The effect of non-insulin-based insulin resistance indices on the prediction of recurrence in patients with atrial fibrillation undergoing radiofrequency catheter ablation.

BACKGROUND: Atrial fibrillation (AF) is acknowledged as a disease continuum. Despite catheter ablation being recommended as a primary therapy for AF, the high recurrence rates have tempered the initial enthusiasm. Insulin resistance (IR) has been established as an independent predictor for the onset of AF. However, the correlation between non-insulin-based IR indices and late AF recurrence in patients undergoing radiofrequency catheter ablation remains unknown. METHODS: A retrospective cohort of 910 AF patients who underwent radiofrequency catheter ablation was included in the analysis. The primary endpoint was late AF recurrence during the follow-up period after a defined blank period. The relationship between non-insulin-based IR indices and the primary endpoint was assessed using multivariate Cox hazards regression models and restricted cubic splines (RCS). Additionally, the net reclassification improvement and integrated discrimination improvement index were calculated to further evaluate the additional predictive value of the four IR indices beyond established risk factors for the primary outcome. RESULTS: During a median follow-up period of 12.00 months, 189 patients (20.77%) experienced late AF recurrence, which was more prevalent among patients with higher levels of IR. The multivariate Cox hazards regression analysis revealed a significant association between these IR indices and late AF recurrence. Among the four indices, METS-IR provided the most significant incremental effect on the basic model for predicting late AF recurrence. Multivariable-adjusted RCS curves illustrated a nonlinear correlation between METS-IR and late AF recurrence. In subgroup analysis, METS-IR exhibited a significant correlation with late AF recurrence in patients with diabetes mellitus (HR: 1.697, 95% CI 1.397 - 2.063, P < 0.001). CONCLUSION: All the four non-insulin-based IR indices were significantly associated with late AF recurrence in patients undergoing radiofrequency catheter ablation. Addressing IR could potentially serve as a viable strategy for reducing the late AF recurrence rate.

Sex-related differences in left atrial substrate among patients with atrial fibrillation: evidence from high-density voltage mapping.

BACKGROUND: There is sufficient evidence that women with atrial fibrillation (AF) have a greater symptom burden than men with AF and are more likely to experience recurrence after catheter ablation. However, the mechanisms underlying these sex differences are unclear. METHODS: We prospectively enrolled 125 consecutive patients, including 40 non-AF patients and 85 AF patients, who underwent high-density voltage mapping during sinus rhythm and AF patients who underwent first ablation. RESULTS: Overall, 37 (44%) female patients with AF and 24 (60%) female non-AF patients with a mean age of 61.7 ± 11.6 years and 53.6 ± 16.7 years, respectively, were enrolled in this study. The results showed that the atrial voltage of female AF patients was significantly lower than that of male AF patients (1.11 ± 0.58 mV vs. 1.53 ± 0.65 mV; P = 0.003), while there were no significant sex differences in non-AF patients (3.02 ± 0.86 mV vs. 3.21 ± 0.84 mV; P = 0.498). Multiple linear regression analysis revealed that female sex (- 0.29, 95% confidence interval [CI] - 0.64 to - 0.13, P = 0.004) and AF type (- 0.32, 95% CI - 0.69 to - 0.13, P = 0.004) were the only factors independently associated with voltage. Compared with men, women in the paroxysmal AF group had a 3.5-fold greater incidence of recurrence (adjusted hazard ratio 4.49; 95% CI 1.101-18.332, P = 0.036). Both globally and regionally, the results showed that sex-related differences in voltage values occurred prominently in paroxysmal AF patients but not in nonparoxysmal AF patients. CONCLUSION: Sex-related differences in atrial substrates and arrhythmia-free survival were found in paroxysmal AF patients, suggesting the existence of sex-related pathophysiological factors.

Nitrogen-Blowing Assisted Strategy for Fabricating Large-Area Organic Solar Modules with an Efficiency of 15.6.

