Molar Incisor Hypomineralization: Optimizing Treatment Protocols for Hypersensitivity: A Randomized Clinical Trial.

Dentin hypersensitivity (DH) is a common challenge in pediatric patients with molar incisor hypomineralization (MIH), stemming from enamel porosity or exposed dentin after enamel breakdown. This three-arm randomized controlled clinical trial aims to evaluate the effectiveness of three different desensitizing treatment protocols. The study was conducted on 39 children, aged 6-14 years old, with MIH and DH. Group A received casein phosphopeptide plus amorphous calcium phosphate fluoride (CPP-ACPF) mousse and sham light therapy, Group B received placebo mousse and photo-bio-modulation therapy (PMBT), and Group C received both CPP-ACPF mousse and PMBT. DH evaluation using a visual analogue scale was performed at multiple time points. Both CPP-ACPF mousse and PMBT individually demonstrated desensitizing effects on dental elements affected by MIH. While PMBT had a greater immediate effect, the combination of the two therapies proved most effective in reducing DH. The VAS scores were statistically lower in group C compared to groups A and B, both after the first session (p = 0.0001) and after 28 days (p = 0.0005). This study suggests promising avenues for managing DH in MIH patients, highlighting the potential of combined therapies, specifically CPP-ACPF mousse and PMBT, for enhanced clinical outcomes.

Radioiodine versus radiofrequency ablation to treat autonomously functioning thyroid nodules: a systematic review and comparative meta-analysis.

PURPOSE: Radioiodine (RAI) is a well-established first-line therapy for autonomously functioning thyroid nodules (AFTN). Radiofrequency ablation (RFA) is a minimally invasive procedure that has been proposed as an alternative treatment option for hyperthyroidism caused by AFTN. Although RFA has been shown to be useful for reducing nodule volume and improving TSH levels in AFTN, no comprehensive comparative clinical studies have been proposed to evaluate the overall response to RFA treatment. The aim of this comparative systematic review and meta-analysis was to evaluate the response of RAI and RFA treatments in AFTN. METHODS: A systematic search strategy was applied in PubMed, Web of Science, Scopus, Cochrane Library, and ClinicalTrials.gov until July 2023 without time or language restrictions. Studies investigating the response to RAI and/or RFA treatment in AFTN patients 6 and/or 12 months after treatment were included. The risk of bias was assessed based on the study design. Random-effect models were used for the meta-analysis. RESULTS: Twenty-three articles (28 reports) met the inclusion criteria and were included in the study. Overall, RAI therapy was found to have a significantly higher treatment response (94%) than RFA (59%), although the volume of AFTNs was reduced to a similar extent. In the direct comparison (n = 3 studies), RFA showed a higher risk of non-response than RAI (RR, 1.24; 95% CI, 0.94-1.63; z = 1.55; p = 0.12). CONCLUSIONS: Our results demonstrate the superiority of RAI over RFA in terms of success rates and safety profile and confirm RAI as the first choice for the treatment of AFTNs.

Brain-Heart Axis: Brain-Derived Neurotrophic Factor and Cardiovascular Disease-A Review of Systematic Reviews.

BACKGROUND: The brain-heart axis is an intra- and bidirectional complex that links central nervous system dysfunction and cardiac dysfunction. In recent decades, brain-derived neurotrophic factor (BDNF) has emerged as a strategic molecule involved in both brain and cardiovascular disease (CVD). This systematic review of systematic reviews aimed to (1) identify and summarize the evidence for the BDNF genotype and BDNF concentration in CVD risk assessment, (2) evaluate the evidence for the use of BDNF as a biomarker of CVD recovery, and (3) evaluate rehabilitation approaches that can restore BDNF concentration. METHODS: A comprehensive search strategy was developed using PRISMA. The risk of bias was assessed via ROBIS. RESULTS: Seven studies were identified, most of which aimed to evaluate the role of BDNF in stroke patients. Only two systematic reviews examined the association of BDNF concentration and polymorphism in CVDs other than stroke. CONCLUSIONS: The overall evidence showed that BDNF plays a fundamental role in assessing the risk of CVD occurrence, because lower BDNF concentrations and rs6265 polymorphism are often associated with CVD. Nevertheless, much work remains to be carried out in current research to investigate how BDNF is modulated in different cardiovascular diseases and in different populations.

