2025年 · 第138卷第24期

Heart failure (HF) represents a multifaceted clinical syndrome featured by cardiac structural or functional abnormalities secondary to diverse etiologies.

Acute-on-chronic liver failure (ACLF) is an acute decompensation of liver function in patients with chronic liver disease, characterized by high short-term mortality and recognized as a leading cause of death in this population.^[1]It requires refined clinical classification to achieve precise diagnosis, targeted treatment, and stratified management. Currently, multiple definitions of ACLF exist worldwide with notable discrepancies, hindering the comparability of research data and creating confusion in clinical diagnosis, treatment, and management.^[2,3]To standardize ACLF clinical practice in China, the Severe Liver Disease and Artificial Liver Group and the Nutrition and Regeneration in End-Stage Liver Disease Group of the Chinese Society of Hepatology, Chinese Medical Association, have organized a panel of Chinese experts to develop China’s first clinical guideline for ACLF diagnosis and management.^[4]This guideline integrates the latest advances in global research and clinical practice, aiming to harmonize ACLF diagnostic criteria across regions while ensuring precision and comprehensiveness. By incorporating the characteristics of the Chinese population with ACLF, accumulated clinical experience, and robust medical evidence, we propose a unified ACLF definition and provide authoritative recommendations for its diagnosis, treatment, and clinical management.

Target population for the guidelines: Obstetric health care workers, midwives, and pregnant women.

Recent advancements in cancer therapeutics, including targeted therapies and immunotherapies, have significantly improved treatment outcomes but remain limited by challenges such as off-target toxicity, poor penetration into deep tumor tissues, and the emergence of drug resistance. Engineered bacteria-based cancer therapies present a novel and versatile approach to address these limitations. Leveraging their ability to selectively colonize tumor microenvironments, bacteria can elicit antitumor immune responses and serve as platforms for the localized delivery of therapeutic agents. Through genetic engineering and synthetic biology, bacteria can be programmed to produce anticancer payloads tailored to clinical needs. This review highlights recent progress in the design and application of engineered bacteria for cancer therapy, emphasizing innovative strategies to enhance therapeutic delivery and efficacy. In addition, we discuss the integration of bacteria-based approaches with conventional therapies to overcome intratumor heterogeneity and improve treatment outcomes. Finally, we discuss insights from past and ongoing clinical trials of tumor-targeting bacteria, alongside challenges that must be surmounted to realize their full therapeutic promise.

The cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway has been extensively documented since its discovery in 2013. The cGAS-STING signaling pathway is activated upon cytoplasmic DNA stimulation and triggers innate immunity. The cGAS-STING signaling pathway is pivotal in antiviral defense and tumor immunity and significantly influences various pathological conditions. Currently, the cGAS-STING signaling pathway has been explored as a potential target for several diseases. Here, we aim to summarize the mechanisms of cGAS-STING signaling pathway activation, signal transduction, and regulation. We review the role of cGAS-STING in pathological conditions across multiple human systems. We also summarize recent progress in the development of drugs targeting this signaling pathway and ongoing clinical trials. This review may deepen our understanding of the cGAS-STING signaling pathway and unlock its translational potential for human diseases.

Historically regarded as inert energy storage depots, lipid droplets (LDs) are now recognized as dynamic organelles that regulate diverse cellular processes, including membrane biosynthesis, stress adaptation, signal transduction, and metabolic homeostasis. In cancer, tumor cells hijack LD-driven metabolic pathways to fuel uncontrolled proliferation, migration, and therapy resistance, thereby promoting tumor progression. Emerging evidence suggests that tumor-associated immune cells similarly utilize LD-mediated mechanisms to reinforce immunosuppression and support tumor progression. However, the intercellular crosstalk and regulatory networks coordinated by LD-associated effectors across malignant and immune cells have not been systematically explored. This review synthesizes current knowledge on LD biogenesis, spatiotemporal distribution, and microenvironment-dependent regulation in both tumor cells and tumor-infiltrating immune cells. We focus on how LD-associated proteins shape the immunosuppressive tumor microenvironment and drive oncogenic progression. Furthermore, we highlight novel therapeutic strategies targeting LD metabolism to simultaneously disrupt tumor survival and counteract immune cell-mediated protumorigenic effects. Finally, we discuss the challenges and future directions of LD-targeted therapies, particularly in combination with immunotherapies, to provide a roadmap for next-generation anticancer interventions.

