Search

Characterizing and evaluating the holistic value of innovative healthcare technologies (e.g. treatments, services) constitutes a crucial goal to maximize limited resources. However, the characteristics of innovation have not been well identified. This review aims to describe the characteristics of healthcare innovation. We performed a comprehensive systematic search using PubMed, Embase, PsycINFO, and Econlit from inception to July 2022. Articles were included if they described innovation or the characteristics of innovation of the technologies in healthcare. Characteristics or definitions of innovation directly or indirectly described as innovation were extracted from the included articles. Two independent reviewers then conceptualized the identified characteristics of innovation to generate innovation attributes in healthcare. In total, 103 articles were included in this review. Eight attributes describing innovation, i.e. novelty, step change, substantial benefits, an improvement over existing technologies, convenience and/or adherence, added value, acceptable cost, and uncounted benefits, were conceptualized. Most of the identified innovation attributes were based on the researchers’ perspective. This study conceptualized innovation attributes in healthcare based on the characteristics of healthcare innovation as defined in the literature. Further research is warranted to obtain a complete understanding of the perspectives of researchers and other stakeholders, including patients, healthcare providers, healthcare payers, and the pharmaceutical industry, on recognizing innovation in healthcare.KEY POINTSThis is the first systematic review to conceptualize attributes of healthcare innovation.We conceptualized eight attributes describing innovation, i.e. novelty, step change, substantial benefits, an improvement over existing technologies, convenience and/or adherence, added value, acceptable cost, and uncounted benefits based on the similar concept.In existing literature, patients’ and caregivers’ perspectives were less frequently found to describe the innovation attributes.Future research is needed to identify, measure, and value various stakeholders, including patients’ and caregivers’ perspectives on healthcare innovation. This is the first systematic review to conceptualize attributes of healthcare innovation. We conceptualized eight attributes describing innovation, i.e. novelty, step change, substantial benefits, an improvement over existing technologies, convenience and/or adherence, added value, acceptable cost, and uncounted benefits based on the similar concept. In existing literature, patients’ and caregivers’ perspectives were less frequently found to describe the innovation attributes. Future research is needed to identify, measure, and value various stakeholders, including patients’ and caregivers’ perspectives on healthcare innovation.

Background Systematic reviews and meta-analyses of randomized clinical trials (RCTs) have reported the benefits of ketogenic diets (KD) in various participants such as patients with epilepsy and adults with overweight or obesity. Nevertheless, there has been little synthesis of the strength and quality of this evidence in aggregate. Methods To grade the evidence from published meta-analyses of RCTs that assessed the association of KD, ketogenic low-carbohydrate high-fat diet (K-LCHF), and very low-calorie KD (VLCKD) with health outcomes, PubMed, EMBASE, Epistemonikos, and Cochrane database of systematic reviews were searched up to February 15, 2023. Meta-analyses of RCTs of KD were included. Meta-analyses were re-performed using a random-effects model. The quality of evidence per association provided in meta-analyses was rated by the GRADE (Grading of Recommendations, Assessment, Development, and Evaluations) criteria as high, moderate, low, and very low. Results We included 17 meta-analyses comprising 68 RCTs (median [interquartile range, IQR] sample size of 42 [20–104] participants and follow-up period of 13 [8–36] weeks) and 115 unique associations. There were 51 statistically significant associations (44%) of which four associations were supported by high-quality evidence (reduced triglyceride (n = 2), seizure frequency (n = 1) and increased low-density lipoprotein cholesterol (LDL-C) (n = 1)) and four associations supported by moderate-quality evidence (decrease in body weight, respiratory exchange ratio (RER), hemoglobin A1c, and increased total cholesterol). The remaining associations were supported by very low (26 associations) to low (17 associations) quality evidence. In overweight or obese adults, VLCKD was significantly associated with improvement in anthropometric and cardiometabolic outcomes without worsening muscle mass, LDL-C, and total cholesterol. K-LCHF was associated with reduced body weight and body fat percentage, but also reduced muscle mass in healthy participants. Conclusions This umbrella review found beneficial associations of KD supported by moderate to high-quality evidence on seizure and several cardiometabolic parameters. However, KD was associated with a clinically meaningful increase in LDL-C. Clinical trials with long-term follow-up are warranted to investigate whether the short-term effects of KD will translate to beneficial effects on clinical outcomes such as cardiovascular events and mortality.

To grade the evidence from published meta-analyses of randomized controlled trials (RCTs) that assessed effects of pharmacist intervention on cardiovascular risk factors and cardiovascular outcomes.MEDLINE, Embase, and the Cochrane Library were searched from database inception to July 2021. Meta-analyses of RCTs were eligible. Quality of evidence were assessed by GRADE approach.From 9308 publications, 149 full-text articles were evaluated for eligibility, and 24 studies with 85 unique meta-analyses that assessed effects of pharmacist intervention on cardiovascular risk factors and cardiovascular outcomes were selected. Overall, 71.7% (61/85) of unique meta-analyses showed significant impacts of pharmacist intervention. For the quality of evidence, 63.4% of meta-analyses had large heterogeneity (IThis umbrella review found convincing evidence that pharmacist intervention can provide a wide range of benefits in cardiovascular disease management, ranging from risk factor control, improvement in medication adherence and, in some settings, reduction in morbidity and mortality.

This meta-analysis was conducted to quantitatively pool the incremental net benefit (INB) of using biologic therapies as an add-on treatment to standard therapy in patients with moderate to severe asthma. We performed a comprehensive search in several databases published until April 2022. Studies were included if they were cost-effectiveness analyses reporting cost per quality-adjusted life-year or life-year on any biologic therapies as an add-on treatment for moderate to severe asthma in patients of all ages. Various monetary units were converted to purchasing power parity, adjusted to 2021 US dollars. The INBs were pooled across studies using a random-effects model, stratified by country income level (high-income countries (HICs) and low- and middle-income countries (LMICs)) and perspectives (health care or payer perspective (HCPP) and societal perspective (SP)) and age group (>12 years and 6–11 years). Heterogeneity was assessed using the I2 statistic. A total of 32 comparisons from 25 studies were included. Pooled INB indicated that the use of omalizumab as an add-on treatment to standard therapy in those aged >12 years was not cost-effective in HICs from the HCPP (n = 8, INB, −6,341 (95% CI, -$25,000 to $12,210), I2=86.18%) and SP (n = 5, -$14,000 (-$170,000 to $140,000), I2=75.64%). A similar finding was observed in those aged 6–11 years from the HCPP in LMICs (n = 2, -$45,000 (-$73,000 to $17,000), I2=00.00%). Subgroup analyses provided no explanations of the potential sources of heterogeneity. The use of biologic therapies in moderate to severe asthma is not cost-effective compared to standard treatment alone.

