Scoping review of trials evaluating adhesive strategies in pediatric dentistry: where do simplified strategies lie?

Abstract Background Adhesive restorations allow a conservative approach to caries management and are increasingly used as a restorative option in pediatric dentistry. Placement can be difficult in children because of the cooperation required for multiple bonding steps. Due to this, it is vital to assess if novel, simpler strategies have been featured in clinical trials and if clinical trials are researching the different existing adhesive strategies. Methods This review followed Preferred Reporting Items for Systematic Reviews and Meta-analysis adapted for Scoping Reviews (PRISMA-ScR) guidelines. PubMed/Medline, Cochrane Central, Scopus and EMBASE were used for systematic search, using free keywords and controlled search terms. Clinical trials of children requiring a restorative intervention which featured adhesive strategies were included. Only peer-reviewed trials of primary teeth restored with resin composites, published in the last 10-year period were eligible. Data charting was accomplished independently by two reviewers, and studies were summarized according to their date, type, intervention, sample size, observation period, outcomes and conclusions. Quality assessment was performed using Cochrane’s Risk of Bias 2.0 tool. Results 700 potentially relevant references were found, which after a rigorous inclusion scheme, resulted in a total of 8 eligible clinical trials. Out of these, 7 were randomized clinical trials. Most trials featured a split-mouth design and the observation period ranged from 12 to 36 months. The trials evaluated interventions of two self-adhesive composites, two bulk-fill composites, two novel composites, one compomer and eight adhesives from different strategies. Most studies (4/8) included were judged to raise some concerns regarding risk of bias, while two were classified as high risk and two as low. Conclusion Few studies comparing adhesive strategies were found, especially adhesives in sound substrates. The existing studies do not reflect all current approaches that could be used in pediatric dentistry. Further studies addressing bioactive composites and contemporary adhesives are necessary.

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Dexamethasone in Patients with Spontaneous Intracerebral Hemorrhage: An Updated Meta-Analysis

Cerebrovascular Diseases ◽

10.1159/000510040 ◽

2020 ◽

Vol 49 (5) ◽

pp. 495-502

Author(s):

Stephanie Wintzer ◽

Josef Georg Heckmann ◽

Hagen B. Huttner ◽

Stefan Schwab

Keyword(s):

Clinical Trials ◽

High Risk ◽

Intracerebral Hemorrhage ◽

Randomized Clinical Trials ◽

Meta Analysis ◽

Risk Of Bias ◽

Spontaneous Intracerebral Hemorrhage ◽

Control Groups ◽

Language Data ◽

Negative Effect

Background: Spontaneous intracerebral hemorrhage (ICH) is a frequent cerebrovascular disorder and still associated with high mortality and poor clinical outcomes. The purpose of this review was to update a 15-year-old former meta-analysis on randomized clinical trials (RCTs) addressing the question of whether ICH patients treated with dexamethasone have better outcomes than controls. Methods: The electronic databases PubMed, SCOPUS, and Cochrane as well as web platforms on current clinical trials were searched for the years 1970–2020 without constriction on language. Data were extracted and outcomes were pooled for conventional and cumulative meta-analysis using a commercial software program (www.Meta-Analysis.com). Results: Finally, 7 RCTs were identified and analyzed including 248 participants in the dexamethasone groups and 242 in the control groups. Five studies showed a high risk of bias. The overall relative risk (RR) for death was 1.32 (95% confidence interval [CI] 0.99–1.76; p = 0.06) and did not differ significantly between the 2 groups. After exclusion of studies with high risk of bias, the RR for death was 1.37 (95% CI 0.54–3.42; p = 0.51). The RR for poor outcome did not differ significantly between the 2 groups analyzed for all included studies (RR = 0.69; 95% CI 0.47–1; p = 0.05) and after exclusion of studies with high risk of bias (RR = 0.7; 95% CI 0.45–1.08; p = 0.11). The RR for complications did not differ significantly including all studies (RR = 1.29; 95% CI 0.77–2.17; p = 0.34) and after exclusion of studies with high risk of bias (RR = 1.27; 95% CI 0.18–8.89; p = 0.81). The cumulative statistics delivered no other results; however, it pointed out fewer complications over time in the dexamethasone group. Conclusion: Clear evidence of a beneficial or negative effect of dexamethasone is still lacking. Modern RCTs or observational studies with propensity design are necessary to evaluate the efficacy and safety of treatment with dexamethasone in patients with ICH.