Organic solar cells (OSCs) are one of the most promising photovoltaic technologies due to their affordability and adaptability. However, upscaling is a critical issue that hinders the commercialization of OSCs. A significant challenge is the lack of cost-effective and facile techniques to modulate the morphology of the active layers. The slow solvent evaporation leads to an unfavorable phase separation, thus resulting in a low power conversion efficiency (PCE) of organic solar modules. Here, a nitrogen-blowing assisted method is developed to fabricate a large-area organic solar module (active area = 12 cm2) utilizing high-boiling-point solvents, achieving a PCE of 15.6%. The device fabricated with a high-boiling-point solvent produces a more uniform and smoother large-area film, and the assistance of nitrogen-blowing accelerates solvent evaporation, resulting in an optimized morphology with proper phase separation and finer aggregates. Moreover, the device fabricated by the nitrogen-blowing assisted method exhibits improved exciton dissociation, balanced carrier mobility, and reduced charge recombination. This work proposes a universal and cost-effective technique for the fabrication of high-efficiency organic solar modules.

In-Doped ZnO Electron Transport Layer for High-Efficiency Ultrathin Flexible Organic Solar Cells.

Sol-gel processed zinc oxide (ZnO) is one of the most widely used electron transport layers (ETLs) in inverted organic solar cells (OSCs). The high annealing temperature (≈200 °C) required for sintering to ensure a high electron mobility however results in severe damage to flexible substrates. Thus, flexible organic solar cells based on sol-gel processed ZnO exhibit significantly lower efficiency than rigid devices. In this paper, an indium-doping approach is developed to improve the optoelectronic properties of ZnO layers and reduce the required annealing temperature. Inverted OSCs based on In-doped ZnO (IZO) exhibit a higher efficiency than those based on ZnO for a range of different active layer systems. For the PM6:L8-BO system, the efficiency increases from 17.0% for the pristine ZnO-based device to 17.8% for the IZO-based device. The IZO-based device with an active layer of PM6:L8-BO:BTP-eC9 exhibits an even higher efficiency of up to 18.1%. In addition, a 1.2-micrometer-thick inverted ultrathin flexible organic solar cell is fabricated based on the IZO ETL that achieves an efficiency of 17.0% with a power-per-weight ratio of 40.4 W g-1, which is one of the highest efficiency for ultrathin (less than 10 micrometers) flexible organic solar cells.

An Ionic Liquid Supramolecular Gel Electrolyte with Unique Wide Operating Temperature Range Properties for Zinc-Ion Batteries.

Zinc-ion batteries are promising candidates for large-scale energy storage. The side reactions of the hydrogen evolution reaction (HER) and zinc dendrite growth are major challenges for developing high-performance zinc-ion batteries. In this paper, a supramolecular gel electrolyte (BLO-ILZE) was self-assembled in an ionic liquid (EMIMBF4) with zinc tetrafluoroborate (Zn(BF4)2) on the separator in situ to obtain a gel electrolyte used in zinc-ion batteries. BLO-ILZE is demonstrated to significantly enhance conductivity over a broad temperature range between -70 and 100 °C. Interestingly, through testing and fitting, it is found that the supramolecular gel electrolyte satisfies the liquid state law over a wide temperature range, and even achieves high conductivity (2.12 mS cm-1) at -40 °C. It is equivalent to the conductivity of aqueous zinc-ion batteries (ZnSO4/H2O) at -10 °C, which is 2.33 mS cm-1. Moreover, the supramolecular gel electrolyte can effectively inhibit the HER, thus exhibiting a longer lifetime in Zn/Zn cells for 3470 h at 1 mA cm-2 compared to the aqueous zinc-ion batteries with the Zn(BF4)2 aqueous electrolyte (400 h at 1 mA cm-2). The assembled V2O5/BLO-ILZE/Zn full cells also showed cycling performance, with 5000 cycles at 0.5 mA g-1 at room temperature, a capacity of 98%, and a coulombic efficiency of about 100%.

Buried interface molecular hybrid for inverted perovskite solar cells.

