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AIMS: Certain critical risk factors of heart failure with preserved ejection fraction (HFpEF) patients were significantly different from those of heart failure with reduced ejection fraction (HFrEF) patients, resulting in the limitations of existing predictive models in real-world situations. This study aimed to develop a machine learning model for predicting 90 day readmission for HFpEF patients. METHODS AND RESULTS: Data were extracted from electronic health records from 1 August 2020 to 1 August 2021 and follow-up records of patients with HFpEF within 3 months after discharge. Feature extraction was performed by univariate analysis combined with the least absolute shrinkage and selection operator (LASSO) algorithms. Machine learning models like eXtreme Gradient Boosting (XGBoost), random forest, neural network and logistic regression were adopted to construct models. The discrimination and calibration of each model were compared, and the Shapley Additive exPlanations (SHAP) method was used to explore the interpretability of the model. The cohort included 746 patients, of whom 103 (13.8%) were readmitted within 90 days. XGBoost owned the best performance [area under the curve (AUC) = 0.896, precision-recall area under the curve (PR-AUC) = 0.868, sensitivity = 0.817, specificity = 0.837, balanced accuracy = 0.827]. The Kolmogorov-Smirnov (KS) statistic was 0.694 at 0.468 in the XGBoost model. SHAP identified the top 12 risk features, including activities of daily living (ADL), left atrial dimension (LAD), left ventricular end-diastolic diameter (LVDD), shortness, nitrates, length of stay, nutritional risk, fall risk, accompanied by other symptoms, educational level, anticoagulants and edema. CONCLUSIONS: Our model could help medical agencies achieve the early identification of 90 day readmission risk in HFpEF patients and reveal risk factors that provide valuable insights for treatments.
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Polymer vesicles are of profound interest for designing delivery vehicles and nanoreactors toward a variety of biomedical and catalytic applications, yet robust synthesis of stable and permeable vesicles remains challenging. Here, we propose an electrostatic-templated polymerization that enables fabrication of polyelectrolyte vesicles with simultaneously regulated stability and permeability. In our design, cationic monomers were copolymerized with cross-linkers in the presence of a polyanionic-neutral diblock copolymer as a template. By properly choosing the block length ratio of the template, we fabricated a type of polyion complex vesicle consisting of a cross-linked cationic membrane, electrostatically assembled with the template copolymer which can be removed by sequential dissociation and separation under concentrated salt. We finally obtained stable polyelectrolyte vesicles of regulated size, membrane permeability, and response properties by tuning the synthesis factors including ionic strength, cross-linker type, and fraction as well as different monomers and concentrations. As a proof-of-concept, lipase was loaded in the designed cationic vesicles, which exhibited enhanced enzyme stability and activity. Our study has developed a novel and robust strategy for controllable synthesis of a new class of stable and permeable polymer (polyelectrolyte) vesicles that feature great potential applications as functional delivery carriers and nanoreactors.
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Polymeric vesicles are perspective vehicles for fabricating enzymatic nanoreactors towards diverse biomedical and catalytic applications, yet the design of stable and permeable vesicles remains challenging. Herein, we developed polyion complex (PIC) vesicles featuring high stability and a permeable membrane for adequate enzyme loading and activation. Our design relies on co-assembly of an anionic diblock copolymer (PSS96-b-PEO113) with cationic branched poly(ethylenimine) (PEI). The polymer combination endows strong electrostatic interaction between the PSS and PEI building blocks, so their assembly can be implemented at a high salt concentration (500 mM NaCl), under which the charge interaction of the enzyme-polymer is inhibited. This control realizes the successful and safe loading of enzymes associated with the formation of stable PIC vesicles with an intrinsic permeable membrane that is favourable for enhancing enzymatic activity. The control factors for vesicle formation and enzyme loading were investigated, and the general application of loading different enzymes for cascade reaction was validated as well. Our study reveals that proper design and combination of polyelectrolytes is a facile strategy for fabricating stable and permeable polymeric PIC vesicles, which exhibit clear advantages for loading and activating enzymes, consequently boosting their diverse applications as enzymatic nanoreactors.
