Construction of the prediction model for multiple myeloma based on machine learning.

INTRODUCTION: The global burden of multiple myeloma (MM) is increasing every year. Here, we have developed machine learning models to provide a reference for the early detection of MM. METHODS: A total of 465 patients and 150 healthy controls were enrolled in this retrospective study. Based on the variable screening strategy of least absolute shrinkage and selection operator (LASSO), three prediction models, logistic regression (LR), support vector machine (SVM), and random forest (RF), were established combining complete blood count (CBC) and cell population data (CPD) parameters in the training set (210 cases), and were verified in the validation set (90 cases) and test set (165 cases). The performance of each model was analyzed using receiver operating characteristic (ROC) curve, calibration curves, and decision curve analysis (DCA). Accuracy, sensitivity, specificity, positive predictive value, negative predictive value, and area under the ROC curve (AUC) were applied to evaluate the models. Delong test was used to compare the AUC of the models. RESULTS: Six parameters including RBC (1012/L), RDW-CV (%), IG (%), NE-WZ, LY-WX, and LY-WZ were screened out by LASSO to construct the model. Among the three models, the AUC of RF model in the training set, validation set, and test set were 0.956, 0.892, and 0.875, which were higher than those of LR model (0.901, 0.849, and 0.858) and SVM model (0.929, 0.868, and 0.846). Delong test showed that there were significant differences among the models in the training set, no significant differences in the validation set, and significant differences only between SVM and RF models in the test set. The calibration curve and DCA showed that the three models had good validity and feasibility, and the RF model performed best. CONCLUSION: The proposed RF model may be a useful auxiliary tool for rapid screening of MM patients.

Encapsulation of Lactobacillus plantarum in W1/O/W2 double emulsions stabilized with the high-intensity ultrasound-treated pea protein and pectin.

This study focuses on developing a water-in-oil-in-water (W1/O/W2) double emulsion system using high-intensity ultrasound (HIU)-treated pea protein isolate (HIU-PPI) and pectin to encapsulate Lactobacillus plantarum (L. plantarum). The effects of ultrasound treatment on pea protein isolate (PPI) characteristics such as solubility, particle size, emulsification, surface hydrophobicity, and surface free sulfhydryl group were examined, determining optimal HIU processing conditions was 400 W for 10 min. The developed W1/O/W2 double emulsion system based on HIU-PPI demonstrated effective encapsulation and protection of L. plantarum, especially at the HIU-PPI concentration of 4 %, achieving an encapsulation efficiency of 52.65 %. Incorporating both HIU-PPI and pectin as emulsifiers increased the particle size and significantly enhanced the emulsion's viscosity. The highest bacterial encapsulation efficiency of the emulsion, 59.94 %, was attained at a HIU to pectin concentration ratio of 3:1. These emulsions effectively encapsulate and protect L. plantarum, with the concentration of HIU-PPI being a critical factor in enhancing probiotic survival under simulated gastrointestinal digestion. However, the concurrent utilization of pectin and HIU-PPI as emulsifiers did not provide a notable advantage compared to the exclusive use of HIU-PPI in enhancing probiotic viability during in vitro simulated digestion. This research offers valuable perspectives for the food industry on harnessing environmentally friendly, plant-based proteins as emulsifiers in probiotic delivery systems. It underscores the potential of HIU-modified pea protein and pectin in developing functional food products that promote the health benefits of probiotics.

Transperineal 3-Core Magnetic Resonance Imaging Ultrasound Fusion Targeted Plus Laterally 6-Core Systematic Biopsy in Prostate Cancer Diagnosis.