The Role of Brain-Derived Neurotrophic Factor (BDNF) in Depression and Cardiovascular Disease: A Systematic Review.

BACKGROUND: Several studies have been conducted to prove the bidirectional relationship between cardiovascular disease (CVD) and depression. These two major illnesses share several common risk factors such that the development of either condition may increase the risk of the occurrence of the other. Brain-derived neurotrophic factor (BDNF) has been suggested as a reliable biomarker for depression and a strong predictor of CVD because it plays an important role in neuron survival and growth, serves as a neurotransmitter modulator, and promotes neuronal plasticity. The aim of this systematic review was to examine the bidirectional relationship between CVD and depression, focusing on the potential role of low serum BDNF levels in the development of either disease in the presence of the other. METHODS: A systematic search strategy was developed using PRISMA guidelines. RESULTS: Six studies (comprising 1251 patients) were identified, all of which examined the association between CVD and depression. CONCLUSIONS: It was found that there may be a strong association between low serum BDNF levels and the risk of post-stroke depression. However, the studies on the role of altered serum BDNF levels and other types of CVD are few. Therefore, the inverse association between depression and CVD cannot be proven.

The role of arts engagement in reducing cognitive decline and improving quality of life in healthy older people: a systematic review.

In recent years, arts engagement has been proposed as a non-pharmacological approach to reduce cognitive decline and increase well-being and quality of life in specific populations such as the elderly or patients with severe disease. The aim of this systematic review was to assess the effects of receptive or active arts engagement on reducing cognitive decline and improving quality of life and well-being in healthy populations, with a particular focus on the role of arts engagement in the long term. A comprehensive search strategy was conducted across four databases from February to March 2023. Ten studies with a total of 7,874 participants were incorporated in accordance with the PRISMA guidelines. Active and receptive arts engagement was found to be an effective approach to reduce cognitive decline and improve well-being and quality of life in healthy populations. The role of the positive effects of arts engagement could be determined by the combination of several factors such as exposure to cultural activities and the group effect. There is limited evidence of the protective effects of active arts engagement over a long period of time. Given the increasing demand for preventive programmes to reduce the negative effects of population ageing, more research on arts engagement should be conducted to identify its mechanisms and long-term effects.

Neo-Adjuvant Treatment in Primary Resectable Pancreatic Cancer: A Systematic Review and PRISMA-Compliant Updated Metanalysis of Oncological Outcomes.

BACKGROUND: Despite advances in treatment, the prognosis of resectable pancreatic adenocarcinoma remains poor. Neoadjuvant therapy (NAT) has gained great interest in hopes of improving survival. However, the results of available studies based on different treatment approaches, such as chemotherapy and chemoradiotherapy, showed contrasting results. The aim of this systematic review and meta-analysis is to clarify the benefit of NAT compared to upfront surgery (US) in primarily resectable pancreatic adenocarcinoma. METHODS: A PRISMA literature review identified 139 studies, of which 15 were finally included in the systematic review and meta-analysis. All data from eligible articles was summarized in a systematic summary and then used for the meta-analysis. Specifically, we used HR for OS and DFS and risk estimates (odds ratios) for the R0 resection rate and the N+ rate. The risk of bias was correctly assessed according to the nature of the studies included. RESULTS: From the pooled HRs, OS for NAT patients was better, with an HR for death of 0.80 (95% CI: 0.72-0.90) at a significance level of less than 1%. In the sub-group analysis, no difference was found between patients treated with chemoradiotherapy or chemotherapy exclusively. The meta-analysis of seven studies that reported DFS for NAT resulted in a pooled HR for progression of 0.66 (95% CI: 0.56-0.79) with a significance level of less than 1%. A significantly lower risk of positive lymph nodes (OR: 0.45; 95% CI: 0.32-0.63) and an improved R0 resection rate (OR: 1.70; 95% CI: 1.23-2.36) were also found in patients treated with NAT, despite high heterogeneity. CONCLUSIONS: NAT is associated with improved survival for patients with resectable pancreatic adenocarcinoma; however, the optimal treatment strategy has yet to be defined, and further studies are required.