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Vaccines to prevent COVID-19: a protocol for a living systematic review with network meta-analysis including individual patient data (The LIVING VACCINE Project)

Systematic Reviews ◽

10.1186/s13643-020-01516-1 ◽

2020 ◽

Vol 9 (1) ◽

Author(s):

Steven Kwasi Korang ◽

Sophie Juul ◽

Emil Eik Nielsen ◽

Joshua Feinberg ◽

Faiza Siddiqui ◽

...

Keyword(s):

Systematic Review ◽

Clinical Trials ◽

Randomized Clinical Trials ◽

Individual Patient Data ◽

Viral Vector ◽

Meta Analysis ◽

Risk Of Bias ◽

Serious Adverse Events ◽

Meta Analyses ◽

Harmful Effects

Abstract Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19) which has rapidly spread worldwide. Several human randomized clinical trials assessing potential vaccines are currently underway. There is an urgent need for a living systematic review that continuously assesses the beneficial and harmful effects of all available vaccines for COVID-19. Methods/design We will conduct a living systematic review based on searches of major medical databases (e.g., MEDLINE, EMBASE, CENTRAL) and clinical trial registries from their inception onwards to identify relevant randomized clinical trials. We will update the literature search once a week to continuously assess if new evidence is available. Two review authors will independently extract data and conduct risk of bias assessments. We will include randomized clinical trials comparing any vaccine aiming to prevent COVID-19 (including but not limited to messenger RNA; DNA; non-replicating viral vector; replicating viral vector; inactivated virus; protein subunit; dendritic cell; other vaccines) with any comparator (placebo; “active placebo;” no intervention; standard care; an “active” intervention; another vaccine for COVID-19) for participants in all age groups. Primary outcomes will be all-cause mortality; a diagnosis of COVID-19; and serious adverse events. Secondary outcomes will be quality of life and non-serious adverse events. The living systematic review will include aggregate data meta-analyses, trial sequential analyses, network meta-analyses, and individual patient data meta-analyses. Within-study bias will be assessed using Cochrane risk of bias tool. The Grading of Recommendations, Assessment, Development and Evaluations (GRADE) and Confidence in Network Meta-Analysis (CINeMA) approaches will be used to assess certainty of evidence. Observational studies describing harms identified during the search for trials will also be included and described and analyzed separately. Discussion COVID-19 has become a pandemic with substantial mortality. A living systematic review assessing the beneficial and harmful effects of different vaccines is urgently needed. This living systematic review will regularly inform best practice in vaccine prevention and clinical research of this highly prevalent disease. Systematic review registration PROSPERO CRD42020196492

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Anti-Tumor Activity and Safety of Multikinase Inhibitors in Advanced and/or Metastatic Thyroid Cancer: A Systematic Review and Network Meta-Analysis of Randomized Controlled Trials

Hormone and Metabolic Research ◽

10.1055/a-1023-4214 ◽

2019 ◽

Vol 52 (01) ◽

pp. 25-31 ◽

Cited By ~ 2

Author(s):

Marina Tsoli ◽

Krystallenia I. Alexandraki ◽

Maria-Eleni Spei ◽

Gregory A. Kaltsas ◽

Kosmas Daskalakis

Keyword(s):