The clonal evolution of breast cancer involves a complex dialogue between tumor cells and their environment. In this process, epigenetic mechanisms play a crucial role in regulating the cellular transcriptome without altering the underlying DNA sequence. Here, we provide an updated summary of three main epigenetic mechanisms: histone modifications, long non-coding RNAs (lncRNAs), and higher-order chromatin structures. Post-translational modifications of DNA or histones influence gene expression by altering chromatin accessibility and/or recruiting regulatory protein complexes. This process is dynamically regulated by enzymes that add or remove these marks, as well as by reader proteins that recognize them. Dysregulated expression or malfunction of these regulators creates an aberrant epigenetic landscape and gene expression profile, contributing to breast cancer initiation, metastasis, and drug resistance. Notably, the donor molecules for chromatin modifications are largely derived from intermediate metabolites shaped by environmental cues, highlighting the intricate crosstalk between epigenetic regulation and both cellular and systemic metabolic states. DNA and histone modifications are further interrelated with lncRNAs and higher-order chromatin architectures, which have been actively investigated in breast carcinogenesis. We also briefly introduce the role of epigenetics in other chromatin-associated events such as replication initiation. Aberrant replication initiation can drive gene duplication and genomic alterations resembling those observed in clinical breast cancer, endowing tumor cells with growth advantages and therapeutic resistance. Finally, we summarize emerging therapeutic strategies that target epigenetic vulnerabilities in breast cancer and discuss their current limitations and future directions.

The metabolic-immune interplay within the tumor microenvironment (TME) is a critical determinant of tumor progression and immune evasion, presenting significant therapeutic opportunities for enhancing antitumor immunity. The TME is characterized by hypoxia, acidosis, and nutrient depletion, and is also profoundly shaped by the metabolic reprogramming of cancer cells, including enhanced glycolysis, as well as amino acid and lipid metabolism. These metabolic alterations establish an immunosuppressive niche, restricting nutrient availability for effector T cells while enriching the environment with metabolites such as lactate, kynurenine, and adenosine. These metabolites impair the function of cytotoxic T lymphocytes and natural killer cells, while also promoting the survival and activity of regulatory T cells, tumor-associated macrophages, and myeloid-derived suppressor cells. Immune cell function within this challenging milieu is dictated by metabolic adaptability: Effector T cells succumb to metabolic exhaustion, whereas regulatory T cells, tumor-associated macrophages, and myeloid-derived suppressor cells exhibit metabolic flexibility that sustains their survival and suppressive functions. Therapeutic strategies that target cancer cell metabolism or enhance the metabolic fitness of immune cells offer promising approaches to mitigating immunosuppression within the TME. Notably, combining metabolic modulators with existing immunotherapies holds great potential for amplifying antitumor responses. Nonetheless, critical hurdles for clinical translation remain, including target specificity, potential toxicities, and adaptive metabolic plasticity. Further investigation into metabolic reprogramming and precision immunotherapy, guided by emerging biomarkers, is critical for optimizing therapeutic efficacy and improving patient outcomes by fully leveraging the metabolic-immune axis.

Personalized medicine for gastric cancer continues to face numerous challenges, primarily due to the complexity of clinical decision making and the difficulty of integrating multimodal data. Artificial intelligence (AI), with its powerful capabilities in feature learning and pattern recognition, is emerging as a key technology to overcome these barriers. It provides critical support in areas such as early screening, histological subtyping, prediction of treatment response, and prognostic risk stratification. This review examines the application of AI in diagnosing and treating gastric cancer, with particular attention to the current mainstream AI methodologies, including feature engineering and deep learning and the rapidly evolving pretrained foundation models and multimodal large models. With the integration of medical images, digital pathology, multiomics data, and structured clinical information, AI systems are increasingly effective at capturing tumor heterogeneity and supporting complex clinical decisions in real time. On the one hand, task-specific models have demonstrated excellent performance in subtyping, staging, and prognosis assessment. On the other hand, the rise of foundation models and general-purpose large models is redefining the limits of AI in cross-task transfer, complex reasoning, and human-machine interaction. These technologies hold promise in addressing key obstacles such as data scarcity, modality heterogeneity, and fragmented clinical workflows, offering a feasible path toward a unified and efficient AI-driven diagnostic and therapeutic system for gastric cancer. As technological maturity progresses alongside the development of robust safety and ethical frameworks, AI is expected to evolve from a static auxiliary interpretation tool into an intelligent decision-making platform capable of semantic understanding, dynamic feedback, and multidisciplinary collaboration—therefore playing a pivotal role across the full spectrum of precision medicine in gastric cancer.

