Glossary for systematic reviews and meta-analyses

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 Ubiquitin/Proteasome System Mediates Entry and Endosomal Trafficking of Kaposi's Sarcoma-Associated Herpesvirus in Endothelial Cells

Ubiquitination, a post-translational modification, mediates diverse cellular functions including endocytic transport of molecules. Kaposi's sarcoma-associated herpesvirus (KSHV), an enveloped herpesvirus, enters endothelial cells primarily through clathrin-mediated endocytosis. Whether ubiquitination and proteasome activity regulates KSHV entry and endocytosis remains unknown. We showed that inhibition of proteasome activity reduced KSHV entry into endothelial cells and intracellular trafficking to nuclei, thus preventing KSHV infection of the cells. Three-dimensional (3-D) analyses revealed accumulation of KSHV particles in a cytoplasmic compartment identified as EEA1+ endosomal vesicles upon proteasome inhibition. KSHV particles are colocalized with ubiquitin-binding proteins epsin and eps15. Furthermore, ubiquitination mediates internalization of both KSHV and one of its receptors integrin β1. KSHV particles are colocalized with activated forms of the E3 ligase c-Cbl. Knock-down of c-Cbl or inhibition of its phosphorylation reduced viral entry and intracellular trafficking, resulting in decreased KSHV infectivity. These results demonstrate that ubiquitination mediates internalization of both KSHV and one of its cognate receptors integrin β1, and identify c-Cbl as a potential E3 ligase that facilitates this process

Effects of chemopreventive agents on the incidence of recurrent colorectal adenomas: a systematic review with network meta-analysis of randomized controlled trials

Sajesh K Veettil,1 Nattawat Teerawattanapong,2 Siew Mooi Ching,3,4 Kean Ghee Lim,5 Surasak Saokaew,6–9 Pochamana Phisalprapa,10 Nathorn Chaiyakunapruk7,8,11,12 1School of Pharmacy/School of Postgraduate Studies, International Medical University, Kuala Lumpur, Malaysia; 2Division of Pharmacy Practice, Faculty of Pharmaceutical Sciences, Ubon Ratchathani University, Ubon Ratchathani, Thailand; 3Department of Family Medicine, Faculty of Medicine and Health Sciences, 4Malaysian Research Institute on Ageing, Universiti Putra Malaysia, Serdang, 5Clinical School, Department of Surgery, International Medical University, Seremban, Negeri Sembilan, 6Center of Health Outcomes Research and Therapeutic Safety (Cohorts), School of Pharmaceutical Sciences, University of Phayao, Phayao, 7School of Pharmacy, Monash University Malaysia, Selangor, Malaysia; 8Centre of Pharmaceutical Outcomes Research, Department of Pharmacy Practice, Faculty of Pharmaceutical Sciences, Naresuan University, Phitsanulok, Thailand; 9Unit of Excellence on Herbal Medicine, School of Pharmaceutical Sciences, University of Phayao, Thailand; 10Division of Ambulatory Medicine, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 11School of Pharmacy, University of Wisconsin, Madison, USA; 12Health and Well-being Cluster, Global Asia Platform in the 21st Century (GA21) Platform, Monash University Malaysia, Selangor, Malaysia Background: Protective effects of several chemopreventive agents (CPAs) against colorectal adenomas have been well documented in randomized controlled trials (RCTs); however, there is uncertainty regarding which agents are the most effective.Methods: We searched for RCTs published up until September 2016. Retrieved trials were evaluated using risk of bias. We performed both pairwise analysis and network meta-analysis (NMA) of RCTs to compare the effects of CPAs on the recurrence of colorectal adenomas (primary outcome). Using NMA, we ranked CPAs based on efficacy.Results: We identified 20 eligible RCTs enrolling 12,625 participants with a history of colorectal cancer or adenomas who were randomly assigned to receive either a placebo or one of 12 interventions. NMA using all trials demonstrated that celecoxib 800 mg/day (relative risk [RR] 0.61, 95% confidence interval [CI] 0.45–0.83), celecoxib 400 mg/day (RR 0.70, 95% CI 0.55–0.87), low-dose aspirin (RR 0.75, 95% CI 0.59–0.96) and calcium (RR 0.81, 95% CI 0.69–0.96) were significantly associated with a reduction in the recurrence of any adenomas. NMA results were consistent with those from pairwise meta-analysis. The evidence indicated a high (celecoxib), moderate (low-dose aspirin) and low (calcium) Grading of Recommendations, Assessment, Development and Evaluation (GRADE) quality. NMA ranking showed that celecoxib 800 mg/day and celecoxib 400 mg/day were the best CPAs, followed by low-dose aspirin and calcium. Considering advanced adenoma recurrence, only celecoxib 800 mg/day and celecoxib 400 mg/day were demonstrated to have a protective effect (RR 0.37, 95% CI 0.27–0.52 vs RR 0.48, 95% CI 0.38–0.60, respectively).Conclusion: The available evidence from NMA suggests that celecoxib is more effective in reducing the risk of recurrence of colorectal adenomas, followed by low-dose aspirin and calcium. Since cyclooxygenase-2 (COX-2) inhibitors (eg, celecoxib) are associated with important cardiovascular events and gastrointestinal harms, more attention is warranted toward CPAs with a favorable benefit-to-risk ratio, such as low-dose aspirin and calcium. Keywords: colorectal adenomas, chemoprevention, systematic review, meta-analysis, network meta-analysis, randomized controlled trial