Clinical Trials ◽

Thyroid Cancer ◽

Randomized Clinical Trials ◽

Meta Analysis ◽

Objective Response ◽

Risk Of Bias ◽

Controlled Trials ◽

Cochrane Central Register ◽

Multikinase Inhibitors ◽

Metastatic Thyroid Cancer

AbstractMany trials have demonstrated prime antitumor activity of novel, small molecule multikinase inhibitors (MKIs) in advanced and/or metastatic thyroid cancer (TC). In this work, the PubMed, EMBASE, Cochrane Central Register of Controlled Trials, Web of Science, SCOPUS, and clinicaltrials.gov databases were searched. Quality/risk of bias were assessed using GRADE criteria. Randomized clinical trials (RCTs) comparing two or more systemic therapies in patients with advanced and/or metastatic thyroid cancer were assessed. A total of 1347 articles and 548 clinical trials in clinicaltrials.gov were screened. We included seven relevant RCTs comprising 1934 unique patients assigned to different MKIs. Two separate network meta-analyses included four RCTs in radioiodine refractory well-differentiated thyroid cancer (RR-WDTC) and three RCTs in medullary thyroid cancer (MTC), respectively; all with a low risk of bias. We identified three therapies for RR-WDTC: sorafenib [disease control rate (DCR) odds ratio (OR): 0.11 (95% CI: 0.03–0.40); progression-free survival (PFS) hazard ratio (HR): 1.99 (95% CI: 1.62–2.46)], vandetanib [DCR_OR:0.26 (95% CI: 0.06–1.24); PFS_HR: 0.99 (95% CI: 0.82–1.20)] and lenvatinib [DCR_OR: 0.26 (95% CI: 0.05–1.33); PFS_HR: 0.99 (95% CI: 0.81–1.22)]; and the following therapies for MTC: vandetanib 300 mg [objective response rate (ORR)_OR: 3.31 (95% CI: 0.68–16.22); vandetanib 150 mg ORR_OR: 0.60 (95% CI: 0.16–2.33)]; and cabozantinib [ORR_OR: 85.32 (95% CI: 5.22–1395.15)]. Serious side effect (SE) analysis per organ/system demonstrated a varying MKI SE profile across both RR-WDTC and MTC diagnoses, more commonly involving metabolic/nutritional disorders [OR: 2.07 [95% CI: 0.82–5.18)] and gastrointestinal SE [OR: 1.63 (95% CI: 1.0–2.66)]. This network meta-analysis on advanced and/or metastatic TC points towards a higher efficacy of lenvatinib in RR-WDTC. The included MKIs exhibit a varying SE profile across different organs/systems favoring a patient-tailored approach with the anticipated toxicities guiding clinicians’ decisions.

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Effects of low-level laser therapy on the orthodontic mini-implants stability: a systematic review and meta-analysis

Progress in Orthodontics ◽

10.1186/s40510-021-00350-y ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Ana Carolina de Figueiredo Costa ◽

Thays Allane Cordeiro Maia ◽

Paulo Goberlânio de Barros Silva ◽

Lucas Guimarães Abreu ◽

Delane Viana Gondim ◽

...

Keyword(s):

Systematic Review ◽

Clinical Trials ◽

Laser Therapy ◽

Randomized Clinical Trials ◽

Meta Analysis ◽

Risk Of Bias ◽

Low Risk ◽

Low Level Laser Therapy ◽

Mini Implants ◽

Level Laser

Abstract Objectives The aim of this systematic review and meta-analysis was to assess the effects of low-level laser therapy (LLLT) on the orthodontic mini-implants (OMI) stability. Materials and methods An unrestricted electronic database search in PubMed, Science Direct, Embase, Scopus, Web of Science, Cochrane Library, LILACS, Google Scholar, and ClinicalTrials.gov and a hand search were performed up to December 2020. Randomized clinical trials (RCTs) or non-randomized clinical trials (Non-RCTs) that assessed the effects of LLLT on the OMI stability were included. Data regarding the general information, LLLT characteristics, and outcomes were extracted. The authors performed risk of bias assessment with Cochrane Collaboration’s or ROBINS-I tool. Meta-analysis was also conducted. Results Five RCTs and one Non-RCT were included and 108 patients were evaluated. The LLLT characteristics presented different wavelength, power, energy density, irradiation time, and protocol duration. Five RCTs had a low risk of selection bias. Two RCTs had a low risk of performance and detection bias. All RCTs had a low risk of attrition bias, reporting bias and other bias. The Non-RCT presented a low risk of bias for all criteria, except for the bias in selection of participants. The meta-analysis revealed that LLLT significantly increased the OMI stability (p < 0.001, Cohen’s d = 0.67) and the highest clinical benefit was showed after 1 (p < 0.001, Cohen’s d = 0.75), 2 (p < 0.001, Cohen’s d = 1.21), and 3 (p < 0.001, Cohen’s d = 1.51) months of OMI placement. Conclusions LLLT shows positive effects on the OMI stability.