Objectives To perform a systematic review and meta-analysis to pool the incremental net benefit (INB) of each herpes zoster vaccine (i.e., Zoster Vaccine Live (ZVL) and Recombinant Zoster Vaccine (RZV)). Methods We initially identified individual studies by hand-searching reference lists of the relevant systematic review articles. An updated comprehensive search was performed in Medline, Scopus, and Embase until June 2020 for additional studies. Studies were eligible if they assessed the cost-effectiveness/utility of any pair among ZVL and RZV, and no vaccine and reported economic outcomes. Details of the study characteristics, economic model inputs, costs, and outcomes were extracted. INB was calculated with monetary units adjusting for purchasing power parity for 2019 US dollars and pooled by meta-analysis. Results A total of 37 studies were pooled for meta-analysis stratified by perspectives (i.e., societal (SP) and third-party payer (TPP)) and vaccine types. In SP, ZVL was cost-effective compared to no vaccine when vaccinated at ages of 50-59 and 70-79 years with INBs (95% CI) of $0.61 (0.37, 0.85) and $9.67 (5.20, 14.14), respectively. RZV was cost-effective for those aged 60-69 and 70-79 years with INBs of $75.61 (17.98, 133.23) and $85.01 (30.02, 140.01), respectively. In TPP, ZVL was cost-effective compared to no vaccine when vaccinated at age 70-79 years with INB of $7.57 (0.27, 14.86) and RZV was cost effective at 60-69 years with INB $220.87 (47.80, 393.93). The cost-effectiveness of RZV was robust across series of sensitivity analyses, but ZVL differs on different vaccination ages. Conclusions RZV may be cost-effective for vaccination in ages of 60-79 years for both SP and TPP perspectives, while ZVL might be cost-effective in some age groups, but results are not robust.

Background: This review aimed to evaluate the efficacy of oral cryotherapy in the prevention of chemotherapy-induced oral mucositis using meta-analysis and trial sequential analysis, as well as to assess the quality of the results by the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. Methods: A comprehensive search of three databases including Medline, Embase and Central was performed to identify randomized controlled trials that used oral cryotherapy for the prevention of chemotherapy-induced oral mucositis. The primary outcome was the incidence of oral mucositis for trials employing oral cryotherapy as the intervention for the prevention of oral mucositis. The meta-analysis was performed using the random-effects model and random errors of the meta-analyses were detected by trial sequential analysis. Results: A total of 14 RCTs with 1577 participants were included in the present meta-analysis. Patients treated with oral cryotherapy were associated with a significantly lower risk of developing oral mucositis of any grade (risk ratio (RR), 0.67 (95% CI: 0.56–0.81, p < 0.05)). Findings from the subgroup analyses showed that oral cryotherapy significantly reduced the risk of oral mucositis in patients undergoing bone marrow transplantation (RR 0.69, CI: 0.54–0.89, p < 0.05) as well as chemotherapy (RR 0.66, CI: 0.58–0.75, p < 0.05). Findings from the trial sequential analysis suggested that the evidence on oral cryotherapy as a preventive intervention for oral mucositis in patients with solid malignancies receiving conventional chemotherapy was conclusive. Conclusion: Oral cryotherapy is effective in preventing oral mucositis in patients undergoing chemotherapy for the management of solid malignancies. The use of oral cryotherapy in preventing oral mucositis in bone marrow transplantation settings showed promising efficacy, but the evidence is not conclusive and requires more high-quality randomized controlled trials.

Background: This systematic review and network meta-analysis aimed to assess comparative efficacy and safety of interventions to treat symptomatic, biopsy-proven oral lichen planus (OLP). Methods: Search was conducted for trials published in Medline, Embase and Cochrane Central Register of Controlled Trials. Network meta-analysis was performed on data from randomized controlled trials that assessed efficacy and safety of interventions used in the treatment of OLP. Agents were ranked according to their effectiveness in treatment of OLP based on outcomes using surface under the cumulative ranking [SUCRA]. Results: In total, 37 articles were included in the quantitative analysis. Purslane was clinically significant and ranked first in improving clinical symptoms [RR = 4.53; 95% CI: 1.45, 14.11], followed by aloe vera [RR = 1.53; 95% CI: 1.05, 2.24], topical calcineurin [RR = 1.38; 95% CI: 1.06, 1.81] and topical corticosteroid [RR = 1.35 95% CI: 1.05, 1.73]. Topical calcineurin demonstrated the highest incidence of adverse effects [RR, 3.25 [95% CI: 1.19, 8.86. Topical corticosteroids were significant in achieving clinical improvement of OLP with RR1.37 [95% CI: 1.03, 1.81]. PDT [MD = −5.91 [95% CI: −8.15, –3.68] and showed statistically significant improvement in the clinical score for OLP. Conclusions: Purslane, aloe vera and photodynamic therapy appear promising in treatment of OLP. More high-quality trials are recommended for strengthening the evidence. Although topical calcineurin is significantly efficacious in the treatment of OLP, significant adverse effects are a concern for clinical use. Based on the current evidence, topical corticosteroids are recommended for treatment of OLP owing to their predictable safety and efficacy.

This systematic review and network meta-analysis aimed to assess the comparative efficacy and safety of antibiotics to prevent early implant failure in patients undergoing dental implant surgery. Methods: The review was registered in PROSPERO [CRD42022319385]. A search was conducted for trials published in Medline, Cochrane, PubMed, and Scopus. A network meta-analysis was performed on the data from randomized controlled trials. Agents were ranked according to their effectiveness based on outcomes (implant failure, prosthetic failure, postsurgical complications, and adverse effects) using the surface under the cumulative ranking [SUCRA]. Results: A total of 15 articles were included in the quantitative analysis. When compared to the placebo, 2 g of amoxicillin given 1 h preoperatively (RR = 0.42 (95%CI: 0.27, 0.67)), 2 g of amoxicillin given 1 h preoperatively with postoperative 500 mg thrice for 5 days (RR = 0.36 (95%CI: 0.15, 0.87)), and post-operative amoxicillin with clavulanic acid 625 mg 3 times daily for 5 days (RR = 0.38 (95%CI: 0.16, 0.90)) were effective in reducing early implant failures. In addition, 2 g of amoxicillin given 1 h preoperatively (RR = 0.42 (95%CI: 0.25, 0.73)) was the only protocol that was significant in the pairwise meta-analysis results. However, sensitivity analysis, which excluded trials with a high risk of bias, showed that none of the protocols were statistically significant in reducing early implant failure. Conclusions: A single 2 g dose of preoperative amoxicillin significantly reduces early implant failure in healthy individuals. More high-quality trials are required to establish this recommendation, as the quality of this evidence is weak.

Attention-deficit/hyperactivity disorder (ADHD) is one of the most common mental disorders affecting children and adults. Previous systematic reviews have provided estimates of ADHD-associated costs but were limited to the USA and Europe. This study aimed to systematically summarise all global evidence on the economic burden of ADHD. A systematic search for published studies on costs of ADHD was conducted in EconLit, EMBASE, PubMed, ERIC, and PsycINFO. Additional literature was identified by searching the reference lists of eligible studies. The quality of the studies was assessed using the Larg and Moss checklist. This review included 44 studies. All studies were conducted in high-income countries and were limited to North America and Europe except for four studies: two in Asia and two in Australia. Most studies were retrospective and undertook a prevalence-based study design. Analysis revealed a substantial economic impact associated with ADHD. Estimates based on total costs ranged from $US831.38 to 20,538 for per person estimates and from $US356 million to 20.27 billion for national estimates. Estimates based on marginal costs ranged from $US244.15 to 18,751.00 for per person estimates and from $US12.18 million to 141.33 billion for national estimates. Studies that calculated economic burden across multiple domains of direct, indirect, and education and justice system costs for both children and adults with ADHD reported higher costs and translated gross domestic product than did studies that captured only a single domain or age group. Despite the wide variation in methodologies in studies reviewed, the literature suggests that ADHD imposes a substantial economic burden on society. There is a dire need for cost-of-illness research in low- and middle-income countries to better inform the treatment and management of ADHD in these countries. In addition, guidelines on the conduct and reporting of economic burden studies are needed as they may improve standardisation of cost-of-illness studies.

