Streptococcal pyrogenic exotoxin B cleaves GSDMA and triggers pyroptosis.

Gasdermins, a family of five pore-forming proteins (GSDMA-GSDME) in humans expressed predominantly in the skin, mucosa and immune sentinel cells, are key executioners of inflammatory cell death (pyroptosis), which recruits immune cells to infection sites and promotes protective immunity1,2. Pore formation is triggered by gasdermin cleavage1,2. Although the proteases that activate GSDMB, C, D and E have been identified, how GSDMA-the dominant gasdermin in the skin-is activated, remains unknown. Streptococcus pyogenes, also known as group A Streptococcus (GAS), is a major skin pathogen that causes substantial morbidity and mortality worldwide3. Here we show that the GAS cysteine protease SpeB virulence factor triggers keratinocyte pyroptosis by cleaving GSDMA after Gln246, unleashing an active N-terminal fragment that triggers pyroptosis. Gsdma1 genetic deficiency blunts mouse immune responses to GAS, resulting in uncontrolled bacterial dissemination and death. GSDMA acts as both a sensor and substrate of GAS SpeB and as an effector to trigger pyroptosis, adding a simple one-molecule mechanism for host recognition and control of virulence of a dangerous microbial pathogen.

Disulfiram blocks inflammatory TLR4 signaling by targeting MD-2.

Toll-like receptor 4 (TLR4) sensing of lipopolysaccharide (LPS), the most potent pathogen-associated molecular pattern of gram-negative bacteria, activates NF-κB and Irf3, which induces inflammatory cytokines and interferons that trigger an intense inflammatory response, which is critical for host defense but can also cause serious inflammatory pathology, including sepsis. Although TLR4 inhibition is an attractive therapeutic approach for suppressing overexuberant inflammatory signaling, previously identified TLR4 antagonists have not shown any clinical benefit. Here, we identify disulfiram (DSF), an FDA-approved drug for alcoholism, as a specific inhibitor of TLR4-mediated inflammatory signaling. TLR4 cell surface expression, LPS sensing, dimerization and signaling depend on TLR4 binding to MD-2. DSF and other cysteine-reactive drugs, previously shown to block LPS-triggered inflammatory cell death (pyroptosis), inhibit TLR4 signaling by covalently modifying Cys133 of MD-2, a key conserved residue that mediates TLR4 sensing and signaling. DSF blocks LPS-triggered inflammatory cytokine, chemokine, and interferon production by macrophages in vitro. In the aggressive N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson's disease (PD) in which TLR4 plays an important role, DSF markedly suppresses neuroinflammation and dopaminergic neuron loss, and restores motor function. Our findings identify a role for DSF in curbing TLR4-mediated inflammation and suggest that DSF and other drugs that target MD-2 might be useful for treating PD and other diseases in which inflammation contributes importantly to pathogenesis.

Radiosurgery versus observation for brainstem cavernous malformations: a 5-year multicentre cohort study.

The role of radiosurgery in preventing haemorrhage in brainstem cavernous malformations remains a subject of debate. This study aims to evaluate whether radiosurgery provides a protective benefit against haemorrhage in these patients. This multicentre, prospective observational study was conducted in 17 centres and enrolled eligible patients with brainstem cavernous malformations consecutively. Data collected included clinical baseline information, radiosurgery planning details, periodic follow-up evaluations, and any adverse radiation effects. The primary outcome of the study was the incidence of first prospective haemorrhage, while the secondary outcome was the development of new or worsening neurological dysfunctions. The impact of radiosurgery was assessed using multivariate Cox regression analysis. From March 2016 to August 2018, the study enrolled 377 patients: 280 in the observation group receiving standard care alone and 97 in the radiosurgery group receiving both radiosurgery and standard care. The overall cohort consisted of 173 females (45.9%) with a mean age of 40.5 years (range, 18-68 years), and there were no significant differences in baseline characteristics between the two groups. After a median follow-up period of 70 months, haemorrhage occurred in 25.0% (n = 70) of patients in the observation group and 10.3% (n = 10) of patients in the radiosurgery group. Multivariate Cox regression analysis identified radiosurgery as an independent protective factor against haemorrhage (hazard ratio 0.379, 95% confidence interval 0.195-0.738, P = 0.004). Following 1:2 propensity score matching, the incidence of prospective haemorrhage were 24.9% (45/181) in the observation group compared to 10.3% (10/97) in the radiosurgery group (hazard ratio 0.379, 95% confidence interval 0.190-0.755, P = 0.006). Adverse radiation effects were observed in 12 patients (12.4%), with none were permanent. Additionally, new or worsening neurological dysfunctions were significantly more common in the observation group (28.9%) compared to the radiosurgery group (16.5%) (P = 0.016). These results suggest that radiosurgery is associated with a low rate of haemorrhage in patients with brainstem cavernous malformations and could provide a benefit in selected patients. However, further research is required to confirm these findings.

