Comparison of crystalloid and colloid co-load combined with norepinephrine prophylaxis on post-spinal anesthesia hypotension during cesarean delivery: a randomized sequential allocation dose-finding study.

Background: Fluid loading is an essential component of treatment for reducing the incidence of post-spinal anesthesia hypotension and is necessary to maintain intravascular volume, perfuse tissues, and control spinal anesthesia hypotension after sympathetic blockade. We performed a randomized sequential allocation dose-finding study to compare the effects of 10 mL/kg crystalloid and 6% hydroxyethyl starch (130/0.4) co-load on the ED90 of prophylactic norepinephrine infusion for preventing post-spinal anesthesia hypotension during cesarean delivery. Methods: Eighty patients were randomly allocated to receive either a 10 mL/kg crystalloid (Crystalloid Group, n = 40) or 6% hydroxyethyl starch (130/0.4) (Colloid Group, n = 40) co-load combined with prophylactic norepinephrine infusion during spinal anesthesia for cesarean delivery. The first patient received an initial prophylactic norepinephrine infusion rate of 0.025 µg/kg/min. Subsequent patients received a 0.005 µg/kg/min gradient dose of prophylactic norepinephrine. This dose was administered as a gradient based on its effectiveness for preventing post-spinal anesthesia hypotension (defined as SBP < 80% of baseline value) and determined by the up-and-down sequential allocation methodology. The primary study outcome was the ED90 of prophylactic norepinephrine infusion. Secondary outcomes included the incidence of post-spinal anesthesia hypotension, bradycardia, hypertension, Apgar scores, and umbilical artery blood gas values were also measured. Results: The ED90 values of prophylactic norepinephrine infusion for preventing post-spinal anesthesia hypotension during cesarean delivery were 0.063 µg (95% CI: 0.050 to 0.064) and 0.062 µg (95% CI: 0.045 to 0.064) using isotonic regression analysis, and 0.068 µg (95% CI: 0.056 to 0.353) and 0.060 µg (95% CI: 0.050 to 3.590) using probit regression analysis in the Crystalloid Group and Colloid Group, respectively. The secondary outcomes were comparable between the two groups. Conclusion: The administration of a 10 mL/kg 6% hydroxyethyl starch (130/0.4) does not provide additional benefits compared to crystalloid co-load in reducing the ED90 of prophylactic norepinephrine infusion for preventing post-spinal anesthesia hypotension during cesarean delivery.

Prophylactic Norepinephrine and Phenylephrine Boluses to Prevent Postspinal Anesthesia Hypotension During Cesarean Section: A Randomized Sequential Allocation Dose-Finding Study.

Background: Norepinephrine and phenylephrine are widely used for obstetric anesthesia. Our central objective was to determine the ED (effective dose) 90 and potency ratio of prophylactic norepinephrine and phenylephrine boluses for preventing postspinal anesthesia hypotension during cesarean section. Methods: Patients scheduled for elective cesarean section (n = 80) were randomly allocated to receive prophylactic norepinephrine (NE) or phenylephrine (PE) boluses immediately after induction of spinal anesthesia. An initial dose of NE (3 µg) and PE (37.5 µg) was given to the first patient, and an up-and-down sequential allocation method was used to determine the next dose level according to the responses (the effectiveness for preventing postspinal anesthesia hypotension [defined as SBP < 80% of baseline value]). Primary outcomes were ED90 and the potency ratio of prophylactic norepinephrine and phenylephrine boluses. Secondary outcomes were the incidence of postspinal anesthesia hypotension, severe postspinal anesthesia hypotension, nausea, vomiting, bradycardia, hypertension, umbilical artery blood gas values, and Apgar scores. Results: The ED90 values for prophylactic norepinephrine and phenylephrine boluses were 8.0 µg (95% CI 7.1-11.0 µg) and 90.9 µg (95% CI 82.0-123.9 µg), respectively. The estimated relative potency ratio was 11.4:1. The incidence of bradycardia was lower in the NE group (2.5% vs 20%, P = 0.034). Other outcomes were comparable between the two groups. Conclusion: An 8-µg prophylactic bolus of norepinephrine and a 90-µg prophylactic bolus of phenylephrine can effectively prevent postspinal anesthesia hypotension in patients during cesarean section.

Dexmedetomidine alleviates host ADHD-like behaviors by reshaping the gut microbiota and reducing gut-brain inflammation.

