Evaluation of a flexible piecewise linear mixed-effects model in the analysis of randomized cross-over trials.

Cross-over designs are commonly used in randomized clinical trials to estimate efficacy of a new treatment. They have received a lot of attention, particularly in connection with regulatory requirements for new drugs. The main advantage of using cross-over designs over conventional parallel designs is increased precision, thanks to within-subject comparisons. In the statistical literature, more recent developments are discussed in the analysis of cross-over trials, in particular regarding repeated measures. A piecewise linear model within the framework of mixed effects has been proposed in the analysis of cross-over trials. In this article, we report on a simulation study comparing performance of a piecewise linear mixed-effects (PLME) model against two commonly cited models-Grizzle's mixed-effects (GME) and Jones & Kenward's mixed-effects (JKME) models-used in the analysis of cross-over trials. Our simulation study tried to mirror real-life situation by deriving true underlying parameters from empirical data. The findings from real-life data confirmed the original hypothesis that high-dose iodine salt have significantly lowering effect on diastolic blood pressure (DBP). We further sought to evaluate the performance of PLME model against GME and JKME models, within univariate modeling framework through a simulation study mimicking a 2 × 2 cross-over design. The fixed-effects, random-effects and residual error parameters used in the simulation process were estimated from DBP data, using a PLME model. The initial results with full specification of random intercept and slope(s), showed that the univariate PLME model performed better than the GME and JKME models in estimation of variance-covariance matrix (G) governing the random effects, allowing satisfactory model convergence during estimation. When a hierarchical view-point is adopted, in the sense that outcomes are specified conditionally upon random effects, the variance-covariance matrix of the random effects must be positive-definite. The PLME model is preferred especially in modeling an increased number of random effects, compared to the GME and JKME models that work equally well with random intercepts only. In some cases, additional random effects could explain much variability in the data, thus improving precision in estimation of the estimands (effect size) parameters.

Maggot Debridement Therapy for Chronic Leg and Foot Ulcers: A Review of Randomized Controlled Trials.

OBJECTIVE: To critically analyze the existing randomized controlled trials (RCTs) on the clinical, economic, and psychological implications of maggot debridement therapy (MDT). DATA SOURCES: An exhaustive literature search for English-language publications was conducted using MEDLINE, EMBASE, and PubMed. STUDY SELECTION: Keywords used for the search were based on the PICO (Population, Intervention, Comparison, Outcome) framework. The titles, abstracts, and relevant full-text articles were screened. Seven RCTs were selected after applying the inclusion and exclusion criteria. DATA EXTRACTION: Data pertaining to the primary and secondary outcomes of each study were extracted. DATA SYNTHESIS: The data extracted were evaluated and categorized into clinical, economic, and psychological outcomes pertaining to MDT. A judicious evaluation of these outcomes was made, and the following conclusions were drawn. CONCLUSIONS: There exists heterogeneity in the extant RCTs, but MDT appears to be effective for a quick early debridement. For diabetic foot ulcers, MDT improves debridement, controls infection, and enhances wound healing. In chronic peripheral vascular disease ulcers, it aids in early debridement, but the final outcome is equivocal. Further robust integrated health economic and parallel qualitative assessment studies are recommended to understand the cost-effectiveness and patient acceptability and experience.

Xuesaitong injection treating acute myocardial infarction: A systematic review and meta-analysis.

BACKGROUND: Although the incidence of acute myocardial infarction (AMI) is decreasing, the mortality in AMI patients remains substantial. Traditional Chinese medicine has shown its role in the prevention and management of AMI. The purpose of this study is to evaluate the clinical efficacy of Xuesaitong injection (XST) for the treatment of AMI by a meta-analysis. METHODS: A literature search was performed in 5 medical databases up to June 1, 2020. Randomized controlled trials involving XST combined with conventional treatment versus conventional treatment were included. A meta-analysis of clinical efficacy, left ventricular function and other objective parameters was performed to evaluate the effects of XST on AMI. RESULTS: Five randomized controlled trials involving 539 participants were eventually included. Meta-analysis showed that the combination of XST and conventional treatment could achieve significantly better effect on improving clinical efficacy (risk ratio: 1.09 [1.01, 1.17]; P = .04), left ventricular ejection fraction (mean difference [MD]: 3.18 [1.69, 4.67]; P < .0001), hypersensitive C-reactive protein (MD: -2.58 [-5.04, -0.12]; P = .04), interleukin 6 (MD: -26.00 [-38.85, -13.16]; P < .0001), cardiac troponin T (MD: -15.85 [-18.09, -13.61]; P < .00001) and creatine kinase myocardial isoenzyme (MD: -73.06 [-79.74, -66.37]; P < .00001). CONCLUSION: XST combined with conventional treatment can achieve better efficacy on clinical performance and some of the AMI related parameters. However the interpretation of the results should be cautious, due to the relatively low quality of included trials. More rigorously designed, large-scaled, randomized controlled trials are warranted to support its clinical use in the future.

Effect of IV High-Dose Vitamin C on Mortality in Patients With Sepsis: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

OBJECTIVES: The aim of this study was to conduct a systematic review and meta-analysis of randomized controlled trials to investigate whether IV high-dose vitamin C improves the short-term mortality of patients with sepsis. DESIGN: This study is a systematic review and meta-analysis of randomized controlled trials. We searched EMBASE, the Cochrane Central Register of Controlled Trials, and MEDLINE for randomized controlled trials that met inclusion criteria. The protocol was registered at the University hospital Medical Information Network Clinical Trials Registry (UMIN000040528). All analyses were presented with the use of random-effects models. The primary outcome was short-term mortality defined as 28-day, 30-day, or in-hospital mortality. PATIENTS: Two authors independently evaluated the following eligibility criteria: 1) randomized controlled trial, 2) patients with sepsis aged ≥18 years, and 3) received intravenous high-dose vitamin C in addition to standard of care, or standard of care alone. Then, two authors independently extracted the selected patient and study characteristics and outcomes from studies that met above eligibility criteria. MEASUREMENTS AND MAIN RESULTS: Eleven randomized controlled trials (n = 1,737 patients) were included in this meta-analysis. High-dose IV vitamin C was not associated with a significantly lower short-term mortality (risk ratio, 0.88; 95% CI, 0.73-1.06; p = 0.18; I2 = 29%) but was associated with a significantly shorter duration of vasopressor use (standardized mean difference, -0.35; 95% CI, -0.63 to -0.07; p < 0.01; I2 = 80%) and a significantly greater decline in the Sequential Organ Failure Assessment score at 72-96 hours (standardized mean difference, -0.20; 95% CI, -0.32 to -0.08; p < 0.01; I2 = 16%). One study reported significant association with hypernatremia, but adverse effects were rare, and high-dose vitamin C is deemed relatively safe. CONCLUSIONS: In this meta-analysis, the use of IV high-dose vitamin C in patients with sepsis was not associated with lower short-term mortality although it was associated with significantly shorter duration of vasopressor use and greater decline in the Sequential Organ Failure Assessment score at 72-96 hours.

