can efficiently eliminate metastatic tumor cells in the abdominal cavity with minimal toxic or adverse effects.When combined,tumor cell-derived vesicles can sensitize tumor cells,which facilitates the entry of chemotherapeutics into tumor cells,thereby enhancing killing of tumor cells and limiting the risk of drug resistance.In this study,we designed a clinical trial to evaluate the safety and efficacy of intraperitoneal perfusion with tumor vesicle-encapsulated methotrexate for the treatment of cancerous ascites.Methods:Sixty patients with cancerous ascites were enrolled in this open,randomized and controlled clinical trial.Participants were randomly assigned a visit number and,according to their visiting order for which a random numerical table was used,were assigned to the trial group or the control group in a 1:1 ratio.The change in ascetic volume was used as the study outcome and adverse events were monitored during the entire length of the study.Conclusion:In this clinical trial,randomization and electronic case report forms were implemented.The trial indicated that tumor vesicle-encapsulated methotrexate was proposed to be a safe and effective method for treating malignant ascites.Our study may provide at the first time evidence for the clinical application of tumor vesicles in tumor therapy.

Shexian Bupleurum Alleviates Insomnia and Improves Symptoms of Anxiety and Depression:A Randomized Double-Blind Placebo-Controlled Clinical Trial

Objective:To observe the clinical efficacy of Shexian bupleurum on insomnia based on evaluation scales and polysomnogram(PSG).Methods:A total of 260 patients suffering from insomnia admitted to the outpatient department of Handan Central Hospital were included in a randomized,double blind,placebo-controlled trial.The patients were randomly divided into two groups:a control group(receiving placebo,n=150),and an intervention group(receiving Shexian bupleurum treatment,n=110).The clinical trial lasted for 4 weeks.The Pittsburgh Sleep Quality Index(PSQI),Insomnia Severity Index(ISI),Patient Health Questionnaire(PHQ)-9,Generalized Anxiety Disorder(GAD)-7,17 items of Hamilton Depression Scale(HAMD-17),and Hamilton Anxiety Scale(HAMA)were used to evaluate the patients at baseline as well as two weeks and four weeks after treatment;the Treatment Emergent Symptom Scale(TESS)was used to evaluate adverse reactions;polysomnography(PSG)was used to monitor and analyze their sleep characteristics at baseline and four weeks after treatment.Results:The PSQI,ISI,PHQ-9,HAMD-17,and HAMA scores of the intervention group significantly decreased compared to the control group,while the total sleep time,rapid eye movement sleep latency,stage 2 sleep,deep sleep,rapid eye movement sleep,and sleep efficiency of the intervention group significantly increased compared to the control group.The PHQ-9 score of the control group only decreased two weeks after treatment(p<0.05)compared to the intervention group.In addition,there were no obvious adverse events in both the intervention group and the control group.Conclusion:Shexian bupleurum not only improves sleep quality,but also relieves depression and anxiety in patients who suffer from insomnia.

A Randomized Controlled Clinical Trial on Efficacy and Safety of Electroacupuncture on Oral Oxycodone Hydrochloride Prolonged-Release Tablets Related Constipation

Objective:To observe the efficacy and safety of electroacupuncture on oral oxycodone hydrochloride prolonged-release tablets related constipation in Qi(气)deficiency syndrome.Methods:A randomized control trial was conducted in 44 participants,who were divided into the treatment group(electroacupuncture group)and the control group(western medicine group).Two groups were treated by electroacupuncture at Zusanli(ST36),Tianshu(ST25),Zhigou(SJ6)and Shangjuxu(ST37)acupoints every day for 20 mins for 14 consecutive days and lactulose oral solution 30 ml every day for 14 consecutive days respectively.The constipation symptoms,traditional Chinese medicine(TCM)symptoms,quality of life,physical condition before and after the treatments were observed,and the safety indicators were monitored.Results:The treatment group was better than the control group in improving constipation symptom score,improving TCM symptom score and improving quality of life score,and the difference was statistically significant.There was no significant difference between the two groups in improving physical condition score.No acupuncture related adverse events were observed in the treatment group.Two patients in the control group withdrew from the study due to taking emergency defecation therapy and mild diarrhea respectively.Conclusion:Electroacupuncture is better than lactulose in the treatment of Qi deficiency constipation related to oxycodone hydrochloride prolonged-release tablets.It can significantly improve the symptoms of constipation,improve the symptoms of TCM,improve the quality of life.It is safe and effective.