Perovskite solar cells with an inverted architecture provide a key pathway for commercializing this emerging photovoltaic technology because of the better power conversion efficiency and operational stability compared with the normal device structure. Specifically, power conversion efficiencies of the inverted perovskite solar cells have exceeded 25% owing to the development of improved self-assembled molecules1-5 and passivation strategies6-8. However, poor wettability and agglomeration of self-assembled molecules9-12 cause interfacial losses, impeding further improvement in the power conversion efficiency and stability. Here we report a molecular hybrid at the buried interface in inverted perovskite solar cells that co-assembled the popular self-assembled molecule [4-(3,6-dimethyl-9H-carbazol-9-yl)butyl]phosphonic acid (Me-4PACz) with the multiple aromatic carboxylic acid 4,4',4″-nitrilotribenzoic acid (NA) to improve the heterojunction interface. The molecular hybrid of Me-4PACz with NA could substantially improve the interfacial characteristics. The resulting inverted perovskite solar cells demonstrated a record certified steady-state efficiency of 26.54%. Crucially, this strategy aligns seamlessly with large-scale manufacturing, achieving one of the highest certified power conversion efficiencies for inverted mini-modules at 22.74% (aperture area 11.1 cm2). Our device also maintained 96.1% of its initial power conversion efficiency after more than 2,400 h of 1-sun operation in ambient air.

Investigation of Imidazolinone Herbicide Resistance Gene with KASP Markers for Japonica/Geng Rice Varieties in the Huanghuaihai Region of China.

Rice is a staple food for more than half of the global population due to its food security and sustainable development. Weeds compete with crops for sunlight and indispensable nutrients, affecting the yield and quality of crops. Breeding herbicide-tolerant rice varieties paired with herbicide application is expected to help with weed control. In this study, 194 Japonica/Geng rice varieties or lines collected from the Huanghuaihai region of China were screened by Kompetitive Allele-Specific PCR (KASP) markers based on four mutation sites within OsALS1 (LOC_Os02g30630), which is the target of imidazolinone (IMI) herbicides. Only the OsALS1627N haplotype was identified in 18 varieties, including the previously reported Jingeng818 (JG818), and its herbicide resistance was validated by treatment with three IMIs. To investigate the origin of the OsALS1627N haplotype in the identified varieties, six codominant PCR-based markers tightly linked with OsALS1 were developed. PCR analysis revealed that the other 17 IMI-tolerant varieties were derived from JG818. We randomly selected three IMI-tolerant varieties for comparative whole-genome resequencing with known receptor parent varieties. Sequence alignment revealed that more loci from JG818 have been introduced into IMI-tolerant varieties. However, all three IMI-tolerant varieties carried clustered third type single nucleotide polymorphism (SNP) sites from unknown parents, indicating that these varieties were not directly derived from JG818, whereas those from different intermediate improved lines were crossed with JG818. Overall, we found that only OsALS1627N from JG818 has been broadly introduced into the Huanghuaihai region of China. Additionally, the 17 identified IMI-tolerant varieties provide alternative opportunities for improving such varieties along with other good traits.

Ordered Perovskite Structure with Functional Units for High Performance and Stable Solar Cells.

Ion migration is one of the most critical challenges that affects the stability of metal-halide perovskite solar cells (PSCs). However, the current arsenal of available strategies for solving this issue is limited. Here, novel perovskite active layers following the concept of ordered structures with functional units (OSFU) to intrinsically suppress ion migration, in which a three-dimensional (3D) perovskite layer is deposited by vapor deposition for light absorption and a 2D layer is deposited by solution process for ion inhibition, are constructed. As a promising result, the activation energy of ion migration increases from 0.36 eV for the conventional perovskite to 0.54 eV for the OSFU perovskite. These devices exhibit substantially enhanced operational stability in comparison with the conventional ones, retaining >85% of their initial efficiencies after 1200 h under ISOS-L-1. Moreover, the OSFU devices show negligible fatigue behavior with a robust performance under light/dark cycling aging test (ISOS-LC-1 protocol), which demonstrates the promising application of functional motif theory in this field.

