Drug trials are more likely to disclose full placebo control information than non-drug trials: A cross-sectional study of participant information leaflets of placebo-controlled trials.

Background: This study aimed to investigate whether placebo control is differently disclosed in drug and non-drug randomised clinical trial (RCT) participant information leaflets (PILs) and how this might affect participant blinding and direction of study outcomes. Methods: PILs were obtained from trials registered in the International Standard Randomised Controlled Trial Number database via email. Placebo descriptions in PILs were categorised as Full Disclosure (FD), Partial Disclosure (PD), or Missing Information (MI). Associations between intervention type (drug or non-drug)/placebo disclosure (FD or PD/MI) and participant blinding success/trial outcome direction (positive or non-positive) were examined using a two-sided Fisher's exact test. Results: Of 116 collected PILs, 56 % were for drug trials and 44 % were for non-drug trials. Among them, 88 PILs had the corresponding publications available and 68 reports specified primary outcomes. Drug trials were more likely to fully disclose placebo information than non-drug trials (92.3 % vs. 74.5 %, p < 0.05). However, the success rate of blinding was only reported in 3 out of 88 trial publications (3.4 %), precluding further analysis. Furthermore, there was no significant association between the direction of trial results and the type of intervention or placebo disclosure. Conclusion: Our study findings suggest that drug and non-drug RCTs might differ in the way they reveal placebo control information. Further research is warranted to understand what leads to more common PD of placebo information in non-drug trials than drug trials and to determine the optimal placebo control disclosure in specific trial context.

Conversational Agents for Body Weight Management: Systematic Review.

BACKGROUND: Obesity is a public health issue worldwide. Conversational agents (CAs), also frequently called chatbots, are computer programs that simulate dialogue between people. Owing to better accessibility, cost-effectiveness, personalization, and compassionate patient-centered treatments, CAs are expected to have the potential to provide sustainable lifestyle counseling for weight management. OBJECTIVE: This systematic review aimed to critically summarize and evaluate clinical studies on the effectiveness and feasibility of CAs with unconstrained natural language input for weight management. METHODS: PubMed, Embase, the Cochrane Library (CENTRAL), PsycINFO, and ACM Digital Library were searched up to December 2022. Studies were included if CAs were used for weight management and had a capability for unconstrained natural language input. No restrictions were imposed on study design, language, or publication type. The quality of the included studies was assessed using the Cochrane risk-of-bias assessment tool or the Critical Appraisal Skills Programme checklist. The extracted data from the included studies were tabulated and narratively summarized as substantial heterogeneity was expected. RESULTS: In total, 8 studies met the eligibility criteria: 3 (38%) randomized controlled trials and 5 (62%) uncontrolled before-and-after studies. The CAs in the included studies were aimed at behavior changes through education, advice on food choices, or counseling via psychological approaches. Of the included studies, only 38% (3/8) reported a substantial weight loss outcome (1.3-2.4 kg decrease at 12-15 weeks of CA use). The overall quality of the included studies was judged as low. CONCLUSIONS: The findings of this systematic review suggest that CAs with unconstrained natural language input can be used as a feasible interpersonal weight management intervention by promoting engagement in psychiatric intervention-based conversations simulating treatments by health care professionals, but currently there is a paucity of evidence. Well-designed rigorous randomized controlled trials with larger sample sizes, longer treatment duration, and follow-up focusing on CAs' acceptability, efficacy, and safety are warranted.

Efficacy of herbal medicine treatment based on syndrome differentiation for Parkinson's disease: A systematic review and meta-analysis of randomized placebo-controlled clinical trials.

