BACKGROUND:Guidelines recommend a trial of antiarrhythmic drugs before catheter ablation for persistent atrial fibrillation. Whether pulsed field ablation (PFA) may be a preferred initial treatment is unclear. METHODS:We conducted an international, randomized trial involving patients with previously untreated persistent atrial fibrillation. The patients were randomly assigned in a 2:1 ratio to receive PFA performed with a pentaspline catheter or to receive antiarrhythmic-drug therapy. An additional group of patients (PFA-assigned) underwent PFA for the analysis of the primary safety end point alone. All the patients received an insertable cardiac monitor. The primary effectiveness end point was the short-term and long-term success of treatment through 12 months. Short-term success was defined as procedural success in the PFA group and the absence of ablation during the blanking period (90 days after treatment initiation) in the antiarrhythmic-drug group. Long-term success was defined as freedom from recurrence of atrial arrhythmias, repeat ablation, or need for antiarrhythmic drugs from 90 days through 12 months (in the PFA group) and freedom from amiodarone use at any time. The primary safety end point was device- and procedure-related serious adverse events. RESULTS:At 12 months, treatment success was observed in 128 of 207 patients (Kaplan-Meier estimate, 56%; 95% confidence interval [CI], 48 to 63) in the PFA group and in 40 of 103 patients (Kaplan-Meier estimate, 30%; 95% CI, 21 to 40) in the antiarrhythmic-drug group (hazard ratio for composite treatment failure [a lack of short- and long-term success], 0.46; 95% CI, 0.33 to 0.65; P<0.001). A primary safety end-point event occurred in 13 of 257 patients (5.1%) in the combined PFA group (both randomized and PFA-assigned groups). At 12 months, serious adverse events had occurred in 45 patients (25%) in the PFA group and in 20 patients (21%) in the antiarrhythmic-drug group. CONCLUSIONS:Among patients with persistent atrial fibrillation, the risk of recurrence of atrial arrhythmia was significantly lower among those who received PFA as first-line treatment than among those who received antiarrhythmic-drug therapy. (Funded by Boston Scientific; AVANT GUARD ClinicalTrials.gov number, NCT06096337.).
BackgroundThe TAP block has gained wide acceptance in post-cesarean multimodal analgesia, yet its efficacy varies considerably depending on clinical context. We performed a systematic review and meta-analysis to quantify its effect on postoperative opioid consumption and to determine which clinical variables drive that variability.MethodsWe systematically searched PubMed, Embase, and the Cochrane Central Register of Controlled Trials from inception through March 2024. Eligible studies enrolled adult patients undergoing cesarean delivery and compared TAP block with placebo, no block, or an active comparator. The primary outcome was 24 h opioid consumption. Continuous outcomes were pooled as standardized mean differences (SMD) with Hedges' g correction using random-effects modelling, with pre-specified subgroup analyses by anesthetic technique and intrathecal morphine (ITM) use.ResultsEighteen studies (N = 1,824 patients) were included; only four provided sufficiently homogeneous numerical data for quantitative pooling (N = 193). Given extreme heterogeneity (I2 = 97%), the overall pooled estimate (SMD = −2.30, 95% CI −4.24 to −0.36; p = 0.02) should be interpreted with caution and does not constitute a reliable summary of TAP block efficacy. The primary findings derive from structured contextual synthesis: consistent opioid-sparing was observed across all four studies conducted under general anesthesia; no clinically meaningful benefit was demonstrated when intrathecal morphine was co-administered (SMD = 0.12, 95% CI −0.34 to 0.58; p = 0.61); and most studies under spinal anesthesia without intrathecal morphine reported significant opioid-sparing, with magnitude varying by background analgesic regimen.ConclusionsThis systematic review and meta-analysis provides a structured contextual framework for understanding when TAP block is and is not likely to provide meaningful analgesia after cesarean delivery. Derived from 18 heterogeneous studies with limited quantitative depth, available evidence suggests that benefit is most consistent under general anesthesia, meaningful under spinal anesthesia without intrathecal morphine, and negligible when intrathecal morphine is co-administered. These are context-dependent, hypothesis-generating observations that should not be read as definitive clinical prescriptions. Confirmation in adequately powered prospective trials stratified by intrathecal morphine use, anesthetic technique, and standardized multimodal analgesic protocols is required before this framework can serve as the basis for formal clinical guidance.