Pneumococcal conjugate vaccines (PCVs) have significantly reduced disease burden caused by Streptococcus pneumoniae, a leading cause of childhood morbidity and mortality globally. This systematic review and meta-analysis aimed to assess the incremental net benefit (INB) of the 13-valent PCV (PCV13) and 10-valent PCV (PCV10) in children.We performed a comprehensive search in several databases published before May 2022. Studies were included if they were cost-effectiveness or cost-utility analyses of PCV13 or PCV10 compared with no vaccination or with each other in children. Various monetary units were converted to purchasing power parity, adjusted to 2021 US dollars. The INBs were calculated and then pooled across studies stratified by country income level, perspective, and consideration of herd effects, using a random-effect model.Seventy studies were included. When herd effects were considered, PCV13 was cost-effective compared with PCV10 from the payer perspective in both high-income countries (HICs) (INB, $103.94; 95% confidence interval, $75.28-$132.60) and low- and middle-income countries (LMICs) (INB, $53.49; 95% confidence interval, $30.42-$76.55) with statistical significance. These findings were robust across a series of sensitivity analyses. PCV13 was cost-effective compared with no vaccination across perspectives and consideration of herd effects in both HICs and LMICs, whereas findings were less consistent for PCV10.PCVs were generally cost-effective compared with no vaccination in HICs and LMICs. Our study found that PCV13 was cost-effective compared with PCV10 when herd effects were considered from the payer perspective in both HICs and LMICs. The results are sensitive to the consideration of herd effects.

This meta-analysis was conducted to quantitatively pool the incremental net benefit (INB) of using direct oral anticoagulants (DOACs) for the prevention of venous thromboembolism (VTE) in patients undergoing total knee or hip replacements (TKR or THR).We performed a comprehensive search in several databases published before June 2021. Studies were included if they were cost-effectiveness analyses reporting cost per quality-adjusted life-year or life-year of DOACs compared to low molecular-weight heparins (LMWHs) or other anticoagulant agents for the prevention of VTE after TKR or THR. Risk of bias was also assessed using the biases in economic studies (ECOBIAS) checklist. Various monetary units were converted to purchasing power parity, adjusted to 2020 US dollars. The INBs were pooled across studies using a random-effects model, stratified by high-income countries (HICs) and low- and middle-income countries (LMICs). Heterogeneity was assessed using the IA total of 49 comparisons (TKR = 25 and THR = 24) from 16 studies was included. In HICs, DOACs were cost-effective compared to LMWHs from the health care system/payer perspective for the prevention of VTE after both TKR and THR with corresponding INBs (95 % CI; IDOACs were cost-effective as compared to LMWHs for VTE prophylaxis following TKR and THR surgeries in HICs. Further studies from LMICs are warranted.

Objective This review examined the comparative efficacy and safety of antifungal agents in preventing oral candidiasis among patients on cancer treatment. Methods We performed a systematic review and network meta-analysis based on randomised controlled trials that compared antifungal agents to placebo or other antifungal agents used in patients undergoing cancer treatment. Relative ranking of antifungal agents was evaluated with surface under the cumulative ranking (SUCRA) probability score. A total of 20 randomised controlled trials (3,215 participants) comparing 11 interventions were included. Results Compared with placebo, clotrimazole was ranked the best agent for preventing the incidence of oral candidiasis (risk ratio (RR), 0.21 [95% CI 0.08 to 0.55]; SUCRA = 0.89). Fluconazole was ranked the safest among other antifungal agents (SUCRA = 0.80), whereas clotrimazole (SUCRA = 0.36) and amphotericin B (SUCRA = 0.18) were ranked low for safety. Amphotericin B was associated with highest risk of adverse events (RR, 3.52 [95% CI 1.27 to 9.75]). Conclusion Clotrimazole is the most effective in preventing oral candidiasis, whereas fluconazole has the most favourable risk-benefit profile in patients undergoing cancer treatment. However, we are unable to recommend clotrimazole as the best choice to prevent oral candidiasis due to unavailability of studies comparing clotrimazole with other antifungal agents.

Invasive fungal infections are a potentially life-threatening complication in immunocompromised patients. The aim of this study was to assess the efficacy and safety of posaconazole as compared with other antifungal agents for preventing invasive fungal infections in immunocompromised patients. Embase, CENTRAL, and MEDLINE were searched for randomized conweekmonthtrolled trials (RCTs) up to June 2020. A systematic review with meta-analysis of RCTs was performed using random-effects model. Trial sequential analysis (TSA) was conducted for the primary outcome to assess random errors. A total of five RCTs with 1,617 participants were included. Posaconazole prophylaxis was associated with a significantly lower risk of IFIs (RR, 0.43 [95% CI 0.28 to 0.66, p = 0.0001]) as compared to other antifungal agents. No heterogeneity was identified between studies (I2 = 0%). No significant associations were observed for the secondary outcomes measured, including risk reduction of invasive aspergillosis and candidiasis, clinical failure, all-cause mortality, and treatment-related adverse events, except for infection-related mortality (RR, 0.31 [95% CI 0.15 to 0.64, p = 0.0001]). Subgroup analysis favoured posaconazole over fluconazole for the prevention of IFIs (RR, 0.44 [95% CI 0.28 to 0.70, p = 0.0004]). TSA confirmed the prophylactic benefit of posaconazole against IFIs. Posaconazole is effective in preventing IFIs among immunocompromised patients, particularly those with hematologic malignancies and recipients of allogenic hematopoietic stem cell transplantation.

The exponential increase in published articles makes a thorough and expedient review of literature increasingly challenging. This review delineated automated tools and platforms that employ artificial intelligence (AI) approaches and evaluated the reported benefits and challenges in using such methods. A search was conducted in 4 databases (Medline, Embase, CDSR, and Epistemonikos) up to April 2021 for systematic reviews and other related reviews implementing AI methods. To be included, the review must use any form of AI method, including machine learning, deep learning, neural network, or any other applications used to enable the full or semi-autonomous performance of one or more stages in the development of evidence synthesis. Twelve reviews were included, using nine different tools to implement 15 different AI methods. Eleven methods were used in the screening stages of the review (73%). The rest were divided: two in data extraction (13%) and two in risk of bias assessment (13%). The ambiguous benefits of the data extractions, combined with the reported advantages from 10 reviews, indicating that AI platforms have taken hold with varying success in evidence synthesis. However, the results are qualified by the reliance on the self-reporting of the review authors. Extensive human validation still appears required at this stage in implementing AI methods, though further evaluation is required to define the overall contribution of such platforms in enhancing efficiency and quality in evidence synthesis.

