Distribution characteristics of the Legionella CRISPR-Cas system and its regulatory mechanism underpinning phenotypic function.

Legionella is a common intracellular parasitic bacterium that infects humans via the respiratory tract, causing Legionnaires' disease, with fever and pneumonia as the main symptoms. The emergence of highly virulent and azithromycin-resistant Legionella pneumophila is a major challenge in clinical anti-infective therapy. The CRISPR-Cas acquired immune system provides immune defense against foreign nucleic acids and regulates strain biological functions. However, the distribution of the CRISPR-Cas system in Legionella and how it regulates gene expression in L. pneumophila remain unclear. Herein, we assessed 915 Legionella whole-genome sequences to determine the distribution characteristics of the CRISPR-Cas system and constructed gene deletion mutants to explore the regulation of the system based on growth ability in vitro, antibiotic sensitivity, and intracellular proliferation of L. pneumophila. The CRISPR-Cas system in Legionella was predominantly Type II-B and was mainly concentrated in the genome of L. pneumophila ST1 strains. The Type II-B CRISPR-Cas system showed no effect on the strain's growth ability in vitro but significantly reduced resistance to azithromycin and decreased proliferation ability due to regulation of the lpeAB efflux pump and the Dot/Icm type IV secretion system. Thus, the Type II-B CRISPR-Cas system plays a crucial role in regulating the virulence of L. pneumophila. This expands our understanding of drug resistance and pathogenicity in Legionella, provides a scientific basis for the prevention of Legionnaires' disease outbreaks and the rational use of clinical drugs, and facilitates effective treatment of Legionnaires' disease.

What outcomes do studies use to measure the impact of prognostication on people with advanced cancer? Findings from a systematic review of quantitative and qualitative studies.

BACKGROUND: Studies evaluating the impact of prognostication in advanced cancer patients vary in the outcomes they measure, and there is a lack of consensus about which outcomes are most important. AIM: To identify outcomes previously reported in prognostic research with people with advanced cancer, as a first step towards constructing a core outcome set for prognostic impact studies. DESIGN: A systematic review was conducted and analysed in two subsets: one qualitative and one quantitative. (PROSPERO ID: CRD42022320117; 29/03/2022). DATA SOURCES: Six databases were searched from inception to September 2022. We extracted data describing (1) outcomes used to measure the impact of prognostication and (2) patients' and informal caregivers' experiences and perceptions of prognostication in advanced cancer. We classified findings using the Core Outcome Measures in Effectiveness Trials (COMET) initiative taxonomy, along with a narrative description. We appraised retrieved studies for quality, but quality was not a basis for exclusion. RESULTS: We identified 42 eligible studies: 32 quantitative, 6 qualitative, 4 mixed methods. We extracted 70 outcomes of prognostication in advanced cancer and organised them into 12 domains: (1) survival; (2) psychiatric outcomes; (3) general outcomes; (4) spiritual/religious/existential functioning/wellbeing, (5) emotional functioning/wellbeing; (6) cognitive functioning; (7) social functioning; (8) global quality of life; (9) delivery of care; (10) perceived health status; (11) personal circumstances; and (12) hospital/hospice use. CONCLUSION: Outcome reporting and measurement varied markedly across the studies. A standardised approach to outcome reporting in studies of prognosis is necessary to enhance data synthesis, improve clinical practice and better align with stakeholders' priorities.

Biodistribution of Graphene Oxide Determined through Postadministration Labeling with DNA-Conjugated Gold Nanoparticles and ICPMS.

