BackgroundDespite the recognized link between immune responses and frailty, the association between immune cell counts and frailty based on previous observational studies remains disputed, with uncertain causal nexus. This study aimed to elucidate causal association between genetically predicted circulating immune cell counts and frailty.MethodsWe conducted the two-sample Mendelian randomization (MR) study with independent genetic variants associated with six immune cell subtype counts from genome-wide association studies in 563,946 European individuals. Frailty summary data, assessed via frailty index (FI), was obtained from study comprising 175,226 subjects. Univariate MR, reverse MR and multivariate MR were conducted to comprehensive investigate the association between immune cell counts and FI, with two-step MR analysis for mediation analysis.ResultsUnivariate MR evidence indicated that among six leukocyte subtype counts, only elevated eosinophil count was significantly correlated with higher FI (β = 0.059, 95% confidence interval [CI], 0.042–0.078, P=5.63E-11), with no reverse causal relationship identified in reverse MR. In multivariate MR, the causal effect of eosinophil count retained statistical significance (β = 0.063, 95% CI, 0.021–0.104, P = 0.003). Ultimately, the two-step MR analysis demonstrated two mediators in this causal pathway: asthma (β= 0.019, 95% CI, 0.013–0.025, P = 35.84E-10, mediated proportion, 31.732%) and rheumatoid arthritis (β= 0.004, 95% CI, 0.001–0.006, P=1.75E-03, mediated proportion, 6.411%).ConclusionsWithin immune cell subtypes, MR evidence indicated only genetically predicted circulating eosinophil count had irreversible and independent causal effect on frailty, with asthma and rheumatoid arthritis possibly serving as partial mediators. The finding stressed the need for further exploring physiological functions of eosinophils in order to develop effective strategies against frailty.

Background and Aims: Hypoxemia is one of the most common adverse events during colonoscopy, particularly among patients who are diagnosed with obstructive sleep apnea (OSA) or are overweight. Consequently, the objective of this study was to evaluate the effectiveness of bilevel positive airway pressure (BPAP) ventilation for patients with high-risk hypoxemia during colonoscopy with sedation. Methods: In this trial, 127 patients who met the eligibility criteria were randomly assigned to the BPAP oxygen group and nasal cannula (NC) group. The primary endpoint was the incidence of hypoxemia. Results: Compared with the use of NC, BPAP ventilation exhibited a significant reduction in the incidence of hypoxemia, decreasing it from 23.8% to 6.3% (absolute risk difference, 17.5%; 95% confidence interval, 5.4-29.6; P = .006). Importantly, BPAP ventilation prevented the occurrence of severe hypoxemia (9.5% vs 0%; absolute risk difference, 9.5%; 95% confidence interval, 2.3-16.7; P = .035). In addition, the BPAP group required fewer airway interventions (P < .05). Conclusions: In individuals with OSA or overweight status, the use of BPAP ventilation during colonoscopy significantly reduced the incidence of hypoxemia. (Clinical trial registration number: ChiCTR2300073193.)

Purpose: Explore the median effective dose of ciprofol for inducing loss of consciousness in elderly patients and investigate how frailty influences the ED 50 of ciprofol in elderly patients.Patients and Methods: A total of 26 non-frail patients and 28 frail patients aged 65-78 years, with BMI ranging from 15 to 28 kg/ m 2 , and classified as ASA grade II or III were selected.Patients were divided into two groups according to frailty: non-frail patients (CFS<4), frail patients (CFS≥4).With an initial dose of 0.3 mg/kg for elderly non-frail patients and 0.25 mg/kg for elderly frail patients, using the up-and-down Dixon method, and the next patient's dose was dependent on the previous patient's response.Demographic information, heart rate (HR), oxygen saturation (SpO 2 ), mean blood pressure (MBP), and bispectral index (BIS) were recorded every 30 seconds, starting from the initiation of drug administration and continuing up to 3 minutes post-administration.Additionally, the total ciprofol dosage during induction, occurrences of hypotension, bradycardia, respiratory depression, and injection pain were recorded.Results: The calculated ED 50 (95% confidence interval [CI]) and ED 95 (95% CI) values for ciprofol-induced loss of consciousness were as follows: 0.267 mg/kg (95% CI 0.250-0.284)and 0.301 mg/kg (95% CI 0.284-0.397)for elderly non-frail patients; and 0.263 mg/kg (95% CI 0.244-0.281)and 0.302 mg/kg (95% CI 0.283-0.412)for elderly frail patients.Importantly, no patients reported intravenous injection pain, required treatment for hypotension, or experienced significant bradycardia.Conclusion: Frailty among elderly patients does not exert a notable impact on the median effective dose of ciprofol for anesthesia induction.Our findings suggest that anesthesiologists may forego the necessity of dosage adjustments when administering ciprofol for anesthesia induction in elderly frail patients.