INTRODUCTION: It is important to explore strategies reducing the number of SB cores taken to minimize biopsy-related morbidity and patient's discomfort during biopsy. This study aims to optimize prostate biopsy procedures by reducing the number of systematic biopsy (SB) cores while preserving cancer detection rates in the era of combined biopsy. PATIENTS AND METHODS: We prospectively recruited patients with ≥1 magnetic resonance imaging (MRI) lesions and they underwent transperineal combined 12-core SB+3-core targeted prostate biopsy (TB, reference standard). New strategy was defined as a laterally 6-core SB+3-core TB. Patients were served as their own control. Detection rates for overall prostate cancer (PCa) and clinically significant PCa (csPCa) were compared among the standard SB, MRI-TB, 6-core SB +3-core TB, and reference standard. Pathology consistency was assessed using the Kappa test. RESULTS: A total of 204 men were included, of which 111 (54.41%) and 92 (45.10%) harbored overall PCa and csPCa. Referenced combined biopsy detected significantly 6.86% (P = .0005) or 4.90% (P = .0044) more csPCa than performing only SB or 3-core TB, but was comparable to the new biopsy strategy. (45.10% vs. 43.14%, P = .1336) Similar results persisted when limiting patients in biopsy-naïve men or stratified by Prostate Imaging Reporting and Data System scores, PSAD, and index lesion parameters. Additionally, performing 6-core SB+3-core TB demonstrated high consistency with reference standard in grade group distribution (Kappa coefficient: 0.952 for all, 0.961 for biopsy-naïve men) and achieved superior sensitivity of 95.7% (All: 95% CI: 89.2%-99.8%) and 96.9% (Biopsy-naïve: 95% CI: 91.1%-99.7%), respectively. CONCLUSIONS: The 6-core SB+3-core TB approach maintains expected detection rates while reducing the total core count, offering a promising alternative to the reference standard, which may help to tailor transperineal combined biopsy procedures.

Contribution to the Chinese Intybia Pascoe, 1866 (Coleoptera, Melyridae, Malachiinae), with descriptions of two new species groups and one new species.

A contribution to the knowledge of the malachiine genus Intybia Pascoe, 1866 from China is given. Two new species groups: Intybiaklapperichi group and Intybiaeversi group are defined and described. A new species, Intybiahainanensis Wang & Liu, sp. nov., of the Intybiaklapperichi group is described from Hainan Province. Intybiaerectodentatus (Wittmer, 1982) and Intybiaconcha Asano, 2015 are redescribed based on new materials collected in mainland China. A key to species groups of the genus Intybia Pascoe, 1866 in China is provided.

Genome evolution of the ancient hexaploid Platanus × acerifolia (London planetree).

Whole-genome duplication (WGD; i.e., polyploidy) and chromosomal rearrangement (i.e., genome shuffling) significantly influence genome structure and organization. Many polyploids show extensive genome shuffling relative to their pre-WGD ancestors. No reference genome is currently available for Platanaceae (Proteales), one of the sister groups to the core eudicots. Moreover, Platanus × acerifolia (London planetree; Platanaceae) is a widely used street tree. Given the pivotal phylogenetic position of Platanus and its 2-y flowering transition, understanding its flowering-time regulatory mechanism has significant evolutionary implications; however, the impact of Platanus genome evolution on flowering-time genes remains unknown. Here, we assembled a high-quality, chromosome-level reference genome for P. × acerifolia using a phylogeny-based subgenome phasing method. Comparative genomic analyses revealed that P. × acerifolia (2n = 42) is an ancient hexaploid with three subgenomes resulting from two sequential WGD events; Platanus does not seem to share any WGD with other Proteales or with core eudicots. Each P. × acerifolia subgenome is highly similar in structure and content to the reconstructed pre-WGD ancestral eudicot genome without chromosomal rearrangements. The P. × acerifolia genome exhibits karyotypic stasis and gene sub-/neo-functionalization and lacks subgenome dominance. The copy number of flowering-time genes in P. × acerifolia has undergone an expansion compared to other noncore eudicots, mainly via the WGD events. Sub-/neo-functionalization of duplicated genes provided the genetic basis underlying the unique flowering-time regulation in P. × acerifolia. The P. × acerifolia reference genome will greatly expand understanding of the evolution of genome organization, genetic diversity, and flowering-time regulation in angiosperms.

Persistent combined type sleep-related rhythmic movement disorder into adolescence: a case report.

SRMD is characterized by repetitive, stereotyped, rhythmic movements of large muscle groups, primarily occurring at the onset of sleep and during sleep. Common in infancy and early childhood, its persistence into adolescence or adulthood is rare. Combined type is rare. This article reviews and analyzes the diagnosis and treatment of a case with combined type SRMD persisting for 15 years aimed at enhancing the level of diagnosis and treatment of the disorder, and reducing misdiagnosis and missed diagnosis.

Association Analysis of Essential Tremor-Associated Genetic Variants in Sporadic Late-Onset Parkinson's Disease.