Recent research has revealed the use of graphene oxide (GO) and its derivatives as a potential biomaterial because of their attractive physicochemical characteristics and functional properties. However, if GO and related derivatives are to become useful materials for biomedical applications, it will be necessary to evaluate their biodistribution for health and safety considerations. To obtain a more accurate biodistribution for GO, we (i) developed a postadministration labeling strategy employing DNA-conjugated gold nanoparticles (DNA-AuNPs) to selectively label administered GO in Solvable-treated tissue samples and (ii) constructed an automatic sample pretreatment scheme (using a C18-packed minicolumn) to effectively separate the DNA-AuNP-labeled GO from the unbound DNA-AuNPs and the dissolved tissue matrices, thereby enabling ultrasensitive, interference-free quantification of GO through measurement (inductively coupled plasma mass spectrometry) of the Au signal intensities. The DNA-AuNPs can bind to GO in a concentration- and time-dependent manner. After optimizing the labeling conditions (DNA length, incubation pH, DNA-AuNP concentration, and incubation time) and the separation scheme (sample loading flow rate, rinsing volume, and eluent composition), we found that A20R20-AuNPs (R20: random DNA sequence including A, T, C, and G) had the strongest binding affinity for labeling of the administered GO (dissociation constant: 36.0 fM) and that the method's detection limit reached 9.3 ag L-1 with a calibration curve having a working range from 10-1 to 1010 fg L-1. Moreover, this approach revealed that the intravenously administered GO accumulated predominantly in the liver and spleen at 1 and 12 h post administration, with apparent discrepancies in the concentrations measured using pre- and postadministration labeling strategies.

Predictive value of single-nucleotide polymorphism signature for recurrence in localised renal cell carcinoma: a retrospective analysis and multicentre validation study.

BACKGROUND: Identification of high-risk localised renal cell carcinoma is key for the selection of patients for adjuvant treatment who are at truly higher risk of reccurrence. We developed a classifier based on single-nucleotide polymorphisms (SNPs) to improve the predictive accuracy for renal cell carcinoma recurrence and investigated whether intratumour heterogeneity affected the precision of the classifier. METHODS: In this retrospective analysis and multicentre validation study, we used paraffin-embedded specimens from the training set of 227 patients from Sun Yat-sen University (Guangzhou, Guangdong, China) with localised clear cell renal cell carcinoma to examine 44 potential recurrence-associated SNPs, which were identified by exploratory bioinformatics analyses of a genome-wide association study from The Cancer Genome Atlas (TCGA) Kidney Renal Clear Cell Carcinoma (KIRC) dataset (n=114, 906 600 SNPs). We developed a six-SNP-based classifier by use of LASSO Cox regression, based on the association between SNP status and patients' recurrence-free survival. Intratumour heterogeneity was investigated from two other regions within the same tumours in the training set. The six-SNP-based classifier was validated in the internal testing set (n=226), the independent validation set (Chinese multicentre study; 428 patients treated between Jan 1, 2004 and Dec 31, 2012, at three hospitals in China), and TCGA set (441 retrospectively identified patients who underwent resection between 1998 and 2010 for localised clear cell renal cell carcinoma in the USA). The main outcome was recurrence-free survival; the secondary outcome was overall survival. FINDINGS: Although intratumour heterogeneity was found in 48 (23%) of 206 cases in the internal testing set with complete SNP information, the predictive accuracy of the six-SNP-based classifier was similar in the three different regions of the training set (areas under the curve [AUC] at 5 years: 0·749 [95% CI 0·660-0·826] in region 1, 0·734 [0·651-0·814] in region 2, and 0·736 [0·649-0·824] in region 3). The six-SNP-based classifier precisely predicted recurrence-free survival of patients in three validation sets (hazard ratio [HR] 5·32 [95% CI 2·81-10·07] in the internal testing set, 5·39 [3·38-8·59] in the independent validation set, and 4·62 [2·48-8·61] in the TCGA set; all p<0·0001), independently of patient age or sex and tumour stage, grade, or necrosis. The classifier and the clinicopathological risk factors (tumour stage, grade, and necrosis) were combined to construct a nomogram, which had a predictive accuracy significantly higher than that of each variable alone (AUC at 5 years 0·811 [95% CI 0·756-0·861]). INTERPRETATION: Our six-SNP-based classifier could be a practical and reliable predictor that can complement the existing staging system for prediction of localised renal cell carcinoma recurrence after surgery, which might enable physicians to make more informed treatment decisions about adjuvant therapy. Intratumour heterogeneity does not seem to hamper the accuracy of the six-SNP-based classifier as a reliable predictor of recurrence. The classifier has the potential to guide treatment decisions for patients at differing risks of recurrence. FUNDING: National Key Research and Development Program of China, National Natural Science Foundation of China, Guangdong Provincial Science and Technology Foundation of China, and Guangzhou Science and Technology Foundation of China.