Potential mental and physical benefits of supplementation with a high-dose, B-complex multivitamin/mineral supplement: What is the evidence?

INTRODUCTION: Objective: to perform a systematic literature review to examine the effects of high-dose, B-complex multivitamin/mineral supplementation on physical, mental, and energy outcomes in healthy and 'at-risk' (suboptimal nutritional status/subclinical symptoms at baseline) adult populations. Methods: PubMed was searched for relevant randomized controlled trials until January 2020. Results: overall, 136 publications were identified. In the seven randomised, double-blind, placebo-controlled studies considered eligible for inclusion, supplementation in healthy populations predominantly showed improvements in perceived stress, physical stamina, concentration, and general mental health, and significant reductions in anxiety and improvements in self-reported vigour. However, not all of these outcomes were significant, and statistical correction for multiple outcomes was not commonly employed. Studies investigating brain mapping following supplementation indicated increased functional activity in brain regions related to processing of attention, executive control, and working memory during cognitive tasks. Conclusions: while there is certainly a need for further studies on the neurocognitive and physical benefits of micronutrient supplementation, this review provides generally supportive evidence for the benefits of a high-dose, B-complex multivitamin/mineral supplement in healthy and at-risk populations in terms of physical, mental, and energy outcomes.

INTRODUCCIÓN: Objetivo: realizar una revisión sistemática de la literatura para valorar los efectos de la administración de suplementos multivitamínicos/minerales del complejo B en dosis altas sobre los resultados físicos, mentales y energéticos en poblaciones adultas sanas y en situaciones especiales de riesgo (estado nutricional subóptimo/síntomas subclínicos al inicio del estudio). Métodos: se realizaron búsquedas en PubMed de ensayos controlados aleatorios relevantes hasta enero 2020. Resultados: en total se identificaron 136 publicaciones. En los siete estudios aleatorizados, doble ciego y controlados con placebo considerados elegibles para la inclusión, la suplementación en poblaciones sanas mostró predominantemente mejoras en la percepción del estrés, la resistencia física, la concentración y la salud mental general, así como una reducción significativa de la ansiedad y mejoras en la vitalidad según la autoevaluación de los participantes. Sin embargo, no todos estos resultados fueron significativos y la corrección estadística para múltiples resultados no se empleó habitualmente. Los estudios sobre el mapeo cerebral después de la suplementación, indicaron un aumento de la actividad funcional en las regiones del cerebro relacionadas con el procesamiento de la atención, el control ejecutivo y la memoria de trabajo durante tareas cognitivas. Conclusiones: si bien ciertamente existe la necesidad de realizar más estudios sobre los beneficios neurocognitivos y físicos de la suplementación con micronutrientes, esta revisión proporciona evidencia en general sobre los beneficios de un suplemento multivitamínico/mineral del complejo B en dosis altas, en poblaciones sanas y en situaciones de riesgo, en términos de resultados físicos, mentales y energéticos.

Efficacy of hypertonic dextrose injection (prolotherapy) in temporomandibular joint dysfunction: a systematic review and meta-analysis.

Hypertonic dextrose prolotherapy (DPT) has been reported to be effective for temporomandibular disorders (TMDs) in clinical trials but its overall efficacy is uncertain. To conduct a systematic review with meta-analysis of randomized controlled trials (RCTs) to synthesize evidence on the effectiveness of DPT for TMDs. Eleven electronic databases were searched from their inception to October, 2020. The primary outcome of interest was pain intensity. Secondary outcomes included maximum inter-incisal mouth opening (MIO) and disability score. Studies were graded by "Cochrane risk of bias 2" tool; if data could be pooled, a meta-analysis was performed. Ten RCTs (n = 336) with some to high risk of bias were included. In a meta-analysis of 5 RCTs, DPT was significantly superior to placebo injections in reducing TMJ pain at 12 weeks, with moderate effect size and low heterogeneity (Standardized Mean Difference: - 0.76; 95% CI - 1.19 to - 0.32, I2 = 0%). No statistically significant differences were detected for changes in MIO and functional scores. In this systematic review and meta-analysis, evidence from low to moderate quality studies show that DPT conferred a large positive effect which met criteria for clinical relevance in the treatment of TMJ pain, compared with placebo injections.Protocol registration at PROSPERO: CRD42020214305.

Effects of select dietary supplements on the prevention and treatment of viral respiratory tract infections: a systematic review of randomized controlled trials.

Introduction: Viral respiratory tract infections (RTIs) have been recognized as a global public health burden. Despite current theories about their effectiveness, the true benefits of dietary supplements on the prevention and treatment of viral RTIs remain elusive, due to contradictory reports. Hence, we aimed to evaluate the effectiveness of dietary supplements on the prevention and treatment of viral RTIs.Areas covered: We systematically searched databases of PubMed, Web of Science, Scopus, and Google Scholar through 4 March 2020, to identify randomized controlled trials that evaluated the effects of consuming selected dietary supplements on the prevention or treatment of viral RTIs.Expert opinion: Thirty-nine randomized controlled trials (n = 16,797 participants) were eligible and included. Namely, vitamin D supplementation appeared to improve viral RTIs across cohorts particulate in those with vitamin D deficiency. Among the evaluated dietary supplements, specific lactobacillus strains were used most commonly with selected prebiotics that showed potentially positive effects on the prevention and treatment of viral RTIs. Further, ginseng extract supplementation may effectively prevent viral RTIs as adjuvant therapy. However, longitudinal research is required to confirm these observations and address the optimal dose, duration, and safety of dietary supplements being publicly recommended.