Temporomandibular joint involvement in patients with Juvenile Idiopathic Arthritis: comparison of ultrasonography and magnetic resonance imaging in assessing the periarticular space width.

OBJECTIVES: This study aimed to compare the performance of Ultrasonography (US) and Magnetic Resonance Imaging (MRI) in assessing the Lateral Periarticular Space (LPAS) of Temporomandibular Joints (TMJs) in patients with Juvenile Idiopathic Arthritis (JIA). METHODS: The LPAS width was evaluated in two different patient groups. In the JIA group, including 29 children (13 ± 2.8 years) with JIA, the LPAS width was measured with both MRI and US. In the healthy group, including 28 healthy children (12.6 ± 2.5 years), the LPAS width was measured only with US. Comparisons of LPAS width based on patient groups and TMJ contrast enhancement in MRI were evaluated by applying the Mann-Whitney U test. Correlation and agreement between MRI and US measurements in JIA group were tested using Spearman rank correlation and Bland-Altman method. RESULTS: The LPAS width was significantly greater in the JIA group than in the healthy group. In the JIA group, the LPAS width was significantly greater in TMJs with moderate/severe enhancement than those with mild enhancement. A positive significant correlation between MRI and US measurements of LPAS width was found in the JIA group. In the same group, Bland-Altman method showed a good level of agreement between MRI and US measurements. CONCLUSION: Although, US cannot replace MRI in the evaluation of TMJ in patients with JIA, US could be used as a supplementary imaging method to MRI in assessing the TMJ disease.

Heart Disease and Microgravity: The Dawn of a New Medical Era?: A Narrative Review.

After a decline in interest in space missions following the cessation of the Apollo missions, there has been a recent resurgence. Activities on the International Space Station have raised awareness of a positive resumption of space travel to more challenging destinations such as Mars and a possible adaptation of human life on the Moon. The biological and physiological studies conducted on these stations in low Earth orbit are crucial in familiarizing humanity with the potential problems that can arise during long journeys. Cosmic rays and microgravity are the 2 main negative phenomena in space flights. Microgravity in the interplanetary environment plays a special role in altering normal organic processes. These studies are compared to studies conducted on Earth with laboratory technologies that mimic the space environment. To date, the molecular and physiological adaptations of the human body to this unnatural environment are very poor. The aim of this review is therefore to provide an overview of the most important findings on the molecular and physiological anomalies that develop during microgravity in short and long space flights.

Prognostic role of early prostate specific antigen changes after [177 Lu]Lu-PSMA radioligand therapy of metastasized prostate cancer: A meta-analysis.

