[Transition metal accumulation and cellular senescence].

Aging refers to a progressive decline in biological functions, leading to age-related diseases and mortality. The transition metals, including iron, copper, and manganese, play important roles in human physiological and pathological processes. Substantial research has demonstrated that senescent cells accumulate higher levels of transition metals, which in turn accelerates the process of cellular senescence and related diseases through mechanisms such as production of excessive reactive oxygen species (ROS), induction of oxidative stress, DNA damage, and mitochondrial dysfunction. This review article provides a comprehensive overview of the causes of transition metal accumulation in senescent cells, as well as the mechanisms by which it further promotes cellular senescence and related diseases. The aim is to provide insights into anti-aging and treatment of aging-related diseases caused by transition metal accumulation.

Image-based molecular representation learning for drug development: a survey.

Artificial intelligence (AI) powered drug development has received remarkable attention in recent years. It addresses the limitations of traditional experimental methods that are costly and time-consuming. While there have been many surveys attempting to summarize related research, they only focus on general AI or specific aspects such as natural language processing and graph neural network. Considering the rapid advance on computer vision, using the molecular image to enable AI appears to be a more intuitive and effective approach since each chemical substance has a unique visual representation. In this paper, we provide the first survey on image-based molecular representation for drug development. The survey proposes a taxonomy based on the learning paradigms in computer vision and reviews a large number of corresponding papers, highlighting the contributions of molecular visual representation in drug development. Besides, we discuss the applications, limitations and future directions in the field. We hope this survey could offer valuable insight into the use of image-based molecular representation learning in the context of drug development.

Mild heat stress promotes the differentiation of odontoblast-like MDPC-23 cells via yes-associated protein.

PURPOSE: Dentin hypersensitivity (DH) is a prevalent condition, but long-term effective treatments are scarce. Differentiation of odontoblast-like cells is promising for inducing tertiary dentinogenesis and ensuring sustained therapeutic efficacy against DH. This study examined the effects and mechanism of action of mild heat stress (MHS) on the differentiation of odontoblast-like MDPC-23 cells. METHODS: We used a heating device to accurately control the temperature and duration, mimicking the thermal microenvironment of odontoblast-like cells. Using this device, the effects of MHS on cell viability and differentiation were examined. Cell viability was assessed using the MTT assay. The expression and nucleoplasmic ratio of the yes-associated protein (YAP) were examined by western blotting and immunofluorescence. The gene expression levels of heat shock proteins (HSPs) and dentin matrix protein-1 (DMP1) were measured using qPCR. Dentin sialophosphoprotein (DSPP) expression was evaluated using immunofluorescence and immunoblotting. Verteporfin was used to inhibit YAP activity. RESULTS: Mild heat stress (MHS) enhanced the odontoblast differentiation of MDPC-23 cells while maintaining cell viability. MHS also increased YAP activity, as well as the levels of HSP25 mRNA, HSP70 mRNA, HSP90α mRNA, DMP1 mRNA, and DSPP protein. However, after YAP inhibition, both cell viability and the levels of HSP90α mRNA, DMP1 mRNA, and DSPP protein were reduced. CONCLUSION: YAP plays a crucial role in maintaining cell viability and promoting odontoblast differentiation of MDPC-23 cells under MHS. Consequently, MHS is a potential therapeutic strategy for DH, and boosting YAP activity could be beneficial for maintaining cell viability and promoting odontoblast differentiation.

Longitudinal strain correlates with 6-minute walk distance whereas ejection fraction and diastolic parameters do not.