Background: Neonatal hypoxic ischemic encephalopathy (HIE) is a main factor of neonatal death and permanent neurologic deficit. This study sought to investigate the functional role of hsa_circ_0007706 (circ_0007706) in modulating neonatal HIE.Methods: In vitro HIE cell model was established in hBMVECs under the condition of oxygen-glucose deprivation/ reperfusion (OGD/R) treatment. qRT-PCR analysis was utilized for detecting the level of circ_0007706, micro -RNA-579-3p (miR-579-3p) and TNF receptor-associated factor 6 (TRAF6). RNase R treatment and Oligo (dT) 18 primers were employed to verify the features of circ_0007706, and nucleocytoplasmic separation was conducted for determining the location of circ_0007706. CCK-8 assay, EdU assay, and flow cytometry were carried out to measure cell proliferation and apoptosis, respectively. The protein expression of Bax, Bcl-2 and TRAF6 was detected using western blot. Meanwhile, the levels of the pro-inflammatory factors were determined via ELISA. SOD activity and MDA level were assessed via the respective kits. Besides, dual-luciferase reporter assay and RNA pull-down were used to identify the association between miR-579-3p and circ_0007706 or TRAF6. Results: Circ_0007706 was elevated in HIE newborns and OGD/R cell model. Knockdown of circ_0007706 greatly alleviated OGD/R-induced injury, inflammatory response and oxidative stress. We found that miR-579-3p was a direct target of circ_0007706, and miR-579-3p inhibitor could reverse the impact of circ_0007706 knockdown on OGD/R-caused cell damage in hBMVECs. In addition, miR-579-3p directly interacted with TRAF6, and the protective effects of miR-579-3p on OGD/R-induced injury in hBMVECs were harbored by TRAF6 over -expression. Our data indicated that circ_0007706 knockdown could downregulate the expression of TRAF6 by sponging miR-579-3p in OGD/R-treated hBMVECs.Conclusion: This study demonstrated that circ_0007706 knockdown assuaged HIE-induced injury by decreasing TRAF6 expression via targeting miR-579-3p.

Microglial activation and inflammatory response play a critical role in spinal cord ischemia reperfusion injury (SCIRI). This study aimed to investigate whether lidocaine relieves SCIRI via modulating myocardial infarction-associated transcript (MIAT)-mediated Notch1 downregulation. Mouse SCIRI was induced by the obstruction of the aortic arch. Lidocaine was injected after reperfusion. Microglial activation and inflammatory response were assessed by Iba1, interleukin 1 beta (IL-1β) and tumour necrosis factor alpha (TNF-α) levels. The interaction between MIAT and Notch1 was assessed by RNA pull-down and RNA immunoprecipitation assays. Lidocaine treatment relieved SCIRI by reducing Iba1 and serum TNF-α and IL-1β levels. After lidocaine treatment, MIAT expression was elevated in lipopolysaccharide-induced BV2 cells. The interference of MIAT and the overexpression of MIAT and Notch1 restored TNF-α and IL-1β levels in supernatants. Notch1 protein was existent in MIAT-pull-down compounds, and the expression of MIAT was markedly elevated in Notch1-immunoprecipitants. The overexpression of MIAT markedly promoted the degradation of Notch1 and increased the level of ubiquitin-bound Notch1 complex. The therapeutic effect of lidocaine on SCIRI mice could be reversed by adeno-associated virus-mediated MIAT knockdown. In conclusion, lidocaine treatment relieved SCIRI via inhibiting microglial activation and reducing the inflammatory response. The molecular mechanism was partly through MIAT-mediated Notch1 downregulation.

The blood flow restoration of ischemic tissues causes myocardial injury. Dexmedetomidine (Dex) protects multi-organs against ischemia/reperfusion (I/R) injury. This study investigated the protective mechanism of Dex post-treatment in myocardial I/R injury. The rat model of myocardial I/R was established. The effects of Dex post-treatment on cardiac function and autophagy flow were observed. Dex attenuated myocardial I/R injury and reduced I/R-induced autophagy in rats. Dex weakened the interactions between Beclin1 and Vps34 and Beclin1 and Atg14L, thus downregulating Vps34 kinase activity. In vitro, the cardiomyocytes subjected to oxygen glucose deprivation/reoxygenation were treated with Dex and PI3K inhibitor LY294002. LY294002 attenuated the myocardial protective effect of DEX, indicating that Dex protected against cardiac I/R by activating the PI3K/Akt pathway. In conclusion, Dex upregulated the phosphorylation of Beclin1 at S295 site by activating the PI3K/Akt pathway and reduced the interactions of Atg14L-Beclin1-Vps34 complex, thus inhibiting autophagy and protecting against myocardial I/R injury.