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From the approval of COVID-19 mRNA vaccines to the 2023 Nobel Prize awarded for nucleoside base modifications, RNA therapeutics have entered the spotlight and are transforming drug development. While the term "RNA therapeutics" has been used in various contexts, this review focuses on treatments that utilize RNA as a component or target RNA for therapeutic effects. We summarize the latest advances in RNA-targeting tools and RNA-based technologies, including but not limited to mRNA, antisense oligos, siRNAs, small molecules and RNA editors. We focus on the mechanisms of current FDA-approved therapeutics but also provide a discussion on the upcoming workforces. The clinical utility of RNA-based therapeutics is enabled not only by the advances in RNA technologies but in conjunction with the significant improvements in chemical modifications and delivery platforms, which are also briefly discussed in the review. We summarize the latest RNA therapeutics based on their mechanisms and therapeutic effects, which include expressing proteins for vaccination and protein replacement therapies, degrading deleterious RNA, modulating transcription and translation efficiency, targeting noncoding RNAs, binding and modulating protein activity and editing RNA sequences and modifications. This review emphasizes the concept of an RNA therapeutic toolbox, pinpointing the readers to all the tools available for their desired research and clinical goals. As the field advances, the catalog of RNA therapeutic tools continues to grow, further allowing researchers to combine appropriate RNA technologies with suitable chemical modifications and delivery platforms to develop therapeutics tailored to their specific clinical challenges.
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Adolescent idiopathic scoliosis (AIS) often necessitates spinal fusion surgery in pediatric patients, posing significant challenges in postoperative pain management. Standard care involves the administration of intravenous opioids perioperatively, often requiring high doses to achieve adequate analgesia following an operation. This increases the risk of adverse events, may delay recovery and prolong hospital stay, and increases the likelihood of future abuse and dependence. In this systematic review and meta-analysis, we assess the safety and effectiveness of intrathecal morphine (ITM) in pediatric patients undergoing posterior spinal fusion. Ovid Embase and MEDLINE were searched in October 2023 for articles that directly compared ITM use with standard pain management approaches for pediatric patients undergoing posterior spinal fusion. Our primary outcome was postoperative pain scores. Secondary outcomes included opioid usage details, adverse events, and blood loss. Of the 384 unique studies identified, nine studies (one randomized control trial, one prospective review, and seven retrospective reviews) met the inclusion criteria. The total number of patients within the ITM and control groups were 1384 and 676, respectively. Meta-analysis revealed significantly lower pain scores in the ITM group (standardized mean difference (SMD): -1.30 (-2.29, -0.31); p = 0.01). Similarly, ITM patients had significantly lower opioid usage, both intraoperatively (mean difference (MD): -0.71 mg/kg (-0.99, -0.44); p < 0.00001) as well as postoperatively (SMD: -2.10 (-3.48, -0.73); p = 0.003), and significantly lower blood loss (MD: -0.88 L (-1.34, -0.43); p = 0.0001). The occurrence of adverse events was similar across both groups. Our analysis of the available data demonstrates that a low to moderate dose of ITM is a safe and effective adjunct to improve standard postoperative care without increasing the risk of respiratory depression. When compared to control, ITM patients had superior analgesia while using fewer opioids had significantly reduced intraoperative blood loss when ITM was administered before spinal fusion, and had a similar complication profile. While further studies are warranted to establish optimal dosing, these findings underscore the potential of ITM as a valuable addition to multimodal pain management.
RESUMO
TOPIC: Comparing the efficacy and safety between combined and sequential pars plana vitrectomy and phacoemulsification for macular hole (MH) and epiretinal membrane (ERM). CLINICAL RELEVANCE: The standard of care for MH and ERM is vitrectomy, which increases the risk of developing cataract. Combined phacovitrectomy eliminates the need for a second surgery. METHODS: Ovid MEDLINE, EMBASE, and Cochrane CENTRAL were searched in May 2022 for all articles comparing combined versus sequential phacovitrectomy for MH and ERM. The primary outcome was mean best-corrected visual acuity (BCVA) at 12 months follow-up. Meta-analysis was conducted using a random effects model. Risk of bias (RoB) was assessed using the Cochrane RoB 2 tool for randomized controlled trials (RCTs) and Risk of Bias in Nonrandomized Studies of Interventions tool for observational studies (PROSPERO, registration number, CRD42021257452). RESULTS: Of the 6470 studies found, 2 RCTs and 8 nonrandomized retrospective comparative studies were identified. Total eyes for combined and sequential groups were 435 and 420, respectively. Meta-analysis suggested no significant difference between combined and sequential surgery for 12-month BCVA (combined = 0.38 logarithm of the minimum angle of resolution [logMAR]; sequential = 0.36 logMAR; mean difference = + 0.02 logMAR; 95% confidence interval = -0.04 to 0.08; P = 0.51; I2 = 0%; n = 4 studies, 398 participants), as well as absolute refractive error (P = 0.76; I2 = 97%; n = 4 studies, 289 participants), risk of myopia (P = 0.15; I2 = 66%; n = 2 studies, 148 participants), MH nonclosure (P = 0.57; I2 = 48%; n = 4 studies, 321 participants), cystoid macular edema (P = 0.15; I2 = 0%; n = 6 studies, 526 participants), high-intraocular pressure (P = 0.09; I2 = 0%; n = 2 studies, 161 participants), posterior capsule opacification (P = 0.46; I2 = 0%; n = 2 studies, 161 participants), posterior capsule rupture (P = 0.41; I2 = 0%; n = 5 studies, 455 participants), and retinal detachment (P = 0.67; I2 = 0%; n = 6 studies, 545 participants). CONCLUSION: No significant difference was detected between combined and sequential surgeries for visual outcomes, refractive outcomes, or complications. Given that most studies were retrospective and contained a high RoB, future high-quality RCTs are warranted. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.