HNRNPC modulates PKM alternative splicing via m6A methylation, upregulating PKM2 expression to promote aerobic glycolysis in papillary thyroid carcinoma and drive malignant progression.

The heterogeneous nuclear ribonucleoprotein C (HNRNPC) plays a crucial role in tumorigenesis, yet its role in papillary thyroid carcinoma (PTC) remains elusive. Herein, we elucidated the function and molecular mechanism of HNRNPC in PTC tumorigenesis and progression. Our study unveiled a significant upregulation of HNRNPC in PTC, and knockdown of HNRNPC markedly inhibited the proliferation, invasion, and metastasis of BCPAP cells. Furthermore, HNRNPC modulated PKM alternative splicing in BCPAP cells primarily through m6A modification. Additionally, by upregulating PKM2 expression, HNRNPC promoted aerobic glycolysis in BCPAP cells, thereby facilitating malignant progression in PTC. In summary, our findings demonstrate that HNRNPC regulates PKM alternative splicing through m6A methylation modification and promotes the proliferation, invasion and metastasis of PTC through glucose metabolism pathways mediated by PKM2. These discoveries provide new biomarkers for screening and diagnosing PTC patients and offer novel therapeutic targets for personalized treatment strategies.

Mutation of TP53 Confers Ferroptosis Resistance in Lung Cancer Through the FOXM1/MEF2C Axis.

Ferroptosis is a highly regulated tumor suppressor process. Loss or mutation of TP53 can cause changes in sensitivity to ferroptosis. Mutations in TP53 may be associated with the malignant or indolent progression of ground glass nodules in early lung cancer, but whether ferroptosis may also be involved in determining this biological process has not yet been determined. Using in vivo and in vitro gain- and loss-of-function approaches, this study used clinical tissue for mutation analysis and pathological research to show that wild-type TP53 inhibited the expression of forkhead box M1 (FOXM1) by binding to peroxisome proliferator-activated receptor-γ coactivator 1α, maintaining the mitochondrial function and thus affecting the sensitivity to ferroptosis. This function was absent in mutant cells, resulting in overexpression of FOXM1 and ferroptosis resistance. Mechanistically, FOXM1 activated the transcription level of myocyte-specific enhancer factor 2C in the mitogen-activated protein kinase signaling pathway, leading to stress protection when exposed to ferroptosis inducers. This study provides new insights into the mechanism of association between TP53 mutation and ferroptosis tolerance, which can aid a deeper understanding of the role of TP53 in the malignant progression of lung cancer.

Ultra-slow-light and dynamically quantitative optical storage modulation via quasi-BICs.

We achieve dynamically tunable dual quasi-bound states in the continuum (quasi-BICs) by implementing them in a silicon-graphene multilayer composite structure and utilize the quasi-BIC modes to achieve ultra-large group delays (velocity of light slows down 105 times), showing 2-3 orders of magnitude higher than the group delays of previous electromagnetically induced transparency modes. The double-layer graphene holds great tuning capability and leads to the dramatically reduced group delay from 1929.82 to 1.58 ps with only 100 meV. In addition, the log-linear variation rule of group delay with Fermi level (Ef) in the range of 0-10 meV is analyzed in detail, and the double-logarithmic function relationship between the group delay and quality factor (Q-factor) is theoretically verified. Finally, the quantitative modulation of the optical storage is further realized in this basis. Our research provides ideas for the reform and upgrading of slow optical devices.

