Zwitterionic Phospholipidation of Cationic Polymers Facilitates Systemic mRNA Delivery to Spleen and Lymph Nodes.

Polymers represent a promising therapeutic platform for extrahepatic messenger RNA (mRNA) delivery but are hampered by low in vivo efficacy due to polyplex serum instability and inadequate endosomal escape following systemic administration. Here, we report the rational design and combinatorial synthesis of zwitterionic phospholipidated polymers (ZPPs) via cationic polymer postmodification by alkylated dioxaphospholane oxides to deliver mRNA to spleen and lymph nodes in vivo. This modular postmodification approach readily produces tunable zwitterionic species for serum resistance and introduces alkyl chains simultaneously to enhance endosomal escape, thereby transforming deficient cationic polymers to efficacious zwitterionic mRNA carriers without the need to elaborately synthesize functional monomers. ZPPs mediated up to 39 500-fold higher protein expression than their parent cationic counterparts in vitro and enabled efficacious mRNA delivery selectively in spleen and lymph nodes following intravenous administration in vivo. This zwitterionic phospholipidation methodology provides a versatile and generalizable postmodification strategy to introduce zwitterions into the side chains of cationic polymers, extending the utility of cationic polymer families for precise mRNA delivery and demonstrating substantial potential for immunotherapeutic applications.

Sex Differences in the Clinical Outcomes of Patients With Takotsubo Stress Cardiomyopathy: A Meta-Analysis of Observational Studies.

The incidence of takotsubo stress cardiomyopathy (TSCM) in males is low compared with females. Gender-based differences in clinical outcomes of TSCM are not well characterized. The aim of this meta-analysis was to analyze whether gender-based differences are observed in TSCM clinical outcomes. A comprehensive literature search of PubMed, Embase, Cochrane Library database, and Web of Science was performed from inception to June 20, 2022, for studies comparing the clinical outcomes between male and female patients with TSCM. The primary outcome of interest was in-hospital all-cause mortality and cardiogenic shock. The secondary outcomes were cardiovascular mortality, receipt of mechanical ventilation, intra-aortic balloon pump, occurrence of ventricular arrhythmia, and left ventricular thrombus. A random-effects model was used to calculate the risk ratios (RR) and confidence intervals (CI). Heterogenicity was assessed using the Higgins I2 index. Twelve observational studies involving 51,213 patients (4,869 males and 46,344 females) were included in the meta-analysis. Male gender was associated with statistically significant higher in-hospital all-cause mortality compared with females in patients with TSCM (RR 2.17, 95% CI 1.77 to 2.67, p <0.001). The rate of cardiogenic shock was significantly higher in males with TSCM compared with females (RR 1.66, 95% CI 1.29 to 2.12, p <0.001). Our meta-analysis showed a difference in the clinical outcomes of TSCM between men and women. Male gender was associated with a two-fold greater in-hospital all-cause mortality risk compared with female gender. The higher mortality risk associated with male gender deserves further study, particularly whether it represents later recognition of the condition and disparities in treatments.

Comparison of patients who meet criteria for surgical stabilization of rib fractures versus those who actually get rib fixation: A single center review.

BACKGROUND: Surgical stabilization of rib fractures (SSRF) has shown benefits for rib fracture patients. However, the incidence of SSRF performed remains low. We compare our institution's rib fracture patients meeting criteria for SSRF versus those actually receiving the operation, hypothesizing a significant portion are not undergoing SSRF. METHODS: A retrospective review of rib fracture patients presenting to our Level 1 trauma center from 1/2016 to 4/2023. Patients were categorized as those who met SSRF inclusion criteria versus those who didn't based on the 2023 Chest Wall Injury Society (CWIS) SSRF Guidelines. Basic demographics were obtained. Patients meeting SSRF criteria were divided into those who received SSRF versus those who didn't. Outcomes of interest included type and frequency of SSRF indications and frequency of absolute/relative contraindications. Descriptive statistics were used. Median test and t-test were used for statistical analysis. Statistical significance was set at p < 0.05. RESULTS: A total of 3,432 patients presented with ≥1 rib fracture(s). Of those, 1,573(45.8 %) met SSRF inclusion criteria. These patients were predominantly male, with mean age of 57.4(±18.5) and a similar Injury Severity Score but significantly higher chest-Abbreviated Injury Score of 3 (Interquartile range 3,4)(p = 0.048). Only 458(29.1 %) patients underwent SSRF, leaving 1,115(70.9 %) managed non-operatively, of which 215(19.3 %) were ventilated and "failure to wean from the ventilator" was the most common (81.4 %) indication for SSRF. Of the 900(80.7 %) non-ventilated patients managed non-operatively, 659 (69.9 %) had ≥two indications for SSRF, 382(34.3 %) had zero relative contraindications and 394(35.3 %) had one relative contraindication for SSRF. Lastly, 52.6 % of patients in this cohort had reported "clicking/popping" of their fractures. CONCLUSION: Only 29.1 % of patients meeting criteria for SSRF had the operation based on data from our institution. There may be additional opportunity to benefit this cohort of patients meeting SSRF criteria but not undergoing surgery.