Attention-deficit/hyperactivity disorder (ADHD) is one of the most prevalent psychiatric disorders that affects children and even continues into adulthood. Dexmedetomidine (DEX), a short-term sedative, can selectively activate the α2-adrenoceptor. Treatment with α2-adrenergic agonists in patients with ADHD is becoming increasingly common. However, the therapeutic potential of DEX for the treatment of ADHD is unknown. Here, we evaluated the effect of DEX on ADHD-like behavior in spontaneously hypertensive rats (SHRs), a widely used animal model of ADHD. DEX treatment ameliorated hyperactivity and spatial working memory deficits and normalized θ electroencephalogram (EEG) rhythms in SHRs. We also found that DEX treatment altered the gut microbiota composition and promoted the enrichment of beneficial gut bacterial genera associated with anti-inflammatory effects in SHRs. The gut pathological scores and permeability and the level of inflammation observed in the gut and brain were remarkably improved after DEX administration. Moreover, transplantation of fecal microbiota from DEX-treated SHRs produced effects that mimicked the therapeutic effects of DEX administration. Therefore, DEX is a promising treatment for ADHD that functions by reshaping the composition of the gut microbiota and reducing inflammation in the gut and brain.

Dysregulation of prefrontal parvalbumin interneurons leads to adult aggression induced by social isolation stress during adolescence.

Social isolation during the juvenile stage results in structural and functional impairment of the brain and deviant adult aggression. However, the specific subregions and cell types that underpin this deviant behavior are still largely unknown. Here, we found that adolescent social isolation led to a shortened latency to attack onset and extended the average attack time, accompanied by anxiety-like behavior and deficits in social preference in adult mice. However, when exposed to social isolation during adulthood, the mice did not show these phenotypes. We also found that the structural plasticity of prefrontal pyramidal neurons, including the dendritic complexity and spine ratio, was impaired in mice exposed to adolescent social isolation. The parvalbumin (PV) interneurons in the prefrontal infralimbic cortex (IL) are highly vulnerable to juvenile social isolation and exhibit decreased cell numbers and reduced activation in adulthood. Moreover, chemogenetic inactivation of IL-PV interneurons can mimic juvenile social isolation-induced deviant aggression and social preference. Conversely, artificial activation of IL-PV interneurons significantly attenuated deviant aggression and rescued social preference during adulthood in mice exposed to adolescent social isolation. These findings implicate juvenile social isolation-induced damage to IL-PV interneurons in long-term aggressive behavior in adulthood.

Gut metagenomic characteristics of ADHD reveal low Bacteroides ovatus-associated host cognitive impairment.

Attention-deficit/hyperactivity disorder (ADHD) is a highly heterogeneous psychiatric disorder that can have three phenotypical presentations: inattentive (I-ADHD), hyperactive-impulsive (HI-ADHD), and combined (C-ADHD). Environmental factors correlated with the gut microbiota community have been implicated in the development of ADHD. However, whether different ADHD symptomatic presentations are associated with distinct microbiota compositions and whether patients could benefit from the correction of aberrant bacterial colonization are still largely unclear. We carried out metagenomic shotgun analysis with 207 human fecal samples to characterize the gut microbial profiles of patients with ADHD grouped according to their phenotypical presentation. Then, we transplanted the candidate low-abundance bacteria identified in patient subgroups into ADHD rats and evaluated ADHD-associated behaviors and neuronal activation in these rats. Patients with C-ADHD had a different gut microbial composition from that of healthy controls (HCs) (p = .02), but not from that of I-ADHD patients. Eight species became progressively attenuated or enriched when comparing the compositions of HCs to those of I-ADHD and C-ADHD; in particular, the abundance of Bacteroides ovatus was depleted in patients with C-ADHD. In turn, Bacteroides ovatus supplementation ameliorated spatial working memory deficits and reversed θ electroencephalogram rhythm alterations in ADHD rats. In addition, Bacteroides ovatus induced enhanced neuronal activation in the hippocampal CA1 subregion. These findings indicate that gut microbial characteristics that are unique to patients with C-ADHD may be masked when considering a more heterogeneous group of patients. We link the gut microbiota to brain function in an ADHD animal model, suggesting the relevance of testing a potential bacteria-based intervention for some aspects of ADHD.

Contribution of prognostic ferroptosis-related subtypes classification and hub genes of sepsis.