Pharmacists can play an important role in pain management.This review aims to summarize the effects of any type of pharmacist intervention, whether led by a pharmacist or in a supportive role, on pain intensity over time in individuals with pain of any etiology.Three electronic databases (MEDLINE, Embase, and Cochrane Central Register of Controlled Trials) were searched from inception to the end of May 2021 to identify randomized controlled trials (RCTs) that reported the effect of pharmacist interventions on pain intensity. Two reviewers independently extracted data and evaluated study quality. The analyses used a random-effects models and the Grading of Recommendations, Assessment, Development and Evaluation to rate the certainty of the evidence. The primary outcome was reduction in pain intensity and presented as standardized mean differences (SMD).Twelve RCTs including 1710 participants were included. Pooled estimate of 12 studies demonstrated a statistically significant reduction in pain intensity compared with control (SMD -0.22 [95% CI -0.31 to -0.12], IThere is some promising evidence to suggest that multicomponent pharmacist interventions including medication review or any other pharmaceutical care services, rather than merely educational interventions, are beneficial in reducing pain intensity, particularly in patients with chronic pain. High-quality RCTs are required to confirm the clinical significance of this findings before advocating for its widespread implication in clinical practice.

Multiple sclerosis (MS) is multifactorial in nature, with both genetic and environmental factors contributing to disease risk. In this umbrella review, we aimed to summarize various non-HLA genes that have been investigated for their association with MS risk in meta-analyses (MAs) of observational studies.Medline, Embase, Epistemonikos, and Cochrane Database of Systematic Reviews were searched for MAs up to July 2021. Evidence of association was ranked according to established criteria as follows: convincing, highly suggestive, suggestive, weak, or not significant.From 1,533 publications, 85 full-text articles were evaluated for eligibility, and 15 articles were selected that described 114 genetic associations. No associations were supported by convincing evidence. One association between the rs2104286 (A vs G contrast) polymorphism of the interleukin 2RA (IL2RA) gene and increased MS susceptibility was initially supported by highly suggestive evidence (OR 1.17; 95% CI 1.10-1.25) but it was downgraded to suggestive in the sensitivity and subgroup analyses. We also found six associations supported by suggestive evidence in the main analysis.The findings of this study imply that the cytokines genes interleukin IL2RA and IL7R may play a role in the development of MS. Data from more and better-designed studies are needed to establish robust evidence.

AIMS: The aim was to perform an umbrella review to summarise the existing evidence on proton-pump inhibitor (PPI) use and adverse outcomes and to grade the certainty of evidence. METHODS: Electronic databases were searched up to July 2021 for meta-analyses of cohort studies and/or randomised controlled trials (RCTs). Summary effect sizes from a random-effects model, between-study heterogeneity, 95% prediction interval, small-study effect, excess significance and credibility ceilings were devised to classify the credibility of evidence from meta-analyses of cohort studies, whereas the GRADE approach was used for meta-analyses of RCTs. RESULTS: In meta-analyses of cohort studies, 52 of the 91 examined associations were statistically significant (P ≤ .05). Convincing evidence emerged from main analysis for the association between PPI use and risk of all-site fracture and chronic kidney disease in the elderly population. However, none of these associations remained supported by convincing evidence after sensitivity analyses. The use of PPI is also associated with an increased risk of mortality due to COVID-19 infection and other related adverse outcomes, but the quality of evidence was weak. In meta-analyses of RCTs, 38 of the 63 examined associations were statistically significant. However, no associations were supported by high or moderate-quality evidence. CONCLUSION: This study's findings imply that most putative adverse outcomes associated with PPI use may not be supported by high-quality evidence and are likely to have been affected by underlying confounding factors. Future research is needed to confirm the causal association between PPI use and risk of fracture and chronic kidney disease.

To compare the clinical and radiographic outcomes of pulpotomies in primary molars using bioactive endodontic materials and ferric sulfate.The search was conducted in PubMed, Ebscohost, ProQuest, and Scopus databases till June 2021. Children undergoing pulpotomy therapy in primary molars treated with ferric sulfate (FS) and bioactive endodontic materials were evaluated for clinical and radiographic success. Meta-analysis was performed on a random-effects model to assess the success at 6,12,18, and 24 months. The quality of studies was evaluated using the Cochrane risk of bias tool for randomized trials RESULTS: No significant difference was observed between Mineral trioxide aggregate (MTA) and FS at 24 months for both clinical [RR0.98 (95%CI 0.15,6.34), IAmongst bioactive materials, MTA and FS demonstrated equal success rates in both clinical and radiographic outcomes with follow-up periods of up to 24 months. Future, high-quality trials are required to verify the result of the current review.

Many interventions have been investigated for the treatment of nonalcoholic steatohepatitis (NASH). This study aims to summarize all investigated options to date and review the use of specific endpoints at different stages of ongoing trials of noncirrhotic NASH treatments. Using a horizon scanning approach, evidence were identified including meta-analyses of randomized controlled trials (RCTs) in PubMed, EMBASE, Cochrane, and AMED (up to February 2020), recently published RCTs in PubMed (2015-April 2020), RCTs presented at conferences (AASL and EASL, 2015-2020), and ongoing RCTs in ClincalTrials.gov (2015-November 2020). We included 6 meta-analyses of RCTs, 30 published RCTs, 11 conference abstracts, and 62 ongoing RCTs. An evidence map was created to demonstrate the treatment effects of 49 therapeutic modalities for NASH. Only six interventions (6/49, 12.24%) met the histological surrogate endpoints for potential conditional FDA approval. Obeticholic acid is the only therapy demonstrating positive benefits in ≥1-point improvement in fibrosis with no worsening of NASH in a phase 3 trial. The other therapies were all phase 2 studies. ≥1-point improvement in fibrosis with no worsening of NASH was shown in patients treated with cenicriviroc. NASH resolution with no worsening of fibrosis was shown in patients treated with liraglutide, semaglutide and resmetirom. Lanifibranor achieved both surrogate histological endpoints. Five ongoing RCTs (5/62, 8.06%) will investigate histological progression to cirrhosis, death, or liver-related clinical outcomes. In conclusion, some therapeutic modalities showed promising benefits, but further studies are warranted to find a definite treatment of NASH which prevents progression to cirrhosis and adverse liver outcomes.

The underutilization of immunization services remains a big public health concern. Pharmacists can address this concern by playing an active role in immunization administration.We performed a systematic review and meta-analysis to assess the impact of pharmacist-involved interventions on immunization rates and other outcomes indirectly related to vaccine uptake.A systematic literature search was conducted using MEDLINE, Embase, and Cochrane Central Register of Controlled Trials databases from inception to February 2022 to identify randomized controlled trials (RCTs) and observational studies in which pharmacists were involved in the immunization process. Studies were excluded if no comparator was reported. Two reviewers independently completed data extraction and bias assessments using standardized forms. Meta-analyses were performed using a random-effects model.A total of 14 RCTs and 79 observational studies were included. Several types of immunizations were provided, including influenza, pneumococcal, herpes zoster, Tdap, and others in a variety of settings (community pharmacy, hospital, clinic, others). Pooled analyses from RCTs indicated that a pharmacist as immunizer (risk ratio 1.14 [95% CI 1.12-1.15]), advocator (1.31 [1.17-1.48]), or both (1.14 [1.12-1.15]) significantly increased immunization rates compared with usual care or non-pharmacist-involved interventions. The quality of evidence was assessed as moderate or low for those meta-analyses. Evidence from observational studies was consistent with the results found in the analysis of the RCTs.Pharmacist involvement as immunizer, advocator, or both roles has favorable effects on immunization uptake, especially with influenza vaccines in the United States and some high-income countries. As the practice of pharmacists in immunization has been expanded globally, further research on investigating the impact of pharmacist involvement in immunization in other countries, especially developing ones, is warranted.