Hypoxia Reversion by Low-Immunogenic Ultra-Acid-Sensitive Comicelles of Protein-Polymer Conjugates Sensitizes Tumors to Photodynamic Therapy.

Hypoxia is characteristic of the tumor microenvironment, which is correlated with resistance to photodynamic therapy (PDT), radiotherapy, chemotherapy, and immunotherapy. Catalase is potentially useful to catalyze the conversion of endogenous H2O2 to O2 for hypoxia reversion. However, the efficient delivery of catalase into the hypoxia regions of tumors is a huge challenge. Here, we report the self-assembly of ultra-acid-sensitive polymer conjugates of catalase and albumin into nanomicelles that are responsive to the acidic tumor microenvironment. The immunogenicity of catalase is mitigated by the presence of albumin, which reduces the cross-linking of catalase with B cell receptors, resulting in improved pharmacokinetics. The ultra acid sensitivity of the nanomicelles makes it possible to efficiently escape the lysosomal degradation after endocytosis and permeate into the interior of tumors to reverse hypoxia in vitro and in vivo. In mice bearing triple-negative breast cancer, the nanomicelles loaded with a photosensitizer effectively accumulate and penetrate into the whole tumors to generate a sufficient amount of O2 to reverse hypoxia, leading to enhanced efficacy of PDT without detectable side effects. These findings provide a general strategy of self-assembly to design low-immunogenic ultra-acid-sensitive comicelles of protein-polymer conjugates to reverse tumor hypoxia, which sensitizes tumors to PDT.

Structural stabilities and natural half-metallic properties of OsXCoSi (X=Ti, Zr, Hf) quaternary Heusler alloys series first-principles calculations.

Based on first-principles calculation of density functional theory, this study investigates the structural stability, magnetic properties, and electronic properties of the three different phases (i.e. type 1, type 2, and type 3) of OsXCoSi (X=Ti, Zr, Hf) in a new quaternary Heusler alloy series. The corresponding equilibrium lattice constants of each type are optimized, and the change of formation enthalpy and elastic constant phonon spectrum show that the OsXCoSi (X=Ti, Zr, Hf) alloy is thermodynamically, dynamically and mechanically stable. Furthermore, the bonding features of each phase are discussed. It is found that all type 1 structures of OsXCoSi (X=Ti, Zr, Hf) exhibit natural half-metallicity (HM) in equilibrium lattice constant, and their equilibrium lattice constants in the ground state were determined to be 5.909 Å for OsTiCoSi, 6.155 Å for OsZrCoSi, and 6.100 Å for OsHfCoSi. Meanwhile, by testing the alloy under different pressures, the range of the integer magnetic moment non-equilibrium lattice constants for the three alloys OsTiCoSi, OsZrCoSi, and OsHfCoSi are 5.710 Š∼ 6.329 Å, 5.696 Š∼ 6.1557 Å and 5.716 Š∼6.1009 Å, respectively, which is wide and is more close to the practical application for spin-polarized materials. In addition, its magnetic moment is consistent with the values given by the Slater-Pauling rule. Furthermore, the forming of the HM gap is examined by analysing the total and partial density of states, energy bands of alloy's electronic property, with respect to the calculated results. What's more, special attention is paid to the differences of the properties for series Heusler alloys. It is found that the electronics properties distinction is mainly based on valence electron changes. However, the lattice constants are susceptible to size of a nucleus.

Novel superhard semiconducting structures of C8B2N2 predicted using the first-principles approach.