Effect of Buyang Huanwu decoction for the rehabilitation of ischemic stroke patients: a meta-analysis of randomized controlled trials.

PURPOSE: Buyang Huanwu decoction (BHD) is a widely used traditional Chinese medicine for the rehabilitation of ischemic stroke patients in China, but its clinical efficacy and safety have not been adequately assessed. In this paper, we conducted a systematic review and meta-analysis to evaluate the efficacy and safety of BHD. METHODS: We searched seven electronic databases from inception to 31 March 2019. The language was limited to Chinese and English. Randomized controlled trials evaluating the efficacy and safety of BHD for the rehabilitation of ischemic stroke patients were included in the meta-analysis. Reviewers independently performed the screening, data extraction, bias assessment, and data analysis. The treatment efficacy was pooled in a meta-analysis using RevMan 5.3 software with a random-effect model. Any disagreement was resolved by discussion among all reviewers. The PRISMA statement was used in the review process. RESULTS: A total of 11 studies with 1084 patients were included in the meta-analysis. The results suggested that BHD was superior to other treatments in terms of clinical efficacy in symptoms and daily activities (n = 684, RR = 1.12, 95% CI: 0.99 to 1.27), clinical efficacy in TCM symptoms (n = 280, RR = 1.45, 95% CI: 1.03 to 2.03), National Institute of Health stroke scale (n = 192, MD = 1.66, 95% CI: -1.08 to 4.40), and activities of daily living (n = 200, MD = 8.20, 95% CI: -3.95 to 20.35). CONCLUSIONS: The results supported the clinical use of BHD for the rehabilitation of ischemic stroke patients. However, the methodological qualities of the included studies were relatively low, and there were limited reports on adverse events. The clinical efficacy and safety of BHD need to be further confirmed by more well-designed and high-quality randomized controlled trials to warrant the clinical recommendation of BHD for the rehabilitation of ischemic stroke patients.

Intraoperative local injection of uterosacral ligaments with ropivacaine during uterine surgery: A systematic review and meta-analysis of randomized controlled trials.

AIM: To perform a systematic review and meta-analysis of all randomized controlled trials that examined the efficacy of intraoperative local injection of the uterosacral ligaments with ropivacaine on postoperative pain and opioids consumption in patients undergoing uterine surgery for hysterectomy/myomectomy. METHODS: PubMed, Scopus, Web of Science and Cochrane Library databases were screened from inception to September 5th, 2020. We appraised the risk of bias using the Cochrane's risk of bias tool. Resting postoperative pain scores and cumulative consumption of postoperative opioids were regarded as continuous data, analyzed using the inverse variance method and reported as standardized mean difference (SMD) and weighted mean difference (MD), respectively, with 95 % confidence intervals (95 % CIs). RESULTS: Five studies met the inclusion criteria comprising 230 patients (117 and 113 patients received ropivacaine and placebo, respectively). The studies had an overall low risk of bias. Resting postoperative pain scores were not significantly different between both groups at 2 h (SMD = -0.30, 95 % CI [-0.70, 0.11], p = 0.15), 12 h (SMD = 0.04, 95 % CI [-0.26, 0.37], p = 0.81) and 24 h (SMD = -0.06, 95 % CI [-0.32, 0.20], p = 0.68). However, the ropivacaine group had significantly reduced cumulative opioid consumption during the first 24 h postoperatively (MD = -9.07, 95 % CI [-14.47, -3.66], p = 0.001). CONCLUSION: Intraoperative local infiltration of uterosacral ligaments with ropivacaine is technically feasible and significantly reduces postoperative opioid consumption in women undergoing gynecologic surgery of the uterus.

Immediate-release methylphenidate for attention deficit hyperactivity disorder (ADHD) in adults.

BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is characterized by symptoms of inattention or impulsivity or both, and hyperactivity, which affect children, adolescents, and adults. In some countries, methylphenidate is the first option to treat adults with moderate or severe ADHD. However, evidence on the efficacy and adverse events of immediate-release (IR) methylphenidate in the treatment of ADHD in adults is limited and controversial. OBJECTIVES: To evaluate the efficacy and harms (adverse events) of IR methylphenidate for treating ADHD in adults. SEARCH METHODS: In January 2020, we searched CENTRAL, MEDLINE, Embase, eight additional databases and three trial registers. We also searched internal reports on the European Medicines Agency and the US Food and Drug Administration websites. We checked citations of included trials to identify additional trials not captured by the electronic searches. SELECTION CRITERIA: Randomized controlled trials (RCTs) comparing IR methylphenidate, at any dose, with placebo or other pharmacological interventions (including extended-release formulations of methylphenidate) for ADHD in adults. Primary outcomes comprised changes in the symptoms of ADHD (efficacy) and harms. Secondary outcomes included changes in the clinical impression of severity and improvement, level of functioning, depression, anxiety and quality of life. Outcomes could have been rated by investigators or participants. DATA COLLECTION AND ANALYSIS: Two review authors extracted data independently on the characteristics of the trials, participants, interventions; outcomes and financial conflict of interests. We resolved disagreements by discussion or consulting a third review author. We obtained additional, unpublished information from the authors of one included trial that had reported efficacy data in a graph. We calculated mean differences (MDs) or standardized MDs (SMDs) with 95% confidence intervals (CIs) for continuous data reported on the same or different scales, respectively. We summarized dichotomous variables as risk ratios (RRs) with 95% CI. MAIN RESULTS: We included 10 trials published between 2001 and 2016 involving 497 adults with ADHD. Three trials were conducted in Europe and one in Argentina; the remaining trials did not report their location. The RCTs compared IR methylphenidate with placebo, an osmotic-release oral system (OROS) of methylphenidate (an extended-release formulation), an extended-release formulation of bupropion, lithium, and Pycnogenol® (maritime pine bark extract). Participants comprised outpatients, inpatients in addiction treatment, and adults willing to attend an intensive outpatient program for cocaine dependence. The duration of the follow-up ranged from 6 to 18 weeks. IR methylphenidate versus placebo We found very low-certainty evidence that, compared with placebo, IR methylphenidate may reduce symptoms of ADHD when measured with investigator-rated scales (MD -20.70, 95% CI -23.97 to -17.43; 1 trial, 146 participants; end scores; Adult ADHD Investigator Symptom Report Scale (AISRS), scored from 0 to 54), but the evidence is uncertain. The effect of IR methylphenidate on ADHD symptoms when measured with participant-rated scales was moderate, but the certainty of the evidence is very low (SMD -0.59, 95% CI -1.25 to 0.06; I2 = 69%; 2 trials, 138 participants; end scores). There is very low-certainty evidence that, compared with placebo, IR methylphenidate may reduce the clinical impression of the severity of ADHD symptoms (MD -0.57, 95% CI -0.85 to -0.28; 2 trials, 139 participants; I2 = 0%; change and end scores; Clinical Global Impression (CGI)-Severity scale (scored from 1 (very much improved) to 7 (very much worse))). There is low-certainty evidence that, compared with placebo, IR methylphenidate may slightly impact the clinical impression of an improvement in symptoms of ADHD (MD -0.94, 95% CI -1.37 to -0.51; 1 trial, 49 participants; end scores; CGI-Improvement scale (scored from 1 (very much improved) to 7 (very much worse))). There is no clear evidence of an effect on anxiety (MD -0.20, 95% CI -4.84 to 4.44; 1 trial, 19 participants; change scores; Hamilton Anxiety Scale (HAM-A; scored from 0 to 56); very low-certainty evidence) or depression (MD 2.80, 95% CI -0.09 to 5.69; 1 trial, 19 participants; change scores; Hamilton Depression Scale (HAM-D; scored from 0 to 52); very low-certainty evidence) in analyses comparing IR methylphenidate with placebo. IR methylphenidate versus lithium Compared with lithium, it is uncertain whether IR methylphenidate increases or decreases symptoms of ADHD (MD 0.60, 95% CI -3.11 to 4.31; 1 trial, 46 participants; end scores; Conners' Adult ADHD Rating Scale (scored from 0 to 198); very low-certainty evidence); anxiety (MD -0.80, 95% CI -4.49 to 2.89; 1 trial, 46 participants; end scores; HAM-A; very low-certainty evidence); or depression (MD -1.20, 95% CI -3.81 to 1.41, 1 trial, 46 participants; end scores; HAM-D scale; very low-certainty evidence). None of the included trials assessed participant-rated changes in symptoms of ADHD, or clinical impression of severity or improvement in participants treated with IR methylphenidate compared with lithium. Adverse events were poorly assessed and reported. We rated all trials at high risk of bias due to selective outcome reporting of harms and masking of outcome assessors (failure to blind outcome assessor to measure adverse events). Overall, four trials with 203 participants who received IR methylphenidate and 141 participants who received placebo described the occurrence of harms. The use of IR methylphenidate in these trials increased the risk of gastrointestinal complications (RR 1.96, 95% CI 1.13 to 2.95) and loss of appetite (RR 1.77, 95% CI 1.06 to 2.96). Cardiovascular adverse events were reported inconsistently, preventing a comprehensive analysis. One trial comparing IR methylphenidate to lithium reported five and nine adverse events, respectively. We considered four trials to have notable concerns of vested interests influencing the evidence, and authors from two trials omitted information related to the sources of funding and conflicts of interest. AUTHORS' CONCLUSIONS: We found no certain evidence that IR methylphenidate compared with placebo or lithium can reduce symptoms of ADHD in adults (low- and very low-certainty evidence). Adults treated with IR methylphenidate are at increased risk of gastrointestinal and metabolic-related harms compared with placebo. Clinicians should consider whether it is appropriate to prescribe IR methylphenidate, given its limited efficacy and increased risk of harms. Future RCTs should explore the long-term efficacy and risks of IR methylphenidate, and the influence of conflicts of interest on reported effects.

Behavioural interventions for smoking cessation: an overview and network meta-analysis.