Background: Parkinson's disease (PD), the second most common progressive neurodegenerative disease, causes heterogeneous clinical symptoms. Patients experience a range of motor and non-motor symptoms, and personalized diagnosis and treatment are needed. In traditional East Asian medicine, syndrome differentiation (SD) is a diagnostic approach for customized therapy that uses a comprehensive analysis and varies for the same disease. We aimed to evaluate the efficacy of herbal medicine (HM) prescribed according to the SD of PD. Methods: Ten electronic databases were searched from inception to August 2021 without language limitations. All randomized controlled trials (RCTs) involving HM for SD of PD were included. Assessment of Cochrane's risk of bias and meta-analysis and Grading of Recommendations Assessment, Development, and Evaluation was also performed. Effect measurement was summarized using the mean difference (MD) with 95% confidence interval, through a meta-analysis. Results: Thirteen RCTs involving 843 participants were included. The overall risk of bias was either low or unclear. Compared with the placebo, a combined therapy of HM and Western medicine (WM) significantly improved the total Unified Parkinson's Disease Rating Scale (UPDRS) (MD = -8.03, [-10.27, -5.79], p < 0.00001; I2 = 0%) and was more beneficial, as assessed using the UPDRS (I-III), the Parkinson's Disease Questionnaire-39, and the Non-Motor Symptoms Scale. Adverse events did not differ between the groups. Conclusion: The findings suggest that the combined treatment of WM and HM based on SD diagnosis has additional benefits in PD treatment. However, the methodological quality of the included RCTs was suboptimal. Nevertheless, this systematic review is the first to investigate the efficacy of HM treatment according to the SD diagnosis in PD. The clinically meaningful improvement in HM according to SD in PD needs to be tested in further studies with rigorous designs and longer follow-up periods. Systematic Review Registration: [https://inplasy.com/inplasy-2021-10-0020/], identifier [INPLASY2021100020].

Individualized herbal prescriptions for delayed union: A case series.

Background Bone fractures are important clinical events for both patients and professionals. Active treatment options are limited for delayed unions and for nonunions; surgery is common but not entirely risk-free. This report describes three cases of delayed union successfully treated with herbal decoction. Participants Three patients had trapezoid and 3rd metacarpal bone fractures, 2nd, and 5th metatarsal bone fractures, respectively. All three patients were diagnosed with delayed union by an independent orthopedic surgeon based on computed tomography (CT) scan/radiographic imaging and fracture duration without a healing process. Patients took herbal decoction, Jeopgol-tang, with individually added herbs based on symptom manifestations, twice daily for 56, 85 and 91 days with no additional interventions except for a splint that they had been wearing since fracture diagnosis. Outcomes Improvement of delayed union was evaluated using radiographic imaging or CT during treatment with Jeopgol-tang. Results After taking herbal medicine, callus and bony bridging were confirmed on follow-up imagings and the patients described their experience with pain reduction at an interview after recovery. Conclusions This case series suggests that the herbal decoction Jeopgol-tang warrants further investigation to establish its role as a complementary and integrative medicine treatment option for delayed unions.

Safety of acupuncture by Korean Medicine Doctors: a prospective, practice-based survey of 37,490 consultations.

BACKGROUND: To evaluate safety of acupuncture treatment by Korean Medicine Doctors (KMDs), a prospective, practice-based survey on adverse events (AEs) associated with acupuncture was conducted. METHODS: From July 2016 to October 2017, KMDs were invited to participate in an online survey. Frequency was calculated as the number of AEs per 10,000 treatments; severity was assessed with the Common Terminology Criteria for Adverse Events Grading (Severity) Scale; and causality was evaluated using the World Health Organisation-Uppsala Monitoring Centre system for standardised case causality assessment. Associations between AE occurrence and KMDs' type of practice/clinical experience and patient age/gender/current medication(s) were analysed. RESULTS: Data on 37,490 acupuncture treatments were collected from 222 KMDs. At least one AE was reported from 4,518 acupuncture treatments, giving a frequency rate of 1,205 per 10,000 acupuncture treatments; this increased to 4,768 treatments when administrative problems related to defective devices or medical negligence were added, for a rate of 1,272 per 10,000 acupuncture treatments. Commonly reported AEs were bleeding, needle site pain, and bruising. Approximately 72.9% of AEs/administrative problems were assessed as they certainly occurred by acupuncture treatment in causality assessment. Most AEs/administrative problems were considered mild in severity and two life-threatening AEs were resolved with no sequelae. Compared to males, female patients were more likely to experience AEs and KMDs' clinical experience was not associated with reported AE occurrence. CONCLUSIONS: Although acupuncture-associated AEs occur commonly, they are largely transient and mild. Acupuncture performed by qualified KMDs may serve as a reliable medical treatment with acceptable safety profiles.

Robustness of meta-analysis results in Cochrane systematic reviews: A case for acupuncture trials.