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Acupuncture for Managing Cancer-Related Insomnia: A Systematic Review of Randomized Clinical Trials

Integrative Cancer Therapies ◽

10.1177/1534735416664172 ◽

2016 ◽

Vol 16 (2) ◽

pp. 135-146 ◽

Cited By ~ 19

Author(s):

Tae-Young Choi ◽

Jong In Kim ◽

Hyun-Ja Lim ◽

Myeong Soo Lee

Keyword(s):

Systematic Review ◽

Clinical Trials ◽

Sleep Quality ◽

Randomized Clinical Trials ◽

Data Extraction ◽

Meta Analysis ◽

Sham Acupuncture ◽

Risk Of Bias ◽

The Other ◽

Level Of Evidence

Background. Insomnia is a prominent complaint of cancer patients that can significantly affect their quality of life and symptoms related to sleep quality. Conventional drug approaches have a low rate of success in alleviating those suffering insomnia. The aim of this systematic review was to assess the efficacy of acupuncture in the management of cancer-related insomnia. Methods. A total of 12 databases were searched from their inception through January 2016 without language restriction. Randomized controlled trials (RCTs) and quasi-RCTs were included if acupuncture was used as the sole intervention or as an adjunct to another standard treatment for any cancer-related insomnia. The data extraction and the risk of bias assessments were performed by 2 independent reviewers. Results. Of the 90 studies screened, 6 RCTs were included. The risk of bias was generally unclear or low. Three RCTs showed equivalent effects on the Pittsburgh Sleep Quality Index and 2 RCTs showed the similar effects on response rate to those of conventional drugs at the end of treatment. The other RCT showed acupuncture was better than hormone therapy in the numbers of hours slept each night and number of times woken up each night. The 3 weeks of follow-up in 2 RCTs showed superior effects of acupuncture compared with conventional drugs, and a meta-analysis showed significant effects of acupuncture. Two RCTs tested the effects of acupuncture on cancer-related insomnia compared with sham acupuncture. One RCT showed favourable effects, while the other trial failed to do so. Conclusion. There is a low level of evidence that acupuncture may be superior to sham acupuncture, drugs or hormones therapy. However, the number of studies and effect size are small for clinical significance. Further clinical trials are warranted.

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Effect of Combined Diclofenac and B Vitamins (Thiamine, Pyridoxine, and Cyanocobalamin) for Low Back Pain Management: Systematic Review and Meta-analysis

Pain Medicine ◽

10.1093/pm/pnz216 ◽

2019 ◽

Vol 21 (4) ◽

pp. 766-781 ◽

Cited By ~ 6

Author(s):

Carlos-Alberto Calderon-Ospina ◽

Mauricio Orlando Nava-Mesa ◽

Carlos Emilio Arbeláez Ariza

Keyword(s):

Clinical Trials ◽

Low Back Pain ◽

Back Pain ◽

Combination Therapy ◽

Randomized Clinical Trials ◽

Meta Analysis ◽

Risk Of Bias ◽

Selective Reporting ◽

Low Back ◽

High Quality

Abstract Background Cumulative evidence suggests an analgesic effect of thiamine, pyridoxine, and cyanocobalamin (TPC) in monotherapy, and also when combined with nonsteroidal anti-inflammatory drugs (NSAIDs), particularly diclofenac, in a synergistic manner. The aim of this review was to determine the effects of diclofenac combined with TPC compared with diclofenac monotherapy for low back pain (LBP) management. Methods We searched for randomized clinical trials on the MEDLINE, EMBASE, LILACS, and Cochrane databases of records of clinical trials, among other sources. We evaluated the risk of bias regarding randomization, allocation concealment, blinding, incomplete outcome data, selective reporting, and other biases. A random-effects meta-analysis to examine patients with acute LBP (N = 1,108 adults) was performed, along with a subsequent sensitivity analysis. Results Five studies in patients with LBP were included in the qualitative synthesis. Four of these studies in acute LBP were included in the first meta-analysis. A sensitivity test based on risk of bias (three moderate- to high-quality studies) found that the combination therapy of diclofenac plus TPC was associated with a significant reduction in the duration of treatment (around 50%) compared with diclofenac monotherapy (odds ratio = 2.23, 95% confidence interval = 1.59 to 3.13, P < 0.00001). We found no differences in the safety profile and patient satisfaction. Conclusions This meta-analysis demonstrated that combination therapy of diclofenac with TPC might have an analgesic superiority compared with diclofenac monotherapy in acute LBP. However, there is not enough evidence to recommend this therapy in other types of pain due to the scarcity of high-quality studies.