The Role of Descending Pain Modulation in Chronic Primary Pain: Potential Application of Drugs Targeting Serotonergic System.

Chronic primary pain (CPP) is a group of diseases with long-term pain and functional disorders but without structural or specific tissue pathologies. CPP is becoming a serious health problem in clinical practice due to the unknown cause of intractable pain and high cost of health care yet has not been satisfactorily addressed. During the past decades, a significant role for the descending pain modulation and alterations due to specific diseases of CPP has been emphasized. It has been widely established that central sensitization and alterations in neuroplasticity induced by the enhancement of descending pain facilitation and/or the impairment of descending pain inhibition can explain many chronic pain states including CPP. The descending serotonergic neurons in the raphe nuclei target receptors along the descending pain circuits and exert either pro- or antinociceptive effects in different pain conditions. In this review, we summarize the possible underlying descending pain regulation mechanisms in CPP and the role of serotonin, thus providing evidence for potential application of analgesic medications based on the serotonergic system in CPP patients.

Low-dose Sinapic Acid Abates the Pyroptosis of Macrophages by Downregulation of lncRNA-MALAT1 in Rats With Diabetic Atherosclerosis.

Pyroptosis is a type of programmed cell death, which has been associated with multiple inflammatory diseases including diabetic atherosclerosis (DA). This study aims to explore the role of sinapic acid (SA) in the pyroptosis of macrophages in DA. Our results from the in vivo experiments showed that low-dose (≤50 mg/kg) chronic SA administration suppressed serum endothelin 1 (ET-1) and interleukin-1ß (IL-1ß) contents, pyroptotic death of bone marrow-derived macrophages, and the expression of pyroptotic proteins ASC, NRLP3, and caspase-1. Besides, lncRNA-metastasis associated lung adenocarcinoma transcript 1 (MALAT1) was robustly upregulated in the macrophages of rats with DA and could be lowered by low-dose SA administration. Gene overexpression and knockdown experiments showed that MALAT1 had a modestly positive effect on the pyroptosis of normal macrophages. Moreover, in macrophages incubated with high-glucose and Ox-LDL, 1-µM SA treatment displayed a suppressive effect on the cell pyroptosis similar to that of MALAT1 knockdown. Transfection of the pcDNA-MALAT1 expression vector counteracted the decrease in MALAT1 expression and macrophage pyroptosis caused by SA. In conclusion, low-dose SA can abate the pyroptosis of macrophages by downregulation of lncRNA-MALAT1 in rats with DA.

Synthesis of acyloxyl pyrazolines by copper-mediated aminoacyloxylation of unsaturated ketohydrazones.

An efficient and step-economical copper-mediated intra-/intermolecular aminoacyloxylation of ß,γ-unsaturated hydrazones has been developed. Copper carboxylates serve as both reaction promoters and carboxylate sources in these easily conducted reactions. This method provides straightforward access to diversely useful acyloxyl pyrazolines, which are hard to access traditionally, in good to excellent yields.

Morphological Type Identification of Self-Incompatibility in Dendrobium and Its Phylogenetic Evolution Pattern.