The objective of this study was to assess the comparative efficacy and safety of different antifungal agents used for the treatment of oropharyngeal candidiasis (OPC) in adult patients with HIV. A systematic search was performed on the four major databases (Medline, Embase, CENTRAL and Scopus) to identify randomized controlled trials (RCTs) that evaluated the efficacy of antifungal agents in HIV patients with OPC. A network meta-analysis was performed from the data extracted from the selected studies. The agents were ranked according using surface under the cumulative ranking (SUCRA). The Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach was used to determine the quality of evidence. A total of 15 trials were included in the quantitative analysis involving the data from a total of 2883 participants. Fluconazole was ranked as the most effective antifungal agent to achieve clinical cure (SUCRA = 0.87) in OPC followed by posaconazole and itraconazole. Posaconazole was ranked the most efficacious agent in achieving mycological cure (SUCRA = 0.81), followed by fluconazole. While nystatin was ranked the safest, the effect estimates of none of the other systemic antifungal agents were significantly higher than fluconazole. Based on the available evidence, fluconazole can be considered as the most effective drug in the treatment of OPC among HIV-infected adults and has a favorable safety profile, followed by posaconazole.

A systematic review aims to answer a focussed research question through a structured review of the evidence, using a predefined methodology, which often includes a meta‐analysis. A meta‐analysis is a statistical method used to combine the effect estimates from the individual studies included in a systematic review. Systematic reviews and meta‐analyses are positioned at the highest level in the hierarchy of clinical evidence. The Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) statement was introduced in 2009 to help authors improve the quality and reliability of systematic reviews and meta‐analyses. Recently, the volume of systematic reviews and meta‐analyses in the field of Endodontology has increased; however, the quality of the published manuscripts has been reported to be sub‐optimal, which does not take account of the systematic reviews that were rejected because of more obvious deficiencies. The aim of this paper is to present a comprehensive glossary of terminology commonly used in systematic reviews and meta‐analyses in an attempt to provide easily understood definitions and explanations to assist authors when reporting systematic reviews and meta‐analyses and to allow those wishing to read them to become better informed.

The management of pain during root canal treatment is important. The aim of this systematic review and network meta-analysis was to identify the anaesthetic solution that would provide the best pulpal anaesthesia for inferior alveolar nerve blocks (IANB) treating mandibular teeth with irreversible pulpitis. Two electronic databases (PubMed and Scopus) were searched to identify studies up to October 2018. Randomized clinical trials comparing at least two anaesthetic solutions (lidocaine (lignocaine), articaine, bupivacaine, prilocaine or mepivacaine) used for IANB for treatment of irreversible pulpitis were included. The revised Cochrane risk of bias tool for randomized trials was used to assess the quality of the included studies. Pairwise meta-analysis, network meta-analysis using a random-effects model, and SUCRA ranking were performed. The network meta-analysis estimated the probability of each treatment performing best. The quality of evidence was assessed using the Grading of Recommendations, Assessment, Development and Evaluations approach. In total, 11 studies (n = 750) were included in the meta-analysis. The network meta-analysis revealed that only mepivacaine significantly increased the success rate of IANB compared to lidocaine (RR, 1.42 [95% CI 1.04-1.95]). However, no significant differences in the success rate of IANB were observed between mepivacaine and other anaesthetic agents (articaine and bupivacaine). Of all anaesthetic agents, mepivacaine (SUCRA = 0.81) ranked first in increasing the success rate of IANB, followed by prilocaine (SUCRA = 0.62), articaine (SUCRA = 0.54), bupivacaine (SUCRA = 0.41) and lidocaine (SUCRA = 0.13). The overall quality of evidence was very low to moderate. In conclusion, based on the evidence from the randomized clinical trials included in this review, mepivacaine with epinephrine demonstrated the highest probability of providing effective pulpal anaesthesia using IANB for teeth with irreversible pulpitis compared to prilocaine, articaine, bupivacaine and lidocaine. Further, high-quality clinical trials are needed to support the conclusion of this review.

Background Celecoxib has previously been shown to be effective in reducing recurrent colorectal adenomas, but its long-term effects are unknown. In addition, safety issues are of major concern. Therefore, we examined the efficacy and safety of celecoxib as a chemopreventive agent along with its posttreatment effect. Methods We performed a meta-analysis based on a systematic review of randomized controlled trials (RCTs) comparing celecoxib at various doses (400 mg once daily, 200 mg twice daily, and 400 mg twice daily) vs placebo in persons with history of colorectal adenomas. Several databases were searched from inception up to April 2018. Long-term follow-ups of RCTs were also included to evaluate posttreatment effect. Primary outcome was the incidence of recurrent colorectal adenomas. Various safety outcomes were evaluated, especially cardiovascular (CV) events. Risk-benefit integrated analyses were also performed. Results A total of three RCTs (4,420 patients) and three post-trial studies (2,159 patients) were included in the analysis. Use of celecoxib at any dose for 1-3 years significantly reduced the incidence of recurrent advanced adenomas (risk ratio, 0.42 [95% CI, 0.34-0.53]) and any adenomas (0.67 [95% CI, 0.62-0.72]) compared with placebo. Subgroup analysis on different dosing suggested a greater effect with 400 mg twice daily. However, celecoxib 400 mg twice daily significantly increased the risk of serious adverse (1.2 [95% CI, 1.0-1.5]) and CV events (3.42 [95% CI, 1.56-7.46]), while celecoxib at 400 mg/day, especially with once daily dosing, did not increase CV risk (1.01 [95% CI, 0.70-1.46]). Analysis of post-trial studies indicated that the treatment effect disappeared (1.15 [95% CI, 0.88-1.49]) after discontinuing celecoxib for >2 years. Conclusion Celecoxib 400 mg once daily dosing could potentially be considered as a viable chemopreventive option in patients with high risk of adenomas but with low CV risk. Long-term trials on celecoxib at a dose of ≤400 mg either once or twice daily are warranted.

Introduction: Oral submucous fibrosis (OSMF) is a chronic premalignant condition and is characterized by fibroblastic change of lamina propria and stiffness of oral mucosa. Though there are several treatment options available, the best agent is not yet identified. This study assessed the comparative efficacy and safety of medical interventions in the management of OSMF. Methods: A systematic review was performed to identify randomized controlled trials (RCTs) that compared the efficacy of interventions for OSMF with each other, or placebo. A network meta-analysis was performed, and the interventions were ranked according to their efficacy based on the surface under the cumulative ranking. (PROSPERO Registration no: CRD42021255094). Results: Thirty-two RCTs comprising 2063 patients were eligible for quantitative analysis. In terms of therapeutic efficacy in the improvement of mouth opening Oxitard, a herbal formulation was ranked as the most efficacious agent, [MD, 10.29 (95%CI 6.34–14.25)] followed by combination therapy of Lycopene with corticosteroids and hyaluronidase [MD, 7.07 (95%CI 1.82–12.31)]. For improvement of burning sensation aloe vera was ranked first [MD, 6.14 (95%CI 4.58–7.70)] followed by corticosteroids with antioxidants [MD, 6.13 (95%CI 4.12–8.14)] and corticosteroids in combination with hyaluronidase with antioxidants [MD, 5.95 (95%CI 3.79–8.11)]. In terms of safety, most of the drugs were reported to cause mild adverse effects only. Significant inconsistencies could be identified in the analysis for both the outcomes assessed and were further explored. Conclusions: Our study highlighted the potential efficacy of several agents over placebo in the improvement of mouth opening and burning sensation in OSMF patients. However, the RCTs lacked methodological soundness. Well-designed studies with a larger number of participants with a rigorous randomization process and stringent methodology are recommended to strengthen the results obtained, which may help to construct a clinical guideline for OSMF management.