BACKGROUND: Sepsis in patients is a great threat to human health due to its high incidence rate, its rapid and unpredictable progression, as well as it is difficult to treat, and it has poor prognosis. Ferroptosis is a newly discovered type of cell death characterized by the iron-dependent peroxide aggregation. Furthermore, ferroptosis is different from other forms of cell death, namely apoptosis, necrosis, pyroptosis and autophagy. Our study investigated the role of ferroptosis-related genes in sepsis. METHODS: The GSE65682 dataset from the Gene Expression Omnibus (GEO) database was used to screen ferroptosis-related genes associated with sepsis, and the GSE134347 dataset for the external validation of selected hub genes. The univariate Cox regression analysis, Kaplan-Meier (K-M) survival analysis and weighted gene co-expression network analysis (WGCNA) were used to identify hub genes. Evaluation of the immune cell infiltration in sepsis was used to explain the immune heterogeneity among the cell subtypes. Gene set variation analysis (GSVA) and transcriptional regulatory analysis of selected hub genes further elucidated the probable mechanism of ferroptosis-related genes associated with prognosis in sepsis. Finally, we constructed a competing endogenous RNA (ceRNA) network model. RESULTS: A total of 479 RNA-seq data points were used for analysis, including 365 samples from patients who survived sepsis and 114 samples from patients who succumbed to sepsis from the available GSE65682 dataset. Consequently, the univariate Cox regression analysis and consensus clustering analysis divide all 479 sepsis samples into two clusters of "survivals" vs. "non-survivals". Following complex analysis were identified as the most important ferroptosis-related genes. Indeed, the WGCNA and K-M analyses associated the expression patterns of NEDD4L and SIAH2 hub genes as the best prognosis for the survival of sepsis (p < 0.05). The expression trend was also consistent with the survival trend of the NEDD4L and SIAH2 hub genes by the external validation of GSE134347 (p < 0.05). Immune cell infiltration analysis indicated that the types and numbers of different immune cells vary among different subtypes and NEDD4L and SIAH2 hub genes. For example, NEDD4L and SIAH2 gene expression had a positive correlation with M0 macrophages and a negative correlation with neutrophils (p > 0.05). Finally, analysis of two hub genes and transcription factors (TFs) showed that 71 TFs were predicted to be related to NEDD4L while 64 TFs to SIAH2 by the Cistrome DB online database. CONCLUSION: We suggest that NEDD4L and SIAH2 hub genes are involved in the ferroptosis-associated sepsis. The pattern of NEDD4L and SIAH2 expression in patients undergoing sepsis may have prognostic potential for the severity of sepsis and eventually for patients' survival.

Experimental and Numerical Study on the Mechanical Behavior of Composite Steel Structure under Explosion Load.

Most engineering structures are composed of basic components such as plates, shells, and beams, and their dynamic characteristics under explosion load determine the impact resistance of the structure. In this paper, a three-dimensional composite steel structure was designed using a beam, plate, and other basic elements to study its mechanical behavior under explosion load. Subsequently, experiments on the composite steel structure under explosion load were carried out to study its mechanical behavior, and the failure mode and deformation data of the composite steel structure were obtained, which provided important experimental data regarding the dynamic response and mechanical behavior of the composite steel structure under explosion load. Then, we independently developed a parallel program with the coupled calculation method to solve the numerical simulation of the dynamic response and failure process of the composite steel structure under explosion load. This program adopts the Euler method as a whole, and Lagrange particles are used for materials that need to be accurately tracked. The numerical calculation results are in good agreement with the experimental data, indicating that the developed parallel program can effectively deal with the large deformation problems of multi-medium materials and the numerical simulation of the complex engineering structure failures subjected to the strong impact load.

Theoretical Investigation on Failure Behavior of Ogive-Nose Projectile Subjected to Impact Loading.

Experimental and theoretical investigations on the failure behaviors of projectile during high-speed impact into concrete slabs were performed in this study. The ogive-nose projectiles after impact experiments were recovered and their microstructures were observed by scanning electron microscope and metallographic microscope. Mass abrasion and nose blunting are the typical failure models of steel projectile. Furthermore, thermal melting and cutting are the two main failure mechanisms. Based on the microscopic experimental results, a theoretical model of ogive-nose projectile subjected to impact loading considering the melting and cutting mechanisms was proposed. A modified cap model is introduced for describing the failure behavior of concrete targets, and then the dynamic cavity expansion theory is used to determine the resistance of projectiles during penetration. Besides, combining with the two-dimensional heat conduction equation and abrasive wear theory, the two main abrasion mechanisms of melting and cutting are included in the proposed model, which breaks through the framework of previous abrasion models with single abrasion mechanism. The predicted results of the present abrasion model are in good agreement with the experimental data, which indicates that the proposed model can effectively predict the failure behavior and penetration performance parameters of high-speed projectiles during penetration into concrete targets, such as mass loss, nose blunting, and depth of penetration.