Self-incompatibility (SI) is a type of reproductive barrier within plant species and is one of the mechanisms for the formation and maintenance of the high diversity and adaptation of angiosperm species. Approximately 40% of flowering plants are SI species, while only 10% of orchid species are self-incompatible. Intriguingly, as one of the largest genera in Orchidaceae, 72% of Dendrobium species are self-incompatible, accounting for nearly half of the reported SI species in orchids, suggesting that SI contributes to the high diversity of orchid species. However, few studies investigating SI in Dendrobium have been published. This study aimed to address the following questions: (1) How many SI phenotypes are in Dendrobium, and what are they? (2) What is their distribution pattern in the Dendrobium phylogenetic tree? We investigated the flowering time, the capsule set rate, and the pollen tube growth from the representative species of Dendrobium after artificial pollination and analysed their distribution in the Asian Dendrobium clade phylogenetic tree. The number of SI phenotypes exceeded our expectations. The SI type of Dendrobium chrysanthum was the primary type in the Dendrobium SI species. We speculate that there are many different SI determinants in Dendrobium that have evolved recently and might be specific to Dendrobium or Orchidaceae. Overall, this work provides new insights and a comprehensive understanding of Dendrobium SI.

Determination of Lead with a Copper-Based Electrochemical Sensor.

This work demonstrates determination of lead (Pb) in surface water samples using a low-cost copper (Cu)-based electrochemical sensor. Heavy metals require careful monitoring due to their toxicity, yet current methods are too complex or bulky for point-of-care (POC) use. Electrochemistry offers a convenient alternative for metal determination, but the traditional electrodes, such as carbon or gold/platinum, are costly and difficult to microfabricate. Our copper-based sensor features a low-cost electrode material-copper-that offers simple fabrication and competitive performance in electrochemical detection. For anodic stripping voltammetry (ASV) of Pb, our sensor shows 21 nM (4.4 ppb) limit of detection, resistance to interfering metals such as cadmium (Cd) and zinc (Zn), and stable response in natural water samples with minimum sample pretreatment. These results suggest this electrochemical sensor is suitable for environmental and potentially biological applications, where accurate and rapid, yet inexpensive, on-site monitoring is necessary.

CPP-Assisted Intracellular Drug Delivery, What Is Next?

For the past 20 years, we have witnessed an unprecedented and, indeed, rather miraculous event of how cell-penetrating peptides (CPPs), the naturally originated penetrating enhancers, help overcome the membrane barrier that has hindered the access of bio-macromolecular compounds such as genes and proteins into cells, thereby denying their clinical potential to become potent anti-cancer drugs. By taking the advantage of the unique cell-translocation property of these short peptides, various payloads of proteins, nucleic acids, or even nanoparticle-based carriers were delivered into all cell types with unparalleled efficiency. However, non-specific CPP-mediated cell penetration into normal tissues can lead to widespread organ distribution of the payloads, thereby reducing the therapeutic efficacy of the drug and at the same time increasing the drug-induced toxic effects. In view of these challenges, we present herein a review of the new designs of CPP-linked vehicles and strategies to achieve highly effective yet less toxic chemotherapy in combating tumor oncology.

Clinical effects of Angelica dahurica dressing on patients with I-II phase pressure sores.

OBJECTIVE: Angelica dahurica is a well-known traditional Chinese Medicine (TCM), while little information is available about its effects on pressure sores. We aimed to investigate the clinical effect of Angelica dahurica on patients with I-II phase pressure sores, as well as the underlying mechanism. METHODS: Patients (n = 98) with phase I and phase II pressure sores were enrolled and randomly assigned to control and treated groups. In addition to holistic nursing, patients in the control group received compound clotrimazole cream, while patients in the treated group received continuous 4 weeks of external application of Angelica dahurica dressing. Therapeutic effect was recorded, along with the levels of interleukin-8 (IL-8), epidermal growth factor (EGF), transforming growth factor (TGF)-ß, and vascular endothelial growth factor (VEGF). Besides, HaCaT cells were cultured with different concentrations of Angelica dahurica, and then cell viability, clone formation numbers, cell cycle, and levels of cyclin D1 and cyclin-dependent kinase (CDK) 2 were determined. RESULTS: The total effective rate in the treated group was significantly higher than in the control group. Levels of IL-8, EGF, TGF-ß, and VEGF were statistically increased by Angelica dahurica. In addition, the cell viability and clone formation numbers were significantly upregulated by Angelica dahurica in a dose-dependent manner. Also, the percentage of cells in G0/G1 phase, and levels of cyclin D1 and CDK2 were significantly elevated. CONCLUSION: Our results suggest that Angelica dahurica may provide an effective clinical treatment for I-II phase pressure sores.