Introduction: Fragility index (FI) refers to the smallest value that change statistical significance of study results. Meta-analyses of Cochrane systematic reviews are considered as the best evidence for stake holders because they enable effect size estimation that cannot be derived by individual studies, particularly in the field of complementary and integrative medicine (CIM). Thus, this study aimed to evaluate robustness of meta-analysis in Cochrane systematic reviews of acupuncture, one of the most used CIM treatment, using FI of meta-analysis. Methods: Meta-analyses of acupuncture Cochrane systematic reviews with binary benefit outcome measures were searched in PubMed, Embase, and CENTRAL and subject to analysis. Randomized clinical trials (RCTs) or quasi RCTs adopted penetrating needles as treatment and compared with controls such as sham acupuncture, usual care, and active control were included. FI of meta-analyses was calculated in web (https://clinicalepidemio.fr/fragility_ma/); and fragility quotient (FQ) was calculated by dividing FI by total sample size of meta-analysis. Results: Of 248 retrieved studies, 12 Cochrane systematic reviews with 48 meta-analyses were analyzed. The median FI for statistically significant and non-significant meta-analyses was 7 [interquartile range: 3 - 12] and 6 [interquartile range: 3 - 10]. FQ was similar irrespective of statistical significance. Among controls, meta-analyses adopting sham acupuncture displayed the widest range of FI and FQ. Conclusion: Robustness of meta-analyses in Cochrane systematic reviews for acupuncture was similar irrespective of statistical significance. Impact of control intervention cannot be determined in this study. As FI enables intuitive interpretation, applications for CIM field can be useful.

Safety of acupotomy in a real-world setting: A prospective pilot and feasibility study.

OBJECTIVE: Acupotomy is a modern acupuncture method that includes modern surgical methods. Since acupotomy is relatively more invasive than filiform acupuncture treatment, it is important to establish the safety profile of this practice. To justify further large-scale prospective observational studies, this preliminary study was performed to assess the feasibility of the approach and investigate the safety profile and factors potentially associated with adverse events (AEs). METHODS: This was a prospective pilot study that assessed the feasibility of a large-scale forthcoming safety study on acupotomy treatment in a real-world setting. The feasibility (call response rate, drop-out rate, response rate for each variable and recruitment per month) and safety profile (incidence, type, severity and causality of AEs, and factors potentially associated with AEs) were measured. RESULTS: A total of 28 participants joined the study from January to May 2018. A follow-up assessment was achieved in 258 (1185 treatment points) out of 261 sessions (1214 treatment points). The response rate via telephone on the day after treatment was 87.3%. There were 8 systemic AEs in all the sessions (8/258; 3.11%) and 27 local AEs on the total points treated (27/1185; 2.28%). Severe AEs did not occur. Total AE and local AE occurrence were associated with blade width and the number of needle stimulations per treatment point. CONCLUSION: The findings suggest that it could be feasible to analyze the safety of acupotomy in a real-world setting. Moreover, the primary data on some relevant AEs could be determined. We are planning large-scale prospective studies based on these findings. TRIAL REGISTRATION: Clinical Research Information Service (CRIS) KCT0002849 (https://cris.nih.go.kr/cris/search/detailSearch.do/11487).

Reporting quality of sham needles used as controls in acupuncture trials: a methodological evaluation.

OBJECTIVE: The description of controls is important in acupuncture clinical trials to interpret its effectiveness without fallacy. This paper aims to evaluate the reporting quality of acupuncture studies on the characteristics of sham needles. STUDY DESIGN AND SETTING: Using a checklist developed from previously published reporting guidelines, the distribution of reported items and changes of reporting rates over time were investigated. Two-way ANOVA and linear regression were conducted. RESULTS: Original articles of RCTs of any design involving sham needles as controls were eligible for assessment. 117 trials from three 2-year time periods between 2009 and 2018 were included. Seven items out of 25 were reported in more than 50% of the studies. While significant differences of reporting scores among categories were observed, there were no significant differences among time periods; no significant improvement was observed over time. CONCLUSIONS: Low reporting qualities of sham needles used in acupuncture studies may influence how researchers understand the effectiveness of acupuncture. This study evaluated previous publications from 2009 to 2018 and found that reporting qualities on sham needles did not improve over time. Further studies are required to validate the items used in this study to endorse better reporting of controls in acupuncture trials.

The Role of Skin Mast Cells in Acupuncture Induced Analgesia in Animals: A Preclinical Systematic Review and Meta-analysis.