Nonreciprocal polarized transmission via bound states in the continuum.

We realize the observation of near-unity nonreciprocal polarized transmission via the bound states in the continuum (BICs) in a double-layer grating structure. By introducing out-of-plane perturbations and topological defects that break the mirror symmetry between the upper and lower layers, the far-field polarization states in momentum space are inverted vertically and horizontally, showing mirrored polarization characteristics for incident channels from different upper and lower ports. During the process of introducing mirror perturbations in the upper and lower layers, a π/2 phase inversion occurs in the Г-M direction, making chirality possible. Utilizing this bidirectionally tunable nonreciprocal spatiotemporal phase transition enables multiple modulations of polarization states and opens up more possibilities for asymmetric light manipulation in chiral optical effects.

Hemorrhagic Outcome of Brainstem Cavernous Malformations following Radiosurgery: Dose-Response Relationship.

INTRODUCTION: This study aimed to assess the impact of gamma knife radiosurgery on brainstem cavernous malformations (CMs). METHODS: A total of 85 patients (35 females; median age 41.0 years) who underwent gamma knife radiosurgery for brainstem CMs at our institute between 2006 and 2015 were enrolled in a prospective clinical observation trial. Risk factors for hemorrhagic outcomes were evaluated, and outcomes were compared across different margin doses. RESULTS: The pre-radiosurgery annual hemorrhage rate (AHR) was 32.3% (44 hemorrhages during 136.2 patient-years). The median planning target volume was 1.292 cc. The median margin and maximum doses were 15.0 and 29.2 Gy, respectively, with a median isodose line of 50.0%. The post-radiosurgery AHR was 2.7% (21 hemorrhages during 769.9 patient-years), with a rate of 5.5% within the first 2 years and 2.0% thereafter. The post-radiosurgery AHR for patients with margin doses of ≤13.0 Gy (n = 15), 14.0-15.0 Gy (n = 50), and ≥16.0 Gy (n = 20) was 5.4, 2.7, and 0.6%, respectively. Correspondingly, transient adverse radiation effects were observed in 6.7 (1/15), 10.0 (5/50), and 30.0% (6/20) of cases, respectively. An increased margin dose per 1 Gy (hazard ratio: 0.530, 95% CI: 0.341-0.826, p = 0.005) was identified as an independent protective factor against post-radiosurgery hemorrhage. Margin doses of ≥16.0 Gy were associated with improved hemorrhagic outcomes (hazard ratio: 0.343, 95% confidence interval [CI]: 0.157-0.749, p = 0.007), but an increased risk of adverse radiation effects (odds ratio: 3.006, 95% CI: 1.041-8.677, p = 0.042). CONCLUSION: The AHR of brainstem CMs decreased following radiosurgery, and our study revealed a significant dose-response relationship. Margin doses of 14-15 Gy were recommended. Further studies are required to validate our findings.

Phytochemical Profile of Alkaloid Extract from Dendrobium huoshanense and Inhibitory Effects against Oxidative Stress in H2 O2 -Induced PC12 Cells.

This study aimed to explore the alkaloid profile of Dendrobium huoshanense and determine the potential protective effect against oxidative damage. The crude D. huoshanense alkaloid extract (DHAE) was obtained by 70 % ethanol extraction and liquid-liquid partition. DHAE contained specific alkaloid components with abundant 6-hydroxynobiline (58.15 %) and trace dendrobine (3.23 %) in the preliminary HPLC fingerprint and GC-MS analysis, which was distinguished from D. officinale or D. nobile. Subsequently, six alkaloids including 6-hydroxynobiline, 2-hydroxy dendrobine, nobilonine, dendrobine, Findlayines D and trans-dendrochrysanine were identified in the purified DHAE (namely DHSAE-3, DHSAE-3') via further solid phase extraction coupled with UPLC-MS/MS analysis. Meanwhile, pretreatment with DHAE or DHSAE (0.5, 5 µg/mL) increased cell viability by 14.0-57.4 % compared to that of H2 O2 -induced PC12 Model cells. Among them, 5 µg/mL DHSAE-3-treated cells displayed a pronounced reversion than the positive vitamin E (p<0.01). Furthermore, a clear cellular morphological restoration and 38.4 % reduction in intracellular reactive oxidative species level were achieved. Our findings suggest that D. huoshanense has a characteristic alkaloid profile represented by abundant 6-hydroxynobiline, and DHAEs exhibit obvious protection against oxidative neuronal damage. Overall, this study indicates that DHAEs might be used to inhibit oxidative stress and provide a source to develop novel neuroprotective drugs.