Ferroptosis is an iron-catalyzed form of regulated cell death mediated by lipid peroxidation. Novel ferroptosis-based therapeutic strategies could selectively target core pathways associated with the proliferation and survival of malignant tumors, not only directly inducing tumor cell death but also overcoming resistance to conventional therapies, paving a new path for precision cancer treatment. Ferroptosis suppresses tumor progression through lethal lipid peroxidation, yet is co-opted by cancers through antioxidant adaptations. This review highlights the dual role of ferroptosis in tumor biology and explores the dynamic interplay between ferroptosis and the tumor microenvironment to modulate both immunogenic cell death and immunosuppressive signaling. We discuss the therapeutic potential of ferroptosis induction through synergistic integration with chemotherapy, targeted therapy, radiotherapy, hyperthermia therapy, and immunotherapy to simultaneously suppress tumor progression, overcome resistance mechanisms, and potentiate antitumor immunity, thereby offering innovative strategies to address treatment-refractory malignancies. Challenges include identifying predictive biomarkers, developing tumor-selective ferroptosis inducers, and modulating ferroptosis-immune interactions within the tumor microenvironment. By addressing these issues, ferroptosis has the potential to overcome treatment-resistant and immune-evasive tumors, reshaping oncology therapeutics.

Prostate cancer (PCa) is one of the most common malignancies worldwide, and metabolic reprogramming plays a crucial role, particularly in tumor progression and therapeutic resistance. As PCa progresses into advanced stages, such as castration-resistant prostate cancer, significant alterations in tumor metabolic pathways, including glycolysis, amino acid utilization, and lipid acid metabolism, occur. These reprogrammed metabolic pathways support the survival and proliferation of tumor cells in altered tumor microenvironments. Glutamine metabolism is significant in advanced PCa because this pathway not only contributes to the tricarboxylic acid cycle by providing energy and carbon skeletons but also supports the synthesis of macromolecules such as nucleotides and lipids and acts as a key driver of therapeutic resistance. In addition, pioneer transcription factors, such as the androgen receptor, either regulate the activity of metabolic pathways or are influenced by specific signaling metabolites. Targeting metabolic vulnerability is an ideal therapeutic strategy for advanced PCa. The aim of this review was to describe distinct metabolic features in different stages of PCa and highlight how to improve therapeutic effects by targeting tumor metabolism.

Sleep apnea is a sleep disorder and a common comorbidity among patients with diabetes worldwide. Previous studies have demonstrated a high prevalence of prediabetes and diabetes in individuals with obstructive sleep apnea (OSA). The physiopathology of OSA is characterized by recurrent collapse of the upper airway during sleep, resulting in intermittent hypoxia and fragmented sleep. These cardinal features can induce sympathetic activation, systemic inflammation, and oxidative stress, thereby increasing the risk and severity of diabetes. OSA has been reported to be associated with the worsening or the development of type 2 diabetes (T2D) and other types. Although there is a strong correlation between OSA and T2D, accumulated data on traditional treatments for OSA, such as continuous positive airway pressure, seem to show conflicting results regarding glucose metabolism. As novel approaches to T2D, glucagon-like peptide-1 receptor agonists and bariatric surgery also offer the potential for treating OSA. This review discusses the complex and bidirectional interplay among sleep disruption, insulin resistance, and diabetes. Advances in OSA treatment and their effects on glucose metabolism have also been discussed in this review.

Multiple myeloma (MM), a clonal plasma cell malignancy characterized by high chromosomal instability and inevitable relapse. Increased understanding of immune dysregulation and suppression during MM progression has led to the development of various immunotherapies over the past two decades. Immunotherapeutic strategies, including immunomodulatory imide drugs, monoclonal antibodies, immune checkpoint inhibitors, antibody-drug conjugates, chimeric antigen receptor T cells, and bispecific T cell engagers, have been evaluated in numerous clinical trials and demonstrated significant clinical efficacy, particularly in patients with relapsed and refractory MM. However, despite these substantial advances in immunotherapy, heavily pretreated patients continue to face challenges due to limited therapeutic options and the emergence of multiple drug resistance. Therefore, it is imperative to identify new targets and develop additional treatments aimed at preventing immune escape while enhancing the efficacy of existing immunotherapies.