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The adaptive potential of livestock under a warming climate is increasingly relevant in relation to the growing pressure of global food security. Studies on heat tolerance demonstrate the interplay of adaptation and acclimatization in functional traits, for example, a reduction in body size and enhanced tolerance in response to a warming climate. However, current lack of understanding of functional traits and phylogenetic history among phenotypically distinct populations constrains predictions of climate change impact. Here, we demonstrate evidence of parallel evolution in adaptive tolerance to heat stress in dwarf cattle breeds (DCB, Bos taurus indicus) and compare their thermoregulatory responses with those in standard size cattle breeds (SCB, crossbred, Bos taurus indicus × Bos taurus taurus). We measured vital physiological, hematological, biochemical, and gene expression changes in DCB and SCB and compared the molecular phylogeny using mitochondrial genome (mitogenome) analysis. Our results show that SCB can acclimatize in the short term to higher temperatures but reach their tolerance limit under prevailing tropical conditions, while DCB is adapted to the warmer climate. Increased hemoglobin concentration, reduced cellular size, and smaller body size enhance thermal tolerance. Mitogenome analysis revealed that different lineages of DCB have evolved reduced size independently, as a parallel adaptation to heat stress. The results illustrate mechanistic ways of dwarfing, body size-dependent tolerance, and differential fitness in a large mammal species under harsh field conditions, providing a background for comparing similar populations during global climate change. These demonstrate the value of studies combining functional, physiological, and evolutionary approaches to delineate adaptive potential and plasticity in domestic species. We thus highlight the value of locally adapted breeds as a reservoir of genetic variation contributing to the global domestic genetic resource pool that will become increasingly important for livestock production systems under a warming climate.The adaptive potential of livestock under a warming climate is increasingly relevant in relation to the growing pressure of global food security. Studies on heat tolerance demonstrate the interplay of adaptation and acclimatization in functional traits, for example, a reduction in body size and enhanced tolerance in response to a warming climate. However, current lack of understanding of functional traits and phylogenetic history among phenotypically distinct populations constrains predictions of climate change impact. Here, we demonstrate evidence of parallel evolution in adaptive tolerance to heat stress in dwarf cattle breeds (DCB, Bos taurus indicus) and compare their thermoregulatory responses with those in standard size cattle breeds (SCB, crossbred, Bos taurus indicus × Bos taurus taurus). We measured vital physiological, hematological, biochemical, and gene expression changes in DCB and SCB and compared the molecular phylogeny using mitochondrial genome (mitogenome) analysis. Our results show that SCB can acclimatize in the short term to higher temperatures but reach their tolerance limit under prevailing tropical conditions, while DCB is adapted to the warmer climate. Increased hemoglobin concentration, reduced cellular size, and smaller body size enhance thermal tolerance. Mitogenome analysis revealed that different lineages of DCB have evolved reduced size independently, as a parallel adaptation to heat stress. The results illustrate mechanistic ways of dwarfing, body size-dependent tolerance, and differential fitness in a large mammal species under harsh field conditions, providing a background for comparing similar populations during global climate change. These demonstrate the value of studies combining functional, physiological, and evolutionary approaches to delineate adaptive potential and plasticity in domestic species. We thus highlight the value of locally adapted breeds as a reservoir of genetic variation contributing to the global domestic genetic resource pool that will become increasingly important for livestock production systems under a warming climate.Not Availabl