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Polietileneimina , Polietileneimina/química , Permeabilidad , Polímeros/química , Polielectrolitos/químicaRESUMEN
Enzyme immobilization in nanoparticles is of interest for boosting their catalytic applications, yet rational approaches to designs achieving both high enzyme loading and activation remain a challenge. Herein, we report an electrostatically mediated in situ polymerization strategy that simultaneously realizes enzyme immobilization and activation. This was achieved by copolymerizing cationic monomers with a cross-linker in the presence of the enzyme lipase (anionic) as the template, which produces enzyme-loaded nanogels. The effects of different control factors such as pH, lipase dosage, and cross-linker fraction on nanogel formation are investigated systematically, and optimal conditions for enzyme loading and activation have been determined. A central finding is that the cationic polymer network of the nanogel creates a favorable environment that not only protects the enzyme but also boosts enzymatic activity nearly 2-fold as compared to free lipase. The nanogels improve the stability of the lipase to tolerate a broader working range of pH (5.5-8.5) and temperature (25-70 °C) and allow recycling such that after six cycles of reaction, 70% of the initial activity is conserved. The established fabrication strategy can be applied generally to different cationic monomers, and most of these nanogels exhibit adequate immobilization and activation of lipase. Our study confirms that in situ polymerization based on electrostatic interaction provides a facile and robust strategy for enzyme immobilization and activation. The wide variety of ionic monomers, therefore, features great potential for developing functional platforms toward satisfying enzyme immobilization and demanding applications.
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Enzimas Inmovilizadas , Lipasa , Polietilenglicoles , Polietileneimina , Nanogeles , Estabilidad de Enzimas , Polimerizacion , Enzimas Inmovilizadas/metabolismo , Lipasa/metabolismo , Concentración de Iones de HidrógenoRESUMEN
Protein-polyelectrolyte complex coacervation is of particular interest for mimicking intracellular phase separation and organization. Yet, the challenge arises from regulating the coacervation due to the globular structure and anisotropic distributed charges of protein. Herein, we fully investigate the different control factors and reveal their effects on protein-polyelectrolyte coacervation. We prepared mixtures of BSA (bovine serum albumin) with different cationic polymers, which include linear and branched polyelectrolytes covering different spacer and charge groups, chain lengths, and polymer structures. With BSA-PDMAEMA [poly(N,N-dimethylaminomethyl methacrylate)] as the main investigated pair, we find that the moderate pH and ionic strength are essential for the adequate electrostatic interaction and formation of coacervate droplets. For most BSA-polymer mixtures, excess polyelectrolytes are required to achieve the full complexation, as evidenced by the deviated optimal charge mixing ratios from the charge stoichiometry. Polymers with longer chains or primary amine groups and a branched structure endow a strong electrostatic interaction with BSA and cause a bigger charge ratio deviation associated with the formation of solid-like coacervate complexes. Nevertheless, both the liquid- and solid-like coacervates hardly interrupt the BSA structure and activity, indicating the safe encapsulation of proteins by the coacervation with polyelectrolytes. Our study validates the crucial control of the diverse factors in regulating protein-polyelectrolyte coacervation, and the revealed principles shall be instructive for establishing other protein-based coacervations and boosting their potential applications.
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Polímeros , Albúmina Sérica Bovina , Polielectrolitos/química , Albúmina Sérica Bovina/química , Polímeros/química , Concentración OsmolarRESUMEN
BACKGROUND: Chlamydia Trachomatis (CT) is among the most prevalent sexually transmitted diseases (STDs) globally. According to the World Health Organization, more than 131 million people get infected with CT annually. CT is usually transmitted via sexual contact or perinatal exposure and can result in severe long-term complications. In developing nations, particularly, the prevention and control of CT is challenging. Hence, this study will explore the feedback mechanisms of chlamydia prevention and control, as well as identify the essential factors affecting the control and prevention of this infection in China. METHODS: Our study will employ a mixed-methods research design that encompasses both qualitative and quantitative methods. Firstly, we will develop a causal loop diagram (CLD) based on the literature review and optimize it via in-depth interviews with stakeholders. Additionally, we will utilize a quantitative method called MICMAC(Impact Matrix Cross-Reference Multiplication Applied to a Classification tool) to obtain consensus among different stakeholders and pinpoint the key information. Next, the CLD will be transformed into a system dynamics model (SDM) to evaluate the feedback mechanisms within the CLD. The causality in the CLD will be modeled using mathematical equations, which facilitate the transformation into an SDM. As such, we will be able to analyze the dynamic behavior of the system and its response to different decisions. DISCUSSION: Our study offers a systematic perspective on the control and prevention of chlamydia infection through system dynamics modeling, examining the dynamic properties and background factors of the system. The creation of the CLD affords stakeholders the chance to comprehend the functionality of their relationships and improve cooperation. Consequently, by evaluating the outcomes of these simulations, it will be possible to analyze and determine potential interventions and their effects on chlamydia infections. This modeling approach can help us gain insight into the dynamic characteristics of the system, evaluate the potential outcomes of different decisions, and design control strategies to either stabilize the system or adjust its behavior.