Background: Parkinson's disease (PD) and Essential tremor (ET) are the two most common tremor diseases with recognized genetic pathogenesis. The overlapping clinical features suggest they may share genetic predispositions. Our previous study systematically investigated the association between rare coding variants in ET-associated genes and early-onset PD (EOPD), and found the suggestive association between teneurin transmembrane protein 4 (TENM4) and EOPD. In the current research, we explored the potential genetic interplay between ET-associated genetic loci/genes and sporadic late-onset PD (LOPD). Methods: We performed whole-genome sequencing in the 1962 sporadic LOPD cases and 1279 controls from mainland China. We first used logistic regression analysis to test the top 16 SNPs identified by the ET genome-wide association study for the association between ET and LOPD. Then we applied the optimized sequence kernel association testing to explore the rare variant burden of 33 ET-associated genes in this cohort. Results: We did not observe a significant association between the included SNPs with LOPD. We also did not discover a significant burden of rare deleterious variants of ET-associated genes in association with LOPD risk. Conclusion: Our results do not support the role of ET-associated genetic loci and variants in LOPD. Highlights: 1962 cases and 1279 controls were recruited to study the potential genetic interplay between ET-associated genetic loci/variants and sporadic LOPD.No significant association between the ET-associated SNPs and LOPD were observed.No significant burden of rare deleterious variants of ET-associated gene in LOPD risk were found.

High-fat diet during early life reshapes the gut microbiome and is associated with the disrupted mammary microenvironment in later life in mice.

The influence of gut microbiota on gut health is well-documented, but it remains obscure for extraintestinal diseases such as breast cancer. Moreover, it is entirely unknown how gut dysbiosis during early life contributes to breast tumorigenesis later in life. In this study, we hypothesized that a high-fat diet during early life leads to alterations in the gut microbiome and is associated with disruptions in the mammary microenvironment. Female C57BL/6 mice were fed a low-fat diet (10% kcal fat) or a high-fat diet (HF, 60% kcal fat) for 8 weeks from the age of 4 to 12 weeks, which is equivalent to human childhood and adolescence. Twelve mice were sacrificed immediately after the 8-week feeding, the remainder were euthanized after switching to a normal lifecycle-supporting diet for an additional 12 weeks; the gut microbiome was then sequenced. The 8-week HF diet feeding altered the beta-diversity (Bray & Jaccard P < .01), and the difference remained significant after switching the diet (Bray & Jaccard P < .05). Immediately after HF feeding, a greater number of microbial taxa (>50) were altered, and about half of the taxa (25) remained significantly changed after switching the diet. The abundance of Alistipes, Bilophila, and Rikenellaceae stood out as significantly associated with multiple metabolic and inflammatory biomarkers in mammary tissue, including aromatase, Ccl2, and Cox2. In conclusion, an 8-week early-life HF feeding reshaped the gut microbiome, which connected with disrupted mammary microenvironments.

Platyintybia, a new genus of Apalochrini (Coleoptera, Melyridae, Malachiinae) from China.

A new genus of malachiine Melyridae, Platyintybiagen. nov., is described based on several male-specific characters, along with description of its type species, Platyintybiazhongshanensissp. nov., from China. A new combination, Platyintybiasarawakensis (Champion, 1921), comb. nov., is proposed after examining the type specimen; this species is newly recorded from China. A key to the genera of Chinese Apalochrini is provided for the first time.

Mental health and insomnia problems in healthcare workers after the COVID-19 pandemic: A multicenter cross-sectional study.

BACKGROUND: Healthcare workers (HCWs) are at increased risk of contracting coronavirus disease 2019 (COVID-19) as well as worsening mental health problems and insomnia. These problems can persist for a long period, even after the pandemic. However, less is known about this topic. AIM: To analyze mental health, insomnia problems, and their influencing factors in HCWs after the COVID-19 pandemic. METHODS: This multicenter cross-sectional, hospital-based study was conducted from June 1, 2023 to June 30, 2023, which was a half-year after the end of the COVID-19 emergency. Region-stratified population-based cluster sampling was applied at the provincial level for Chinese HCWs. Symptoms such as anxiety, depression, and insomnia were evaluated by the Generalized Anxiety Disorder-7, Patient Health Questionnaire-9, and Insomnia Severity Index. Factors influencing the symptoms were identified by multivariable logistic regression. RESULTS: A total of 2000 participants were invited, for a response rate of 70.6%. A total of 1412 HCWs [618 (43.8%) doctors, 583 (41.3%) nurses and 211 (14.9%) nonfrontline], 254 (18.0%), 231 (16.4%), and 289 (20.5%) had symptoms of anxiety, depression, and insomnia, respectively; severe symptoms were found in 58 (4.1%), 49 (3.5%), and 111 (7.9%) of the participants. Nurses, female sex, and hospitalization for COVID-19 were risk factors for anxiety, depression, and insomnia symptoms; moreover, death from family or friends was a risk factor for insomnia symptoms. During the COVID-19 outbreak, most [1086 (76.9%)] of the participating HCWs received psychological interventions, while nearly all [994 (70.4%)] of them had received public psychological education. Only 102 (7.2%) of the HCWs received individual counseling from COVID-19. CONCLUSION: Although the mental health and sleep problems of HCWs were relieved after the COVID-19 pandemic, they still faced challenges and greater risks than did the general population. Identifying risk factors would help in providing targeted interventions. In addition, although a major proportion of HCWs have received public psychological education, individual interventions are still insufficient.