BACKGROUND: Approximately 10%-20% of prostate cancers progress to metastatic and castration-resistant forms (mCRPC). Radioligand (RLT) therapy with [177 Lu]Lu-prostate-specific membrane antigen (PSMA) is an emerging treatment for metastasized mCRPC and its efficacy is assessed not only but also by prostate specific antigen (PSA) measurement after 12 weeks or more after treatment. Our aim was to evaluate the role of early PSA measurement after RLT in predicting overall survival (OS) of mCRPC patients. METHODS: A systematic search on PubMed, Web Of Science and Scopus was performed from January to December 2022. PRISMA guidelines for prognostic studies was adopted. Risk of bias was assessed using quality of prognostic studies (QUIPS). RESULTS: Twelve studies at low-intermediate risk of bias, were included in the meta-analysis (1646 patients, mean age 70 years). About 50% of patients showed a PSA decline after 1-2 of [177 Lu]Lu-PSMA, and more than 30% reported a PSA decline ≥50%. The median OS range for patients with any PSA decline was 13-20 months, while for patients with stable or increased PSA, the median OS fell to 6-12 months. The OS rate for a PSA decline after the one-two [177 Lu]Lu-PSMA cycles was 0.39 (95% CI: 0.31-0.50), while OS for a PSA decline ≥50% was 0.69 (95% CI: 0.57-0.83). CONCLUSIONS: A PSA decline is observed in almost 50% of mCRPC patients after 1-2 [177 Lu]Lu-PSMA cycles, with a significantly longer OS compared to stable or increased PSA levels, respectively. Accordingly, any PSA decline after 1-2 cycles of therapy should be regarded as a favourable prognostic factor for OS.

Comparison of 1.1 GBq and 2.2 GBq Activities in Patients with Low-Risk Differentiated Thyroid Cancer Requiring Postoperative 131I Administration: A Real Life Study.

OBJECTIVES: To compare the efficacy of low and moderate 131I activities in low-risk differentiated thyroid carcinoma (DTC) patients requiring postoperative thyroid remnant ablation in a real-world clinical setting. METHODS: We retrospectively reviewed the records of 299 low-risk DTC patients (pT1-T2, Nx(0) Mx) who had undergone (near)-total thyroidectomy followed by 131I therapy, using either low (1.1 GBq) or moderate (2.2 GBq) radioiodine activities. The response to initial treatments was evaluated after 8-12 months, and patient responses were classified according to the 2015 American Thyroid Association guidelines. RESULTS: An excellent response was observed in 274/299 (91.6%) patients, specifically, in 119/139 (85.6%) and 155/160 (96.9%) patients treated with low and moderate 131I activities, respectively (p = 0.029). A biochemically indeterminate or incomplete response was observed in seventeen (22.2%) patients treated with low 131I activities and three (1.8%) patients treated with moderate 131I activities (p = 0.001). Finally, five patients showed an incomplete structural response, among which three and two received low and moderate 131I activities, respectively (p = 0.654). CONCLUSIONS: When 131I ablation is indicated, we encourage the use of moderate instead of low activities, in order to reach an excellent response in a significantly larger proportion of patients, including patients with the unexpected persistence of the disease.

Thyroid Hormone Withdrawal versus Recombinant Human TSH as Preparation for I-131 Therapy in Patients with Metastatic Thyroid Cancer: A Systematic Review and Meta-Analysis.

BACKGROUND: Differentiated thyroid carcinoma (DTC) is characterized by an excellent prognosis with a 10-year survival rate > 90%. However, when DTC develops in a metastatic form, it has been shown to significantly impact patient survival and quality of life. Although I-131 has been shown to be an effective therapy in patients with metastatic DTC, whether its efficacy after recombinant human TSH (rhTSH) is comparable to endogenous TSH stimulation by thyroid hormone deprivation (THW) is still debated. Our present study was prompted to compare clinical results obtained in metastatic DTC by I-131 administered after rhTSH and THW stimulation protocols, respectively. METHODS: A systematic search on PubMed, Web of Science, and Scopus was performed from January to February 2023. Pooled risk ratios with 95% CI were determined for evaluating the initial response after to I-131 therapy after preparation with rhTSH or THW and the disease progression. To track the accumulation of evidence and reduce type I errors because of small data, a cumulative meta-analysis was performed. A sensitivity analysis was also performed to examine the impact of individual studies on overall prevalence results. RESULTS: Ten studies were included with a total of 1929 patients pre-treated with rhTSH (n = 953) and THW (n = 976), respectively. The cumulative data of our systematic review and meta-analysis showed an increase in the risk ratio over the years without any change in favour of a pre-treatment or the other on the effectiveness of I-131 therapy of metastatic DTC. CONCLUSIONS: Our data suggest that pretreatment with rhTSH or THW has no significant impact on the effectiveness of I-131 therapy for metastatic DTC. This implies that concerns about the use of one or the other pretreatment should be deferred to clinical evaluations made considering patient characteristics and reduction in side effects.