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Infecciones por Chlamydia , Chlamydia trachomatis , Femenino , Embarazo , Humanos , Infecciones por Chlamydia/epidemiología , Infecciones por Chlamydia/prevención & control , Causalidad , China/epidemiología , ConsensoRESUMEN
Paeonol (PAE) is a natural phenolic monomer isolated from the root bark of Paeonia suffruticosa that has been widely used in the clinical treatment of some inflammatory-related diseases and cardiovascular diseases. Much preclinical evidence has demonstrated that PAE not only exhibits a broad spectrum of anticancer effects by inhibiting cell proliferation, invasion and migration and inducing cell apoptosis and cycle arrest through multiple molecular pathways, but also shows excellent performance in improving cancer drug sensitivity, reversing chemoresistance and reducing the toxic side effects of anticancer drugs. However, studies indicate that PAE has the characteristics of poor stability, low bioavailability and short half-life, which makes the effective dose of PAE in many cancers usually high and greatly limits its clinical translation. Fortunately, nanomaterials and derivatives are being developed to ameliorate PAE's shortcomings. This review aims to systematically cover the anticancer advances of PAE in pharmacology, pharmacokinetics, nano delivery systems and derivatives, to provide researchers with the latest and comprehensive information, and to point out the limitations of current studies and areas that need to be strengthened in future studies. We believe this work will be beneficial for further exploration and repurposing of this natural compound as a new clinical anticancer drug.
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Antineoplásicos , Neoplasias , Línea Celular Tumoral , Reposicionamiento de Medicamentos , Apoptosis , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Acetofenonas/farmacología , Acetofenonas/uso terapéutico , Neoplasias/tratamiento farmacológicoRESUMEN
In food manufacturing and particular biomedical products selected proteins are often required. Obtaining the desired proteins in a pure form from natural resources is therefore important, but often very challenging. Herein, we design a sequential coacervation process that allows to efficiently isolate and purify proteins with different isoelectric points (pIs) from a mixed solution, namely Bovine Serum Albumin (BSA, pI = 4.9) and Peroxidase from Horseradish (HRP, pI = 7.2). The key to separation is introducing a suitable polyelectrolyte that causes selective complex coacervation at appropriate pH and ionic strength. Specifically, polyethyleneimine (PEI), when added into the mixture at pH 6.0, produces a coacervation which exclusively contains BSA, leading to a supernatant solution containing 100 % HRP with a purity of 91 %. After separating the dilute and dense phases, BSA is recovered by adding poly(acrylic acid) (PAA) to the concentrated phase, which displaces BSA from the complex because it interacts more strongly with PEI. The supernatant phase after this step contains approximately 75 % of the initial amount of BSA with a purity of 99 %. Our results confirm that coacervation under well-defined conditions can be selective, enabling separation of proteins with adequate purity. Therefore, the established approach demonstrates a facile and sustainable strategy with potential for protein separation at industrial scale.