As a populous country in the world, China ranks among the top in terms of new cancer cases and deaths worldwide. This study aims to provide a detailed evaluation of the cancer burden in China, considering the evolving social, economic, and environmental factors that may have influenced cancer incidence and mortality rates.

The cancer incidence, mortality, and the contributions of risk factors were estimated using data from the Global Burden of Disease Study (GBD) 2021. The number of new cases and deaths with their 95% uncertainty intervals (UIs) were analyzed. The trends of cancer age-standardized incidence rates (ASIR) from 1990 to 2021 and age-standardized death rates (ASDR) from 1980 to 2021 were estimated. Besides, risk factor contributions were also assessed.

In 2021, the total burden of cancer in China comprised 13.66 million new cases (95% UI: 11.79 to 15.85 million) and 2.82 million deaths (95% UI: 2.35 to 3.36 million). In 2021, ASIR and ASDR of cancers were 790.2 (95% UI: 676.8-926.3) per 100,000 population and 137.5 (95% UI: 115.1-163.4) per 100,000 population, respectively. In 2021, tracheal, bronchus, and lung cancer showed the highest ASIR of 44.0 (95% UI: 35.4-53.3) per 100,000 population among site-specific tumors, followed by non-melanoma skin cancer (37.5 [95% UI: 32.4-42.7] per 100,000 population), colon and rectum cancer (31.4 [95% UI: 25.5-38.0] per 100,000 population), stomach cancer (29.1 [95% UI: 22.4-36.2] per 100,000 population), breast cancer (19.4 [95% UI: 15.0-24.3] per 100,000 population), esophageal cancer (15.0 [95% UI: 12-18.4] per 100,000 population), and liver cancer (9.5 [95% UI: 7.7-11.8] per 100,000 population). Besides, the ASDR of cancers decreased about 29.78% in males and 42.00% in females in the past forty years in China. Tracheal, bronchus, and lung cancer showed the highest ASIR (62.63 per 100,000 population) and ASDR (56.45 per 100,000 population) in males. Of note, 31.73% of all cancer deaths in China were digestive cancers in 2021. For level 1 risks in 2021, behavioral risks were linked to 73.57% of cancer deaths.

The disease burden of cancers remains a major public health concern in China. The ASIR increased from 1990 to 2021 and the ASDR decreased from 1980 to 2021 in cancers. Tracheal, bronchus, and lung cancer remain the most common types of cancer in China.

Monitoring the progression of human immunodeficiency virus (HIV) and other sexually transmitted infections (STIs) is crucial for evidence-based decision-making in prevention and control strategies. This study aimed to delineate the global, regional, and national burden of these infections from 1990 to 2021 and forecast trends to 2030.

We retrieved data from the Global Burden of Disease (GBD) study 2021, including incidence and disability-adjusted life-years (DALYs) of HIV and other STIs from 1990 to 2021. Trends were quantified using estimated annual percentage changes (EAPCs) in age-standardized incidence and DALY rates. The Bayesian age-period-cohort (BAPC) model was used to forecast the future burden from 2022 to 2030.

In 2021, global epidemiological surveillance documented 1,645,333 incident cases of HIV and 722,752,642 incident cases of other STIs. Concurrently, the burden of disease analysis revealed 40,266,792 DALYs attributable to HIV and 7,953,311 DALYs linked to STIs worldwide. The global age-standardized incidence rate (ASIR) of HIV declined from 36.7 (95% uncertainty interval [UI]: 33.0-40.6) per 100,000 population in 1990 to 20.7 (95% UI: 17.7-24.4) in 2021 per 100,000 population, with an EAPC of -2.58% (95% confidence interval [CI]: -2.95% to -2.20%). In contrast, the ASIR of other STIs remained relatively stable, changing from 8692.6 (95% UI: 6256.5-11,811.2) per 100,000 in 1990 to 8871.7 (95% UI: 6388.4-12,055.1) per 100,000 in 2021, with an EAPC of -0.02% (95% CI: -0.07% to 0.03%). The BAPC model predicts a decline in the ASIR of HIV to 12.9 (95% UI: 4.3-21.5) per 100,000 by 2030, whereas the ASIR of other STIs is expected to increase to 9150.0 (95% UI: 7913.6-10,386.3) per 100,000. Regionally, Sub-Saharan Africa is projected to have the highest ASIRs of HIV and other STIs in 2030, with estimates of 38.4 (95% UI: 11.7-65.2) and 13,865.8 (95% UI: 11,915.6-15,816.0) per 100,000 population, respectively.