Effectiveness of light therapy as adjunctive treatment in bipolar depression: A pilot study.

BACKGROUND: About 1 and 4 % of people suffering from depression is affected by bipolar disorder. Few patients respond to the first-line antidepressants, and a 4-week latency pharmacological treatment period has been observed. This pilot study aimed to evaluate the effectiveness and safety of bright light therapy (BLT) in accelerating and increasing therapeutic response in patients with bipolar depression. METHODS: A pilot study was conducted. Patients with bipolar depression, already treated with antidepressants, were included. The treatment group was composed of patients treated with antidepressants combined with BLT (30 min/4 days a week at 10,000 lx for eight weeks). The control group included patients treated with antidepressants with exposure to red light (30 min/4 days a week at a red light for eight weeks). MADRS, HAMD-17, CGI-S, FSS, and QoLS were collected at the baseline and after 4 and 8 weeks of treatments. RESULTS: Forty-one patients (18 males and 23 females; mean age 49.1 ± 15 years) were included in the study. After four weeks, MADRS and HAMD-17 scores in treatment groups were significantly lower than those reported in the control group (p < 0.001). After eight weeks, all scales except FSS reported significantly lower values in patients treated with BLT (p < 0.0001). LIMITATIONS: Small sample size and significant heterogeneity in the antidepressant treatments. CONCLUSION: BLT has shown reliable effectiveness and safety in treating patients with bipolar depression and should be considered a clinically relevant approach in accelerating patients' therapeutic response and reducing the impact of long-lasting therapy.

Evolution of thyroid cancer biomarkers: from laboratory test to patients' clinical management.

Over the past three decades, laboratory medicine has significantly evolved thanks to technological advances made possible by new materials and evidence. Clinicians' ongoing requests for powerful, rapid, and minimally invasive tests has led manufacturers to develop rapid, accurate, and sensitive tests that can increase diagnostic accuracy and improve follow-up, bringing laboratory medicine ever closer to personalized medicine. The aim of this study was to critically review the main problems of the current Tg and CT biomarkers for the diagnosis/monitoring of DTC and MTC, respectively, and to identify the advantages and challenges of using the new laboratory biomarkers in the clinical management of patients with differentiated and medullary thyroid cancer. Insufficient harmonization of Tg and CT assays and lack of interchangeability of laboratory results and cutoff values pose challenges for comparability and standardization of procedures and methods. New diagnostic and monitoring approaches such as PCT or the Tg doubling time have proven to be effective. Close collaboration between clinicians and laboratory specialists remains essential to translate the advantages and limitations of current assays into appropriate clinical interpretation criteria. Over the years, the journal Clinical Chemistry and Laboratory Medicine (CCLM) has taken many steps to develop advanced research and technology in the diagnosis and monitoring of tumor cancer and to help clinicians translate it into clinical practice.

Is thyroglobulin a reliable biomarker of differentiated thyroid cancer in patients treated by lobectomy? A systematic review and meta-analysis.

