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Objective To observe the systemic reactions （SRs） associated with subcutaneous immunotherapy （SCIT） using dust mite allergen and to analyze potential risk factors. Methods The occurrence of SRs among 230 patients with allergic rhinitis （AR） who received house dust mite SCIT from December 2019 to December 2022 was retrospectively analyzed， and related risk factors were identified. Results A total of 5 422 injections were given to 230 patients， with an SRs incidence rate of 2.4% per injection and 20.0% per patient. Most SRs were grade I （51.9%）， and no fatal SRs occurred. Symptoms primarily affected the respiratory system for 111 times （84.7%）. Elevated peripheral blood eosinophil count （OR （95% CI）=6.02 （1.76， 20.60）， P = 0.004） and high levels of house dust mite-specific IgE （OR （95% CI）=1.01 （1.00， 1.01）， P = 0.016） were identified as risk factors for SRs， respectively. Conclusions Children with AR allergic to dust mites may experience SRs during SCIT with standardized dust mite allergen preparations， whereas the overall safety of SCIT is good. High eosinophil count and high levels of house dust mite-specific IgE are risk factors for SRs during SCIT.

BackgroundMany patients with heart failure with preserved ejection fraction have metabolic syndrome and develop exercise-induced pulmonary hypertension (EIPH). Increases in pulmonary vascular resistance in patients with heart failure with preserved ejection fraction portend a poor prognosis; this phenotype is referred to as combined precapillary and postcapillary pulmonary hypertension (CpcPH). Therapeutic trials for EIPH and CpcPH have been disappointing, suggesting the need for strategies that target upstream mechanisms of disease. This work reports novel rat EIPH models and mechanisms of pulmonary vascular dysfunction centered around the transcriptional repression of the soluble guanylate cyclase (sGC) enzyme in pulmonary artery (PA) smooth muscle cells.MethodsWe used obese ZSF-1 leptin-receptor knockout rats (heart failure with preserved ejection fraction model), obese ZSF-1 rats treated with SU5416 to stimulate resting pulmonary hypertension (obese+sugen, CpcPH model), and lean ZSF-1 rats (controls). Right and left ventricular hemodynamics were evaluated using implanted catheters during treadmill exercise. PA function was evaluated with magnetic resonance imaging and myography. Overexpression of nuclear factor Y α subunit (NFYA), a transcriptional enhancer of sGC β1 subunit (sGCβ1), was performed by PA delivery of adeno-associated virus 6. Treatment groups received the SGLT2 inhibitor empagliflozin in drinking water. PA smooth muscle cells from rats and humans were cultured with palmitic acid, glucose, and insulin to induce metabolic stress.ResultsObese rats showed normal resting right ventricular systolic pressures, which significantly increased during exercise, modeling EIPH. Obese+sugen rats showed anatomic PA remodeling and developed elevated right ventricular systolic pressure at rest, which was exacerbated with exercise, modeling CpcPH. Myography and magnetic resonance imaging during dobutamine challenge revealed PA functional impairment of both obese groups. PAs of obese rats produced reactive oxygen species and decreased sGCβ1 expression. Mechanistically, cultured PA smooth muscle cells from obese rats and humans with diabetes or treated with palmitic acid, glucose, and insulin showed increased mitochondrial reactive oxygen species, which enhanced miR-193b-dependent RNA degradation of nuclear factor Y α subunit (NFYA), resulting in decreased sGCβ1-cGMP signaling. Forced NYFA expression by adeno-associated virus 6 delivery increased sGCβ1 levels and improved exercise pulmonary hypertension in obese+sugen rats. Treatment of obese+sugen rats with empagliflozin improved metabolic syndrome, reduced mitochondrial reactive oxygen species and miR-193b levels, restored NFYA/sGC activity, and prevented EIPH.ConclusionsIn heart failure with preserved ejection fraction and CpcPH models, metabolic syndrome contributes to pulmonary vascular dysfunction and EIPH through enhanced reactive oxygen species and miR-193b expression, which downregulates NFYA-dependent sGCβ1 expression. Adeno-associated virus-mediated NFYA overexpression and SGLT2 inhibition restore NFYA-sGCβ1-cGMP signaling and ameliorate EIPH.

As organelles of the innate immune system, inflammasomes activate caspase-1 and other inflammatory caspases that cleave gasdermin D (GSDMD). Caspase-1 also cleaves inactive precursors of the interleukin (IL)-1 family to generate mature cytokines such as IL-1β and IL-18. Cleaved GSDMD forms transmembrane pores to enable the release of IL-1 and to drive cell lysis through pyroptosis1-9. Here we report cryo-electron microscopy structures of the pore and the prepore of GSDMD. These structures reveal the different conformations of the two states, as well as extensive membrane-binding elements including a hydrophobic anchor and three positively charged patches. The GSDMD pore conduit is predominantly negatively charged. By contrast, IL-1 precursors have an acidic domain that is proteolytically removed by caspase-110. When permeabilized by GSDMD pores, unlysed liposomes release positively charged and neutral cargoes faster than negatively charged cargoes of similar sizes, and the pores favour the passage of IL-1β and IL-18 over that of their precursors. Consistent with these findings, living-but not pyroptotic-macrophages preferentially release mature IL-1β upon perforation by GSDMD. Mutation of the acidic residues of GSDMD compromises this preference, hindering intracellular retention of the precursor and secretion of the mature cytokine. The GSDMD pore therefore mediates IL-1 release by electrostatic filtering, which suggests the importance of charge in addition to size in the transport of cargoes across this large channel.

