Delivery of nucleic acid based genome editing platforms via lipid nanoparticles: Clinical applications.

CRISPR/Cas technology presents a promising approach for treating a wide range of diseases, including cancer and genetic disorders. Despite its potential, the translation of CRISPR/Cas into effective in-vivo gene therapy encounters challenges, primarily due to the need for safe and efficient delivery mechanisms. Lipid nanoparticles (LNPs), FDA-approved for RNA delivery, show potential for delivering also CRISPR/Cas, offering the capability to efficiently encapsulate large mRNA molecules with single guide RNAs. However, achieving precise targeting in-vivo remains a significant obstacle, necessitating further research into optimizing LNP formulations. Strategies to enhance specificity, such as modifying LNP structures and incorporating targeting ligands, are explored to improve organ and cell type targeting. Furthermore, the development of base and prime editing technology presents a potential breakthrough, offering precise modifications without generating double-strand breaks (DSBs). Prime editing, particularly when delivered via targeted LNPs, holds promise for treating diverse diseases safely and precisely. This review assesses both the progress made and the persistent challenges faced in using LNP-encapsulated CRISPR-based technologies for therapeutic purposes, with a particular focus on clinical translation.

Functional outcome following intracapsular resection of head and neck peripheral nerve sheath tumors: a retrospective cohort.

BACKGROUND: Intracapsular resection of head and neck peripheral nerve sheath tumors (PNST) has emerged as a nerve-preserving technique compared to en bloc resection. The aim of this study was to evaluate and compare the functional outcome of both surgical techniques performed at a single tertiary referral center. METHODS: This is a retrospective cohort of patients with head and neck PNST undergoing surgical resection from 2011 to 2021 at the Tel Aviv Sourasky Medical Center. Demographic data, the nerve of origin and surgical technique, including the use of intraoperative nerve monitoring were recorded and analyzed in association with postoperative functional outcomes. RESULTS: Overall, 25 patients who had a cervical or parapharyngeal PNST resected were included. Nerve function was preserved in 11 of 18 patients (61%) who underwent intracapsular resection, while all those who underwent en bloc resections inevitably suffered from neurologic deficits (100%, N = 7). Sympathetic chain origin and an apparent neurologic deficit pre-operatively were associated with postoperative neural compromise. CONCLUSION: Improved functional outcome can be anticipated following intracapsular resection of extracranial head and neck PNST compared to complete resection, particularly in asymptomatic patients.

The Prognostic Value and Clinical Utility of the 40-Gene Expression Profile (40-GEP) Test in Cutaneous Squamous Cell Carcinoma: Systematic Review and Meta-Analysis.

BACKGROUND: The current tumor staging systems for cutaneous squamous cell carcinoma (cSCC) are considered inadequate and insufficient for evaluating the risk of metastasis and for identifying patients at high risk of cSCC. This meta-analysis aimed to assess the prognostic significance of a 40-gene expression profile (40-GEP) both independently and integrated with clinicopathologic risk factors and established staging systems (American Joint Committee on Cancer, eighth edition (AJCC8) and Brigham and Women's Hospital (BWH)). METHODS: Electronic databases, including PubMed (MEDLINE), Embase, the Cochrane Library, and Google Scholar, were systematically searched to identify cohort studies and randomized controlled trials on evaluations of the prediction value of 40-GEP in cSCC patients up to January 2023. The metastatic risk analysis of a given 40-GEP class combined with tumor stage and/or other clinicopathologic risk factors was based upon log hazard ratios (HRs) and their standard error (SE). Heterogeneity and subgroup analyses were performed, and data quality was assessed. RESULTS: A total of 1019 patients from three cohort studies were included in this meta-analysis. The overall three-year metastatic-free survival rates were 92.4%, 78.9%, and 45.4% for class 1 (low risk), class 2A (Intermediate risk), and class 2B (high risk) 40-GEP, respectively, indicating a significant variation in survival rates between the risk classification groups. The pooled positive predictive value was significantly higher in class 2B when compared to AJCC8 or BWH. The subgroup analyses demonstrated significant superiority of integrating 40-GEP with clinicopathologic risk factors or AJCC8/BWH, especially for class 2B patients. CONCLUSIONS: The integration of 40-GEP with staging systems can improve the identification of cSCC patients at high risk of metastasis, potentially leading to improved care and outcomes, especially in the high-risk class 2B group.