The efficacy of simulation-based learning versus non-simulation-based learning in endocrinology education: a systematic review and meta-analysis.

BACKGROUND: Simulation-Based Learning (SBL) is increasingly adopted in medical education across various specialties, employing realistic simulations to significantly enhance learning experiences. However, a comprehensive evaluation of its effectiveness specifically in endocrinology has not yet been conducted. The study aims to systematically review and meta-analyze the impact of SBL versus Non-Simulation-Based Learning (NSBL) on knowledge acquisition, skills, satisfaction, and interest in learning among endocrinology trainees. METHODS: This systematic review and meta-analysis adhered to the PRISMA guidelines, searching PubMed, Web of Science, Embase, Cochrane library, China National Knowledge Infrastructure (CNKI), Wanfang Data, Weipu, and Chinese Biomedical Database (CBM) until March 2024. We included randomized controlled trials comparing SBL to NSBL in endocrinology education. The quality evaluation relied on the Cochrane risk-of-bias assessment tool. The main results included evaluations from both theoretical and practical assessments. Additional measures consisted of assessing satisfaction and interest in learning. RESULTS: We identified 22 studies suitable for systematic review and 21 for meta-analysis, involving a total of 2517 participants. SBL greatly enhanced theoretical knowledge [standardized mean difference (SMD) = 1.00, 95% confidence interval (CI): 0.68-1.32, P < 0.00001, I2 = 89%] and practical skills (SMD = 1.56, 95% CI: 1.11-2.01, P < 0.00001, I2 = 93%) compared to NSBL. Additionally, SBL was associated with higher satisfaction and greater interest in learning. No significant publication bias was detected, and sensitivity analysis confirmed the stability of these findings. CONCLUSIONS: SBL significantly enhances knowledge, skills, satisfaction, and interest in learning within endocrinology education compared to NSBL. These findings support the integration of high-quality SBL into endocrinology curricula to improve educational outcomes. Future research should explore the lasting effects of SBL on knowledge retention and clinical practice, as well as to evaluate its cost-effectiveness and compatibility with various educational tools in diverse settings.

A LiF-Rich Solid Electrolyte Interphase in a Routine Carbonate Electrolyte by Tuning the Interfacial Chemistry Behavior of LiPF6 for Stable Li Metal Anodes.

Lithium (Li) dendrite growth in a routine carbonate electrolyte (RCE) is the main culprit hindering the practical application of Li metal anodes. Herein, we realize the regulation of the LiPF6 decomposition pathway in RCE containing 1.0 M LiPF6 by introducing a "self-polymerizing" additive, ethyl isothiocyanate (EITC), resulting in a robust LiF-rich solid electrolyte interphase (SEI). The effect of 1 vol % EITC on the electrode/electrolyte interfacial chemistry slows the formation of the byproduct LixPOFy. Such a LiF-rich SEI with EITC polymer winding exhibits a high Young's modulus and a uniform Li-ion flux, which suppresses dendrite growth and interface fluctuation. The EITC-based Li metal cell using a Li4Ti5O12 cathode delivers a capacity retention of 81.4% over 1000 cycles at 10 C, outperforming its counterpart. The cycling stability of 1 Ah pouch cells was further evaluated under EITC. We believe that this work provides a new method for tuning the interfacial chemistry of Li metal through electrolyte additives.

Engineering Triple-Phase Interfaces Enabled by Layered Double Perovskite Oxide for Boosting Polysulfide Redox Conversion.