Homologous Recombination Repair Gene Mutations in Prostate Cancer: Prevalence and Clinical Value.

Despite advances in our understanding of the molecular landscape of prostate cancer and the development of novel biomarker-driven therapies, the prognosis of patients with metastatic prostate cancer that is resistant to conventional hormonal therapy remains poor. Data suggest that a significant proportion of patients with metastatic castration-resistant prostate cancer (mCRPC) have mutations in homologous recombination repair (HRR) genes and may benefit from poly(ADP-ribose) polymerase (PARP) inhibitors. However, the adoption of HRR gene mutation testing in prostate cancer remains low, meaning there is a missed opportunity to identify patients who may benefit from targeted therapy with PARP inhibition, with or without novel hormonal agents. Here, we review the current knowledge regarding the clinical significance of HRR gene mutations in prostate cancer and discuss the efficacy of PARP inhibition in patients with mCRPC. This comprehensive overview aims to increase the clinical implementation of HRR gene mutation testing and inform future efforts in personalized treatment of prostate cancer.

Comprehensive variant analysis of phospholipase A2 superfamily genes in large Chinese Parkinson' s disease cohorts.

To clarify the genetic role of phospholipase A2 (PLA2) genes in Parkinson's disease (PD), we performed a genetic association study in large Chinese population cohorts using next-generation sequencing. In this study, we analyzed both rare and common variants of 38 phospholipase A2 genes in two large cohorts. We detected 1558 and 1115 rare variants in these two cohorts, respectively. In both cohorts, we observed suggestive associations between specific subgroups and the risk of PD. At the single-gene level, several genes (PLA2G2D, PLA2G12A, PLA2G12B, PLA2G4F, PNPLA1, PNPLA3, PNPLA7, PLA2G7, PLA2G15, PLAAT5, and ABHD12) are suggestively associated with PD. Meanwhile, 364 and 2261 common variants were identified in two cohorts, respectively. Our study has expanded the genetic spectrum of the PLA2 family genes and suggested potential pathogenetic roles of PLA2 superfamily in PD.

Infertility risk assessment with ultrasound in congenital adrenal hyperplasia male patients.

Testicular adrenal rest tumor (TART) is a prevalent complication associated with congenital adrenal hyperplasia (CAH), culminating in gonadal dysfunction and infertility. Early hormonal intervention is preventive, but excessive glucocorticoid poses risks. Developing reliable methods for early TART diagnosis and monitoring is crucial. The present study aims to formulate a scoring system to identify high-risk infertility through analysis of TART ultrasound features. Grayscale and power Doppler ultrasound were employed in this retrospective study to evaluate testicular lesions in male CAH patients. Lesion assessment encompassed parameters such as range, echogenicity, and blood flow, and these were subsequently correlated with semen parameters. Results of 49 semen analyzes from 35 patients demonstrated a notable inverse correlation between lesion scores and both sperm concentration (rs = - 0.83, P < 0.001) and progressive motility (rs = - 0.56, P < 0.001). The ROC curve areas for evaluating oligospermia and asthenozoospermia were calculated as 0.94 and 0.72, respectively. Establishing a lesion score threshold of 6 revealed a sensitivity of 75.00% and specificity of 93.94% for oligospermia and a sensitivity of 53.85% and specificity of 100.00% for asthenozoospermia. These findings underscore the potential utility of incorporating ultrasound into routine CAH patient management, facilitating timely interventions to preserve male fertility.

Genetic evaluation in indeterminate acute liver failure: A post hoc analysis.