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Polietileneimina , Albúmina Sérica Bovina , Concentración de Iones de Hidrógeno , Albúmina Sérica Bovina/metabolismo , Polielectrolitos , Punto IsoeléctricoRESUMEN
INTRODUCTION: As direct-to-consumer teleconsultation (hereafter referred to as 'teleconsultation') has gained popularity, an increasing number of patients have been leaving online reviews of their teleconsultation experiences. These reviews can help guide patients in identifying doctors for teleconsultation. However, few studies have examined the validity of online reviews in assessing the quality of teleconsultation against a gold standard. Therefore, we aim to use unannounced standardised patients (USPs) to validate online reviews in assessing both the technical and patient-centred quality of teleconsultations. We hypothesise that online review results will be more consistent with the patient-centred quality, rather than the technical quality, as assessed by the USPs. METHODS AND ANALYSIS: In this cross-sectional study, USPs representing 11 common primary care conditions will randomly visit 253 physicians via the three largest teleconsultation platforms in China. Each physician will receive a text-based and a voice/video-based USP visit, resulting in a total of 506 USP visits. The USP will complete a quality checklist to assess the proportion of clinical practice guideline-recommended items during teleconsultation. After each visit, the USP will also complete the Patient Perception of Patient-Centeredness Rating. The USP-assessed results will be compared with online review results using the intraclass correlation coefficient (ICC). If ICC >0.4 (p<0.05), we will assume reasonable concordance between the USP-assessed quality and online reviews. Furthermore, we will use correlation analysis, Lin's Coordinated Correlation Coefficient and Kappa as supplementary analyses. ETHICS AND DISSEMINATION: This study has received approval from the Institutional Review Board of Southern Medical University (#Southern Medical Audit (2022) No. 013). Results will be actively disseminated through print and social media, and USP tools will be made available for other researchers. TRIAL REGISTRATION: The study has been registered at the China Clinical Trials Registry (ChiCTR2200062975).
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Médicos , Consulta Remota , Humanos , Estudios Transversales , Consulta Remota/métodos , Pacientes , ChinaRESUMEN
Incorporating copper (Cu) ions into polymeric particles can be a straightforward strategy for mimicking copper enzymes, but it is challenging to simultaneously control the structure of the nanozyme and of the active sites. In this report, we present a novel bis-ligand (L2) containing bipyridine groups connected by a tetra-ethylene oxide (4EO) spacer. In phosphate buffer the Cu-L2 mixture forms coordination complexes that (at proper composition) can bind polyacrylic acid (PAA) to produce catalytically active polymeric nanoparticles with well-defined structure and size, which we refer to as 'nanozymes'. Manipulating the L2/Cu mixing ratio and using phosphate as a co-binding motif, cooperative copper centres are realized that exhibit promoted oxidation activity. The structure and activity of the so-designed nanozymes remain stable upon increasing temperature and over multiple cycles of application. Increasing ionic strength causes enhanced activity, a response also seen for natural tyrosinase. By means of our rational design we obtain nanozymes with optimized structure and active sites that in several respects outperform natural enzymes. This approach therefore demonstrates a novel strategy for developing functional nanozymes, which may well stimulate the application of this class of catalysts.
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The enzyme encoded by slr1022 gene from Synechocystis sp. PCC6803 was reported to function as N-acetylornithine aminotransferase, γ-aminobutyric acid aminotransferase, and ornithine aminotransferase, which played important roles in multiple metabolic pathways. Among these functions, N-acetylornithine aminotransferase catalyzes the reversible conversion of N-acetylornithine to N-acetylglutamate-5-semialdehyde with PLP as cofactor, which is a key step in the arginine biosynthesis pathway. However, the investigation of the detailed kinetic characteristics and catalytic mechanism of Slr1022 has not been carried out yet. In this study, the exploration of kinetics of recombinant Slr1022 illustrated that Slr1022 mainly functioned as N-acetylornithine aminotransferase with low substrate specificity to γ-aminobutyric acid and ornithine. Kinetic assay of Slr1022 variants and the model structure of Slr1022 with N-acetylornithine-PLP complex revealed that Lys280 and Asp251 residues were the key amino acids of Slr1022. The respective mutation of the above two residues to Ala resulted in the activity depletion of Slr1022. Meanwhile, Glu223 residue was involved in substrate binding and it served as a switch between the two half reactions. Other residues such as Thr308, Gln254, Tyr39, Arg163, and Arg402 implicated a substrate recognition and catalytic process of the reaction. The results of this study further enriched the understanding of the catalytic kinetics and mechanism of N-acetylornithine aminotransferase, especially from cyanobacteria.