Under the influences of AC-DC coupling， uncoordinated network-source development， and new energies that fail to meet the demand of grid-related performance， power system stability is becoming a point of extreme gravity. The correlation characteristics of transient voltage and power angle stability of the receiving-end grid are analyzed. Two transient instability modes with transient voltage and transient power angle instability as the dominant causal factors and their specific evolution processes are discussed based on the transient stability mechanism. Afterward， the effects of the optimal control measures on grid layout， power structure， network-source coordination， power distribution， and source-load interaction on optimizing the transient stability are reviewed and verified， and the traditional stability control measure of limiting unit output is not adopted. The study of the evolution of transient instability patterns and simulation analysis provides a reliable reference for identifying transient instability scenarios of key units in the receiving-end grid and formulating control measures.

With the rapid load growth and the increasing density of power grids， the overrun short-circuit current becomes increasingly aggravated. To accurately assess the short-circuit current level of the system is crucial to ensure the safe and stable operation of the power grid. Therefore， a short-circuit current evaluation method based on the branch fault current of the circuit breaker is proposed. In view of the double-bus double-section wiring substations at voltage levels of 220 kV and below and 500 kV three-to-two wire substations， the paper analyzes the short circuit current flowing through the circuit breaker in case of different fault locations， switch-off of circuit breakers， etc. Moreover， it proposes a calculation method of the short circuit current that the circuit breaker requires in the single-jump single-weight stage of single-phase fault occurring at the line outlet and determines the maximum short circuit current required to block the circuit breaker in the substation. Additionally， it specifies a short circuit current calibration standard that the maximum short circuit current flowing through the circuit breakers after the fault should not exceed their breaking capacities. Finally， the effectiveness of the proposed evaluation method is verified through case analysis.

ObjectivePulmonary hypertension (PH) due to left heart disease (group 2), especially in the setting of heart failure with preserved ejection fraction (HFpEF), is the most common cause of PH worldwide; however, at present, there is no proven effective therapy available for its treatment. PH-HFpEF is associated with insulin resistance and features of metabolic syndrome. The stable prostacyclin analog, treprostinil, is an effective and widely used Food and Drug Administration-approved drug for the treatment of pulmonary arterial hypertension. While the effect of treprostinil on metabolic syndrome is unknown, a recent study suggests that the prostacyclin analog beraprost can improve glucose intolerance and insulin sensitivity. We sought to evaluate the effectiveness of treprostinil in the treatment of metabolic syndrome-associated PH-HFpEF. Approach and Results: Treprostinil treatment was given to mice with mild metabolic syndrome-associated PH-HFpEF induced by high-fat diet and to SU5416/obese ZSF1 rats, a model created by the treatment of rats with a more profound metabolic syndrome due to double leptin receptor defect (obese ZSF1) with a vascular endothelial growth factor receptor blocker SU5416. In high-fat diet-exposed mice, chronic treatment with treprostinil reduced hyperglycemia and pulmonary hypertension. In SU5416/Obese ZSF1 rats, treprostinil improved hyperglycemia with similar efficacy to that of metformin (a first-line drug for type 2 diabetes mellitus); the glucose-lowering effect of treprostinil was further potentiated by the combined treatment with metformin. Early treatment with treprostinil in SU5416/Obese ZSF1 rats lowered pulmonary pressures, and a late treatment with treprostinil together with metformin improved pulmonary artery acceleration time to ejection time ratio and tricuspid annular plane systolic excursion with AMPK (AMP-activated protein kinase) activation in skeletal muscle and the right ventricle.ConclusionsOur data suggest a potential use of treprostinil as an early treatment for mild metabolic syndrome-associated PH-HFpEF and that combined treatment with treprostinil and metformin may improve hyperglycemia and cardiac function in a more severe disease.

The transient forced excitation of the traditional excitation system used for synchronous condenser is limited and unmaintainable. A flexible excitation system can improve the crest value of transient forced excitation and maintain the forced excitation capacity during and after faults through DC bus voltage control. Therefore， a study is conducted on applying a flexible excitation system for critical units to improve the transient stability characteristics of local power grids. The hardware topology and control method of flexible excitation are introduced， and the flexible excitation control objective to enhance the transient stability characteristics of the units is analyzed. The flexible excitation is applied to the critical units in the actual grid at the receiving end with transient stability problems. The transient stability enhancement effect of the grid is verified in the simulation after the application. The results show that applying flexible excitation to a limited number of critical units can effectively improve the transient stability characteristics of power grid.