Disposable copper-based electrochemical sensor for anodic stripping voltammetry.

In this work, we report the first copper-based point-of-care sensor for electrochemical measurements demonstrated by zinc determination in blood serum. Heavy metals require careful monitoring, yet current methods are too complex for a point-of-care system. Electrochemistry offers a simple approach to metal detection on the microscale, but traditional carbon, gold (Au), or platinum (Pt) electrodes are difficult or expensive to microfabricate, preventing widespread use. Our sensor features a new low-cost electrode material, copper, which offers simple fabrication and compatibility with microfabrication and PCB processing, while maintaining competitive performance in electrochemical detection. Anodic stripping voltammetry of zinc using our new copper-based sensors exhibited a 140 nM (9.0 ppb) limit of detection (calculated) and sensitivity greater than 1 µA/µM in the acetate buffer. The sensor was also able to determine zinc in a bovine serum extract, and the results were verified with independent sensor measurements. These results demonstrate the advantageous qualities of this lab-on-a-chip electrochemical sensor for clinical applications, which include a small sample volume (µL scale), reduced cost, short response time, and high accuracy at low concentrations of analyte.

Copper-based electrochemical sensor with palladium electrode for cathodic stripping voltammetry of manganese.

In this work, we report on the development of a palladium-based, microfabricated point-of-care electrochemical sensor for the determination of manganese using square wave cathodic stripping voltammetry. Heavy metals require careful monitoring, yet current methods are too complex for a point-of-care system. Voltammetry offers an attractive approach to metal detection on the microscale, but traditional carbon, gold, or platinum electrodes are difficult or expensive to microfabricate, preventing widespread use. Our sensor uses palladium working and auxiliary electrodes and integrates them with a copper-based reference electrode for simple fabrication and compatibility with microfabrication and printed circuit board processing, while maintaining competitive performance in electrochemical detection. Copper electrodes were prepared on glass substrate using a combination of microfabrication procedures followed by electrodeposition of palladium. The disposable sensor system was formed by bonding a poly(dimethylsiloxane) (PDMS) well to the glass substrate. Cathodic stripping voltammetry of manganese using our new disposable palladium-based sensors exhibited 334 nM (18.3 ppb) limit of detection in borate buffer. The sensor was used to demonstrate manganese determination in natural water samples from a pond in Burnet Woods, located in Cincinnati, OH, and the Ohio River.

Highly sensitive electrochemical methyltransferase activity assay.

A simple and highly sensitive electrochemical DNA methyltransferase (MTase) activity assay is presented in this report. The assay employs the electrocatalytic oxidation of ascorbic acid (AA) by a threading intercalator (N,N'-bis(3-propylimidazole)-1,4,5,8-naphthalene diimide (PIND) functionalized with electrocatalytic redox Os(bpy)2Cl(+) moieties (PIND-Os)). Briefly, a double-stranded DNA (ds-DNA) containing the symmetric sequence of 5'-CCGG-3' is first immobilized on a gold electrode. The electrode is then incubated with M.SssI CpG methyltransferase (M.SssI MTase) which catalyzes the methylation of the specific CpG dinucleotides, and the electrode is subsequently treated with a restriction endonuclease HpaII which recognizes the 5'-CCGG-3' sequence. Once the CpG site in the 5'-CCGG-3' is methylated, HpaII recognition is blocked. Higher M.SssI MTase activity leads to more CpG sites being methylated and consequently impedes more the restriction endonuclease HpaII digestion process. Thus, a larger amount of ds-DNA remains on the electrode surface after the HpaII treatment. Thereafter, the electrode is incubated with PIND-Os during which PIND-Os specifically inserts itself between base pairs of ds-DNA and catalyzes the electrooxidation of AA. The methylation event corresponding to the MTase activity can therefore be monitored and amplified by the electrocatalytic oxidation of AA. A linear correlation between the catalytic oxidation current of AA and the activity of M.SssI MTase ranged from 0 to 120 U/mL with a current sensitivity of 0.046 µA mL U(-1) is obtained. The inhibitor screening ability of the developed MTase activity assay is also demonstrated.