PURPOSE:Previous work demonstrated that supraphysiological glucose remodels TGF-β1 and NF-κB signaling in human limbal stromal cells (LSCs) and congenital aniridia-derived LSCs (AN-LSCs). The present study investigated whether the same metabolic stress also alters apoptotic pathways in these cells. METHODS:Primary LSCs (n = 12) and AN-LSCs (n = 8) were cultured for 48 hours in DMEM containing either normal (17.5 mM) or high (70 mM) glucose. Apoptosis was quantified by Annexin V/propidium iodide (PI) flow cytometry (FC). Expression levels of apoptosis-related genes-including CASP3/7/8/9/10, BCL2, BID, BAX, CDKN1A (p21), CDKN1B (p27), TNFα, XIAP, and BIRC5 (Survivin)-were assessed by qPCR. Protein levels of these markers were analyzed by FC, and TNFα protein concentrations in culture supernatants were measured by ELISA. RESULTS:High glucose significantly reduced the proportion of apoptotic cells in both LSCs (p = 0.0170) and AN-LSCs (p = 0.0181). In both cell types, CASP8 (p = 0.0448; p = 0.0171) and CASP10 (p = 0.0001; p = 0.0007) mRNA levels decreased, while XIAP (p = 0.0375; p = 0.0442) and BIRC5 (p = 0.0196; p = 0.0003) were upregulated. AN-LSCs additionally showed reductions in CASP3 (p = 0.0138) and CDKN1A (p = 0.0331), and exhibited lower BAX levels than LSCs under high glucose (p = 0.0255). Protein analysis corroborated these findings in AN-LSCs: Caspase-3 (p = 0.0154) and Caspase-8 (p = 0.0257) decreased, while Bcl-2 (p = 0.0284) and Survivin (p = 0.0467) levels increased. XIAP protein levels rose in both LSCs (p = 0.0451) and AN-LSCs (p = 0.0134). CONCLUSIONS:A 48-hour exposure to 70 mM glucose induces a marked anti-apoptotic shift in human limbal stromal cells, more pronounced in cells derived from congenital aniridia patients. Together with previous evidence on TGF-β1 and NF-κB regulation, these findings suggest that limbal cells may mount an early protective response to metabolic stress, which could be harnessed therapeutically to manage aniridia-associated keratopathy through coordinated survival and stress pathways.
Background/Objectives: Cervical dysplasia, a precursor to cervical cancer, represents a significant global health challenge, particularly in regions like Central America, Africa, and Southeast Asia. Current management approaches rely on surgical or ablative interventions, which can lead to complications, for example, preterm birth and cervical insufficiency. Therefore, developing non-invasive, localized therapeutic alternatives is of great clinical interest. Curcumin is a natural compound that suppresses the progression of cervical cancer, but it has poor oral bioavailability and high clearance. Methods: We incorporated curcumin into solid lipid nanoparticles, which were then loaded into rapidly dissolving films. These films show the sustained release profile of curcumin at the localized vaginal site, demonstrating release kinetics consistent with the Korsmeyer-Peppas model. Results: The curcumin solid lipid nanoparticles yielded a size of 341 nm and a polydispersity index of 0.373, and the zeta potential was -23.4 mV. The encapsulation efficiency of curcumin solid lipid nanoparticles was 77.27% using a validated HPLC method. FTIR analysis supported successful incorporation of curcumin into the lipid matrix. A Box-Behnken Design of Experiments optimized the key film formulation parameters and yielded a film with a tensile strength of 2.8 mPa, disintegration time of 3 min, folding endurance of 263, film thickness of 0.426 mm and a pH of 4.0. Conclusions: In vitro assays in human cervical carcinoma cells demonstrated enhanced mortality and autophagosome formation by the curcumin solid lipid nanoparticles when compared to free curcumin. Surface expression of MHC I, MHCII, CD40 and CD80 in peripheral dendritic cells was significantly higher in the curcumin solid lipid nanoparticles than in free curcumin. Results show that solid lipid nanoparticles loaded with curcumin effectively stimulate and activate dendritic cells, supporting immune cell activation outside the tumor microenvironment. The proposed pain-free self-administration strategies will lead to increased patient compliance.