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Effect of Foot Reflexology on Constipation: A Systematic Review and Meta-Analysis

Shiraz E-Medical Journal ◽

10.5812/semj.100585 ◽

2020 ◽

Vol 22 (1) ◽

Author(s):

Zahra Anjoman Azari ◽

Mojgan Mirghafourvand ◽

Ciara Hughes ◽

Shiva Havizari

Keyword(s):

Clinical Trials ◽

Fixed Effects ◽

Primary Outcome ◽

Randomized Clinical Trials ◽

Meta Analysis ◽

Risk Of Bias ◽

Gastrointestinal Disorders ◽

P Value ◽

Prevalent Symptom

Context: Constipation is a prevalent symptom of gastrointestinal disorders, which has an annoying impact on health and quality of life. On the other hand, reflexology is a popular type of complementary and alternative medicine in medical practices. Objectives: The present study aimed to assess the effect of foot reflexology on constipation symptoms. Methods: Nine databases were systematically searched to detect relevant Randomized Clinical Trials. The current used the Cochrane Risk of Bias tool to evaluate the methodological quality of the included articles. The primary outcome was the improvement of constipation symptoms. The Standardized Mean Difference (SMD) was measured, and random effects were reported instead of the fixed effects due to the high heterogeneity. Results: Out of the 693 articles retrieved from the databases and eight additional records identified through other sources, 496 titles, 48 abstracts, and 16 full-texts were reviewed, and 11 articles were included in this study, out of which nine articles entered the meta-analysis. The findings of the meta-analysis indicated that foot reflexology had a significant effect on the constipation score (SMD: -0.82; 95% CI: -1.47 to -0.17; P value = 0.0001; I2 = 93%) Conclusions: Foot reflexology can effectively improve constipation symptoms; however, clinical trials with better designs are recommended.

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A Systematic Review of Nutraceuticals for the Treatment of Bipolar Disorder: Une revue systématique des nutraceutiques pour le traitement du trouble bipolaire

The Canadian Journal of Psychiatry ◽

10.1177/0706743720961734 ◽

2020 ◽

pp. 070674372096173 ◽

Cited By ~ 2

Author(s):

Melanie M. Ashton ◽

Bianca E. Kavanagh ◽

Wolfgang Marx ◽

Michael Berk ◽

Jerome Sarris ◽

...

Keyword(s):

Bipolar Disorder ◽

Clinical Trials ◽

Meta Analysis ◽

Risk Of Bias ◽

Mitochondrial Activity ◽

Cochrane Central Register ◽

Omega 3 ◽

Large Variability ◽

Search Terms ◽

Revue Systématique

Background: Certain nutrient supplements (nutraceuticals) may target neurobiological pathways perturbed in bipolar disorder (BD) such as inflammation, oxidative stress, and mitochondrial dysfunction. Nutraceuticals thus may have a potential role as adjunctive treatments for BD. Methods: A search of Embase via embase.com , PubMed via PubMed, Cumulated index to nursing and allied health literature (CINAHL) Complete via EBSCO, and Cochrane Central Register of Controlled Clinical Trials via cochranelibrary.com was conducted to identify published randomized controlled trials assessing the efficacy of nutraceuticals on mood symptomatology in adults with BD. Search terms for BD, nutraceuticals, and clinical trials (total search terms = 75) were used to search from inception to February 20, 2020. The Cochrane Collaboration’s tool for assessing the risk of bias in randomized trials was used to assess the risk of bias. Results: A total of 1,712 studies were identified through the search. After rigorous screening, 22 studies were included in the review. There was large variability across the studies with 15 different nutraceutical agents assessed and as such insufficient homogeneity for a meta-analysis to be conducted ( I 2 > 50%). Studies revealed promising, albeit conflicting, evidence for omega-3 fatty acids and N-acetylcysteine. Isolated positive results were reported for coenzyme Q10. Conclusion: Given nutraceuticals are tolerable and accessible, they may be useful as potential adjunctive treatments for BD. Nutraceuticals targeting neuroinflammation or mitochondrial activity may have the most potential for the depressive phase. However, further studies are required to determine efficacy.