Xi-Feng-Hua-Shi granules for diarrhea-predominant irritable bowel syndrome:protocol for a randomized,double-blind,placebo-controlled multi-center clinical trial

Background:Irritable bowel syndrome(IBS)is a common functional bowel disorder that can severely affect the quality of life of patients.Limited drugs have been reported for modern medical IBS treatment.The advantages of traditional Chinese medicine(TCM)treatment are gradually becoming prominent.Xi-Feng-Hua-Shi granules have been clinically used for diarrhea-predominant IBS(IBS-D)treatment for many years in TCM practice.Thus,this study aimed to further verify the effectiveness and safety of Xi-Feng-Hua-Shi(XFHS)granules in IBS-D treatment through a randomized,double-blind,placebo-controlled multi-center clinical trial and provide high-quality evidence for its effectiveness and safety in treatment,as well as provide a basis for clinical rational drug use and explore new clinical IBS-D treatment plans.Methods:A randomized,double-blind,placebo-controlled multi-center clinical trial will be performed in 23 hospitals.A total of 300 participants will be randomly divided into the experimental group(prescribed with XFHS granules)and the control group(prescribed with the placebo granules),with 150 participants in each group.The appearance,shape,color,and taste of the placebo granules are the same as those of XFHS granules.All participants will receive a 4-week treatment and a 6-month follow-up.The primary outcome is the overall clinical efficacy;the secondary outcomes are the IBS-Symptom Severity Score(IBS-SSS),TCM Syndrome Evaluation,and the IBS-Quality of Life(IBS-QoL)score,mental state assessment,and recurrence rate.Outcome measures(including primary and secondary outcome measures)are collected at baseline,as well as 2,4,16,and 28 weeks post-intervention.Discussion:This randomized,placebo-controlled,multi-center trial may provide high-quality evidence for the clinical XFHS granule efficacy in IBS-D treatment.Additionally,this study will conduct safety evaluations to provide a basis for clinical rational drug use.

Can propensity score matching replace randomized controlled trials?

Randomized controlled trials(RCTs)have long been recognized as the gold standard for establishing causal relationships in clinical research.Despite that,various limitations of RCTs prevent its widespread implementation,ranging from the ethicality of withholding potentially-lifesaving treatment from a group to relatively poor external validity due to stringent inclusion criteria,amongst others.However,with the introduction of propensity score matching(PSM)as a retrospective statistical tool,new frontiers in establishing causation in clinical research were opened up.PSM predicts treatment effects using observational data from existing sources such as registries or electronic health records,to create a matched sample of participants who received or did not receive the intervention based on their propensity scores,which takes into account characteristics such as age,gender and comorbidities.Given its retrospective nature and its use of observational data from existing sources,PSM circumvents the aforementioned ethical issues faced by RCTs.Majority of RCTs exclude elderly,pregnant women and young children;thus,evidence of therapy efficacy is rarely proven by robust clinical research for this population.On the other hand,by matching study patient characteristics to that of the population of interest,including the elderly,pregnant women and young children,PSM allows for generalization of results to the wider population and hence greatly increases the external validity.Instead of replacing RCTs with PSM,the synergistic integration of PSM into RCTs stands to provide better research outcomes with both methods complementing each other.For example,in an RCT investigating the impact of mannitol on outcomes among participants of the Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial,the baseline characteristics of comorbidities and current medications between treatment and control arms were significantly different despite the randomization protocol.Therefore,PSM was incorporated in its analysis to create samples from the treatment and control arms that were matched in terms of these baseline characteristics,thus providing a fairer comparison for the impact of mannitol.This literature review reports the applications,advantages,and considerations of using PSM with RCTs,illustrating its utility in refining randomization,improving external validity,and accounting for non-compliance to protocol.Future research should consider integrating the use of PSM in RCTs to better generalize outcomes to target populations for clinical practice and thereby benefit a wider range of patients,while maintaining the robustness of randomization offered by RCTs.

Chinese herbal medicine Xinfeng Capsule in treatment of rheumatoid arthritis:study protocol of a multicenter randomized controlled trial