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Synechocystis , Synechocystis/genética , Synechocystis/metabolismo , Transaminasas/metabolismo , Ornitina-Oxo-Ácido Transaminasa , Ácido gamma-AminobutíricoRESUMEN
Planning a practical three-dimensional (3-D) flight path for unmanned aerial vehicles (UAVs) is a key challenge for the follow-up management and decision making in disaster emergency response. The ideal flight path is expected to balance the total flight path length and the terrain threat, to shorten the flight time and reduce the possibility of collision. However, in the traditional methods, the tradeoff between these concerns is difficult to achieve, and practical constraints are lacking in the optimized objective functions, which leads to inaccurate modeling. In addition, the traditional methods based on gradient optimization lack an accurate optimization capability in the complex multimodal objective space, resulting in a nonoptimal path. Thus, in this article, an accurate UAV 3-D path planning approach in accordance with an enhanced multiobjective swarm intelligence algorithm is proposed (APPMS). In the APPMS method, the path planning mission is converted into a multiobjective optimization task with multiple constraints, and the objectives based on the total flight path length and degree of terrain threat are simultaneously optimized. In addition, to obtain the optimal UAV 3-D flight path, an accurate swarm intelligence search approach based on improved ant colony optimization is introduced, which can improve the global and local search capabilities by using the preferred search direction and random neighborhood search mechanism. The effectiveness of the proposed APPMS method was demonstrated in three groups of simulated experiments with different degrees of terrain threat, and a real-data experiment with 3-D terrain data from an actual emergency situation.
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Remote sensing image scene classification methods based on deep learning have been widely studied and discussed. However, most of the network architectures are directly reliant on natural image processing methods and are fixed. A few studies have focused on automatic search mechanisms, but they cannot weigh the interpretation accuracy and the parameter quantity for practical application. As a result, automatic global search methods based on multiobjective evolutionary computation have more advantages. However, in the ranking process, the network individuals with large parameter quantities are easy to eliminate, but a higher accuracy may be obtained after full training. In addition, evolutionary neural architecture search methods often take several days. In this article, in order to solve the above concerns, we propose an efficient multiobjective evolutionary automatic search framework for remote sensing image scene classification deep learning network architectures (E2SCNet). In E2SCNet, eight kinds of lightweight operators are used to build a diversified search space, and the coding connection mode is flexible. In the search process, a large model retention mechanism is implemented through two-step multiobjective modeling and evolutionary search, where one step involves the "parameter quantity and accuracy", and the other step involves the "parameter quantity and accuracy growth quantity." Moreover, a super network is constructed to share the weight in the process of individual network evaluation and promote the search speed. The effectiveness of E2SCNet is proven by comparison with several networks designed by human experts and networks obtained by gradient and evolutionary computing-based search methods.
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BACKGROUND: Despite abundant research on AIDS prevention and intervention, many residual factors influence the actual impact of the intervention at a population level. Misconceptions held by subjects lead to patterns of behavior, which do not reflect levels of cognition. METHODS: Cognition and behavioral patterns relating to HIV were investigated without intervention in freshmen before and after a two-year study period. A total of 461 freshmen studying at the university in Wuhan, Hubei Province, China, were enrolled in September 2019. Data management and analysis were performed by SPSS 25.0 software. RESULTS: Throughout the two years' study, no significant changes in the cognitive level regarding AIDS were found while the frequency of sexual behavior increased significantly. A trend of inconsistency between cognition and behavior was identified. CONCLUSION: During a two-year period without intervention, it was found that the sexual behavior of university students gradually increased, perceptions regarding AIDS-related subjects were incomplete and awareness of HIV infection risk was still weak. A phenomenon described as the separation of knowledge from behavior was detected. Misconceptions that influenced behavioral patterns were identified as critical factors. Therefore, we propose that cognitive behavioral therapy may change the actual impact of AIDS prevention interventions.
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Síndrome de Inmunodeficiencia Adquirida , Terapia Cognitivo-Conductual , Infecciones por VIH , Humanos , Infecciones por VIH/prevención & control , Síndrome de Inmunodeficiencia Adquirida/prevención & control , Síndrome de Inmunodeficiencia Adquirida/epidemiología , Conocimientos, Actitudes y Práctica en Salud , Conducta Sexual , Estudiantes/psicología , Condones , Encuestas y CuestionariosRESUMEN
Polyelectrolyte nanogels containing cross-linked ionic polymer networks feature both soft environment and intrinsic charges which are of great potential for enzyme encapsulation. In this work, well-defined poly(acrylic acid) (PAA) nanogels have been synthesized based on a facile strategy, namely, electrostatic assembly directed polymerization (EADP). Specifically, AA monomers are polymerized together with a cross-linker in the presence of a cationic-neutral diblock copolymer as the template. Effects of control factors including pH, salt concentration, and cross-linking degree have been investigated systematically, based on which the optimal preparation of PAA nanogels has been established. The obtained nanogel features not only compatible pocket for safely loading enzymes without disturbing their structures, but also abundant negative charges which enable selective and efficient encapsulation of cationic enzymes. The loading capacities of PAA nanogels for cytochrome (cyt c) and lysozyme are 100 and 125 µg/mg (enzyme/nanogel), respectively. More notably, the PAA network seems to modulate a favorable microenvironment for cyt c and induces 2-fold enhanced activity for the encapsulated enzymes, as indicated by the steady-state kinetic assay. Our study reveals the control factors of EADP for optimal synthesis of anionic nanogels and validates their distinctive advances with respect to efficient loading and activation of cationic enzymes.