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Treatment of Sleep Apnea with Positive Airway Pressure and Its Association with Diastolic Dysfunction: A Systematic Review and Meta-Analysis

Respiration ◽

10.1159/000519406 ◽

2021 ◽

pp. 1-11

Author(s):

Mohammed Al-Sadawi ◽

Farzane Saeidifard ◽

Smadar Kort ◽

Kerry Cao ◽

Violeta Capric ◽

...

Keyword(s):

Clinical Trials ◽

Sleep Apnea ◽

Diastolic Dysfunction ◽

Airway Pressure ◽

Randomized Clinical Trials ◽

Positive Airway Pressure ◽

Meta Analysis ◽

Risk Of Bias ◽

Mitral Inflow

Background: This meta-analysis assessed the effect of long-term (>6 weeks) noninvasive positive airway pressure (PAP) on diastolic function in patients with obstructive sleep apnea (OSA). Methods: We searched the databases for randomized clinical trials including Ovid MEDLINE, Ovid Embase Scopus, Web of Science, Google Scholar, and EBSCO CINAHL from inception up to December 20, 2019. The search was not restricted to time, publication status, or language. Two independent investigators screened the studies and extracted the data, in duplicate. Risk of bias was assessed using Cochrane collaboration tools. Results: A total of 2,753 abstracts were resulted from literature search. A total of 9 randomized clinical trials assessing the effect of long-term (>6 weeks) PAP on diastolic function in patients with OSA including 833 participants were included. The following echo parameters were found in treated patients: a decrease in deceleration time (−39.49 ms CI [−57.24, −21.74]; p = 0.000), isovolumic relaxation time (−9.32 ms CI [−17.08, −1.57]; p = 0.02), and the ratio of early mitral inflow velocity to mitral annular early diastolic velocity (−1.38 CI [−2.6, −0.16]; p = 0.03). However, changes in left-atrial volume index and the ratio of early to late mitral inflow velocities were not statistically different. The risk of bias was mild to moderate among the studies. Conclusion: Our results suggest that chronic treatment of moderate to severe OSA with noninvasive PAP is associated with improvement in echocardiographic findings of diastolic dysfunction.

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Does Caffeine Consumption Affect the Symptoms of Parkinson’s Disease? A Systematic Review of Clinical Trials

Archives of Neuroscience ◽

10.5812/ans.115878 ◽

2021 ◽

Vol 8 (4) ◽

Author(s):

Anita Reyhanifard ◽

Sarvin Sanaie ◽

Mojgan Mirghafurvand ◽

Sama Rahnemayan ◽

Arezoo Fathalizadeh ◽

...

Keyword(s):

Systematic Review ◽

Parkinson’S Disease ◽

Parkinson's Disease ◽

Clinical Trials ◽

Randomized Clinical Trials ◽

Assessment Tool ◽

Meta Analysis ◽

Experimental Studies ◽

Risk Of Bias ◽

Cochrane Library

Objectives: This systematic review of the literature was carried out to see whether coffee consumption could affect Parkinson’s disease (PD) symptoms. Methods: Randomized controlled trials (RCTs), crossover studies, and quasi-experimental studies were assessed to evaluate the effect of caffeine on PD. The databases including Medline/PubMed, ProQuest, Embase, Cochrane Library, and ClinicalTrials.gov were systematically searched. The Cochrane Collaboration’s tool for assessing the risk of bias in randomized clinical trials and the Cochrane risk of bias assessment tool for non-randomized studies of interventions (ROBINS-I) were used to assess the quality of RCTs and non-randomized clinical trials, respectively. A meta-analysis of the results was not possible because of reporting different outcomes. Results: Four papers were included in this study. Only one study reported the significant effect of caffeine on ESS and UPDRS. Another study observed no significant effect of caffeine on ESS during three- and six-week interventions. However, a significant reduction in ESS scores in the sixth week was reported after excluding four protocol violations. This study reported that the UPDRS score reduced in the third week, but significant changes were observed after six weeks. The other two studies did not show a significant effect of caffeine on ESS and UPDRS. Conclusions: Since a meta-analysis was not conducted, there was insufficient evidence to evaluate the effect of caffeine on PD. Thus, it is recommended to conduct more well-designed RCTs with a larger sample size to assess the effect of caffeine on PD.

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