While mast cells (MCs) are previously well-known as a pathological indicator of pain, their role in alleviating pain is recently emerged in acupuncture research. Thus, this study systematically reviews the role of MC in acupuncture analgesia. Animal studies on MC changes associated with the acupuncture analgesia were searched in PubMed and EMBASE. The MC number, degranulation ratio and pain threshold changes were collected as outcome measures for meta-analyses. Twenty studies were included with 13 suitable for meta-analysis, most with a moderate risk of bias. A significant MC degranulation after acupuncture was indicated in the normal and was significantly higher in the pain model. In the subgroup analysis by acupuncture type, manual (MA) and electrical (EA, each P < .00001) but not sham acupuncture had significant MC degranulation. Meta-regression revealed the linear proportionality between MC degranulation and acupuncture-induced analgesia (P < .001), which was found essential in MA (P < .00001), but not in EA (P = .45). MC mediators, such as adenosine and histamine, are involved in its mechanism. Taken together, skin MC is an essential factor for acupuncture-induced analgesia, which reveals a new aspect of MC as a pain alleviator. However, its molecular mechanism requires further study. PERSPECTIVE: This systematic review synthesizes data from studies that examined the contribution of skin MC in acupuncture analgesia. Current reports suggest a new role for skin MC and its mediators in pain alleviation and explain a peripheral mechanism of acupuncture analgesia, with suggesting the need of further studies to confirm these findings.

Lifetime risks and health impacts of hemorrhagic and ischemic stroke in South Korea.

This study is aimed toward estimating the lifetime risks, life expectancy, expected years of life lost (EYLL), and lifetime costs related to different subtypes of stroke in South Korea. We included 13,994 patients diagnosed with stroke (ICD-10, I60-I63) in the National Health Insurance Service-National Sample Cohort of Korea between 2006 and 2015. Lifetime risks were calculated using the cumulative incidence rate for patients aged 18-84. Lifetime survival data were obtained through the Kaplan-Meier method and extrapolated with a rolling-over extrapolation algorithm. The lifetime costs were estimated by multiplying the average monthly expenditures with the survival probabilities and adding the values over lifetime. The lifetime risks of stroke in Korea have been decreasing consistently over the last decade with the exception of subarachnoid hemorrhage in females, which appears to have slightly increased. The EYLL is higher in hemorrhagic stroke than in ischemic stroke (6-9.7 vs. 4.7). Expected lifetime costs reimbursed by the NHIS would amount to about $71,406 accompanied with $14,921 copayment from the patients for hemorrhagic stroke, and $50,551 and $11,666, respectively, for ischemic stroke. Further studies are warranted to combine survival with quality of life and functional disability to obtain a more detailed outcome assessment of the potential impact of the prevention of stroke.

Trial registration as a safeguard against outcome reporting bias and spin? A case study of randomized controlled trials of acupuncture.

BACKGROUND AND OBJECTIVE: Trial registration is widely endorsed as it is considered not only to enhance transparency and quality of reporting but also to help safeguard against outcome reporting bias and probably spin, known as specific reporting that could distort the interpretation of results thus mislead readers. We planned to investigate the current registration status of recently published randomized controlled trials (RCTs) of acupuncture, outcome reporting bias in the prospectively registered trials, and the association between trial registration and presence of spin and methodological factors in acupuncture RCTs. METHODS: Acupuncture RCTs published in English in recent 5 years (January 2013 to December 2017) were searched in PubMed, Cochrane Central Register of Controlled Trials, and EMBASE. Trial registration records identified in the publications and trial registries were classified into prospectively registered, retrospectively registered, or unregistered. Primary outcomes were identified and the direction of the results was judged as statistically significant (positive) or statistically nonsignificant (negative). We compared registered and published primary outcomes to assess outcome reporting bias and assessed whether discrepancies favored statistically significant outcomes. Frequency and strategies of spin in published reports with statistically nonsignificant results for primary outcomes were then identified. We also analyzed whether the trial registration status was associated with spin and quality of methodological factors. RESULTS: Of the 322 included RCTs, 41.9% (n = 135) were prospectively registered. Among 64 studies that were prospectively registered and specified primary outcomes, 25 trials had the discrepancies between the registered and published primary outcomes and 60% of them (15 trials) favored the statistically significant findings. Among 169 studies that specified primary outcomes, trial registration status was not associated with the direction of results, i.e., statistically significant or not. Spin was identified in 56.4% out of 78 studies with statistically nonsignificant primary outcomes and claiming efficacy with no consideration of statistically nonsignificant primary outcomes was the most common strategy for spin. Trial registration status was not statistically different between studies with and without spin. CONCLUSION: While trial registration seemed to have improved over time, primary outcomes in registered records and publications were often inconsistent, tending to favor statistically significant findings and spin was common in studies with statistically nonsignificant primary outcomes. Journal editors and researchers in this field should be alerted to still prevalent reporting bias and spin.