OBJECTIVES: The prognostic role of thyroglobulin in predicting recurrence in differentiated thyroid cancer (DTC) patients treated by lobectomy is controversial. This systematic review with meta-analysis aimed to update the current evidence deepening the reliability of circulating thyroglobulin in assessing the early response and in predictive recurrence. METHODS: The methodology was registered in the PROSPERO database under the protocol number CRD42021288189. A systematic search was carried out on PubMed, Embase, Web of Science, and Scopus from September to November 2021 without time and language restrictions. The literature search strategy was based on the following keywords: Thyroglobulin AND (Lobectomy OR Hemithyroidectomy). RESULTS: After screening 273 articles, seven studies were included in the systematic review, and only six of them were included in the meta-analysis for a total of 2,455 patients. Circulating thyroglobulin was found non-reliable in assessing early response and predicting recurrence in patients with hemithyroidectomy, especially those with a low initial ATA classification. CONCLUSIONS: Our study does not support serum thyroglobulin levels for monitoring patients with low-risk DTC treated with lobectomy, and weak evidence supports its role for intermediate- or high-risk patients. Studies with longer follow-up, different study designs, and stringent inclusion/exclusion criteria are needed to evaluate the role of thyroglobulin in recurrence prediction.

Impact of the Cognitive-Behavioral Approach and Psychoeducational Intervention in Breast Cancer Management: A Prospective Randomized Clinical Trial.

(1) Background: Breast cancer (BC) is the most prevalent malignancy in women. High cancer-related psychological distress levels have been observed in BC patients, with a potentially relevant impact on disease management, compliance with disease treatments, and everyday life activities and relationships. This work evaluated the effectiveness of three individual cognitive−behavioral therapy psychoeducational sessions versus a self-managed informative guide with individual counseling sessions without specific psychological treatment. (2) Methods: the intervention group received three individual 50-min sessions of psychoeducational training, and the control group received a self-managed informative guide with individual counseling sessions without any kind of psychological treatment. The Hospital Anxiety Depression Scale (HADS), the Distress Thermometer (DT), and the EORTC (European Organization for Research and Treatment of Cancer) QLQ-C30 were administered at baseline and two months after study inclusion. (3) Results: A total of 60 participants were included in the study (intervention group: 30, control group: 30). Significant improvements were observed in both groups after two months (p < 0.05), but no statistically significant differences emerged between groups. (4) Conclusions: Psychoeducational interventions and CBT help BC patients manage disease-related fear and distress, allowing them to achieve a good quality of life.

18F-FDG PET Radiomics as Predictor of Treatment Response in Oesophageal Cancer: A Systematic Review and Meta-Analysis.

The best treatment strategy for oesophageal cancer patients achieving a complete clinical response after neoadjuvant chemoradiation is a burning topic. The available diagnostic tools, such as 18F-FDG PET/CT performed routinely, cannot accurately evaluate the presence or absence of the residual tumour. The emerging field of radiomics may encounter the critical challenge of personalised treatment. Radiomics is based on medical image analysis, executed by extracting information from many image features; it has been shown to provide valuable information for predicting treatment responses in oesophageal cancer. This systematic review with a meta-analysis aims to provide current evidence of 18F-FDG PET-based radiomics in predicting response treatments following neoadjuvant chemoradiotherapy in oesophageal cancer. A comprehensive literature review identified 1160 studies, of which five were finally included in the study. Our findings provided that pooled Area Under the Curve (AUC) of the five selected studies was relatively high at 0.821 (95% CI: 0.737-0.904) and not influenced by the sample size of the studies. Radiomics models exhibited a good performance in predicting pathological complete responses (pCRs). This review further strengthens the great potential of 18F-FDG PET-based radiomics to predict pCRs in oesophageal cancer patients who underwent neoadjuvant chemoradiotherapy. Additionally, our review imparts additional support to prospective studies on 18F-FDG PET radiomics for a tailored treatment strategy of oesophageal cancer patients. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42021274636.

Corrigendum: Irrigating Solutions and Activation Methods Used in Clinical Endodontics: A Systematic Review.

[This corrects the article DOI: 10.3389/froh.2022.838043.].

The role of thyroglobulin doubling time in differentiated thyroid cancer: a meta-analysis.