Using first-principles calculations, we predicted three novel superhard semiconducting structures of C8B2N2 with a space group of P3m1. We investigated their mechanical properties and electronic structures up to 100 GPa. These three structures were successfully derived by substituting carbon (C) atoms with isoelectronic boron (B) and nitrogen (N) atoms in the P3m1 phase, which is the most stable structure of BCN and exhibits exceptional mechanical properties. Our results indicated that these structures had superior energy over previously reported t-C8B2N2, achieved by replacing C atoms in the diamond supercell with B and N atoms. To ensure their stable existence, we thoroughly examined their mechanical and dynamical stabilities, and we found that their hardness values reached 82.4, 83.1, and 82.0 GPa, which were considerably higher than that of t-C8B2N2 and even surpassing the hardness of c-BN. Calculations of the electron localization function revealed that the stronger carbon-carbon covalent bonds made them much harder than t-C8B2N2. Additionally, our further calculations of band structures revealed that these materials had indirect bandgaps of 4.164, 4.692, and 3.582 eV. These findings suggest that these materials have the potential to be used as superhard semiconductors, potentially surpassing conventional superhard materials.

Including hemoglobin levels and female sex provide the additional predictive value of the APPLE score for atrial fibrillation recurrence post-catheter ablation.

OBJECTIVE: We probed whether the addition of hemoglobin (HGB) or the female sex (SEX) as variables would provide additional prognostic value to the APPLE score. METHODS: An optimized APPLE score was used to evaluate the AF recurrence risk in the consecutive populations with AF post-catheter ablation including the development (n = 562) and validation (n = 239) cohorts. RESULTS: In the populations of AF recurrence, most patients were female sex (103/164, 62.8%), and had the lower HGB levels. After adjusting for the APPLE score, HGB level (Odds Ratio [OR], 0.828; 95% Confidence Interval [CI], 0.749-0.915; P < 0.001) and female sex (OR, 1.596; 95% CI, 1.140-2.235; P = 0.006) independently predicted AF recurrence. Adjusting the APPLE score by HGB variable improved its predictive ability for AF recurrence (C-statistic value from 0.675 to 0.711, P = 0.010), which also increased the C-indexes in the external validation (from 0.653 to 0.725, p = 0.023). The female sex variable also enhanced the C-statistic value of the APPLE score for AF recurrence at both development and external validation (C-indices from 0.675 to 0.691, P = 0.004; C-indices from 0.653 to 0.704, p = 0.037, respectively). Decision curve analysis showed that the HGB plus APPLE score was better than the SEX plus APPLE score in predicting AF recurrence in two following AF populations. CONCLUSION: The inclusion of HGB level and female sex variables improved the predictability and clinical usefulness of adjusted APPLE score. Adjustment of the APPLE score by HGB levels may provide better predictive value than inclusion of the female sex variable.

Platelet-to-Lymphocyte Ratio Improves the Predictive Ability of the Risk Score for Atrial Fibrillation Recurrence After Radiofrequency Ablation.

Purpose: To investigate the effect and comprehensive predictive value of the platelet-to-lymphocyte ratio (PLR) for long-term recurrence in patients with atrial fibrillation (AF) post ablation. Patients and Methods: We retrospectively analysed 638 consecutive AF patients who underwent ablation, including 302 (47.3%) with paroxysmal AF and 336 (52.7%) with nonparoxysmal AF. Patients were grouped into the recurrence and nonrecurrence groups. Results: After a mean follow-up of 15.1±9.3 months, 175 patients (27.4%) with AF had long-term recurrence, including 114 patients (33.9%) with nonparoxysmal AF and 61 patients (20.2%) with paroxysmal AF. In the entire cohort and in patients with nonparoxysmal AF, but not in those with paroxysmal AF, the PLR was significantly higher in the recurrence group than in the nonrecurrence group (P<0.05). After adjusting for the APPLE score, the PLR as a continuous variable independently predicted AF recurrence (hazard ratio [HR], 1.003; 95% confidence interval [CI], 1.001-1.005; P<0.01). The addition of the PLR to the APPLE score improved its predictive ability for recurrence (the C-statistic value increased from 0.645 to 0.675, P=0.02; the net reclassification improvement was 0.221, 95% CI 0.049-0.394, P=0.01; and the integrated discrimination improvement was 0.029, 95% CI 0.013-0.045, P<0.01). For nonparoxysmal AF, the PLR was stratified into tertiles, the PLR independently increased the nonparoxysmal AF recurrence risk after adjusting for multiple confounding factors (HR, 1.393; 95% CI, 1.102-1.762; P<0.01), and the addition of the PLR to the left atrial diameter improved its predictive ability for arrhythmia recurrence (the C-statistic value increased from 0.601 to 0.667, P<0.01). Conclusion: The PLR is an independent predictive factor of long-term AF recurrence post ablation after adjusting for the APPLE score and can improve the predictive ability and clinical usefulness of the APPLE score. However, the PLR is an effective predictor of recurrence in patients with nonparoxysmal AF rather than in paroxysmal AF.