BACKGROUND: Smoking is a leading cause of disease and death worldwide. In people who smoke, quitting smoking can reverse much of the damage. Many people use behavioural interventions to help them quit smoking; these interventions can vary substantially in their content and effectiveness. OBJECTIVES: To summarise the evidence from Cochrane Reviews that assessed the effect of behavioural interventions designed to support smoking cessation attempts and to conduct a network meta-analysis to determine how modes of delivery; person delivering the intervention; and the nature, focus, and intensity of behavioural interventions for smoking cessation influence the likelihood of achieving abstinence six months after attempting to stop smoking; and whether the effects of behavioural interventions depend upon other characteristics, including population, setting, and the provision of pharmacotherapy. To summarise the availability and principal findings of economic evaluations of behavioural interventions for smoking cessation, in terms of comparative costs and cost-effectiveness, in the form of a brief economic commentary. METHODS: This work comprises two main elements. 1. We conducted a Cochrane Overview of reviews following standard Cochrane methods. We identified Cochrane Reviews of behavioural interventions (including all non-pharmacological interventions, e.g. counselling, exercise, hypnotherapy, self-help materials) for smoking cessation by searching the Cochrane Library in July 2020. We evaluated the methodological quality of reviews using AMSTAR 2 and synthesised data from the reviews narratively. 2. We used the included reviews to identify randomised controlled trials of behavioural interventions for smoking cessation compared with other behavioural interventions or no intervention for smoking cessation. To be included, studies had to include adult smokers and measure smoking abstinence at six months or longer. Screening, data extraction, and risk of bias assessment followed standard Cochrane methods. We synthesised data using Bayesian component network meta-analysis (CNMA), examining the effects of 38 different components compared to minimal intervention. Components included behavioural and motivational elements, intervention providers, delivery modes, nature, focus, and intensity of the behavioural intervention. We used component network meta-regression (CNMR) to evaluate the influence of population characteristics, provision of pharmacotherapy, and intervention intensity on the component effects. We evaluated certainty of the evidence using GRADE domains. We assumed an additive effect for individual components. MAIN RESULTS: We included 33 Cochrane Reviews, from which 312 randomised controlled trials, representing 250,563 participants and 845 distinct study arms, met the criteria for inclusion in our component network meta-analysis. This represented 437 different combinations of components. Of the 33 reviews, confidence in review findings was high in four reviews and moderate in nine reviews, as measured by the AMSTAR 2 critical appraisal tool. The remaining 20 reviews were low or critically low due to one or more critical weaknesses, most commonly inadequate investigation or discussion (or both) of the impact of publication bias. Of note, the critical weaknesses identified did not affect the searching, screening, or data extraction elements of the review process, which have direct bearing on our CNMA. Of the included studies, 125/312 were at low risk of bias overall, 50 were at high risk of bias, and the remainder were at unclear risk. Analyses from the contributing reviews and from our CNMA showed behavioural interventions for smoking cessation can increase quit rates, but effectiveness varies on characteristics of the support provided. There was high-certainty evidence of benefit for the provision of counselling (odds ratio (OR) 1.44, 95% credibility interval (CrI) 1.22 to 1.70, 194 studies, n = 72,273) and guaranteed financial incentives (OR 1.46, 95% CrI 1.15 to 1.85, 19 studies, n = 8877). Evidence of benefit remained when removing studies at high risk of bias. These findings were consistent with pair-wise meta-analyses from contributing reviews. There was moderate-certainty evidence of benefit for interventions delivered via text message (downgraded due to unexplained statistical heterogeneity in pair-wise comparison), and for the following components where point estimates suggested benefit but CrIs incorporated no clinically significant difference: individual tailoring; intervention content including motivational components; intervention content focused on how to quit. The remaining intervention components had low-to very low-certainty evidence, with the main issues being imprecision and risk of bias. There was no evidence to suggest an increase in harms in groups receiving behavioural support for smoking cessation. Intervention effects were not changed by adjusting for population characteristics, but data were limited. Increasing intensity of behavioural support, as measured through the number of contacts, duration of each contact, and programme length, had point estimates associated with modestly increased chances of quitting, but CrIs included no difference. The effect of behavioural support for smoking cessation appeared slightly less pronounced when people were already receiving smoking cessation pharmacotherapies. AUTHORS' CONCLUSIONS: Behavioural support for smoking cessation can increase quit rates at six months or longer, with no evidence that support increases harms. This is the case whether or not smoking cessation pharmacotherapy is also provided, but the effect is slightly more pronounced in the absence of pharmacotherapy. Evidence of benefit is strongest for the provision of any form of counselling, and guaranteed financial incentives. Evidence suggested possible benefit but the need of further studies to evaluate: individual tailoring; delivery via text message, email, and audio recording; delivery by lay health advisor; and intervention content with motivational components and a focus on how to quit. We identified 23 economic evaluations; evidence did not consistently suggest one type of behavioural intervention for smoking cessation was more cost-effective than another. Future reviews should fully consider publication bias. Tools to investigate publication bias and to evaluate certainty in CNMA are needed.