The electrocatalytic conversion of polysulfides is crucial to lithium-sulfur batteries and mainly occurs at triple-phase interfaces (TPIs). However, the poor electrical conductivity of conventional transition metal oxides results in limited TPIs and inferior electrocatalytic performance. Herein, a TPI engineering approach comprising superior electrically conductive layered double perovskite PrBaCo2O5+δ (PBCO) is proposed as an electrocatalyst to boost the conversion of polysulfides. PBCO has superior electrical conductivity and enriched oxygen vacancies, effectively expanding the TPI to its entire surface. DFT calculation and in situ Raman spectroscopy manifest the electrocatalytic effect of PBCO, proving the critical role of enhanced electrical conductivity of this electrocatalyst. PBCO-based Li-S batteries exhibit an impressive reversible capacity of 612 mAh g-1 after 500 cycles at 1.0 C with a capacity fading rate of 0.067% per cycle. This work reveals the mechanism of the enriched TPI approach and provides novel insight into designing new catalysts for high-performance Li-S batteries.

Tuning Shortwave-Infrared J-aggregates of Aromatic Ring-Fused Aza-BODIPYs by Peripheral Substituents for Combined Photothermal and Photodynamic Therapies at Ultralow Laser Power.

Achieving photothermal therapy (PTT) at ultralow laser power density is crucial for minimizing photo-damage and allowing for higher maximum permissible skin exposure. However, this requires photothermal agents to possess not just superior photothermal conversion efficiency (PCE), but also exceptional near-infrared (NIR) absorptivity. J-aggregates, exhibit a significant redshift and narrower absorption peak with a higher extinction coefficient. Nevertheless, achieving predictable J-aggregates through molecular design remains a challenge. In this study, we successfully induced desirable J-aggregation (λabs max : 968 nm, ϵ: 2.96×105  M-1 cm-1 , λem max : 972 nm, ΦFL : 6.2 %) by tuning electrostatic interactions between π-conjugated molecular planes through manipulating molecular surface electrostatic potential of aromatic ring-fused aza-BODIPY dyes. Notably, by controlling the preparation method for encapsulating dyes into F-127 polymer, we were able to selectively generate H-/J-aggregates, respectively. Furthermore, the J-aggregates exhibited two controllable morphologies: nanospheres and nanowires. Importantly, the shortwave-infrared J-aggregated nanoparticles with impressive PCE of 72.9 % effectively destroyed cancer cells and mice-tumors at an ultralow power density of 0.27 W cm-2 (915 nm). This phototherapeutic nano-platform, which generates predictable J-aggregation behavior, and can controllably form J-/H-aggregates and selectable J-aggregate morphology, is a valuable paradigm for developing photothermal agents for tumor-treatment at ultralow laser power density.

Novel roles of PIWI proteins and PIWI-interacting RNAs in human health and diseases.

Non-coding RNA has aroused great research interest recently, they play a wide range of biological functions, such as regulating cell cycle, cell proliferation, and intracellular substance metabolism. Piwi-interacting RNAs (piRNAs) are emerging small non-coding RNAs that are 24-31 nucleotides in length. Previous studies on piRNAs were mainly limited to evaluating the binding to the PIWI protein family to play the biological role. However, recent studies have shed more lights on piRNA functions; aberrant piRNAs play unique roles in many human diseases, including diverse lethal cancers. Therefore, understanding the mechanism of piRNAs expression and the specific functional roles of piRNAs in human diseases is crucial for developing its clinical applications. Presently, research on piRNAs mainly focuses on their cancer-specific functions but lacks investigation of their expressions and epigenetic modifications. This review discusses piRNA's biogenesis and functional roles and the recent progress of functions of piRNA/PIWI protein complexes in human diseases. Video Abstract.

Overexpression of TPM4 is associated with worse prognosis and immune infiltration in patients with glioma.