A Novel Fused SiO2 and h-BN Modified Quartz Fiber/Benzoxazine Resin Ceramizable Composite with Excellent Flexural Strength and Ablation Resistance.

Hypersonic vehicles encounter hostile service environments of thermal/mechanical/chemical coupling, so thermal protection materials are crucial and essential. Ceramizable composites have recently attracted intensive interest due to their ability to provide large-area thermal protection for hypersonic vehicles. In this work, a novel ceramizable composite of quartz fiber/benzoxazine resin modified with fused SiO2 and h-BN was fabricated using a prepreg compression molding technique. The effects of the fused SiO2 and h-BN contents on the thermal, mechanical, and ablative properties of the ceramizable composite were systematically investigated. The ceramizable composite with an optimized amount of fused SiO2 and h-BN exhibited superb thermal stability, with a peak degradation temperature and residue yield at 1400 °C of 533.2 °C and 71.5%, respectively. Moreover, the modified ceramizable composite exhibited excellent load-bearing capacity with a flexural strength of 402.2 MPa and superior ablation resistance with a linear ablation rate of 0.0147 mm/s at a heat flux of 4.2 MW/m2, which was significantly better than the pristine quartz fiber/benzoxazine resin composite. In addition, possible ablation mechanisms were revealed based on the microstructure analysis, phase transformation, chemical bonding states, and the degree of graphitization of the ceramized products. The readily oxidized pyrolytic carbon (PyC) and the SiO2 with a relatively low melting point were converted in situ into refractory carbide. Thus, a robust thermal protective barrier with SiC as the skeleton and borosilicate glass as the matrix protected the composite from severe thermochemical erosion and thermomechanical denudation.

Spatiotemporally-Programmed Dual-Acid-Sensitive Nanoworms of Albumin-Poly(tertiary amine)-Doxorubicin Conjugates for Enhanced Cancer Chemotherapy.

Nanomedicines are potentially useful for targeted cancer chemotherapy; however, it is difficult to design nanomedicines with controllable structures and functions to overcome a series of biological and pathological barriers to efficiently kill cancer cells in vivo. Here, this work reports in situ growth of dual-acid-sensitive poly(tertiary amine)-doxorubicin conjugates from albumin to form dual-acid-sensitive albumin-poly(tertiary amine)-doxorubicin conjugates that self-assemble into nanospheres and nanoworms in a controlled manner. Both nanospheres and nanoworms rapidly dissociate into positively-charged unimers at pH < 6.9 and quickly releases the conjugated drug of doxorubicin at pH < 5.6, leading to enhanced penetration in tumor cell spheroids as well as improved uptake and cytotoxicity to tumor cells at pH < 6.9. Notably, nanoworms are less taken up by endothelial cells than nanospheres and doxorubicin, leading to improved pharmacokinetics. In a mouse model of triple negative breast cancer, nanoworms accumulate and penetrate into tumors more efficiently than nanospheres and doxorubicin, leading to enhanced tumor accumulation and penetration. As a result, nanoworms outperform nanospheres and doxorubicin in suppressing tumor growth and elongating the animal survival time, without observed side effects. These findings demonstrate that intelligent nanoworms with spatiotemporally programmed dual-acid-sensitive properties are promising as next-generation nanomedicines for targeted cancer chemotherapy.