ANTECEDENTES: El tabaquismo es una causa principal de enfermedad y muerte en todo el mundo. En las personas que fuman, dejar de fumar puede revertir gran parte del daño. Muchas personas utilizan intervenciones conductuales para ayudarles a dejar de fumar y estas intervenciones pueden variar considerablemente en contenido y efectividad. OBJETIVOS: Resumir la evidencia de las revisiones Cochrane que evaluaron el efecto de las intervenciones conductuales diseñadas para apoyar los intentos de abandono del hábito de fumar y realizar un metanálisis en red para determinar cómo las modalidades de prestación; la persona que administra la intervención; y la naturaleza, el enfoque y la intensidad de las intervenciones conductuales para el abandono del hábito de fumar influyen en la probabilidad de lograr la abstinencia seis meses después de intentar dejar de fumar; y si los efectos de las intervenciones conductuales dependen de otras características, como la población, el contexto y la administración de farmacoterapia. Resumir la disponibilidad y los hallazgos principales de las evaluaciones económicas de intervenciones conductuales para dejar de fumar, en términos de costes y coste­efectividad, mediante un breve comentario económico. MÉTODOS: Este artículo comprende dos elementos principales. 1. Se realizó una revisión global Cochrane de revisiones según los métodos estándar de Cochrane. Mediante una búsqueda en la Biblioteca Cochrane en julio de 2020 se identificaron las revisiones Cochrane de intervenciones conductuales (incluidas todas las intervenciones no farmacológicas, p.ej., orientación, ejercicio, hipnoterapia, materiales de autoayuda) para el abandono del hábito de fumar. La calidad metodológica de las revisiones se evaluó mediante AMSTAR 2 y los datos de las revisiones se resumieron de manera narrativa. 2. Las revisiones incluidas se utilizaron para identificar los ensayos controlados aleatorizados de intervenciones conductuales para el abandono del hábito de fumar en comparación con otras intervenciones conductuales o ninguna intervención para el abandono del hábito de fumar. Para ser incluidos, los estudios debían incluir a fumadores adultos y medir la abstinencia de fumar a los seis meses o más. La selección, la extracción de los datos y la evaluación del riesgo de sesgo siguieron los métodos Cochrane estándar. Los datos se resumieron mediante un metanálisis en red de componentes (MARC) bayesiano, y se examinaron los efectos de 38 componentes diferentes en comparación con una intervención mínima. Los componentes incluyeron elementos conductuales y motivacionales, proveedores de la intervención, modos de administración, naturaleza, enfoque e intensidad de la intervención conductual. Se utilizó la metarregresión en red de componentes (MRRC) para evaluar la influencia de las características de la población, la administración de farmacoterapia y la intensidad de la intervención sobre los efectos de los componentes. La certeza de la evidencia se evaluó mediante los dominios de GRADE. Se presupuso un efecto aditivo para los componentes individuales. RESULTADOS PRINCIPALES: Se incluyeron 33 revisiones Cochrane, de las cuales 312 ensayos controlados aleatorizados, que representaban a 250 563 participantes y 845 grupos de estudio distintos, cumplieron los criterios para su inclusión en el metanálisis en red de componentes. Esto representó 437 combinaciones diferentes de componentes. De las 33 revisiones, la confianza en los hallazgos de la revisión fue alta en cuatro y moderada en nueve, medida con la herramienta de lectura crítica AMSTAR 2. Las 20 revisiones restantes tuvieron una confianza baja o críticamente baja debido a una o más deficiencias graves, las más habituales fueron una investigación o discusión (o ambas) insuficiente acerca del impacto del sesgo de publicación. Cabe señalar que las debilidades críticas identificadas no afectaron los elementos de la búsqueda, la selección o la extracción de los datos del proceso de revisión, que mantienen una relación directa en este MARC. Entre los estudios incluidos, 125/312 tuvieron un riesgo general de sesgo bajo, 50 un riesgo de sesgo alto y el resto un riesgo de sesgo poco claro. Los análisis de las revisiones contribuyentes y de este MARC mostraron que las intervenciones conductuales para dejar de fumar pueden aumentar las tasas de abandono del hábito, pero la efectividad varía según las características del apoyo proporcionado. Hubo evidencia de certeza alta de un efecto beneficioso de la prestación de orientación (odds ratio [OR] 1,44; intervalo de credibilidad [ICr] del 95%: 1,22 a 1,70, 194 estudios, n = 72 273) y de los incentivos económicos garantizados (OR 1,46; ICr del 95% 1,15 a 1,85, 19 estudios, n = 8877). La evidencia de un efecto beneficioso se mantuvo cuando se eliminaron los estudios con alto riesgo de sesgo. Estos hallazgos fueron concordantes con los metanálisis pareados de las revisiones contribuyentes. Hubo evidencia de certeza moderada de un efecto beneficioso de las intervenciones administradas a través de mensajes de texto (la certeza se disminuyó debido a una heterogeneidad estadística inexplicada en la comparación pareada), y de los siguientes componentes en los que las estimaciones puntuales indicaron un efecto beneficioso pero los ICr no incorporaron una diferencia clínicamente significativa: personalización; contenido de la intervención con componentes motivacionales; contenido de la intervención centrado en cómo dejar de fumar. Los otros componentes de la intervención tuvieron evidencia de certeza muy baja a baja, y sus problemas principales fueron la imprecisión y el riesgo de sesgo. No hubo evidencia que indicara un aumento de los efectos perjudiciales en los grupos que recibieron apoyo conductual para dejar de fumar. Los efectos de la intervención no cambiaron al ajustar las características de la población, pero los datos fueron limitados. El aumento de la intensidad del apoyo conductual, medido a través del número de contactos, la duración de cada contacto y la duración del programa, tuvo estimaciones puntuales asociadas con un modesto aumento de las posibilidades de dejar de fumar, pero los ICr no incluyeron una diferencia. El efecto del apoyo conductual para dejar de fumar pareció ser ligeramente menos pronunciado cuando las personas ya recibían farmacoterapias para dejar de fumar. CONCLUSIONES DE LOS AUTORES: El apoyo conductual para dejar de fumar puede aumentar las tasas de abandono a los seis meses o más, sin evidencia de que este apoyo aumente los efectos perjudiciales. Esto es así tanto si se proporciona una farmacoterapia para dejar de fumar como si no, pero el efecto es ligeramente más pronunciado sin farmacoterapia. La evidencia de un efecto beneficioso es más sólida para la prestación de cualquier tipo de orientación y de incentivos económicos garantizados. La evidencia indicó un posible efecto beneficioso, pero la necesidad de realizar más estudios para evaluar: la personalización; la administración mediante mensajes de texto, correos electrónicos y grabaciones de audio; la administración por parte de un asesor de salud no profesional; y el contenido de la intervención con componentes motivacionales y centrada en cómo dejar de fumar. Se identificaron 23 evaluaciones económicas; la evidencia no indicó de manera homogénea que un tipo de intervención conductual para el abandono del hábito de fumar fuera más coste­efectiva que otra. Las revisiones futuras deberían examinar a fondo el sesgo de publicación. Se necesitan herramientas para investigar el sesgo de publicación y evaluar la certeza en MARC.

Effects of mindfulness- and acceptance-based interventions on diabetes distress and glycaemic level in people with type 2 diabetes: Systematic review and meta-analysis.

AIM: For people with type 2 diabetes, self management and fear of disease complication often cause psychological distress. Mindfulness and acceptance might be beneficial for reducing diabetes-related distress and glycaemic level. We systematically review the effects of mindfulness- and acceptance-based interventions on diabetes distress and glycaemic level in community-dwelling adults with type 2 diabetes. METHODS: Seven electronic databases (English and Chinese) were searched comprehensively from inception to June 2020. Data extraction and methodological quality assessment were independently performed by two reviewers using Grading of Recommendations, Assessment, Development and Evaluations criteria. RESULTS: Nine RCTs (801 participants) examining the effects of acceptance and commitment therapy, mindfulness-based cognitive therapy, mindfulness-based stress reduction and self-directed mindfulness practice were included. In the reviewed RCTs, the majority of participants (mean age: 50-66 years, average disease duration: 4-10 years) had suboptimal diabetes control (HbA1c >7.0%, 53 mmol/mol). Compared with controls, the interventions significantly reduced diabetes distress (standardised mean difference, SMD = -0.37, 95% confidence intervals, CI: -0.63, -0.12; p < 0.01) and HbA1c (mean difference, MD = -0.35, 95% CI: -0.67, -0.04; p = 0.03) up to 1-month post-intervention. However, the underpowered studies may have led to overestimation, the interventions for diabetes distress and HbA1c were heterogeneous. CONCLUSIONS: Within evidenced-based diabetes education programmes, mindfulness- and acceptance-based approaches may reduce distress and HbA1c levels and promote self care in people with type 2 diabetes. Further controlled trials are recommended to examine the clinical effectiveness of such programmes for people with type 2 diabetes of diverse clinical, cultural and socio-demographic backgrounds.

Therapeutic effect of Chinese herbal medicines for post-stroke depression: A meta-analysis of randomized controlled trials.