BACKGROUND： Rheumatoid arthritis （RA）, as a common systemic inflammatory autoimmune disease, affects approximately 1 in 100 individuals. Effective treatment for RA is not yet available because current research does not have a clear understanding of the etiology and pathogenesis of RA. Xinfeng Capsule, a patent Chinese herbal medicine, has been used in the treatment of RA in recent years. Despite its reported clinical efficacy, there are no large-sample, multicenter, randomized trials that support the use of Xinfeng Capsule for RA. Therefore, we designed a randomized, double-blind, multicenter, placebo-controlled trial to assess the efficacy and safety of Xinfeng Capsule in the treatment of RA. METHODS AND DESIGN： This is a 12-week, randomized, placebo-controlled, double-blind, multicenter trial on the treatment of RA. The participants will be randomly assigned to the experimental group and the control group at a ratio of 1：1. Participants in the experimental group will receive Xinfeng Capsule and a pharmaceutical placebo （imitation leflunomide）. The control group will receive leflunomide and an herbal placebo （imitation Xinfeng Capsule）. The American College of Rheumatology （ACR） Criteria for RA will be used to measure the efficacy of the Xinfeng Capsule. The primary outcome measure will be the percentage of study participants who achieve an ACR 20% response rate （ACR20）, which will be measured every 4 weeks after randomization. Secondary outcomes will include the ACR50 and ACR70 responses, the side effects of the medications, the Disease Activity Score 28, RA biomarkers, quality of life, and X-rays of the hands and wrists. The first four of the secondary outcomes will be measured every 4 weeks and the others will be measured at baseline and after 12 weeks of treatment. DISCUSSION： The result of this trial will help to evaluate whether Xinfeng Capsule is effective and safe in the treatment of RA. TRIAL REGISTRATION： This trial has been registered in ClinicalTrials.gov. The identifier is N CT01774877.

Evaluation on the efficacy and safety of Chinese herbal medication Xifeng Dingchan Pill in treating Parkinson's disease: study protocol of a multicenter, open-label, randomized active-controlled trial

BACKGROUND： Parkinson＇s disease （PD） is a complicated disease, commonly diagnosed among the elderly, which leads to degeneration of the central nervous system. It presently lacks an effective therapy for its complex pathogenesis. Adverse effects from Western drug-based medical intervention prevent long-term adherence to these therapies in many patients. Traditional Chinese medicine （TCM） has long been used to improve the treatment of PD by alleviating the toxic and adverse effects of Western drug-based intervention. Therefore, the aim of this study is to evaluate the efficacy and safety of Xifeng Dingchan Pill （XFDCP）, a compound traditional Chinese herbal medicine, taken in conjunction with Western medicine in the treatment of PD patients at different stages in the progression of the disease. METHODS AND DESIGN： This is a multicenter, randomized controlled trial. In total, 320 patients with early- （n = 160） and middle-stage PD （n = 160） will be enrolled and divided evenly into control and trial groups. Of the 160 patients with early-stage PD, the trial group （n = 80） will be given XFDCP, and the control group （n = 80） will be given Madopar. Of the 160 patients with middle-stage PD, the trial group （n = 80） will be given XFDCP combined with Madopar and Piribedil, and the control group （n = 80） will be given Madopar and Piribedil. The Unified Parkinson＇s Disease Rating Scale scores, TCM symptoms scores, quality of life, change of Madopar＇s dosage and the toxic and adverse effects of Madopar will be observed during a 3-month treatment period and through a further 6-month follow-up period. DISCUSSION： It is hypothesized that XFDCP, combined with Madopar and Piribedil, will have beneficial effects on patients with PD. The results of this study will provide evidence for developing a comprehensive therapy regimen, which can delay the progress of the disease and improve the quality of life for PD patients in different stages. TRIAL REGISTRATION： This trial has been registered in the Chinese Clinical Trial Registry with the identifer ChiCTR-TRC-12002150.

Usefulness of the clip-flap method of endoscopic submucosal dissection: A randomized controlled trial

AIM To prospectively investigate the efficacy and safety of clipflap assisted endoscopic submucosal dissection(ESD) for gastric tumors.METHODS From May 2015 to October 2016, we enrolled 104 patients with gastric cancer or adenoma scheduled for ESD at Shiga University of Medical Science Hospital. We randomized patients into two subgroups using the minimization method based on location of the tumor(upper, middle or lower third of the stomach), tumor size(< 20 mm or > 20 mm) and ulcer status: ESD using an endoclip(the clip-flap group) and ESD without an endoclip(the conventional group). Therapeutic efficacy(procedure time) and safety(complication: Gastrointestinal bleeding and perforation) were assessed. RESULTS En bloc resection was performed in all patients. Four patients had delayed bleeding(3.8%) and two had perforation(1.9%). No significant differences in en bloc resection rate(conventional group: 100%, clip flap group: 100%), curative endoscopic resection rate(conventional group: 90.9%, clip flap group: 89.8%, P = 0.85), procedure time(conventional group: 70.8 ± 46.2 min, clip flap group: 74.7 ± 53.3 min, P = 0.69), area of resected specimen(conventional group: 884.6 ± 792.1 mm^2, clip flap group: 1006.4 ± 1004.8 mm^2, P = 0.49), delayed bleeding rate(conventional group: 5.5%, clip flap group: 2.0%, P = 0.49), or perforation rate(conventional group: 1.8%, clip flap group: 2.0%, P = 0.93) were found between the two groups. Lessexperienced endoscopists did not show any differences in procedure time between the two groups.CONCLUSION For patients with early-stage gastric tumors, the clipflap method has no advantage in efficacy or safety compared with the conventional method.