Background Individuals with advanced colorectal adenomas (ACAs) are at high risk for colorectal cancer (CRC), and it is unclear which chemopreventive agent (CPA) is safe and cost-effective for secondary prevention. We aimed to determine, firstly, the most suitable CPA using network meta-analysis (NMA) and secondly, cost-effectiveness of CPA with or without surveillance colonoscopy (SC). Methods Systematic review and NMA of randomised controlled trials were performed, and the most suitable CPA was chosen based on efficacy and the most favourable risk–benefit profile. The economic benefits of CPA alone, 3 yearly SC alone, and a combination of CPA and SC were determined using the cost-effectiveness analysis (CEA) in the Malaysian health-care perspective. Outcomes were reported as incremental cost-effectiveness ratios (ICERs) in 2018 US Dollars ($) per quality-adjusted life-year (QALY), and life-years (LYs) gained. Results According to NMA, the risk–benefit profile favours the use of aspirin at very-low-dose (ASAVLD, ≤ 100 mg/day) for secondary prevention in individuals with previous ACAs. Celecoxib is the most effective CPA but the cardiovascular adverse events are of concern. According to CEA, the combination strategy (ASAVLD with 3-yearly SC) was cost-saving and dominates its competitors as the best buy option. The probability of being cost-effective for ASAVLD alone, 3-yearly SC alone, and combination strategy were 22%, 26%, and 53%, respectively. Extending the SC interval to five years in combination strategy was more cost-effective when compared to 3-yearly SC alone (ICER of $484/LY gain and $1875/QALY). However, extending to ten years in combination strategy was not cost-effective. Conclusion ASAVLD combined with 3-yearly SC in individuals with ACAs may be a cost-effective strategy for CRC prevention. An extension of SC intervals to five years can be considered in resource-limited countries.

Background The benefits of qigong for systolic and diastolic blood pressure (BP) reduction have been noted in previously published systematic reviews; however, the data on its effectiveness has been at best scarce. We aimed to update the evidence of qigong on blood pressure reduction after taking into consideration the risks of random error and reliability of data in the cumulative meta-analysis using trial sequential analysis (TSA). Methods Included trials were assessed using Cochrane risk of bias instrument. We performed meta-analysis with random-effects model and random errors were evaluated with TSA. We performed the search for the eligible randomized controlled trial (RCT) through Medline, Cinahl, Cochrane Central Register of Controlled Trials and also PubMed. Results A total of 370 subjects sourced from seven eligible RCTs were entered into the analysis. The pooled results demonstrated the significant reduction with the use of qigong of the systolic blood pressure [weighted mean difference (WMD), − 10.66 mmHg (95% confidence interval (CI) = − 17.69,-3.62, p p Conclusions Significant reductions in BP is seen with the use of qigong as compared with the control group, suggesting that qigong may be used as a complementary therapy in the somewhat complicated management of hypertension.

Additional file 1: Appendix 1 Search Analysis. Appendix 2 Assessment of Systolic Blood Pressure Weighted Mean Difference (The Funnel Plot Asymmetry Test). Appendix 3 Assessment of Diastolic Blood Pressure Weighted Mean Difference (The Funnel Plot Asymmetry Test). Appendix 4: Assessment of small-study effects by using Egger’s regression test for the effect of Qigong on reduction of systolic blood pressure. Appendix 5: Assessment of small-study effects by using Egger’s regression test for the effect of Qigong on reduction of diastolic blood pressure. Appendix 6: Results of GRADE.

Additional file 1. Supporting information.

Background\ud The scientific literature is contradictory in relation to selecting the appropriate volume of local anaesthetic solution for inferior alveolar nerve blocks (IANB) when attempting to anaesthetize mandibular teeth with irreversible pulpitis.\ud \ud Objectives\ud To compare the efficacy of 1.8 and 3.6 mL of the same anaesthetic solution for IANBs when treating mandibular teeth with irreversible pulpitis.\ud \ud Methods\ud A literature search was performed in PubMed, Scopus and EBSCOhost databases until May 2020. Randomized clinical trials published in English, comparing 1.8 with 3.6 mL of the same anaesthetic solution for IANBs in permanent mandibular teeth with irreversible pulpitis, were included. The risk of bias of the included trials was appraised using the revised Cochrane risk of bias tool. A meta-analysis was performed using the random-effects model. The effect of random errors on the results of the meta-analysis was evaluated by trial sequential analysis and the quality of evidence was appraised using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach.\ud \ud Results\ud Four clinical trials involving 280 teeth from patients with ages ranging from 18 to 65 years were included. Among the four trials, three were categorized as having a ‘low’ risk of bias and one was categorized as having ‘some concerns’. The primary meta-analysis revealed that 3.6 mL of anaesthetic solution when administered for IANBs was associated with significantly greater success rates compared with 1.8 mL (RR = 1.94; 95% CI, 1.07, 3.52; I2 = 77%). Similarly, the results of the sensitivity analysis (restricting trials only to those that used the Heft-Parker visual analogue pain scale) revealed that the use of 3.6 mL significantly increased the success of IANBs compared with 1.8 mL. The trial sequential analysis confirmed the evidence for the beneficial effect of 3.6 mL to achieve success for IANBs was ‘conclusive’. The quality of evidence was graded as ‘high’.\ud \ud Conclusion\ud Increasing the volume of anaesthetic solution from 1.8 to 3.6 mL improved the success rate for IANBs in mandibular molars with irreversible pulpitis. The quality of the evidence was ‘high’. Future high-quality clinical trials are required with different types of anaesthetic solutions and other types of teeth.

Introduction Negotiation, glide path, and preflaring are essential steps in root canal shaping procedures. This report aimed to discuss the terminology, basic concepts, and clinical considerations of negotiation, glide path, and preflaring procedures and the influence of these steps on root canal shaping. Methods This systematic review was undertaken following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The protocol has been registered with the International Prospective Register of Systematic Reviews (number CRD42019127021). A comprehensive literature search was performed by 2 independent reviewers using a selected search strategy in 2 electronic databases (PubMed and Scopus) until January 28, 2019. A further search was performed manually in endodontic journals. Studies investigating or comparing at least 1 shaping property resulting from root canal instrumentation with a glide path or preflaring in human extracted teeth or clinical studies were included. Results The literature shows that the definition of glide path and preflaring procedures remains controversial, which requires an elaboration in the American Association of Endodontists’ Glossary of Endodontic Terms. After the removal of irrelevant and duplicated articles, 98 articles were included. The impact of glide path preparation and preflaring on working length determination, apical file size determination, canal transportation, separation of endodontic files, shaping time, dentinal microcrack formation, and extrusion of debris was discussed. Because of heterogeneity among the included studies, quantitative synthesis was not performed for most of the parameters. Conclusions An evidence-based guideline is needed to define and correlate the basic concepts and current applications of each step of contemporary advancements in root canal instruments. Glide path preparation reduces the risk of debris extrusion, has no influence on the incidence of dentinal crack formation, and improves the preservation of the original canal anatomy. The creation of a glide path may have no impact on Reciproc files (VDW, Munich, Germany) in reaching the full working length. Preflaring increases the accuracy of working length determination. Further randomized clinical trials are required to evaluate the effect of a glide path and preflaring on root canal treatment outcomes.