BACKGROUND: Impaired functional capacity is a common symptom in patients with heart failure. Standard measures of left ventricular (LV) function, such as ejection fraction (EF) and LV diastolic parameters, do not correlate with measures of functional capacity. The aim of this study is to determine if measures of global and regional LV strain better correlate with 6-minute walk distance than does EF or measures of LV diastolic function. METHODS: 120 patients referred to a cardiology clinic for evaluation of known or suspected heart failure were approached for enrollment. Of those 120 patients, 58 had an echocardiogram within 3 months of enrollment with images adequate for regional and global strain assessment, had no contra-indication to exercise testing, and had no previously documented non-cardiac explanation for dyspnea on exertion. In those 58 patients, 6-minute walk distance was measured, LV EF was determined with Simpson's biplane method, and global and regional longitudinal strain were measured with TomTec Image Arena 4.5.1 software. RESULTS: LV EF had no correlation with 6-minute walk distance (r = 0.22, p = 0.09) even when controlling for age, gender, and BMI (p = 0.07). No measures of LV diastolic function (including E velocity, Deceleration Time, e' annular velocities, or E/e') had a correlation with 6-minute walk distance. Multiple measures of global and regional LV longitudinal systolic function had a correlation with 6-minute walk distance. Longitudinal strain of the basal LV segments had the strongest correlation with 6-minute walk distance (r= -0.36, p = 0.005), and correlation persisted after controlling for age, gender, BMI, and systolic blood pressure (p = 0.004). CONCLUSIONS: Longitudinal strain correlates with a measure of functional capacity, but LVEF and traditional measures of LV diastolic dysfunction do not. Measures of longitudinal strain, especially in basal LV segments, will likely be an important marker of clinically relevant LV function.

Automatic detection of cognitive impairment in patients with white matter hyperintensity and causal analysis of related factors using artificial intelligence of MRI.

PURPOSE: White matter hyperintensity (WMH) is a common feature of brain aging, often linked with cognitive decline and dementia. This study aimed to employ deep learning and radiomics to develop models for detecting cognitive impairment in WMH patients and to analyze the causal relationships among cognitive impairment and related factors. MATERIALS AND METHODS: A total of 79 WMH patients from hospital 1 were randomly divided into a training set (62 patients) and a testing set (17 patients). Additionally, 29 patients from hospital 2 were included as an independent testing set. All participants underwent formal neuropsychological assessments to determine cognitive status. Automated identification and segmentation of WMH were conducted using VB-net, with extraction of radiomics features from cortex, white matter, and nuclei. Four machine learning classifiers were trained on the training set and validated on the testing set to detect cognitive impairment. Model performances were evaluated and compared. Causal analyses were conducted among cortex, white matter, nuclei alterations, and cognitive impairment. RESULTS: Among the models, the logistic regression (LR) model based on white matter features demonstrated the highest performance, achieving an AUC of 0.819 in the external test dataset. Causal analyses indicated that age, education level, alterations in cortex, white matter, and nuclei were causal factors of cognitive impairment. CONCLUSION: The LR model based on white matter features exhibited high accuracy in detecting cognitive impairment in WMH patients. Furthermore, the possible causal relationships among alterations in cortex, white matter, nuclei, and cognitive impairment were elucidated.

Stabilizing High-Valence Copper(I) Sites with Cu-Ni Interfaces Enhances Electroreduction of CO2 to C2+ Products.

In this study, the copper-nickel (Cu-Ni) bimetallic electrocatalysts for electrochemical CO2 reduction reaction(CO2RR) are fabricated by taking the finely designed poly(ionic liquids) (PIL) containing abundant Salen and imidazolium chelating sites as the surficial layer, wherein Cu-Ni, PIL-Cu and PIL-Ni interaction can be readily regulated by different synthetic scheme. As a proof of concept, Cu@Salen-PIL@Ni(NO3)2 and Cu@Salen-PIL(Ni) hybrids differ significantly in the types and distribution of Ni species and Cu species at the surface, thereby delivering distinct Cu-Ni cooperation fashion for the CO2RR. Remarkably, Cu@Salen-PIL@Ni(NO3)2 provides a C2+ faradaic efficiency (FEC2+) of 80.9% with partial current density (jC 2+) of 262.9 mA cm-2 at -0.80 V (versus reversible hydrogen electrode, RHE) in 1 m KOH in a flow cell, while Cu@Salen-PIL(Ni) delivers the optimal FEC2+ of 63.8% at jC2+ of 146.7 mA cm-2 at -0.78 V. Mechanistic studies indicates that the presence of Cu-Ni interfaces in Cu@Salen-PIL@Ni(NO3)2 accounts for the preserve of high-valence Cu(I) species under CO2RR conditions. It results in a high activity of both CO2-to-CO conversion and C-C coupling while inhibition of the competitive HER.