Improving Reproducibility of Lab-on-a-Chip Sensor with Bismuth Working Electrode for Determining Zn in Serum by Anodic Stripping Voltammetry.

This work reports on the continuing development of a lab-on-a-chip electrochemical sensor for determination of zinc in blood serum using square wave anodic stripping voltammetry. The microscale sensor consists of a three electrode system, including an environmentally friendly bismuth working electrode, an integrated silver/silver chloride reference electrode, and a gold auxiliary electrode. The sensor demonstrates a linear response in 0.1 M acetate buffer at pH 6 for zinc concentrations in the 1-30 µM range. By optimizing bismuth film deposition and better control of the fabrication process, repeatability of the sensor was improved, reducing variability from 42% to <2%. Through optimization of electrolyte and stripping voltammetry parameters, limit of detection was greatly improved to 60 nM. The optimized sensor was also able to measure zinc in the extracted blood serum. Ultimately, with integrated sample preparation, the sensor will permit rapid (min) measurements of zinc from a sub-mL sample (a few drops of blood) for clinical applications.

Early diagnosis of renal pelvis villous adenoma: A case report.

BACKGROUND: Villous adenoma is a rare tumor in the urinary system that usually occurs in the bladder. It is extremely uncommon in the renal pelvis. Most of the previously reported cases have been diagnosed with severe hydronephrosis associated with renal parenchyma atrophy prior to surgery. Because of its rarity, available information on the pathogenesis, diagnosis, treatment and prognosis of the disease is limited. We reported a case of kidney stones with hydronephrosis. During percutaneous nephroscopic lithotripsy, a renal pelvis tumor was found. Biopsy confirmed that the tumor was a villous adenoma of the renal pelvis. CASE SUMMARY: A 68-year-old female was admitted to the hospital due to right kidney stones with right hydronephrosis. After admission, a urinary system plain computed tomography scan was performed, which revealed right kidney stones with right hydronephrosis and right upper ureteral dilatation. Multiple new cauliflower-like papillary masses were then discovered in the renal pelvis and calyces during right percutaneous nephroscopic lithotripsy. Biopsy results indicated villous adenoma with high-grade glandular intraepithelial neoplasia. The patient underwent laparoscopic radical resection of the right kidney and ureter. Based on histopathological and immunohistochemical examination, the patient was diagnosed with villous adenoma without adenocarcinoma. CONCLUSION: Villous adenoma is rare in the urinary system. We reported a case of renal pelvis villous adenoma, which may provide useful information for the early diagnosis and treatment of this tumor.

Legionnaires' Disease in China Caused by Legionella pneumophila Corby.

Legionella pneumophila is an intracellular pathogen causing pneumonia in humans. In February 2022, Legionnaires' disease caused by L. pneumophila strain Corby in a patient with lung adenocarcinoma was identified for the first time in China. This paper includes the case report and phenotypic and genomic analysis of the Corby (ICDC) strain. Its biological characteristics were evaluated by antibiotic sensitivity testing and cytology experiments, and genomic analysis was performed to understand its genetic evolution. The patient's clinical manifestations included cough, fever, pulmonary infiltration, and significantly decreased activity endurance. After empirical antimicrobial therapy, infection indicators decreased. The Corby (ICDC) strain was susceptible to nine antibiotics and exhibited strong intracellular proliferation ability. A phylogenetic tree showed that the Corby (ICDC) strain was closely related to the Corby strain, but under the pressure of a complex environment, its genome had undergone more rearrangement and inversion. The type IF CRISPR-Cas system was identified in its genome, and spacer analysis indicated that it had been invaded by several foreign plasmids, bacteria, and viruses during evolution. Legionnaires' disease caused by L. pneumophila strain Corby may be ignored in China, and it is urgent to improve long-term monitoring and investigation of aquatic environments and patients with respiratory infections to prevent a large-scale outbreak of Legionnaires' disease.