Age, creatinine, and ejection fraction (ACEF) score as predictive values for late non-valvular atrial fibrillation recurrence after radiofrequency ablation.

The clinical risk factors associated with late recurrence in patients with non-valvular atrial fibrillation (AF) (NVAF) undergoing radiofrequency catheter ablation (RFCA) remain unknown. Furthermore, the current prognostic risk score system is commonly used in such patients as a noninvasive method to assess late AF recurrence. According to recent research, the Age, creatinine, and ejection fraction (ACEF) score is a useful risk score for cardiovascular morbidity and mortality. As a result, we hypothesized that pre-ablation ACEF score could be used to assess late recurrence in patients with NVAF. We included 325 NVAF patients undergoing RFCA. During a median follow-up period of 12 months, patients with late AF recurrence had higher ACEF scores (P < .001). The pre-ablation ACEF score was a risk factor for late AF recurrence after RFCA (P = .027). The ACEF score was a predictor of late AF recurrence after RFCA, with an AUC of 0.624 (P = .001). Moreover, the AUC of left atrial diameter (LAD) was 0.7 (P < .001), which was higher than the ACEF score, but no significant difference was found (P = .104). The ACEF score was positively correlated with LAD, advanced age, and B-type natriuretic peptide. In patients with NVAF, the pre-ablation ACEF score is a valuable risk score for assessing late AF recurrence after RFCA, as with LAD.

Adjustment of the GRACE score by the stress hyperglycemia ratio improves the prediction of long-term major adverse cardiac events in patients with acute coronary syndrome undergoing percutaneous coronary intervention: A multicenter retrospective study.

AIMS: The predictive value of the stress hyperglycemia ratio (SHR) for long-term prognosis in acute coronary syndrome (ACS) is inconsistent. Whether the SHR provides additional prognostic value in addition to the GRACE score in ACS patients undergoing percutaneous coronary intervention (PCI) remains unknown. METHODS: A development-validation method was adopted to develop an algorithm to adjust the GRACE score using the SHR in ACS patients undergoing PCI from 11 hospitals. RESULTS: During a median follow-up of 31.33 months, the occurrence of major adverse cardiac events (MACEs), defined as a composite of all-cause mortality and nonfatal myocardial infarction, was more frequent in the patients with a higher level of SHR. The SHR independently predicted long-term MACEs (hazard ratio 3.3479; 95% CI 1.4103-7.9475; P = 0.0062). Adjustment of the GRACE risk by addition of the SHR increased the C-statistic from 0.706 (95% CI: 0.599-0.813) to 0.727 (95% CI: 0.616-0.837) (P < 0.01), with a continuous net reclassification improvement of 30.5% and an integrated discrimination improvement of 0.042 (P < 0.01) in the derivation cohort; and addition of the SHR showed superior discrimination and good calibration in the validation cohort. CONCLUSIONS: The SHR is an independent predictor of long-term MACEs in ACS patients undergoing PCI and markedly improves the performance of the GRACE score.

The Alpha Subunit of Mitochondrial Processing Peptidase Participated in Fertility Restoration in Honglian-CMS Rice.

The cytoplasmic male sterility (CMS) and nuclear-controlled fertility restoration system is a favorable tool for the utilization of heterosis in plant hybrid breeding. Many restorer-of-fertility (Rf) genes have been characterized in various species over the decades, but more detailed work is needed to investigate the fertility restoration mechanism. Here, we identified an alpha subunit of mitochondrial processing peptidase (MPPA) that is involved in the fertility restoration process in Honglian-CMS rice. MPPA is a mitochondrial localized protein and interacted with the RF6 protein encoded by the Rf6. MPPA indirectly interacted with hexokinase 6, namely another partner of RF6, to form a protein complex with the same molecular weight as the mitochondrial F1F0-ATP synthase in processing the CMS transcript. Loss-of-function of MPPA resulted in a defect in pollen fertility, the mppa+/- heterozygotes showed semi-sterility phenotype and the accumulation of CMS-associated protein ORFH79, showing restrained processing of the CMS-associated atp6-OrfH79 in the mutant plant. Taken together, these results threw new light on the process of fertility restoration by investigating the RF6 fertility restoration complex. They also reveal the connections between signal peptide cleavage and the fertility restoration process in Honglian-CMS rice.