Nanosecond-pulsed plasma protects against bacterial fruit blotch and promotes melon seedling growth.

BACKGROUND: Bacterial fruit blotch (BFB), known as the 'cancer' of cucurbits, is a seed-borne disease of melons caused by Acidovorax citrulli. Traditional chemical treatments for BFB are ineffective and adversely affect the environment. Using dielectric barrier discharge (DBD) nanosecond-pulsed plasma technology, melon seeds were treated to promote germination and growth and to control BFB. RESULTS: Based on the evaluation parameters of seed germination, seedling growth, leaf yellowing and bacterial infection after seed plasma treatments, 9 min at 20 kV was selected as the optimal plasma discharge parameter. In this study, seedling growth was significantly improved after treating melon seeds carrying A. citrulli using this discharge parameter. The number of first true leaves measured on the eighth day was 2.3 times higher and the disease index was reduced by 60.5% compared to the control group. Attenuated total reflectance-Fourier transform infrared measurements show that plasma treatments penetrate the seed coat and denature polysaccharides and proteins in the seed kernel, affecting their growth and sterilization properties. CONCLUSION: Pre-sowing treatment of melon seeds carrying A. citrulli using nanosecond-pulsed plasma technology can effectively control seedling BFB disease and promote melon seedling growth by optimizing DBD parameters. © 2024 Society of Chemical Industry.

The gut microbial composition in polycystic ovary syndrome with hyperandrogenemia and its association with steroid hormones.

Background: Polycystic ovary syndrome (PCOS) is characterized by excess androgens, ovulatory dysfunction, and polycystic ovaries. The mechanisms underlying ovulatory and metabolic disorders in PCOS remain elusive, hampering therapeutic development. Enhanced metabolic health correlates with increased microbiota gene content and microbial diversity. We aimed to explore the impact of gut microbiota and serum steroids on PCOS regulation associated with androgen excess. Methods: The fecal samples of patients with hyperandrogenic PCOS (n = 14) and control group with PCOS (n = 14) were analyzed by 16S rRNA gene sequencing. The peripheral venous blood of all subjects was collected to detect serum hormones. The association between gut microbiota and serum hormones was analyzed with the R language. Results: Our findings reveal that the hyperandrogenic PCOS group exhibits lower richness and diversity of gut microbiota compared to the control group. Characteristic genera in PCOS patients with hyperandrogenism include Bifidobacterium, Enterobacteriaceae_unclassified, Streptococcus, Saccharimonadaceae, Enterococcus, and Eubacterium_nodatum_group. Five hormones, including 5ß-androsterone, deoxycorticosterone, corticosterone, 11-dehydrocorticosterone, and cortexolone, emerge as potential serum biomarkers for identifying patients with hyperandrogenic-PCOS (HA-PCOS). Furthermore, a lower vitamin D3 level may act as a susceptibility factor, suggesting that vitamin D3 supplementation could serve as a potential intervention for PCOS with hyperandrogenism. Conclusion: Specific fecal microbiota and serum steroids may be used as characteristic markers for clinical diagnosis of hyperandrogenic-PCOS. This research enhances our understanding of the intricate interplay among hormones, gut microbiota, and hyperandrogenemia in patients with PCOS.

Chemical-Free Recycling of Cathode Material and Aluminum Foil from Waste Lithium-Ion Batteries by Combining Plasma and Ultrasonic Technology.

With the rapid demand for lithium-ion batteries due to the widespread application of electric vehicles, a significant amount of battery electrode pieces requiring urgent treatment are generated during battery production and disposal. The strong bonding caused by the presence of binders makes it challenging to achieve thorough separation between the cathode active materials and Al foil, posing difficulties in efficient battery material recycling. To address this issue, a plasma-ultrasonically combined physical separation method is proposed in this study. This method utilizes plasma-generated excited-state radicals assisted by ultrasonic waves to separate active materials and current collectors. The results indicate that the binders are effectively decomposed under plasma treatment at 13.56 MHz, 100 W, and 10 min in an oxygen atmosphere, resulting in a separation efficiency of 96.8 wt % for the cathode materials. Characterization results demonstrate that the morphology, crystal structure, and chemical composition of the recycled cathode active materials remain unchanged, facilitating subsequent direct restoration and hydrometallurgical recycling. Simultaneously, the Al foil is also completely recycled for subsequent reuse. Compared with traditional methods of separating cathode active materials and aluminum foil, the method proposed in this study has significant economic and environmental potential. It can promote the recycling of battery materials and the development of sustainable transportation.