Bell's palsy and pregnancy: Incidence, comorbidities and complications. A meta-analysis and systematic review of the literature.

OBJECTIVES: Data on the association between Bell's palsy (BP) and pregnancy is scarce and there is an ongoing debate regarding the association of BP and pregnancy. MAIN OUTCOME MEASURES: We aimed to investigate the prevalence of BP among pregnant patients and determine the frequency of pregnant women in BP cohorts and vice versa, assess which term of the pregnancy and peripartum bears a higher risk for BP occurrence, and determine the prevalence of maternal comorbidities associated with BP during pregnancy. DESIGN: Meta analysis. SETTINGS: Screening standard articles and extracting data from Ovid MEDLINE (1960-2021), Embase (1960-2021), and Web of Science (1960-2021). All study types were included except for case reports. MEASURES: Data were pooled by means of both fixed and random-effects models. RESULTS: The search strategy identified 147 records. Twenty-five of the studies that met our inclusion criteria described 809 pregnant patients with BP in a total of 11,813 BP patients and they were included in the meta-analysis. The incidence of BP among the pregnant patients was 0.05%; The incidence of pregnant patients among all BP patients was 6.62%. Most of the BP occurrences were during the third trimester (68.82%). The pooled incidence of gestational diabetes mellitus; hypertension; pre-eclampsia/eclampsia and fetal complications among the pregnant patients with BP was 6.3%, 13.97%, 9.54%, and 6.74%, respectively. CONCLUSIONS: This meta-analysis revealed a low incidence of BP during pregnancy. A Higher proportion occurred during the third trimester. The association of BP and pregnancy warrants further exploration.

The impact of thyroidectomy on obstructive sleep apnea: a systematic review and meta-analysis.

PURPOSE: Various thyroid pathologies are speculated to contribute to obstructive sleep apnea (OSA). The underlying mechanisms of the intricate relationship between OSA and thyroid structure and function, and whether thyroidectomy can alleviate OSA symptoms remain unclear. An assessment of the impact of thyroidectomy on OSA is warranted. METHODS: A systematic review of four electronic databases (PubMed (Medline), Embase, the Cochrane library, and ClinicalTrials.gov) was performed up to February 2022. The primary outcomes were preoperative and postoperative Apnea/Hypopnea Index (AHI), Epworth Sleepiness Scale (ESS), Berlin questionnaire scores, and continuous positive airway pressure (CPAP) use. A meta-analysis of continuous measures and odd ratios was conducted. Small-scale studies underwent a qualitative meta-analysis. RESULTS: Six cohort studies on 221 OSA patients who underwent thyroidectomies were included. The results showed that thyroidectomy was associated with significant reduction in postoperative AHI (Mean difference [MD], -6.39, 95% CI, -12.46 to -0.32), however, no significant association was found with CPAP withdrawal (Odd ratio [OR], 0.38, 95% CI, 0.12-1.18). Neither the Berlin questionnaire score (OR, 0.19, 95% CI, 0.03-1.17) nor the ESS improved postoperatively (MD, -1.04, 95% CI, -6.37 to 4.29). CONCLUSION: This meta-analysis provides a quantitative estimate for the effect of the thyroidectomy on OSA and suggests that thyroidectomy is associated with limited clinical improvement of polysomnographic measures. Future large-scale, well-designed prospective studies are necessary to validate these findings and to refine accordingly the preoperative assessment of both medical conditions individually and in combination.

Neoadjuvant PD-1/PD-L1 Inhibitors for Resectable Head and Neck Cancer: A Systematic Review and Meta-analysis.