Hypoxia-Triggered Bioreduction of Poly(N-oxide)-Drug Conjugates Enhances Tumor Penetration and Antitumor Efficacy.

PEGylation prolongs the blood circulation time of drugs; however, it simultaneously reduces the tumor penetration of drugs due to the nonfouling function and bulky hydrodynamic volume of PEG, leading to unsatisfactory outcomes in the treatment of solid tumors. Herein, we report the in situ growth of a bioreducible polymer of poly(N-oxide) from an important protein drug of interferon alpha (IFN) to generate site-specific IFN-poly(N-oxide) conjugates with higher bioactivity than a clinically used PEGylated IFN of PEGASYS. An IFN-poly(N-oxide) conjugate is screened out to have a circulating half-life as long as 51 h, which is similar to that of PEGASYS but 96-fold greater than that of IFN. However, the conjugate greatly outperforms PEGASYS and IFN in tumor penetration and antitumor efficacy in mice bearing melanoma. This enhanced tumor penetration is ascribed to the adsorption-mediated transcytosis of the conjugate whose poly(N-oxide) is biologically reduced into poly(tertiary amine), under hypoxia, which can be further protonated in the acidic tumor microenvironment. These novel findings demonstrate that poly(N-oxide)s are not only long-circulating but also bioreducible under hypoxia and are of great promise as next-generation carriers to deliver drugs into the interior of solid tumors to enhance their antitumor efficacy.

Acute and long-term outcomes of pulmonary vein isolation and left atrial substrate modification for non-paroxysmal atrial fibrillation: a non-randomized trial.

Background: The long-term success rate of nonparoxysmal atrial fibrillation (AF) treated with pulmonary vein isolation (PVI) alone is not ideal. This may indicate atrial fibrosis as a major cause of recurrence. Therefore, the aim of this study is to investigate the efficacy of left atrial substrate modification (LASM) by targeting low-voltage area. Methods: A total of 157 consecutive patients with drug-refractory nonparoxysmal AF who underwent radiofrequency ablation during hospitalization in the Third People's Hospital of Chengdu from April 2017 to August 2021 were prospectively included. Stepwise ablation was performed in two different orders: LASM first (n=53) and PVI first (n=104) group. All patients underwent ablation during AF, and the procedural endpoint was AF termination during ablation. In the LASM first group, LASM was performed first and if AF was terminated, PVI was not performed. Similarly, in the PVI first groups, LASM was performed if AF was not terminated. The primary outcome were AF termination and freedom from AF. The secondary outcome was adverse events. Cox regression analysis was used to define predictors of AF termination, and Kaplan-Meier analysis was used to assess differences between groups in AF freedom. Results: The baseline characteristics of the two groups were similar. At a median follow-up of 16 months, the 112 patients (39 in LASM first group and 73 in PVI first group) with AF termination had a higher success rate than the 45 patients who had no AF termination (78.6% vs. 57.8%; P<0.01). The AF termination rate (24/53, 45.3% vs. 12/104, 11.5%; P<0.01) and AF freedom (20/24, 83.3% vs. 7/12, 58.3%; P=0.13) by LASM alone was higher than PVI alone. There were 3 cases of heart failure and 1 case of stroke (4/53) in the LASM first group, and 1 case of pericardial tamponade, 5 cases of heart failure and 1 case of stroke (7/104) in the LASM first group (7.5% vs. 6.7%; P>0.05). Conclusions: LASM provides higher immediate success and a slightly better long-term success rate compared to PVI. Patients who terminated AF were more likely to have AF freedom than those who did not. AF termination during procedure may improve symptoms and reduce hospitalization.