Au nanozyme-based colorimetric sensor array integrates machine learning to identify and discriminate monosaccharides.

As different monosaccharides exhibit different redox characteristics, this paper presented a novel colorimetric sensor array based on the glucose oxidase-like (GOx-like) activity of Au nanoparticles (NPs) for monosaccharides identification. AuNPs can use O2, ABTS+•, or [Ag(NH3)2]+ as an electron acceptor to catalyze the oxidation of monosaccharides in different velocity, resulting in cross-responsive signals. The current sensor array can distinguish between different monosaccharides or their mixtures through linear discriminant analysis (LDA) and hierarchical clustering analysis (HCA). Moreover, the glucose and fructose concentrations can be estimated simultaneously using a neural network regression model based on the sensor array. This method shows potential for monosaccharide detection in industrial, medical, and biological applications.

Is it a normal phenomenon for pediatric patients to have brain leptomeningeal contrast enhancement on 3-tesla magnetic resonance imaging?

Determining whether sevoflurane sedation in children leads to "pseudo" prominent leptomeningeal contrast enhancement (pLMCE) on 3 Tesla magnetic resonance imaging will help reduce overdiagnosis by radiologists and clarify the pathophysiological changes of pLMCE.

Sodium-glucose cotransporter-2 inhibitors and incidence of atrial fibrillation in older adults with type 2 diabetes: a retrospective cohort analysis.

Objectives: To investigate the risk of atrial fibrillation (AF) with sodium-glucose cotransporter-2 inhibitors (SGLT2is) compared to dipeptidyl peptidase-4 inhibitor (DPP4i) use in older US adults and across diverse subgroups. Methods: We conducted a retrospective cohort analysis using claims data from 15% random samples of Medicare fee-for-service beneficiaries. Patients were adults with type 2 diabetes (T2D), no preexisting AF, and were newly initiated on SGLT2i or DPP4i. The outcome was the first incident AF. Inverse probability treatment weighting (IPTW) was used to balance the baseline covariates between the treatment groups including sociodemographics, comorbidities, and co-medications. Cox regression models were used to assess the effect of SGLT2i compared to DPP4i on incident AF. Results: Of the 97,436 eligible individuals (mean age 71.2 ± 9.8 years, 54.6% women), 1.01% (n = 983) had incident AF over a median follow-up of 361 days. The adjusted incidence rate was 8.39 (95% CI: 6.67-9.99) and 11.70 (95% CI: 10.9-12.55) per 1,000 person-years in the SGLT2i and DPP4i groups, respectively. SGLT2is were associated with a significantly lower risk of incident AF (HR 0.73; 95% CI, 0.57 to 0.91; p = 0.01) than DPP4is. The risk reduction of incident AF was significant in non-Hispanic White individuals and subgroups with existing atherosclerotic cardiovascular diseases and chronic kidney disease. Conclusion: Compared to the use of DPP4i, that of SGLT2i was associated with a lower risk of AF in patients with T2D. Our findings contribute to the real-world evidence regarding the effectiveness of SGLT2i in preventing AF and support a tailored therapeutic approach to optimize treatment selection based on individual characteristics.

Flavan-3-ol monomers intake is associated with osteoarthritis risk in Americans over 40 years of age: results from the National Health and Nutritional Examination Survey database.