Despite declining HIV ASIRs, DALY burdens remain high, with significant regional disparities. HIV and other STIs continue to pose major public health challenges, necessitating targeted interventions, early sexual health education, enhanced screening, and cost-effective policies informed by GBD 2021 data.

Chronic respiratory diseases (CRDs), including chronic obstructive pulmonary disease (COPD), asthma, pneumoconiosis, interstitial lung disease (ILD), and pulmonary sarcoidosis, continue to pose a significant global health challenge. This study aims to assess the global, regional, and national burden of CRDs from 1990 to 2021, using data from the Global Burden of Disease Study (GBD) 2021 to identify key trends and advise future public health strategies.

Data from the GBD 2021 were used to estimate the incidence, prevalence, mortality, and disability-adjusted life years (DALYs) of CRDs and their subtypes across 21 global regions and 204 countries and regions from 1990 to 2021. The temporal trend was analyzed and the relationship between CRD burden and socio-demographic index (SDI) was examined using a smoothing spline model. A Bayesian age-period-cohort model was used to project the burden of CRDs to 2035.

The global age-standardized rate (ASR) of incidence, prevalence, mortality, and DALY for CRDs declined by 24%, 27%, 37%, and 38%, respectively, from 1990 to 2021. However, the absolute burden of CRDs continues to grow due to population aging and demographic changes. Asthma accounts for most of the CRD-related incidence and prevalence, particularly in high-SDI regions, while COPD accounts for most CRD-related deaths and DALYs, especially in low-middle SDI regions. The ASR of incidence, prevalence, mortality, and DALYs for ILD and pulmonary sarcoidosis increased by 21%, 9%, 50%, and 28%, respectively, from 1990 to 2021. Notably, the increase was more pronounced in high SDI regions. Although air pollution decreased globally and in high-SDI, it slightly worsened in low-SDI regions. Since 2009, tobacco use has surpassed air pollution as the leading risk factor for CRD-related deaths and DALYs in high-middle SDI regions, although both are declining. In contrast, the increase in DALYs is because high body mass index (BMI) signals a change in risk factors for CRDs. By 2035, the incidence, prevalence, and mortality rates of CRD are anticipated to decline.

The incidence of CRDs continues to represent a significant public health challenge, with variable trends in different regions influenced by a complex interaction of risk factors. Although progress has been made in reducing mortality and DALYs, particularly in higher SDI regions, the continued high incidence in low- and middle-SDI regions underscores the need for sustained and targeted public health efforts. Therefore, it is essential to address the underlying determinants, including environmental, lifestyle, and occupational risks to mitigate the global impact of CRDs in the coming decades.

Liver cancer remains a significant global health concern, with hepatitis B virus (HBV) as the leading cause. This study aims to systematically evaluate the global epidemiological burden, risk factors, and long-term trends of HBV-related liver cancer.

Data from the Global Burden of Disease (GBD) study 2021 were used to analyze incidence, deaths, and prevalence rates of HBV-related liver cancer across 204 countries and territories. Age-period-cohort (APC) models were applied to assess age-specific trends, period effects, and cohort impacts on age-standardized disease burden. Pearson correlation analyses examined the relationship between liver cancer burden, the socio-demographic index (SDI), and the universal health coverage (UHC) index. We also evaluated the influence of other concomitant risk factors on HBV-related liver cancer deaths. Projections for future death trends were generated using Bayesian APC models.