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Polietilenglicoles , Polímeros , Nanogeles , Polielectrolitos , Polietilenglicoles/química , Polimerizacion , Electricidad EstáticaRESUMEN
BACKGROUND: Short-term starvation (STS) has gradually been confirmed as a treatment method that synergistically enhances the effect of chemotherapy on malignant tumours. In clinical applications, there are still some limitations of poly (ADP-ribose) polymerase inhibitors (PARPi), including understanding their effectiveness and side effects. Here, we sought to investigate the effect and mechanism of the combined use of STS and niraparib in the treatment of ovarian cancer. METHODS: In in vitro experiments, SKOV3 and A2780 ovarian cancer cells were treated with STS and niraparib alone or in combination. Cell viability was assessed with CCK-8, and cell cycle, apoptosis, DNA damage repair and autophagy were examined to explore the molecular mechanisms. Akt and mTOR inhibitors were used to examine any changes in DNA damage repair levels. Xenograft animal models were treated with STS and niraparib, and HE staining and immunohistochemistry were performed to examine the effects. RESULTS: The combined use of STS and niraparib inhibited cell proliferation and increased apoptosis more than niraparib application alone. In addition, compared with the niraparib group, the STS + niraparib group had increased G2/M arrest, DNA damage and autophagy, which indicated that STS pretreatment enhanced the cytotoxicity of niraparib. In animal experiments, STS did not affect the growth of transplanted tumours, but the combined treatment synergistically enhanced the cytotoxicity of niraparib. In in vivo experiments, STS did not affect the growth of transplanted tumours, but the combined treatment synergistically enhanced the cytotoxicity of niraparib and reduced the small intestinal side effects caused by niraparib chemotherapy. CONCLUSION: STS pretreatment can synergistically enhance the cytotoxicity of niraparib. STS + niraparib is a potentially effective strategy in the maintenance therapy of ovarian cancer.
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Remote sensing image data clustering is a tough task, which involves classifying the image without any prior information. Remote sensing image clustering, in essence, belongs to a complex optimization problem, due to the high dimensionality and complexity of remote sensing imagery. Therefore, it can be easily affected by the initial values and trapped in locally optimal solutions. Meanwhile, remote sensing images contain complex and diverse spatial-spectral information, which makes them difficult to model with only a single objective function. Although evolutionary multiobjective optimization methods have been presented for the clustering task, the tradeoff between the global and local search abilities is not well adjusted in the evolutionary process. In this article, in order to address these problems, a multiobjective sine cosine algorithm for remote sensing image data spatial-spectral clustering (MOSCA_SSC) is proposed. In the proposed method, the clustering task is converted into a multiobjective optimization problem, and the Xie-Beni (XB) index and Jeffries-Matusita (Jm) distance combined with the spatial information term (SI_Jm measure) are utilized as the objective functions. In addition, for the first time, the sine cosine algorithm (SCA), which can effectively adjust the local and global search capabilities, is introduced into the framework of multiobjective clustering for continuous optimization. Furthermore, the destination solution in the SCA is automatically selected and updated from the current Pareto front through employing the knee-point-based selection approach. The benefits of the proposed method were demonstrated by clustering experiments with ten UCI datasets and four real remote sensing image datasets.