Objectives: Osteoarthritis (OA) stands as the prevailing progressive musculoskeletal disease, serving as the primary cause of chronic pain and activity limitations among adults over 40. Flavan-3-ols, common polyphenolic compounds, are believed to harbor anti-inflammatory and anti-aging properties. This study explores the relationship between flavan-3-ol intake and osteoarthritis risk in individuals over the age of 40 in the US. Methods: This study included 7452 participants over the age of 40 from three cycles (2007-2008, 2009-2010, and 2017-2018) of the National Health and Nutrition Examination Survey. Information on OA history was obtained via home surveys. Information on flavan-3-ol monomers intake was obtained using a survey from the Food and Nutrient Database for Dietary Studies. We used a logistic regression model and restricted cubic spline to analyze the relationships between flavan-3-ol monomers and OA. Stratified analyses were also conducted in this study. Results: There were 1056 participants with OA and 6396 without OA. Compared to the first tertile (T1) group, the adjusted odds ratio with a 95% confidence interval (CI) of logistic regression model 2 for the flavan-3-ol T2 group was 1.296 (0.979-1.715) (p = 0.068), the OR for (-)-epigallocatechin was 1.292 (1.025-1.629) (p = 0.032), and the OR for (-)-epicatechin 3-gallate was 1.348 (1.013, 1.793) (p = 0.042). A dose-response curve indicated a non-linear association (p for non-linearity <0.05) between OA and total flavan-3-ol monomers (nadir point: 483.29 mg, 95% CI: 0.61-0.90). No interaction effects were found in the subgroup analysis. Conclusions: In individuals over 40 in the US, the average daily dietary intake of flavan-3-ol monomers manifests a J-shaped relationship with OA risk.

KBPT: knowledge-based prompt tuning for zero-shot relation triplet extraction.

Knowledge representation is increasingly recognized as an effective method for information extraction. Nevertheless, numerous studies have disregarded its potential applications in the zero-shot setting. In this article, a novel framework, called knowledge-based prompt tuning for zero-shot relation triplet extraction (KBPT), was developed, founded on external ontology knowledge. This framework serves as a catalyst for exploring relation triplet extraction (RTE) methods within low-resource scenarios, warranting further scrutiny. Zero-shot setting RTE aims to extract multiple triplets that consist of head entities, tail entities, and relation labels from an input sentence, where the extracted relation labels are those that do not exist in the training set. To address the data scarcity problem in zero-shot RTE, a technique was introduced to synthesize training samples by prompting language models to generate structured texts. Specifically, this involves integrating language model prompts with structured text methodologies to create a structured prompt template. This template draws upon relation labels and ontology knowledge to generate synthetic training examples. The incorporation of external ontological knowledge enriches the semantic representation within the prompt template, enhancing its effectiveness. Further, a multiple triplets decoding (MTD) algorithm was developed to overcome the challenge of extracting multiple relation triplets from a sentence. To bridge the gap between knowledge and text, a collective training method was established to jointly optimize embedding representations. The proposed model is model-agnostic and can be applied to various PLMs. Exhaustive experiments on four public datasets with zero-shot settings were conducted to demonstrate the effectiveness of the proposed method. Compared to the baseline models, KBPT demonstrated enhancements of up to 14.65% and 24.19% in F1 score on the Wiki-ZSL and TACRED-Revisit datasets, respectively. Moreover, the proposed model achieved better performance compared with the current state-of-the-art (SOTA) model in terms of F1 score, precision-recall (P-R) curves and AUC. The code is available at https://Github.com/Phevos75/KBPT.

Design, synthesis, and anti-oomycete activity of 3-acyloxymaltol/ethyl maltol derivatives.

Twenty 3-acyloxymaltol/ethyl maltol derivatives (7a-j and 8a-j) were synthesized and evaluated in vitro for their anti-oomycete activity against Phytophthora capsici, respectively. Among all of twenty derivatives, more than half of the compounds 7f, 7h, 8a-h and 8j had anti-oomycete activity higher than the positive control zoxamide (EC50 = 22.23 mg/L), and the EC50 values of 18.66, 20.32, 12.80, 16.18, 10.59, 14.98, 16.80, 10.36, 15.32, 12.64, and 13.59 mg/L, respectively. Especially, compounds 8c and 8f exhibited the best anti-oomycete activity against P. capsici with EC50 values of 10.59 and 10.36 mg/L, respectively. Overall, hydroxyl group of maltol/ethyl maltol is important active modification site.