In 2021, there were 206,365.7 new cases of HBV-related liver cancer and 181,194.3 deaths worldwide. Between 1990 and 2021, both the global age-standardized incidence rate (ASIR) and age-standardized prevalence rate (ASPR) showed an upward trend. The age-standardized death rate (ASDR) declined, particularly in middle SDI countries, where the ASDR dropped by 21.7%. Incidence rates decreased among individuals under 70 years old, while death rates dropped for those under 75 years. Period trends revealed an increase in incidence and deaths from 1995 to 2000, followed by a sharp decline from 2000 to 2010, with death reductions being more pronounced. The downward trend was most notable among birth cohorts from the 1970s onward. A negative correlation was found between the SDI, the UHC, and liver cancer burden. The number of deaths attributable to risk factors increased by 97.8% from 1990 to 2021. Projections indicate a 30.2% reduction in HBV-related liver cancer deaths globally by 2040.

The global burden of HBV-related liver cancer showed significant regional disparities and presented ongoing global health challenges. Socioeconomic factors and healthcare access are closely associated with disease burden. Effective, region-specific interventions are essential to mitigate future HBV-related liver cancer burdens.

Existing literature regarding the influence of vitamin E (VE) supplementation on the risk of gestational hypertension (GH) and preeclampsia (PE) remains controversial. Our study aimed to assess the association between maternal VE supplementation during early pregnancy and the risk of developing GH/PE.

The data included 3587 women from the Jiangsu Birth Cohort (JBC) who conceived through assisted reproductive technology (ART) and had gestational ages of at least 20 weeks. Data about the dietary intake and food supplements were collected using questionnaires. Additionally, blood samples were collected during the first trimester. GH/PE diagnoses were extracted from medical records. We independently assessed the associations of dietary VE intake and VE supplementation with the risk of GH/PE, respectively. We further analyzed the associations between VE-related metabolites and GH/PE development leveraging individual-level plasma untargeted metabolomics data.

Dietary VE intake was not associated with GH/PE risk. However, VE supplementation exceeding 100 mg/day in the early pregnancy was significantly associated with increased risk of GH/PE (odds ratio [OR], 1.68 [95% confidence interval [CI], 1.24-2.26]), particularly when VE supplementation intake of >2 months or >12,000 mg. Among women with low dietary VE intake, the significant adverse effect of VE supplementation was observed at doses exceeding 100 mg/day (OR, 1.61 [95% CI, 1.03-2.50]). Among high dietary VE intake, supplementation at both ≤100 mg/day (OR, 1.61 [95% CI, 1.07-2.44]) and >100 mg/day (OR, 1.74 [95% CI, 1.17-2.57]) were associated with a higher risk of GH/PE. Plasma metabolomics data further validated that elevated α-isomer metabolites were positively associated with GH/PE (OR, 1.55 [95% CI, 1.13-2.13]).

The findings underscore the importance of cautious use of VE supplements during pregnancy, particularly among women with adequate dietary VE intake, to avoid potential risks of GH/PE.

To the Editor: The incidence and mortality of colorectal cancer (CRC) in China have increased significantly in recent years. Surpassing gastric cancer, CRC has become one of the main cancers threatening the life and health of Chinese people and causing a serious social burden.^[1]Early detection of CRC is critical for improving outcomes. Although colonoscopy remains the primary diagnostic and screening method, its invasiveness and low patient compliance hinder broad application.^[2]Non-invasive methods including fecal occult blood tests and carcinoembryonic antigen (CEA) lack sensitivity (20-40%) and specificity for early detection.^[3]Therefore, non-invasive biomarkers with high sensitivity and specificity for detecting CRC and precancerous adenomas are urgently needed. Altered gut microbiota is closely associated with colorectal carcinogenesis but exhibits high interindividual variability, limiting its clinical utility. Microbiota-derived metabolites such as bile acids and short-chain fatty acids are critical in CRC progression.^[4]Serum metabolite levels are strongly correlated with gut microbial abundance, providing a new direction for noninvasive diagnosis of CRC.^[5]

To the Editor: Alzheimer’s disease (AD) is a devastating neurodegenerative disorder frequently accompanied by cerebral small vessel disease (CSVD). The presence of CSVD in AD patients can complicate and intensify the treatment of AD.^[1]To date, research has inadequately addressed the comorbidity of AD and CSVD, leading to a limited understanding of their characteristics and mechanisms. Further investigation into this comorbidity may help develop specific diagnostic and therapeutic strategies for AD patients with CSVD.