Emergence of ehrlichiosis by a new tick-borne Ehrlichia species in China.

OBJECTIVES: From March to June 2021, the reported number of clinically diagnosed endemic typhus in Anhui and Hubei provinces of China nearly increased four-fold compared with the monthly average numbers in last 5 years. An etiological and epidemiological investigation was initiated. METHODS: The clinical specimens from the reported patients and the potential vector ticks were collected for molecular and serological detection, as well as cell culturing assay to identify the potential pathogen. RESULTS: Polymerase chain reaction and sequence analysis of rrs and groEL showed that the pathogen from these patients was Ehrlichia sp., isolated from Haemaphysalis longicornis attached to these patients. The phylogenetic analysis based on 39 Ehrlichia genomes suggested that it should be taxonomically classified as a novel species, tentatively named "Candidatus Ehrlichia erythraense". A total of 19 of 106 cases were confirmed as Candidatus Ehrlichia erythraense infections by polymerase chain reaction, sequencing, and/or serological tests. The most frequent symptoms were fever (100%), rashes (100%), asthenia (100%), anorexia (100%), and myalgia (79%). CONCLUSION: The occurrence of the disease presenting with fever and rashes in Anhui and Hubei provinces was caused by a novel species of the genus Ehrlichia; physicians need to be aware of this newly-discovered pathogen to ensure appropriate testing, treatment, and regional surveillance.

Multimodal recurrence scoring system for prediction of clear cell renal cell carcinoma outcome: a discovery and validation study.

BACKGROUND: Improved markers for predicting recurrence are needed to stratify patients with localised (stage I-III) renal cell carcinoma after surgery for selection of adjuvant therapy. We developed a novel assay integrating three modalities-clinical, genomic, and histopathological-to improve the predictive accuracy for localised renal cell carcinoma recurrence. METHODS: In this retrospective analysis and validation study, we developed a histopathological whole-slide image (WSI)-based score using deep learning allied to digital scanning of conventional haematoxylin and eosin-stained tumour tissue sections, to predict tumour recurrence in a development dataset of 651 patients with distinctly good or poor disease outcome. The six single nucleotide polymorphism-based score, which was detected in paraffin-embedded tumour tissue samples, and the Leibovich score, which was established using clinicopathological risk factors, were combined with the WSI-based score to construct a multimodal recurrence score in the training dataset of 1125 patients. The multimodal recurrence score was validated in 1625 patients from the independent validation dataset and 418 patients from The Cancer Genome Atlas set. The primary outcome measured was the recurrence-free interval (RFI). FINDINGS: The multimodal recurrence score had significantly higher predictive accuracy than the three single-modal scores and clinicopathological risk factors, and it precisely predicted the RFI of patients in the training and two validation datasets (areas under the curve at 5 years: 0·825-0·876 vs 0·608-0·793; p<0·05). The RFI of patients with low stage or grade is usually better than that of patients with high stage or grade; however, the RFI in the multimodal recurrence score-defined high-risk stage I and II group was shorter than in the low-risk stage III group (hazard ratio [HR] 4·57, 95% CI 2·49-8·40; p<0·0001), and the RFI of the high-risk grade 1 and 2 group was shorter than in the low-risk grade 3 and 4 group (HR 4·58, 3·19-6·59; p<0·0001). INTERPRETATION: Our multimodal recurrence score is a practical and reliable predictor that can add value to the current staging system for predicting localised renal cell carcinoma recurrence after surgery, and this combined approach more precisely informs treatment decisions about adjuvant therapy. FUNDING: National Natural Science Foundation of China, and National Key Research and Development Program of China.