Discovery and validation of combined biomarkers for the diagnosis of esophageal intraepithelial neoplasia and esophageal squamous cell carcinoma.

Early diagnosis and intervention of esophageal squamous cell carcinoma (ESCC) can improve the prognosis. The purpose of this study was to identify biomarkers for ESCC and esophageal precancerous lesions (intraepithelial neoplasia, IEN). Based on the proteomic and genomic data of esophageal tissue including previously reported data, up-regulated proteins with copy number amplification in esophageal cancer were screened as candidate biomarkers. Five proteins, including KDM2A, RAD9A, ECT2, CYHR1 and TONSL, were confirmed by immunohistochemistry on ESCC and normal esophagus (NE). Then, we investigated the expression of 5 proteins in 236 participants (60 NEs, 93 IENs and 83 ESCCs) which were randomly divided into training set and test set. When distinguishing ESCC from NE, the area under curve (AUC) of the multiprotein model was 0.940 in the training set, while the lowest AUC of a protein was 0.735. In the test set, the results were similar. When distinguishing ESCC from IEN or distinguishing IEN from NE, the diagnostic efficiency of the multi-protein models were also improved compared with that of single protein. Our findings suggest that combined detection of KDM2A, RAD9A, ECT2, CYHR1 and TONSL can be used as potential biomarkers for the early diagnosis of ESCC and precancerous lesion development prediction. SIGNIFICANCE: Candidate biomarkers including KDM2A, RAD9A, ECT2, CYHR1 and TONSL screened by integrating genomic and proteomic data from the esophagus can be used as potential biomarkers for the early diagnosis of esophageal squamous cell carcinoma and precancerous lesion development prediction.

A Study of the Internal Deformation Fields and the Related Microstructure Evolution during Thermal Fatigue Tests of a Single-Crystal Ni-Base Superalloy.

Ni-base superalloys operate in harsh service conditions where cyclic heating and cooling introduce deformation fields that need to be investigated in detail. We used the high-angular-resolution electron backscatter diffraction method to study the evolution of internal stress fields and dislocation density distributions in carbides, dendrites, and notch tips. The results indicate that the stress concentrations decay exponentially away from the notch, and this pattern of distribution was modified by the growth of cracks and the emission of dislocations from the crack tip. Crack initiation follows crystallographic traces and is weakly correlated with carbides and dendrites. Thermal cycles introduce local plasticity around carbides, the dendrite boundary, and cracks. The dislocations lead to higher local stored energy than the critical value that is often cited to induce recrystallization. No large-scale onset of recrystallization was detected, possibly due to the mild temperature (800 °C); however, numerous recrystallized grains were detected in carbides after 50 and 80 cycles. The results call for a detailed investigation of the microstructure-related, thermally assisted recrystallization phenomenon and may assist in the microstructure control and cooling channel design of turbine blades.

Association of co-exposure to organophosphate esters and per- and polyfluoroalkyl substances and mixture with cardiovascular-kidney-liver-metabolic biomarkers among Chinese adults.

BACKGROUND: Organophosphate esters (OPEs) and Per- and polyfluoroalkyl substances (PFAS) are ubiquitous environmental contaminants with common exposure sources, leading to their widespread presence in human body. However, evidence on co-exposure to OPEs and PFAS and its impact on cardiovascular-kidney-liver-metabolic biomarkers remains limited. METHODS: In this cross-sectional study, 467 adults were enrolled from January to May 2022 during physical visits in Shijiazhuang, Hebei province. Eleven types of OPEs and twelves types of PFAS were detected, among which eight OPEs and six PFAS contaminants were detected in more than 60% of plasma samples. Seventeen biomarkers were assessed to comprehensively evaluate the cardiovascular-kidney-liver-metabolic function. Multiple linear regression, multipollutant models with sparse partial least squares, and Bayesian kernel machine regression (BKMR) models were applied to examine the associations of individual OPEs and PFAS and their mixtures with organ function and metabolism, respectively. RESULTS: Of the over 400 exposure-outcome associations tested when modelling, we observed robust results across three models that perfluorohexanoic acid (PFHxS) was significantly positively associated with alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL), and indirect bilirubin (IBIL). Perfluorononanoic acid was significantly associated with decreased AST/ALT and increased very-low-density lipoprotein cholesterol levels. Besides, perfluorodecanoic acid was correlated with increased high lipoprotein cholesterol and perfluoroundecanoic acid was consistently associated with lower glucose level. BKMR analysis showed that OPEs and PFAS mixtures were positively associated with IBIL and TBIL, among which PFHxS was the main toxic chemicals. CONCLUSIONS: Our findings suggest that exposure to OPEs and PFAS, especially PFHxS and PFNA, may disrupt organ function and metabolism in the general population, providing insight into the potential pathophysiological mechanisms of OPEs and PFAS co-exposure and chronic diseases.

