Daily Anesthesiology Research Analysis

The extensive crosstalk among pyroptosis, apoptosis, and necroptosis limits the efficacy of therapies targeting only one pathway. Here, we show that Prussian blue (PB) nanoparticles act as multi-target PANoptosis inhibitors by binding key PANoptosome components including RIPK1, ZBP1, and AIM2 through multimodal interactions, thereby concurrently suppressing pyroptosis, apoptosis, and necroptosis in myocardial ischemia-reperfusion injury (MIRI). Platelet membrane-coated PB nanoparticles (PB@PM) exhibit enhanced cardiac targeting and efficiently alleviate MIRI-induced cardiac dysfunction, adverse ventricular remodeling, and cardiomyocyte hypertrophy. Mechanistically, PB@PM disrupt PANoptosome assembly, scavenge reactive oxygen species, improve mitochondrial function, and restore immune-inflammatory homeostasis. By integrating single nucleus transcriptomics of human heart samples, molecular dynamics simulations, transcriptomics, medical imaging, and molecular validation, we systematically decipher the therapeutic mechanisms of PB-based PANoptosis inhibition. This study establishes an integrative multi-omics framework for exploring PANoptosis in cardiovascular diseases and provides a promising nanotherapeutic strategy for MIRI treatment.

Understanding the mechanism of oxytocin-induced uterine contractility is critical for addressing conditions at both extremes of the uterine contractility spectrum, preterm labour and uterine atony. We hypothesized that oxytocin induces extracellular calcium influx and uterine contraction through activation of the transient receptor potential vanilloid 4 (TRPV4) channel. To test this hypothesis, uterine tissue was obtained with informed consent from pregnant patients undergoing term, non-labouring caesarean delivery. In human myometrial tissue and smooth muscle cells in primary culture (mSMCs), TRPV4 and oxytocin receptor (OXTR) proteins colocalize at distances less than 40 nm. In mSMCs, both pharmacological blockade of TRPV4 and TRPV4 depletion via small interfering RNA prevent oxytocin-induced calcium influx and contraction. In contrast, voltage-gated calcium channel blockade does not diminish oxytocin-induced calcium transients. Pharmacological blockade of OXTR has no effect on TRPV4 agonist-induced calcium influx or contractility. In uterine tissue from patients with oxytocin-resistant uterine atony, there is a marked reduction in glycosylated OXTR expression and in proximity ligation between OXTR and TRPV4 compared with tissue from control patients with optimal postpartum contractility. Taken together, these findings demonstrate that in the gravid uterine smooth muscle, TRPV4 activation is required for oxytocin-induced uterine contraction. They also suggest reduced OXTR-TRPV4 protein-protein interaction as a novel pathophysiological mechanism underlying uterine atony in non-labouring parturients. These findings highlight the physiological importance of oxytocin signalling via the TRPV4 channel and may motivate the development of targeted, TRPV4-focused treatments to modulate uterine contractility. KEY POINTS: Oxytocin-induced contraction in smooth muscle cells from term pregnant human myometrium requires activation of the TRPV4 calcium channel. TRPV4 and oxytocin receptor (OXTR) colocalize at <40 nM and interact functionally in myometrial smooth muscle cells. TRPV4 antagonism or siRNA-mediated TRPV4 knockdown abolishes oxytocin-induced calcium influx and contractility. In patients with oxytocin-resistant uterine atony, glycosylated OXTR quantity and TRPV4-OXTR colocalization are markedly reduced. These findings identify TRPV4 as a critical mediator of uterine contractility. TRPV4 antagonists may have a role as novel therapeutic agents for preventing or treating preterm labour.

OBJECTIVE: To summarise evidence on the clinical effectiveness of initial vascular attempts via the intraosseous route compared to the intravenous route in adult cardiac arrest. METHODS: We searched MEDLINE and Embase (OVID platform), the Cochrane library, and the International Clinical Trials Registry Platform from inception to September 4th 2024 for randomised clinical trials comparing the intraosseous route with the intravenous route in adult cardiac arrest. Our primary outcome was 30-day survival. Secondary outcomes included favourable neurological outcome at 30-days/hospital discharge and return of spontaneous circulation (both any ROSC and sustained ROSC). We performed meta-analyses using a fixed-effect model. We assessed risk of bias using the Cochrane Risk of Bias-2 tool and evidence certainty using the GRADE approach. RESULTS: We originally included three randomised clinical trials, but one trial was subsequently retracted. As such, two trials were included encompassing 7561 participants with out-of-hospital cardiac arrest. Initial attempts via the intraosseous, compared with intravenous, route did not increase the odds of 30-day survival (odds ratio 0.97, 95% confidence interval 0.80-1.18; 7540 participants; two trials; moderate-certainty evidence) or favourable neurological outcome at 30-days/hospital discharge (odds ratio 1.03, 95% confidence interval 0.81-1.31; 7454 participants; two trials; low-certainty evidence). The odds of achieving sustained return of spontaneous circulation were lower in the intraosseous group (odds ratio 0.89, 95% confidence interval 0.80-0.99; 7518 participants; two trials; moderate-certainty evidence). CONCLUSION: Initial vascular access attempts via the intraosseous, compared with intravenous, route in adult cardiac arrest did not improve 30-day survival and may reduce the odds of a sustained return of spontaneous circulation. REGISTRATION: PROSPERO CRD42024577647.