Comparison of an SMS text messaging and phone reminder to improve attendance at a health promotion center:A randomized controlled trial

Objective: To compare the efficacy of a short messaging service (SMS) text messaging and phone reminder to im-prove attendance rates at a health promotion center. Methods: A total of 1 859 participants who had scheduled appointments in the health promotion center of our hospital from April 2007 to May 2007 were enrolled in the study and randomly assigned into 3 groups: control (no reminder) group,SMS text messaging reminder group and telephone reminder group. Attendance rates and costs of interventions were collected. Results: A total of 1848 participants were eligible for analysis. Attendance rates of control,SMS and telephone groups were 80.5%,87.5% and 88.3%,respectively. The attendance rates were significantly higher in SMS and telephone groups than that in the control group,with odds ratio 1.698,95% confidence interval 1.224 to 2.316,P=0.001 in the SMS group,and odds ratio 1.829,95% confidence interval 1.333 to 2.509,P<0.001 in the telephone group. However,there was no difference between the SMS group and the telephone group (P=0.670). The cost effectiveness analysis showed that the cost per attendance for the SMS group (0.31 Yuan) was significantly lower than that for the telephone group (0.48 Yuan). Conclusion: SMS and telephone are effective reminders for improving attendance rate at a health promotion center. SMS reminder may be more cost-effective compared with the telephone reminder.

Effectiveness of oral motor respiratory exercise and vocal intonation therapy on respiratory function and vocal quality in patients with spinal cord injury:a randomized controlled trial

Singing,as a method of combining respiratory function exercise and vocal intonation therapy,provides a new direction for respiratory function exercise in patients with spinal cord injury.This randomized controlled trial investigated the effects of oral motor respiratory exercise and vocal intonation therapy on respiratory function and vocal quality in patients with spinal cord injury.Among 31 included patients with spinal cord injury,18 completed the treatment.These 18 patients were randomly assigned to undergo music therapy(intervention group,30 min/d,5 times a week,for a total of 12 weeks;n=9,7 males and 2 females;30.33±11.74 years old)or normal respiratory training(control group,n=9;8 males and 1 female;34.78±11.13 years old).Both patient groups received routine treatment concurrently.Before and at 6 and 12 weeks after intervention,a standard respiratory function test,a voice test,the St.George's Respiratory Questionnaire,and a quality of life questionnaire were administered.The results showed that the inspiratory capacity,forced expiratory volume in 1 second,forced vital capacity,maximal mid-expiratory flow rate,sing-loud pressure level,and sustained note length were significantly increased in the intervention group compared with the control group.The St.George's Respiratory Questionnaire and quality of life results of patients in the intervention group were significantly superior to those in the control group.These findings suggest that oral motor respiratory exercise and vocal intonation therapy,as respiratory training methods in music therapy,are effective and valuable for improving respiratory dysfunction and vocal quality in patients with spinal cord injury.This study was approved by the Ethics Committee of China Rehabilitation Research Center(approval No.2019-78-1)on May 27,2019 and was registered with the Chinese Clinical Trial Registry(registration number:Chi CTR1900026922)on October 26,2019.

Evaluation of Blood Pressure Control Medicines Using Health and Medical Checkup Data in Japan: Alternative Methods for Randomized Controlled Trials

Background: Many people take medicines to control high blood pressure (BP), or hypertension. Randomized clinical trials (RCT) are usually used for the evaluation of effects of medicines. However, RCT have some serious problems. Data and Methods: We evaluated the effects of BP medicines in Japan using a dataset containing 113,979 cases. We employed four statistical methods in the analysis. First, we simply compared the systolic blood pressure (SBP) of individuals with and without BP medicines. We then used a regression model with a dummy variable, representing taking medicines or not. We replaced the dummy variable by its expected value, and estimated the regression model again. Finally, we selected individuals who had both taken and not taken medicines at different times. The effect of sample selection was also considered in the estimation. Results: For the simple comparison, SBP with BP medicines was 11 mmHg higher than without medicines. In the next regression analysis, SBP with BP medicines was still 5 mmHg higher. When the dummy variable was replaced by its expected value, SBP with medicines decreased by 7 mmHg. For individuals taking medicines at some times and not at others, SBP decreased by 9 and 8 mmHg in models with and without a sample bias correction, respectively. Conclusion: The methods eliminated some problems of RCT and might be attractive. However, we obtained contradictory conclusions depending on the statistical methods employed, despite using the identical dataset. Statistical methods must be selected carefully to obtain a reliable evaluation. Limitations: The dataset was observatory, and the sample period was only 3 years.