BACKGROUND: Whether the addition of Chinese herbal medicine (CHM) in routine western medicines for post-stroke depression yields additional therapeutic effects still remains to be controversial. This study aimed to assess the efficacy and safety of combination of CHM with routine western medicines versus routine western medicines alone in patients with post-stroke depression (PSD). METHODS: Electronic databases such as PubMed, EmBase, Cochrane library, and China National Knowledge Infrastructure were systematically searched from inception till October 2019. Studies designed as randomized controlled trials (RCTs) and that investigated the therapeutic effects of CHM plus routine western medicines (CHM group) versus routine western medicines alone (control group) in PSD patients were eligible. The relative risk (RR) and weighted mean difference (WMD) with 95% confidence interval (CI) were used to assess the categories and continuous data using random-effects model. Software STATA was applied to perform statistical analysis (Version 10.0; StataCorp, TX,). RESULTS: A total of 18 RCTs involving a total of 1,367 PSD patients were selected for final analysis. The effective rate in CHM group was significantly higher than that in control group (RR: 1.18; 95%CI: 1.12-1.24; P < .001). Moreover, patients in CHM group showed association with lower Hamilton Depression Rating Scale (WMD: -3.17; 95%CI: -4.12 to -2.22; P < .001) and Scandinavian Stroke Scale (WMD: -3.84; 95%CI: -5.73 to -1.96; P < .001) than those in control group. Furthermore, patients in CHM were associated with high level of Barthel Index than those in control group (WMD: 11.06; 95%CI: 4.01 to 18.10; P = .002). Finally, patients in CHM group had lower risk of gastrointestinal (RR: 0.49; 95%CI: 0.31-0.77; P = .002) and neurological (RR: 0.50; 95%CI: 0.33-0.75; P = .001) adverse events than those in control group. CONCLUSIONS: The study findings revealed that addition of CHM to routine therapies could improve the therapeutic effects and reduce gastrointestinal or neurological adverse events.

Exercise & Sports Science Australia (ESSA) position statement on exercise and chronic obstructive pulmonary disease.

OBJECTIVES: Chronic obstructive pulmonary disease (COPD) results in airflow obstruction and a marked reduction in exercise capacity and health-related quality of life (HRQoL). Affecting over 1 in four Australians aged over 75 years, COPD remains one of the major causes of disability and death in the world. To date there have been over 80 randomised controlled trials examining the role of exercise training in a range of settings for individuals with COPD. This review will synthesise existing literature and provide health practitioners with broad evidence-based guidelines for exercise-training in this growing population. DESIGN: Position stand. METHODS: Synthesis of randomised controlled trials of exercise training and of existing guidelines for exercise in COPD. Systematic reviews of alternative modes of exercise training will also be reviewed. RESULTS: There is convincing evidence that in adults with COPD, exercise-training improves exercise capacity, decreases symptoms such as dyspnoea and fatigue, and improves HRQoL. There is emerging evidence in this population that alternative modes of exercise training such as high intensity interval training (HIIT), aquatic based therapy, tai chi and neuromuscular electrical stimulation improve exercise outcomes when compared to no exercise. CONCLUSIONS: For individuals with COPD, an exercise program of aerobic and strength exercises delivered over at least an 8-week period, that engages lower and upper body skeletal muscles, will deliver significant health improvements. Programs should be individualised, take into consideration relevant co-morbid conditions and be delivered appropriately qualified health practitioners experienced in clinical exercise prescription.

Sex and Adverse Events of Adjuvant Chemotherapy in Colon Cancer: An Analysis of 34 640 Patients in the ACCENT Database.

BACKGROUND: Adjuvant chemotherapy is a standard treatment option for patients with stage III and high-risk stage II colon cancer. Sex is one of several factors responsible for the wide inter-patient variability in drug responses. Amalgamated data on the effect of sex on the toxicity of current standard adjuvant treatment for colorectal cancer are missing. METHODS: The objective of our study was to compare incidence and severity of major toxicities of fluoropyrimidine- (5FU or capecitabine) based adjuvant chemotherapy, with or without oxaliplatin, between male and female patients after curative surgery for colon cancer. Adult patients enrolled in 27 relevant randomized trials included in the ACCENT (Adjuvant Colon Cancer End Points) database, a large, multi-group, international data repository containing individual patient data, were included. Comparisons were conducted using logistic regression models (stratified by study and treatment arm) within each type of adjuvant chemotherapy (5FU, FOLFOX, capecitabine, CAPOX, and FOLFIRI). The following major toxicities were compared (grade III or IV and grade I-IV, according to National Cancer Institute Common Terminology Criteria [NCI-CTC] criteria, regardless of attribution): nausea, vomiting, nausea or vomiting, stomatitis, diarrhea, leukopenia, neutropenia, thrombocytopenia, anemia, and neuropathy (in patients treated with oxaliplatin). RESULTS: Data from 34 640 patients were analyzed. Statistically significant and clinically relevant differences in the occurrence of grade III or IV nonhematological {especially nausea (5FU: odds ratio [OR] = 2.33, 95% confidence interval [CI] = 1.90 to 2.87, P < .001; FOLFOX: OR = 2.34, 95% CI = 1.76 to 3.11, P < .001), vomiting (5FU: OR = 2.38, 95% CI = 1.86 to 3.04, P < .001; FOLFOX: OR = 2.00, 95% CI = 1.50 to 2.66, P < .001; CAPOX: OR = 2.32, 95% CI = 1.55 to 3.46, P < .001), and diarrhea (5FU: OR = 1.35, 95% CI = 1.21 to 1.51, P < .001; FOLFOX: OR = 1.60, 95% CI = 1.35 to 1.90, P < .001; FOLFIRI: OR = 1.57, 95% CI = 1.25 to 1.97, P < .001)} as well as hematological toxicities (neutropenia [5FU: OR = 1.55, 95% CI = 1.37 to 1.76, P < .001; FOLFOX: OR = 1.96, 95% CI = 1.71 to 2.25, P < .001; FOLFIRI: OR = 2.01, 95% CI = 1.66 to 2.43, P < .001; capecitabine: OR = 4.07, 95% CI = 1.84 to 8.99, P < .001] and leukopenia [5FU: OR = 1.74, 95% CI = 1.40 to 2.17, P < .001; FOLFIRI: OR = 1.75, 95% CI = 1.28 to 2.40, P < .001]) were observed, with women being consistently at increased risk. CONCLUSIONS: Our analysis confirms that women with colon cancer receiving adjuvant fluoropyrimidine-based chemotherapy are at increased risk of toxicity. Given the known sex differences in fluoropyrimidine pharmacokinetics, sex-specific dosing of fluoropyrimidines warrants further investigation.