Importance: The emerging approach of neoadjuvant immunotherapy for solid cancers has set the ground for the integration of programmed cell death 1 (PD-1)/PD-1 ligand 1 (PD-L1) inhibitors into the neoadjuvant setting of head and neck squamous cell carcinoma (HNSCC) treatment. Objective: To assess the reported efficacy and safety of neoadjuvant immunotherapy for resectable HNSCC. Data Sources and Study Selection: Electronic databases, including PubMed (MEDLINE), Embase, the Cochrane Library, and ClinicalTrials.gov were systematically searched for published and ongoing cohort studies and randomized clinical trials that evaluate neoadjuvant immunotherapy for resectable HNSCC. The search results generated studies from 2015 to July 2021. Data Extraction and Synthesis: Two investigators (R.M. and L.K.) independently identified and extracted articles for potential inclusion. Random and fixed models were used to achieve pooled odds ratios. All results are presented with 95% CIs. Data quality was assessed by means of the Cochrane Collaboration's risk of bias tool. Main Outcomes and Measures: The primary outcomes were reported efficacy, evaluated by major pathological response and pathological complete response in the primary tumors and lymph nodes separately, and safety, assessed by preoperative grade 3 to 4 treatment-related adverse events and surgical delay rate. Results: A total of 344 patients from 10 studies were included. In 8 studies, neoadjuvant immunotherapy only was administered, and the other 2 studies combined immunotherapy with neoadjuvant chemotherapy and/or radiotherapy. The overall major pathological response rate in the primary tumor sites from studies reporting on neoadjuvant immunotherapy only was 9.7% (95% CI, 3.1%-18.9%) and the pathological complete response rate was 2.9% (95% CI, 0%-9.5%). Preoperative grade 3 to 4 treatment-related adverse events were reported at a rate of 8.4% (95% CI, 0.2%-23.2%) and surgical delay at a rate of 0% (95% CI, 0%-0.9%). There was a favorable association of neoadjuvant immunotherapy with all outcome measures. The subgroup analyses did not find one specific anti-PD-1/PD-L1 agent to be superior to another, and the favorable association was demonstrated by either immunotherapy alone or in combination with anti-CTLA-4. Conclusions and Relevance: In this systematic review and meta-analysis, neoadjuvant anti-PD-1/PD-L1 immunotherapy for resectable HNSCC was well tolerated and may confer therapeutic advantages implied by histopathological response. Long-term outcomes are awaited.

Trial of labor after cesarean delivery in twin gestations: systematic review and meta-analysis.

BACKGROUND: Trial of labor after cesarean is offered as a routine option for singleton gestations with previous cesarean delivery. However, adequate data are not available to determine whether the approach is equally valid in women with twin gestation. OBJECTIVE: This systematic review and meta-analysis aimed to assess maternal morbidities associated with trial of labor after cesarean delivery in twin gestations. STUDY DESIGN: Electronic databases were searched for cohort studies and randomized controlled trials evaluating the association between trial of labor after cesarean delivery in twin gestations and pregnancy outcomes. Maternal mortality and severe morbidities, such as uterine rupture and hysterectomy, were compared between women who had trial of labor and women who had a planned repeat cesarean delivery. Pooled odds ratios were calculated using a random-effects model. Additional analyses were performed to compare trial of labor after cesarean outcomes in singleton and twin gestations. RESULTS: Eleven cohort studies including a total of 8209 twin gestations with previous cesarean delivery were included in the present study. Of these gestations, 2484 were intended for planned vaginal birth and 5725 were intended for planned repeat cesarean delivery. The rate of uterine rupture in twin gestations was higher in the trial of labor after cesarean group than the elective cesarean group (odds ratio, 10.09, 95% confidence interval, 4.30-23.69, I2 = 68%). However, no statistically significant difference was found in the rate of uterine rupture between twin and single gestations attempting trial of labor after cesarean delivery (odds ratio, 1.34, 95% confidence interval, 0.54-3.31, I2 = 0%). Women who attempted a trial of labor after cesarean delivery with twins did not have an increased risk of uterine scar dehiscence, hemorrhage, blood transfusion, or neonatal morbidity and mortality compared with elective repeat cesarean delivery. Patients with twins had similar rates of successful vaginal delivery as patients with singletons (odds ratio, 0.85, 95% confidence interval, 0.61-1.18, I2 = 36%). CONCLUSION: This meta-analysis demonstrates that, although trial of labor with twins after previous cesarean delivery is associated with higher rates of uterine rupture compared with elective cesarean delivery, pregnancy outcomes and success rates are similar to a trial of labor after previous cesarean delivery in singleton gestations. Planned vaginal birth for women with twin gestation and previous cesarean delivery may be a safe alternative to a planned repeat cesarean.