BACKGROUND: Tropomyosin 4 (TPM4), a member of the tropomyosin family, is aberrantly expressed and plays an important role in a variety of cancers. However, studies on TPM4 in glioma patients are currently lacking. OBJECTIVE: Our study aimed to evaluate the diagnostic and prognostic characteristics of TPM4 in glioma and its correlation with immune infiltration. METHODS: Bioinformatic analysis was performed to determine whether TPM4 has diagnostic and prognostic value for glioma. The following databases and analytical tools were used to explore the clinical significance of TPM4 in glioma: TCGA, GTEx, GEO, STRING, and TISIDB. RESULTS: Our study showed that the mRNA and protein expression levels of TPM4 were significantly higher in glioma than in healthy brain tissue. Kaplan-Meier analysis indicated that high expression of TPM4 in glioma correlated with poor prognosis. Univariate Cox analysis indicated that the high expression level of TPM4 in glioma was an independent prognostic characteristic for low overall survival (OS). The areas under the 1-year survival ROC, 2-year survival ROC, and 3-year survival ROC were all greater than 0.8. GO and KEGG enrichment analysis and GSEA showed that humoral immune response and cytokine receptor interaction were significantly enriched in the TPM4 high expression group, where M phase of the cell cycle, neutrophil degranulation, signaling by interleukins, and signaling by rho GTPases were significantly enriched. Furthermore, according to the analysis of immune cell infiltration, TPM4 was associated with tumor infiltration of a variety of immune cells. CONCLUSIONS: In conclusion, our study suggests that TPM4 may be an effective prognostic biomarker for glioma patients, providing new ideas and research directions for glioma research.

Percutaneous radiofrequency thermocoagulation and microvascular decompression for treating glossopharyngeal neuralgia: a retrospective clinical study.

OBJECTIVES: This study aimed to investigate the differences in the effectiveness of percutaneous radiofrequency thermocoagulation (PRT) and microvascular decompression (MVD) in treating glossopharyngeal neuralgia (GPN). METHODS: Medical records of patients were reviewed to investigate their baseline characteristics and immediate postoperative prognosis. Long-term outcomes of these patients were obtained through telephone interviews. Visual analog scale (VAS) and Pittsburgh sleep quality index (PSQI) scores at 1 day and 1, 4, 12, 24, and 48 weeks after surgery were compared between the MVD and PRT groups, in addition to complete pain relief rate, effective rate, adverse reactions, length of hospital stay, and economic indicators. RESULTS: The VAS and PSQI scores of the two groups at 1 day and 1, 4, 12, 24, and 48 weeks after surgery were significantly lower (P < 0.05) than those before surgery. At 48 weeks, the complete remission rate was significantly higher (P < 0.05) in the MVD group than in PRT group. No significant difference in adverse reactions was observed between the two groups. The length of hospital stay, operative time, and cost were significantly higher (P < 0.05) in the MVD group than in the PRT group. CONCLUSIONS: Both PRT and MVD can significantly reduce patients' degree of pain and improve their sleep quality. In the medium term, MVD is better than PRT in terms of the complete curative effect. In young patients with GPN, MVD is more often recommended than PRT; however, MVD is costlier than PRT.

Diverse long-term potentiation and depression based on multilevel LiSiOxmemristor for neuromorphic computing.

Memristor-based neuromorphic computing is expected to overcome the bottleneck of von Neumann architecture. An artificial synaptic device with continuous conductance variation is essential for implementing bioinspired neuromorphic systems. In this work, a memristor based on Pt/LiSiOx/TiN structure is developed to emulate an artificial synapse, which shows non-volatile multilevel resistance state memory behavior. Moreover, the high nonlinearity caused by abrupt changes in the set process is optimized by adjusting the initial resistance. 100 levels of continuously modulated conductance states are achieved and the nonlinearity factors are reduced to 1.31. The significant improvement is attributed to the decrease in the Schottky barrier height and the evolution of the conductive filaments. Finally, due to the improved linearity of the long-term potentiation/long-term depression behaviors in LiSiOxmemristor, a robust recognition rate (∼94.58%) is achieved for pattern recognition with the modified National Institute of Standards and Technology handwriting database. The Pt/LiSiOx/TiN memristor shows significant potential in high-performance multilevel data storage and neuromorphic computing systems.