Whether “periodontal disease” can be considered as an independent risk factor for head and neck cancer (HNC) remains controversial. The aim of the current meta-analysis was to quantitatively assess this relationship in order to determine whether this represents a true risk factor, with implications for cancer prevention and management. PubMed, Scopus, and Embase databases were systematically searched. Selective studies were reviewed, and meta-analysis was performed to estimate the pooled odds ratio (OR) with 95% confidence intervals (CIs) on eligible studies using a random effects model. In total, 21 eligible observational studies (4 cohorts and 17 case-controls) were identified for qualitative synthesis after a review of 1051 articles. Significant heterogeneity could be identified in measures utilized for reporting of periodontal disease. Meta-analysis performed on nine studies that employed objective measures for reporting periodontal disease demonstrated a significant association between periodontal disease and HNC [OR 3.17, 95% CI, 1.78–5.64]. A diseased periodontium represents an independent risk marker, and a putative risk factor, for HNC. Prospective studies with standardized measures of periodontal disease severity and extent, integrated with microbiological and host susceptibility facets, are needed to elucidate the mechanisms of this positive association and whether treatment of the former influences the incidence and outcomes for HNC.

BACKGROUND: Colorectal cancer is the second most common cancer in Malaysia. Its disease burden is likely to increase over time owing to its current trends in this region. This study was undertaken to determine the 5-year survival rate and prognostic factors for survival in colorectal cancer patients treated in a tertiary hospital, in Malaysia. METHODS: We reviewed the records of colorectal cancer patients treated in Hospital Tuanku Ja’afar Seremban, Malaysia from 2008 to 2012. Survival analysis at five years was performed using the Kaplan-Meier method. Cox proportional hazard regression analysis was carried out to determine the predictors of 5-year colorectal cancer survival. RESULTS: Of the 275 patients, 43.3% were colon cancers, 51.8% were rectal cancers. Only 2.2% were diagnosed in Stage I. 28.7%, 33.1%, and 16.7% were in Stage II, III and IV respectively; 62/79 (78%) of Stage II patients were in Stage IIb; 15.7% of patients were below the age of 50 and fewer of them presented early (P=0.002). The overall 5-year survival was 46.5%. It was 67.9%, 50.5% and 12.8% for Stage I&II, III and IV patients respectively. Early stage of cancer (P

Key Points Question What are the quality and certainty of evidence for an association between hormonal contraceptive use and the risk of adverse health outcomes in meta-analyses of randomized clinical trials and cohort studies? Findings In this umbrella review of 58 meta-analyses of randomized clinical trials and cohort studies describing 156 associations between hormonal contraceptive use and adverse health outcomes among women, no associations with adverse outcomes, including cardiovascular and cancer risk, were supported by high-quality evidence. However, the association between the use of a levonorgestrel-releasing intrauterine system and reductions in endometrial polyps associated with tamoxifen use was graded as having high-quality evidence. Meaning The results of this umbrella review supported preexisting understandings of the risks and benefits associated with hormonal contraceptive use, suggesting that the associations between hormonal contraceptive use and adverse health outcomes are not supported by high-quality evidence., Importance Meta-analyses have reported conflicting data on the safety of hormonal contraception, but the quality of evidence for the associations between hormonal contraceptive use and adverse health outcomes has not been quantified in aggregate. Objective To grade the evidence from meta-analyses of randomized clinical trials (RCTs) and cohort studies that assessed the associations between hormonal contraceptive use and adverse health outcomes among women. Data Sources MEDLINE, Embase, and the Cochrane Database of Systematic Reviews were searched from database inception to August 2020. Search terms included hormonal contraception, contraceptive agents, progesterone, desogestrel, norethindrone, megestrol, algestone, norprogesterones, and levonorgestrel combined with terms such as systematic review or meta-analysis. Evidence Review The methodological quality of each meta-analysis was graded using the Assessment of Multiple Systematic Reviews, version 2, which rated quality as critically low, low, moderate, or high. The Grading of Recommendation, Assessment, Development and Evaluations approach was used to assess the certainty of evidence in meta-analyses of RCTs, with evidence graded as very low, low, moderate, or high. Evidence of associations from meta-analyses of cohort studies was ranked according to established criteria as nonsignificant, weak, suggestive, highly suggestive, or convincing. Results A total of 2996 records were screened; of those, 310 full-text articles were assessed for eligibility, and 58 articles (13 meta-analyses of RCTs and 45 meta-analyses of cohort studies) were selected for evidence synthesis. Sixty associations were described in meta-analyses of RCTs, and 96 associations were described in meta-analyses of cohort studies. Among meta-analyses of RCTs, 14 of the 60 associations were nominally statistically significant (P ≤ .05); no associations between hormonal contraceptive use and adverse outcomes were supported by high-quality evidence. The association between the use of a levonorgestrel-releasing intrauterine system and reductions in endometrial polyps associated with tamoxifen use (odds ratio [OR], 0.22; 95% CI, 0.13-0.38) was graded as having high-quality evidence, and this evidence ranking was retained in the subgroup analysis. Among meta-analyses of cohort studies, 40 of the 96 associations were nominally statistically significant; however, no associations between hormonal contraceptive use and adverse outcomes were supported by convincing evidence in the primary and subgroup analyses. The risk of venous thromboembolism among those using vs not using oral contraception (OR, 2.42; 95% CI, 1.76-3.32) was initially supported by highly suggestive evidence, but this evidence was downgraded to weak in the sensitivity analysis. Conclusions And Relevance The results of this umbrella review supported preexisting understandings of the risks and benefits associated with hormonal contraceptive use. Overall, the associations between hormonal contraceptive use and cardiovascular risk, cancer risk, and other major adverse health outcomes were not supported by high-quality evidence., This umbrella review assesses evidence from meta-analyses of randomized clinical trials and cohort studies examining the association between hormonal contraceptive use and adverse health outcomes among women.