Systematic review and network meta-analysis: efficacy of drugs for functional dyspepsia

Background Functional dyspepsia (FD) is a relapsing and remitting condition affecting between 5% and 10% of people. Efficacious therapies are available, but their relative efficacy is unknown. Aim To perform a systematic review with network meta‐analysis to resolve this uncertainty. Methods We searched the medical literature through July 2020 for randomised controlled trials (RCTs) assessing efficacy of drugs for adults with FD, compared with each other, or placebo. Trials reported a dichotomous assessment of symptom status after completion of therapy. We pooled data using a random effects model. Efficacy was reported as a pooled relative risk (RR) of remaining symptomatic with a 95% confidence interval (CI) to summarise efficacy of each comparison tested. Relative ranking was assessed with surface under the cumulative ranking curve (SUCRA) probabilities. Results We identified 71 eligible RCTs (19 243 participants). Tricyclic antidepressants (TCAs) were ranked second for efficacy (RR of remaining symptomatic = 0.71; 95% CI 0.58‐0.87, SUCRA 0.87), and first when only low risk of bias trials were included. Most RCTs that used TCAs recruited patients who were refractory to other drugs included in the network. Although sulpiride or levosulpiride were ranked first for efficacy (RR = 0.49; 95% CI 0.36‐0.69, SUCRA 0.99), trial quality was low and only 86 patients received active therapy. TCAs were more likely to cause adverse events than placebo. Conclusions TCAs, histamine‐2 receptor antagonists, standard‐ and low‐dose proton pump inhibitors, sulpiride or levosulpiride, itopride and acotiamide were all more efficacious than placebo for FD

Efficacy and safety of chemopreventive agents on colorectal cancer incidence and mortality: systematic review and network meta-analysis

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 analysi

Evaluation of a simulation-based hospital pharmacy training package for pharmacy students

© 2018, The Author(s). This study describes the process undertaken to develop, implement and evaluate a simulation-based training package focused on medication management and reconciliation processes for final year pharmacy students about a patient’s hospital journey. A five module training package was developed following a literature review and consultation with stakeholders. The simulation-based package immersed students in a real-life scenario and was delivered to final year pharmacy students over a six-week period in 2016. Data on knowledge, skills and confidence was collected via a survey in the week preceding engagement with the online training package and 1 week post completion of the training. The mean score was compared across four student categories: three categories incorporated students who had not completed a hospital pharmacy placement and one category comprised students who had completed a hospital placement. Qualitative feedback was collected via an online survey at the conclusion of the training program. Of the 79 participants, 44 (55.7%) completed both the pre and post- test surveys that showed the change in score was statistically significant. There was a significant positive change in mean test scores across all four student categories for the domains of skills, knowledge and confidence. Assessment of students’ confidence according to 16 ranking statements also improved markedly post-training. Thirty-one students provided qualitative feedback that was generally positive. The positive outcomes reinforce the rationale to include online simulation-based methodologies as part of pharmacy education programs. The model provides a reproducible framework for online simulated learning activities that could be applied within various professions and educational environments