Objective: In patients with differentiated thyroid cancer (DTC), recurrences may occur in up to 20% and may have a fatal outcome in 10% of cases. Thyroglobulin doubling time (Tg-DT) values may contribute to predict response to treatment and disease recurrence in DTC patients. This study aimed to address the following questions: (1) Are Tg-DT values indicative of response to treatments in patients with DTC (i.e. 'treatment monitoring')?; (2) Is Tg-DT predictive of 2-[18F]fluoro-2-deoxy-d-glucose (2-[18F]FDG) PET/CT in patients with DTC?; (3) Are Tg-DT values predictive of DTC prognosis (i.e. 'prediction')? Design: Systematic review and meta-analysis. Methods: Methodology was registered in the PROSPERO database (CRD42021257947). A systematic search was carried out in PubMed, Web Of Science, and Scopus from June to August 2021 without time and language restrictions. Results: Eleven studies were included for a total of 1421 patients. Positive association between Tg-DT < 1 year and recurrence or disease progression was observed. Tg-DT was found to be related with (2-[18F]FDG) PET/CT results in patients with DTC. The area under the curve was 0.86 (95% CI: 0.83-0.89), sensitivity was 0.84 (0.64;0.94), specificity was 0.71 (0.35; 0.92), DOR was 13.1 (3.1; 55.0), LR+ was 2.9 (1.0; 8.1), LR- was 0.22 (0.1; 0.5). For patients with Tg-DT < 1 year (n = 247), the survival risk ratio was 2.09 (95% CI: 1.49; 2.94). Conclusions: Tg-DT values are valuable in predicting response to treatment and disease recurrence in patients with DTC, as well as their overall survival. In addition, Tg-DT significantly increases the detection rate of 2-[18F]-FDG PET/CT.

Irrigating Solutions and Activation Methods Used in Clinical Endodontics: A Systematic Review.

BACKGROUND: Ex vivo and in vitro studies have demonstrated the effectiveness of some irrigation protocols in reducing the bacterial load in the root canal system. However, standardized protocols have not yet been defined for the real clinical context due to many irrigation procedures available. OBJECTIVE: To evaluate the clinical endodontic protocols and limitations of irrigating solutions in the disinfection of the root canal system in patients with apical periodontitis. METHODS: PubMed, Scopus, Embase, Web of Science, and Cochrane databases were searched for randomized controlled trials (RCT) published until January 2021. Hand searching was also performed. Studies focused on evaluating the effectiveness of irrigating solutions and/or irrigation activation methods in reducing the bacterial load in the root canal system were considered. The Cochrane risk-of-bias tool for randomized trials (RoB2) was used to assess the quality of the studies. RESULTS: Four hundred and twenty eight published articles were identified. After removing the duplicate studies and analyzing full texts, seven RCTs were selected. Two studies compared pure NaOCl with some combination of NaOCl with HEDP and MTAD. Two studies analyzed the antibacterial efficacy of NaOCl and chlorhexidine (CHX). Three studies compared conventional needle irrigation with different irrigation activation methods (PUI, XP-endo finisher, F-file activator, EndoVac activator). The review attained a satisfactory methodology. The main results of each included study were described. DISCUSSION: Activation methods provide significantly higher biofilm reduction than conventional needle irrigation methods. Combinations of NaOCl with different chelating agents were ineffective in terms of antimicrobial, but it could potentially increase the risk of irrigant extrusion. However, the irrigating protocols were not carefully detailed, especially those regarding the irrigants application time or total volume. The existing literature lacks high-quality studies. The level of evidence is moderate. CONCLUSIONS: The available data is too heterogeneous to compare and identify the superiority of specific valuable irrigation protocols in each clinical context. Application time, volume, and activation methods should be standardized to determine the optimal irrigating procedures to reduce the bacterial load and ensure higher predictability of the endodontic treatment. SYSTEMATIC REVIEW REGISTRATION: (https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=218555), PROSPERO registration: CRD42020218555.