BACKGROUND AND STUDY AIMS: There are limited data regarding indeterminate acute liver failure (ALF). The study aims to perform a post hoc analysis using genetic methods for the ALF cases with indeterminate etiology. PATIENTS AND METHODS: Stored blood samples from these patients with indeterminate ALF were collected. Whole-exome sequencing (WES) was used to evaluate the pathogenesis of indeterminate ALF. RESULTS: A total of 16 samples from 11 adult patients and 5 pediatric patients with indeterminate ALF were available. Among the adult patients, one female patient was identified with two heterozygous variants (c.2333G > T (p.Arg778Leu) and c.2310C > G (p.Leu770 = )) in the adenosine triphosphatase copper-transporting beta (ATP7B) gene, and two male patients were found to harbor heterozygous and homozygous variants (c.686C > A (p.Pro229Gln) plus homozygousvariantA(TA)6TAAinsTA (-), andc.1456 T > G (p.Tyr486Asp) plus c.211G > A (p.Gly71Arg)) in the uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) gene. For the pediatric patients, single heterozygous variant (c.2890C > T (p.Arg964Cys)) in the polymerase gamma (POLG) gene was found in 1 male child, and two heterozygous variants (c.1909A > G (p.Lys637Glu) and c.3646G > A (p.Val1216Ile)) in the tetratricopeptide repeat domain 37 (TTC37) gene were found in 1 female child. No variants clinically associated with known liver diseases were revealed in the remaining patients. CONCLUSION: These results expand the knowledge of ALF with indeterminate etiology. WES is helpful to reveal possible candidate genes for indeterminate ALF, but incomplete consistency between the genotype and phenotype in some cases still challenge the accurate diagnosis.

miR394 modulates brassinosteroid signaling to regulate hypocotyl elongation in Arabidopsis.

The interplay between microRNAs (miRNAs) and phytohormones allows plants to integrate multiple internal and external signals to optimize their survival of different environmental conditions. Here, we report that miR394 and its target gene LEAF CURLING RESPONSIVENESS (LCR), which are transcriptionally responsive to BR, participate in BR signaling to regulate hypocotyl elongation in Arabidopsis thaliana. Phenotypic analysis of various transgenic and mutant lines revealed that miR394 negatively regulates BR signaling during hypocotyl elongation, whereas LCR positively regulates this process. Genetically, miR394 functions upstream of BRASSINOSTEROID INSENSITIVE2 (BIN2), BRASSINAZOLEs RESISTANT1 (BZR1), and BRI1-EMS-SUPPRESSOR1 (BES1), but interacts with BRASSINOSTEROID INSENSITIVE1 (BRI1) and BRI1 SUPRESSOR PROTEIN (BSU1). RNA-sequencing analysis suggested that miR394 inhibits BR signaling through BIN2, as miR394 regulates a significant number of genes in common with BIN2. Additionally, miR394 increases the accumulation of BIN2 but decreases the accumulation of BZR1 and BES1, which are phosphorylated by BIN2. MiR394 also represses the transcription of PACLOBUTRAZOL RESISTANCE1/5/6 and EXPANSIN8, key genes that regulate hypocotyl elongation and are targets of BZR1/BES1. These findings reveal a new role for a miRNA in BR signaling in Arabidopsis.

High-Dynamic-Range Integrated NV Magnetometers.

High-dynamic-range integrated magnetometers demonstrate extensive potential applications in fields involving complex and changing magnetic fields. Among them, Diamond Nitrogen Vacancy Color Core Magnetometer has outstanding performance in wide-range and high-precision magnetic field measurement based on its inherent high spatial resolution, high sensitivity and other characteristics. Therefore, an innovative frequency-tracking scheme is proposed in this study, which continuously monitors the resonant frequency shift of the NV color center induced by a time-varying magnetic field and feeds it back to the microwave source. This scheme successfully expands the dynamic range to 6.4 mT, approximately 34 times the intrinsic dynamic range of the diamond nitrogen-vacancy (NV) center. Additionally, it achieves efficient detection of rapidly changing magnetic field signals at a rate of 0.038 T/s.

Anti-EGFR ScFv functionalized exosomes delivering LPCAT1 specific siRNAs for inhibition of lung cancer brain metastases.