Sajesh K Veettil,1 Peerawat Jinatongthai,2,3 Surakit Nathisuwan,4 Nattawat Teerawattanapong,2,3 Siew Mooi Ching,5,6 Kean Ghee Lim,7 Surasak Saokaew,3,8–10 Pochamana Phisalprapa,11 Christopher M Reid,12,13 Nathorn Chaiyakunapruk3,9,14,15 1Department of Pharmacy Practice, School of Pharmacy, International Medical University, Kuala Lumpur, Malaysia; 2Division of Pharmacy Practice, Faculty of Pharmaceutical Sciences, Ubon Ratchathani University, Ubon Ratchathani, Thailand; 3School of Pharmacy, Monash University Malaysia, Subang Jaya, Malaysia; 4Clinical Pharmacy Division, Department of Pharmacy, Faculty of Pharmacy, Mahidol University, Bangkok, Thailand; 5Department of Family Medicine, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, Malaysia; 6Malaysian Research Institute on Ageing, Universiti Putra Malaysia, Serdang, Malaysia; 7Clinical School, Department of Surgery, International Medical University, Seremban, Malaysia; 8Center of Health Outcomes Research and Therapeutic Safety (Cohorts), School of Pharmaceutical Sciences, University of Phayao, Phayao, Thailand; 9Center of Pharmaceutical Outcomes Research, Department of Pharmacy Practice, Faculty of Pharmaceutical Sciences, Naresuan University, Phitsanulok, Thailand; 10Unit of Excellence on Herbal Medicine, School of Pharmaceutical Sciences, University of Phayao, Phayao, Thailand; 11Division of Ambulatory Medicine, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand; 12School of Epidemiology and Preventive Medicine, Monash University, Melbourne, VIC, Australia; 13School of Public Health, Curtin University, Perth WA, Australia; 14School of Pharmacy, University of Wisconsin, Madison, WI, USA; 15Asian Centre for Evidence Synthesis in Population, Implementation and Clinical Outcomes (PICO), Health and Well-being Cluster, Global Asia in the 21st Century (GA21) Platform, Monash University Malaysia, Subang Jaya, Malaysia Background: Various interventions have been tested as primary prevention of colorectal cancers (CRC), but comprehensive evidence comparing them is absent. We examined the effects of various chemopreventive agents (CPAs) on CRC incidence and mortality.Methods: We did a network meta-analysis based on a systematic review of randomized controlled trials (RCTs) that compared at least one CPA (aspirin, antioxidants, folic acid, vitamin B6, vitamin B12, calcium, vitamin D, alone or in combination) to placebo or other CPA in persons without history of CRC. Several databases were searched from inception up to March 2017. Primary outcomes were early and long-term CRC incidence and mortality.Results: Twenty-one RCTs comprising 281,063 participants, 9 RCTS comprising 160,101 participants, and 7 RCTs comprising 24,001 participants were included in the network meta-analysis for early risk of CRC incidence, long-term risk of CRC incidence and mortality, respectively. For early CRC incidence, no CPAs were found to be effective. For long-term CRC incidence and mortality, aspirin was the only intervention that showed protective effects with potential dose-dependent effects (risk ratio [RR], 0.74 [95% CI, 0.57–0.97] for high-dose [≥325 mg/day] and RR, 0.81 [95% CI, 0.67–0.98] for very-low-dose [≤100 mg/day]). Similar trend was found for mortality (RR, 0.43 [95% CI, 0.23–0.81] for low-dose [>100–325 mg/day] and RR, 0.65 [95% CI, 0.45–0.94] for very-low-dose). However, in net clinical benefit analysis, when combining risk estimates on mortality from CRC, cardiovascular disease, and pooled risk estimates of major gastrointestinal bleeding, low-dose aspirin provided the highest net survival gain (%) of 1.736 [95% CI, 1.010–2.434].Conclusion: Aspirin at the dose range of 75–325 mg/day is a safe and effective primary prevention for long-term CRC among people at average risk. None of the other CPAs were found to be effective. There may potentially be differential effects among various doses of aspirin that needs further investigation. Keywords: colorectal cancer, primary chemoprevention, chemopreventive agents, aspirin, network meta-analysis, net clinical benefit analysis

Key Points Question What is the association of intermittent fasting with health outcomes and what is the strength of evidence of studies on intermittent fasting? Findings This umbrella review of 11 meta-analyses of randomized clinical trials describing 104 outcomes associated with intermittent fasting on obesity-related health outcomes found 6 statistically significant associations of intermittent fasting supported by moderate to high quality of evidence. Outcomes associated with modified alternate-day fasting included a moderate reduction of body weight, body mass index, and cardiometabolic risk factors in adults with overweight or obesity. Meaning This review suggests that intermittent fasting may have a beneficial role in improving anthropometric and cardiometabolic outcomes, especially for adults with overweight or obesity., This umbrella review of meta-analyses of randomized clinical trials evaluates the association of intermittent fasting with obesity-related health outcomes., Importance Several meta-analyses of randomized clinical trials (RCTs) have demonstrated the many health benefits of intermittent fasting (IF). However, there has been little synthesis of the strength and quality of this evidence in aggregate to date. Objective To grade the evidence from published meta-analyses of RCTs that assessed the associations of IF (zero-calorie alternate-day fasting, modified alternate-day fasting, the 5:2 diet, and time-restricted eating) with obesity-related health outcomes. Evidence Review PubMed, Embase, and Cochrane database of systematic reviews were searched from database inception to January 12, 2021. Data analysis was conducted from April 2021 through July 2021. Meta-analyses of RCTs investigating effects of IF in adults were included. The effect sizes of IF were recalculated using a random-effects model. We assessed the quality of evidence per association by applying the GRADE criteria (Grading of Recommendations, Assessment, Development, and Evaluations) as high, moderate, low, and very low. Findings A total of 11 meta-analyses comprising 130 RCTs (median [IQR] sample size, 38 [24-69] participants; median [IQR] follow-up period, 3 [2-5] months) were included describing 104 unique associations of different types of IF with obesity-related health outcomes (median [IQR] studies per association, 4 [3-5]). There were 28 statistically significant associations (27%) that demonstrated the beneficial outcomes for body mass index, body weight, fat mass, low-density lipoprotein cholesterol, total cholesterol, triglycerides, fasting plasma glucose, fasting insulin, homeostatic model assessment of insulin resistance, and blood pressure. IF was found to be associated with reduced fat-free mass. One significant association (1%) supported by high-quality evidence was modified alternate-day fasting for 1 to 2 months, which was associated with moderate reduction in body mass index in healthy adults and adults with overweight, obesity, or nonalcoholic fatty liver disease compared with regular diet. Six associations (6%) were supported by moderate quality evidence. The remaining associations found to be significant were supported by very low (75 associations [72%]) to low (22 associations [21%]) quality evidence. Conclusions and Relevance In this umbrella review, we found beneficial associations of IF with anthropometric and cardiometabolic outcomes supported by moderate to high quality of evidence, which supports the role of IF, especially modified alternate-day fasting, as a weight loss approach for adults with overweight or obesity. More clinical trials with long-term follow-up are needed to investigate the effects of IF on clinical outcomes such as cardiovascular events and mortality.

Oral mucositis is a debilitating complication of chemotherapy, characterized by erythema, ulcers and oedema of the oral mucosa. This review aimed to evaluate the efficacy of Photobiomodulation in the treatment of oral mucositis using meta-analysis and trial sequential analysis, and also to assess the quality of the results by Grading of Recommendations, Assessment, Development and Evaluation (GRADE). A comprehensive search of three databases, including Embase, Medline and Central, was performed to identify randomized controlled trials studying the efficacy of Photobiomodulation in the treatment of cancer chemotherapy-induced oral mucositis. The primary outcome was reduction in the severity of oral mucositis. Secondary outcomes were pain relief, duration of oral mucositis and adverse effects. The meta-analysis was performed using the random-effects model, and random errors of the meta-analyses were detected by trial sequential analysis. A total of 6 randomized controlled trials with 398 participants were included in our analysis. Photobiomodulation significantly reduced the severity of oral mucositis when compared to sham radiation (RR 0.43, 95% CI 0.20 to 0.93; p < 0.05). Sensitivity analysis by excluding trials with high risk of bias reiterated the robustness of our results (RR 0.28, 95% CI 0.16 to 0.48). Trial sequential analysis illustrated that the evidence from the meta-analysis was conclusive. The result of the meta-analyses with trial sequential analysis illustrated that Photobiomodulation is an effective therapeutic intervention for the treatment of oral mucositis, and the evidence gathered can be considered conclusive with a moderate level of certainty according to GRADE. Further trials are recommended to standardize the laser parameters required for the optimal effect.