Syndrome Differentiation and Treatment Regularity in Traditional Chinese Medicine for Type 2 Diabetes: A Text Mining Analysis.

Objective: The goal of this study was to systematically summarize and categorize the syndrome differentiation, medication rules, and acupoint therapy in the domestic traditional Chinese medicine (TCM) literature on type 2 diabetes mellitus (T2DM), such that guidelines and new insights can be provided for future practitioners and researchers. Methods: Taking randomized controlled trials (RCTs) on the treatment of T2DM in TCM as the research theme, we searched for full-text literature in three major clinical databases, including CNKI, Wan Fang, and VIP, published between 1990 and 2020. We then conducted frequency statistics, cluster analysis, association rules extraction, and topic modeling based on a corpus of medical academic words extracted from 3,654 research articles. Results: The TCM syndrome types, subjective symptoms, objective indicators, Chinese herbal medicine, acupuncture points, and TCM prescriptions for T2DM were compiled based on invigorating the kidney and Qi, nourishing Yin, and strengthening the spleen. Most TCM syndrome differentiation for T2DM was identified as "Zhongxiao" (the lesion in the spleen and stomach) and "Xiaxiao" (the lesion in the kidney) deficiency syndromes, and most medications and acupoint therapies were focused on the "Spleen Channel" and "Kidney Channel." However, stagnation of liver Qi was mentioned less when compared with other syndromes, which did not have symptomatic medicines. Conclusion: This study provides an in-depth perspective for the TCM syndrome differentiation, medication rules, and acupoint therapy for T2DM and provides practitioners and researchers with valuable information about the current status and frontier trends of TCM research on T2DM in terms of both diagnosis and treatment.

The effect of black tea supplementation on blood pressure: a systematic review and dose-response meta-analysis of randomized controlled trials.

The main goal of this work was to clarify the effects of black tea supplementation on blood pressure (BP) by performing a systematic review according to the PRISMA (preferred reporting items for systematic reviews and meta-analyses) guidelines, followed by a dose-response meta-analysis of randomized controlled trials (RCTs). Electronic search was carried out in PubMed, Embase and the Cochrane Library databases published up to March 2020. To be included, RCTs had to report the effect of black tea supplementation on systolic blood pressure (SBP) or diastolic blood pressure (DBP) in adults. A total of 13 trials, including 22 study arms were eligible for inclusion in the final quantitative analysis. It was observed that black tea supplementation significantly reduced SBP (WMD - 1.04 mmHg; 95% CI - 2.05 to -0.03; and P = 0.04) and DBP (WMD - 0.59 mmHg; 95% CI - 1.05 to -0.13; and P = 0.01) compared to the control. However, nonlinear analysis failed to indicate a significant influence of black tea flavonoid supplementation dose or duration on both SBP and DBP. Sensitivity analysis showed that no individual study had a significant impact on our results. In addition, we found no evidence for the presence of small-study effects among studies for both SBP and DBP. Thus, the favorable effect of black tea supplementation emerging from the current meta-analysis suggests the possible use of this tea as an active compound in order to promote cardiovascular health, mostly when used for longer duration (>7 days) and in men. Furthermore RCTs using different doses of black tea and various durations may contribute to confirming our conclusion.

Effectiveness and safety of Xinyin tablet in treatment of chronic heart failure: A protocol of systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Xinyin Tablet (XYT) has been widely used in the treatment of CHF, Which helping to improve the clinical symptoms, enhance exercise, and even may improve the long-term prognosis of patients. However, the exact effectiveness and safety of XYT for CHF has not be comprehensively researched, so we want to generalize the effectiveness and safety of XYT for CHF through the meta-analysis, which may benefit the design of future clinical trials and provide valuable references. METHODS: This protocol complies with the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols. From the inception until September 2020, a systematic and comprehensive electronic search about Relevant randomized controlled trials will be conducted in 4 English literature databases and 4 Chinese literature databases. The registration number: INPLASY2020100015. 2 investigators will be arranged to deal with the study selection and data extraction independently. The New York Heart Function Classification, traditional Chinese medicine (TCM) symptom scores, the scores of quality of life, 6-min walk distance (6MWD), etc. will be systematically measured as outcomes. At last, the data will be handled by Review Manager 5.3 and Stata 15.0. RESULTS AND CONCLUSION: This study is hoping to provide a high-level evidence to prove the therapeutic effect of XYT on CHF, which may enhance the application of Chinese medicine.

Effects of music therapy on depression: A meta-analysis of randomized controlled trials.

BACKGROUND: We aimed to determine and compare the effects of music therapy and music medicine on depression, and explore the potential factors associated with the effect. METHODS: PubMed (MEDLINE), Ovid-Embase, the Cochrane Central Register of Controlled Trials, EMBASE, Web of Science, and Clinical Evidence were searched to identify studies evaluating the effectiveness of music-based intervention on depression from inception to May 2020. Standardized mean differences (SMDs) were estimated with random-effect model and fixed-effect model. RESULTS: A total of 55 RCTs were included in our meta-analysis. Music therapy exhibited a significant reduction in depressive symptom (SMD = -0.66; 95% CI = -0.86 to -0.46; P<0.001) compared with the control group; while, music medicine exhibited a stronger effect in reducing depressive symptom (SMD = -1.33; 95% CI = -1.96 to -0.70; P<0.001). Among the specific music therapy methods, recreative music therapy (SMD = -1.41; 95% CI = -2.63 to -0.20; P<0.001), guided imagery and music (SMD = -1.08; 95% CI = -1.72 to -0.43; P<0.001), music-assisted relaxation (SMD = -0.81; 95% CI = -1.24 to -0.38; P<0.001), music and imagery (SMD = -0.38; 95% CI = -0.81 to 0.06; P = 0.312), improvisational music therapy (SMD = -0.27; 95% CI = -0.49 to -0.05; P = 0.001), music and discuss (SMD = -0.26; 95% CI = -1.12 to 0.60; P = 0.225) exhibited a different effect respectively. Music therapy and music medicine both exhibited a stronger effects of short and medium length compared with long intervention periods. CONCLUSIONS: A different effect of music therapy and music medicine on depression was observed in our present meta-analysis, and the effect might be affected by the therapy process.