Thermal ablation versus radiotherapy for inoperable stage III non-small cell lung cancer: a propensity score matching analysis.

OBJECTIVE: To compare the survival benefits of thermal ablation (TA) and radiotherapy in inoperable patients with stage III non-small cell lung cancer (NSCLC). METHOD: A retrospective analysis was conducted using the data from the Surveillance, Epidemiology, and End Results (SEER) program. Propensity score matching (PSM) was conducted to balance potential baseline confounding factors. Survival analyses were conducted using Kaplan-Meier and Cox regression methods. RESULTS: The present study included 33,393 inoperable patients with stage III NSCLC, including 106 patients treated with TA and 33,287 patients treated with radiotherapy. No statistical difference in overall survival (OS) (p = .065) or cancer-specific survival (CSS) (p = .996) was found between the patients treated with TA and those treated with radiotherapy. Using 1:3 matching, a matched cohort of 420 patients (105 patients treated with TA, 315 patients treated with radiotherapy) was identified. The differences in OS (p = .177) and CSS (p = .605) were still not significant between the radiotherapy and TA groups after PSM. According to subgroup analyses, TA showed comparable survival benefits in almost all subgroups compared to radiotherapy. CONCLUSION: For inoperable stage III NSCLC, the survival benefit of TA was comparable to radiotherapy. TA may be a potential therapeutic modality for inoperable stage III NSCLC.

Brief and long co-incubation of sperm and oocytes for in vitro fertilization: a meta-analysis of randomized controlled trials.

BACKGROUND: There is still no consensus on the optimal time of oocyte-sperm co-incubation during in vitro fertilization and embryo transfer (IVF-ET). The aim of this meta-analysis was to compare the effects of brief (1-6 h) and long (16-24 h) gametes co-incubation time on IVF outcomes. METHODS: The study protocol was registered online through PROSPERO (CRD42022337503) and PRISMA guidelines were followed in the present study. The following databases were searched from inception to May 2022 for randomized controlled trials (RCTs): PubMed, Embase, Cochrane library, Web of Science, using search terms related to IVF, gametes, time of co-incubation and reproductive outcome measure. Studies comparing outcomes of brief co-incubation to that of long co-incubation during IVF, and reporting primary outcome (live birth rate), secondary outcomes (clinical pregnancy rate; ongoing pregnancy rate; miscarriage rate; normal fertilization rate; polyspermy rate; top-quality embryo rate; implantation rate) were searched. A total of 11 studies were included in the meta-analysis. Combined odds ratio (OR) and 95% confidence interval (CI) were calculated for the data. Statistical heterogeneity analysis between studies was assessed by Cochran Q and I2 statistic with a significant threshold of P < 0.05. Methodologic quality assessment of RCTs was made for potential risk of bias with Cochrane Risk of Bias Tool. RESULTS: Compared to long-term co-incubation, brief co-incubation had an advantage in increasing implantation rate (OR: 1.97, 95% CI: 1.52-2.57), ongoing pregnancy rate (OR: 2.18, 95% CI: 1.44-3.29) and top-quality embryo rate (OR: 1.17, 95% CI: 1.02-1.35). However, brief co-incubation of gametes had no advantages in the live-birth rate (OR: 1.09, 95% CI: 0.72-1.65), miscarriage rate (OR: 1.32, 95% CI: 0.55-3.18), clinical pregnancy rate (OR: 1.36, 95% CI: 0.99-1.87) and polyspermy rate (OR: 0.80, 95% CI: 0.48-1.33) than long-term co-incubation. Additionally, the brief co-incubation was associated with lower normal fertilization rate (OR: 0.89, 95% CI: 0.80-0.99), compared with long co-incubation. CONCLUSIONS: Brief co-incubation of gametes had the advantages in increasing implantation rate, ongoing pregnancy rate and top-quality embryo rate than long-term co-incubation. However, the live-birth rate displayed no difference between the two in vitro fertilization methods. Gametes co-incubation time should be individualized according to each patient's IVF history, infertility causes and the semen parameters.