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Objective: To explore the association between serum LH levels and the cumulative live birth rate (CLBR) within one complete cycle, and the impact of serum LH levels on the live birth rate (LBR) after the initial embryo transfer (ET) considering different ET strategies (fresh or freeze-all). Design: A retrospective cohort study. Setting: University-affiliated reproductive center. Patients: 1480 normogonadotrophic women who underwent COS with GnRH antagonist protocol for the first IVF/ICSI attempt. Interventions: The sample was stratified into low and higher LH groups according to serum LH peak levels of <4 (Group A) and ≥4 IU/L (Group B) during COS. Patients were also sub-grouped into conventional fresh/frozen ET cycles and freeze-all cycles. Main outcome measures: The LBR after the initial embryo transfer and the CLBR within one complete cycle. Secondary outcome measures: The numbers of day-3 high-quality embryos, the numbers of embryos available, and the other pregnancy outcomes after the initial ET. Results: In the whole cohort, the CLBRs decreased significantly in the low (63.1% vs. 68.3%, P=.034) LH group compared to the higher LH group. Subgroup analysis revealed that patients with low LH levels had lower LBR after fresh ET (38.0% vs. 51.5%, P=.005) but comparable LBR after the first frozen-thawed ET (FET) in freeze-all cycles (49.8% vs. 51.8%, P=.517) than patients with higher LH peak levels. Likewise, patients with low LH levels had lower CLBR for conventional fresh/frozen ET cycles (54.8% vs. 66.1%, P=.015) but comparable CLBR for the freeze-all cycles (66.8% vs. 69.2%, P=.414) than those with higher LH levels. Following confounder adjustment, multivariable regression analyses showed that low LH level was an independent risk factor for the CLBR in the whole cohort (odds ratio (OR): 0.756, 95% confidence interval (CI): 0.604-0.965, P=.014) and in patients who underwent the conventional ET strategy (OR: 0.596, 95% CI: 0.408-0.917, P=.017). Moreover, the adverse impact of low LH levels on LBRs maintained statistically significant after fresh transfers (OR: 0.532, 95% CI: 0.353-0.800, P=.002) but not after the first FETs in freeze-all cycles (OR: 0.918, 95% CI: 0.711-1.183, P=.508). Conclusions: In comparison with higher LH levels, low LH levels decrease the CLBRs per oocyte retrieval cycle for normogonadotrophic women who underwent COS using GnRH antagonists. This discrepancy may arise due to the significant detrimental effect of low LH levels on the LBRs after fresh embryo transfers.
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Transferencia de Embrión/métodos , Fertilización In Vitro/métodos , Hormona Luteinizante/sangre , Inducción de la Ovulación/métodos , Adulto , Tasa de Natalidad , Femenino , Congelación , Antagonistas de Hormonas , Humanos , Recuperación del Oocito , Embarazo , Resultado del Embarazo , Índice de Embarazo , Estudios Retrospectivos , Inyecciones de Esperma Intracitoplasmáticas/métodos , UniversidadesRESUMEN
RESEARCH QUESTION: Granulosa cells (GCs) surrounding oocytes are crucial for follicular growth, oocyte development, ovulation, and luteinization under the dynamic co-stimulation of follicle stimulating hormone (FSH) and luteinizing hormone (LH). This study aimed to investigate the effect of LH levels on GCs in preovulatory follicles under gonadotropin releasing hormone antagonist-based ovarian stimulation. In vitro experiments were also conducted to study the direct effect of LH on GCs. METHODS: Twelve infertile women were divided into low (L), medium (M), and high (H) LH groups according to their serum LH levels during ovarian stimulation. RNA-sequencing (RNA-seq) was conducted to examine the transcriptome profiles of GCs obtained from the above patients during the oocyte retrieval. The activity of mitochondrial dehydrogenase was measured under the stimulation of recombinant LH (rLH) concentration gradient combined with recombinant FSH. The ultrastructures of subcellular organelles were observed. RESULTS: Bioinformatic analyses showed that compared with the M group, molecule and pathway changes in the L group and in the H group were similar. In cultured GCs, both insufficient and excessive rLH impaired the activity of mitochondrial dehydrogenase. With the medium rLH concentration, numerous cell connections and abundant mitochondria and liposomes were observed. Compared with the medium concentration, GCs showed smaller and rounder mitochondria, more autophagosomes, and massive organelles damages with excessive rLH, and swollen, circular, or forked mitochondria were observed with inadequate rLH. CONCLUSIONS: RNA-seq provided a novel spectrum of transcriptome characteristics of GCs potentially affected by serum LH levels during ovarian stimulation. In vitro, rLH could directly affect GCs at the subcellular level.