Brain metastasis (BM) is one of the leading causes of cancer-related deaths in patients with advanced non-small cell lung cancer (NSCLC). However, limited treatments are available due to the presence of the blood-brain barrier (BBB). Upregulation of lysophosphatidylcholine acyltransferase 1 (LPCAT1) in NSCLC has been found to promote BM. Conversely, downregulating LPCAT1 significantly suppresses the proliferation and metastasis of lung cancer cells. In this study, we firstly confirmed significant upregulation of LPCAT1 in BM sites compared to primary lung cancer by analyzing scRNA dataset. We then designed a delivery system based on a single-chain variable fragment (scFv) targeting the epidermal growth factor receptor (EGFR) and exosomes derived from HEK293T cells to enhance cell-targeting capabilities and increase permeability. Next, we loaded LPCAT1 siRNA (siLPCAT1) into these engineered exosomes (exoscFv). This novel scFv-mounted exosome successfully crossed the BBB in an animal model and delivered siLPCAT1 to the BM site. Silencing LPCAT1 efficiently arrested tumor growth and inhibited malignant progression of BM in vivo without detectable toxicity. Overall, we provided a potential platform based on exosomes for RNA interference (RNAi) therapy in lung cancer BM.

Efficient photocatalytic degradation of perfluorooctanoic acid by bismuth nanoparticle modified titanium dioxide.

Perfluorooctanoic acid (PFOA) is potentially toxic and exceptionally stable attributed to its robust CF bond, which is hard to be removed by UV/TiO2 systems. In this research, bismuth nanoparticle (Bi NP) modified titanium oxides (Bi/TiO2) were synthesized by a simple photochemical deposition-calcination method and were applied as photocatalysts for the first time to degrade PFOA. The removal rate of 50 mg/L PFOA reached 99.3 % with 58.6 % defluorination rate after 30 min of irradiation via a mercury lamp. Bi/TiO2 exhibited superior performance in PFOA degradation compared to commercial photocatalysts (TiO2, Ga2O3, Bi2O3 and In2O3). In addition, Bi/TiO2 showed high degradation activity under actual sunlight, achieved 100 % removal rate and 59.3 % defluorination rate within 2 h. Bi NPs increase the light trapping ability of Bi/TiO2 and promote the separation of photogenerated electron-hole pairs via local surface plasmon resonance (LSPR) effect, which results in more photogenerated holes (h+) and hydroxyl radicals (OH). Combined with DFT calculations and intermediate detections, the degradation reaction is initiated from the oxidation of the PFOA carboxyl group via h+, followed by the loss of the CF2 unit step by step with the participation of OH. This work presents a novel approach for the practical implementation of TiO2-based photocatalysts to achieve highly efficient photocatalytic degradation of perfluorocarboxylic acids (PFCAs).

Alcohol and colorectal cancer risk subclassified by mutational signatures of DNA mismatch repair deficiency.

BACKGROUND: We examined whether the association between alcohol consumption and CRC incidence was stronger for tumors with higher contributions of defective MMR (dMMR)-related tumor mutational signatures (TMSs). METHODS: We used data from 227,916 men and women who participated in the Nurses' Health Study (1980-2016), the Nurses' Health Study II (1991-2017), and the Health Professionals Follow-up Study (1986-2016). Dietary data was collected every 4 years through validated food frequency questionnaires. Relative contributions of two dMMR-related TMSs (c-dMMRa/SBS15 and c-dMMRb/SBS26) were quantified using whole-exome sequencing data in a subset of incident CRC cases. Duplication-method Cox proportional hazards regression models were used to assess the association between alcohol consumption and the risk of CRC subtypes according to different contributions of the TMSs. All statistical tests were 2-sided. RESULTS: We documented 825 incident CRC cases with available TMS data over 26-36 years of follow-up. The association between alcohol consumption and CRC incidence was stronger for tumors with higher contributions of c-dMMRb/SBS26 (P-heterogeneitytrend = 0.02) compared to tumors with lower contributions of this TMS. Compared with nondrinkers, drinkers with ≥15 g/d of alcohol had a high risk of c-dMMRb/SBS26-high CRC [multivariable-adjusted HR: 2.43 (95% CI: 1.55-3.82)], but not c-dMMRb/SBS26-low CRC [0.86 (95% CI: 0.57-1.28)] or c-dMMRb/SBS26-moderate CRC [1.14 (95% CI: 0.76-1.71)]. No significant differential associations were observed for c-dMMRa/SBS15 (P-heterogeneitytrend = 0.41). CONCLUSIONS: High alcohol consumption was associated with an increased incidence of CRC containing higher contributions of c-dMMRb/SBS26, suggesting that alcohol consumption may be involved in colorectal carcinogenesis through the DNA mismatch repair pathway.