Surgery versus no surgery in platinum-sensitive relapsed ovarian cancer: final overall survival analysis of the SOC-1 randomized phase 3 trial.

Surgery for platinum-sensitive, relapsed ovarian cancer (PSROC) is widely practiced but had contradictory survival outcomes in previous studies. In this multicenter, open-label, phase 3 trial, women with PSROC, and having had one previous therapy and no platinum-based chemotherapy (platinum-free interval) of 6 months or more, were randomly assigned to either the surgery group (182 patients) or the no-surgery group (control) (175 patients). Patients with resectable diseases were eligible according to the international model (iMODEL), combined with a positron emission tomography-computed tomography imaging. Overall survival (OS) and progression-free survival were coprimary endpoints in hierarchical testing, and a significantly longer progression-free survival with surgery was previously reported. Final analysis of OS was planned at data maturity of 59%. Between 19 July 2012 and 3 June 2019, 357 patients were enrolled. Median follow-up was 82.5 months. Median OS was 58.1 months with surgery and 52.1 months for control (hazard ratio (HR) 0.80, 95% confidence interval (CI) 0.61-1.05, P = 0.11). The predefined threshold for statistical significance was not met, but prespecified sensitivity analysis was performed. Overall, 61 of 175 (35%) patients in control had crossed over to surgery following subsequent relapse, and adjusted HR for death in the surgery group compared with control was 0.76, 95% CI 0.58-0.99. In subgroup analysis of relapse sites by imaging, median survival was not estimable in the surgery group and was 69.5 months in control in patients with <20 sites (HR 0.69, 95% CI 0.46-1.03). Patients with a complete resection had the most favorable outcome, with a median OS of 73.0 months. Twenty-four of 182 (13.2%) patients remained relapse free and alive >60 months in the surgery group as compared with five of 175 (2.9%) patients in the control group. In patients with PSROC, surgery did not increase OS in the intention-to-treat population but resulted in a prolongation of survival following adjustment of crossover.ClinicalTrials.gov registration: NCT01611766 .

Outcome of Patients with Systolic Heart Failure Undergoing Sympathectomy for Ventricular Arrhythmia.

Cardiac sympathetic denervation (CSD) is a surgical procedure increasingly used for the management of ventricular arrhythmia refractory to conventional medical therapy. Long-term outcomes of CSD in patients with systolic heart failure has not been well studied. This observational study aimed to evaluate the medical comorbidities and outcomes of patients with systolic heart failure who underwent CSD performed as treatment for ventricular arrhythmia refractory to conventional therapy. A retrospective analysis of adult patients with ventricular arrhythmia and systolic heart failure who underwent unilateral or bilateral CSD at a single center was performed. Unadjusted Kaplan-Meier survival curves were constructed to evaluate survival after CSD. Between June 1, 2011 and March 31, 2021, 32 adult patients (age 62 ± 11.6 years, 88% male, left ventricular ejection fraction 22 ± 8.2%) with systolic heart failure underwent unilateral left (n=4), unilateral right (n=1), or bilateral CSD (n=27). Mean survival after CSD was 613 ± 745 days and the mean time from CSD to death was 291 ± 447 days. The cumulative probability of survival 1 year after CSD was 61.4%. In this single-center observational study, CSD performed for refractory ventricular arrhythmia showed favorable survival in patients with systolic heart failure. In conclusion, this study lays the groundwork for a more in-depth analysis of the potential survival benefits of CSD in this patient group.