Immunoglobulin D-Lambda Multiple Myeloma Initially Presenting in the Sphenoid Sinus, Orbital Apex, and Skull Base: A Systematic Review with a Case Report.

Objectives Multiple myeloma (MM) with initial manifestations in the sphenoid sinus, orbital apex, and skull base is exceedingly rare. A systematic review was conducted to investigate the epidemiology and advancements . Methods Relevant cases were identified by searching CNKI, WanFang Data, CQVIP databases, PubMed, Embase, and Web of Science. Additionally, we present a case of IgD-λ (immunoglobulin D-lambda) MM with initial symptoms of dizziness, unilateral pain, blindness, and ophthalmoplegia, leading to a 4-month overall survival. Strictly based on PRISMA standards, we included and summarized existing cases and reflected our case. Results Our systematic review includes 34 case reports, revealing 67.6% of patients initially presented with diplopia and 44.1% underwent endoscopic procedures, notably with only two cases of IgD-λ subtype. In our case, we performed an endoscopic wide trans-ethmoidal sphenoidotomy and biopsy of the skull base and orbital apex lesion. Postoperative pathology confirmed a highly active plasmacytoma, clinically diagnosed as IgD-λ MM with a TP53 deletion mutation and multiple extramedullary metastases. A range of diagnostic tools was employed, including hemoglobin, immunoglobulin, urinary protein analysis, positron emission tomography-computed tomography (CT), bone marrow cytology, and gene detection. Conclusion The subtle clinical manifestations of IgD-λ MM in the paranasal sinuses and skull base hinder early diagnosis. There is a paucity of literature describing MM initially presenting in these locations. CT/magnetic resonance scans are necessary to identify characteristic bone destruction. An endoscopic approach is popular for tissue biopsy. Bone marrow biopsy with a smear, serum or urine protein electrophoresis, and immunofixation electrophoresis are crucial upon the appearance of target organ damage.

The journey of p38 MAP kinase inhibitors: From bench to bedside in treating inflammatory diseases.

The p38 mitogen-activated protein kinase (MAPK) pathway is pivotal in regulating inflammatory responses and has emerged as a key target for the development of small-molecule inhibitors aimed at treating inflammatory diseases. In arthritis, especially rheumatoid arthritis (RA), the p38 MAPK pathway contributes to chronic inflammation and joint destruction by promoting the production of pro-inflammatory cytokines. Preclinical studies have shown that small-molecule inhibitors targeting the p38 MAPK pathway hold significant promise, exhibiting the potential to reduce inflammation and preserve joint integrity. Targeting this pathway presents a novel therapeutic approach to mitigating inflammation. This review traces the evolution of p38 MAP kinase inhibitors from initial laboratory studies to clinical candidates, underscoring their potential to significantly alter the treatment approach for inflammatory diseases.

Cleavage-Stage Embryo Segmentation Using SAM-Based Dual Branch Pipeline: Development and Evaluation with the CleavageEmbryo Dataset.

MOTIVATION: Embryo selection is one of the critical factors in determining the success of pregnancy in in vitro fertilization (IVF) procedures. Using artificial intelligence to aid in embryo selection could effectively address the current time-consuming, expensive, subjectively influenced process of embryo assessment by trained embryologists. However, current deep learning-based methods often focus on blastocyst segmentation, grading, or predicting cell development via time-lapse videos, often overlooking morphokinetic parameters or lacking interpretability. Given the significance of both morphokinetic and morphological evaluation in predicting the implantation potential of cleavage-stage embryos, as emphasized by previous research, there is a necessity for an automated method to segment cleavage-stage embryos to improve this process. RESULTS: In this article, we introduce the SAM-based Dual Branch Segmentation Pipeline for automated segmentation of blastomeres in cleavage-stage embryos. Leveraging the powerful segmentation capability of SAM, the instance branch conducts instance segmentation of blastomeres, while the semantic branch performs semantic segmentation of fragments. Due to the lack of publicly available datasets, we construct the CleavageEmbryo dataset, the first dataset of human cleavage-stage embryos with pixel-level annotations containing fragment information. We train and test a series of state-of-the-art segmentation algorithms on CleavageEmbryo. Our experiments demonstrate that our method outperforms existing algorithms in terms of objective metrics (mAP 0.748 on blastomeres, Dice 0.694 on fragments) and visual quality, enabling more accurate segmentation of cleavage-stage embryos. AVAILABILITY AND IMPLEMENTATION: The code and sample data in this study can be found at: Https://github.com/12austincc/Cleavage-StageEmbryoSegmentation. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Plasma proteomic and polygenic profiling improve risk stratification and personalized screening for colorectal cancer.

This study aims to identify colorectal cancer (CRC)-related proteomic profiles and develop a prediction model for CRC onset by integrating proteomic profiles with genetic and non-genetic factors (QCancer-15) to improve the risk stratification and estimate of personalized initial screening age. Here, using a two-stage strategy, we prioritize 15 protein biomarkers as predictors to construct a protein risk score (ProS). The risk prediction model integrating proteomic profiles with polygenic risk score (PRS) and QCancer-15 risk score (QCancer-S) shows improved performance (C-statistic: 0.79 vs. 0.71, P = 4.94E-03 in training cohort; 0.75 vs 0.69, P = 5.49E-04 in validation cohort) and net benefit than QCancer-S alone. The combined model markedly stratifies the risk of CRC onset. Participants with high ProS, PRS, or combined risk score are proposed to start screening at age 46, 41, or before 40 years old. In this work, the integration of blood proteomics with PRS and QCancer-15 demonstrates improved performance for risk stratification and clinical implication for the derivation of risk-adapted starting ages of CRC screening, which may contribute to the decision-making process for CRC screening.

Speech-language performance and comorbid disorders in children with perisylvian syndrome induced by viral encephalitis.

Importance: Viral encephalitis is one of the main causes of the perisylvian syndrome, which can cause damage to children's language-speech, feeding, and swallowing functions. Comprehensive assessment of language-speech and swallowing function and comorbidity research on these children will help children's rehabilitation workers to better understand the disease and strengthen the systematic management of comorbid disorders. Objective: To describe speech and language pathology and the occurrence of comorbid disorders in children with perisylvian syndrome induced by viral encephalitis. Methods: Twenty-two children with acquired perisylvian syndrome were recruited in this study. Language and speech functions, including oral motor function, swallowing function, language ability, and dysarthria were assessed in these patients. Craniocerebral magnetic resonance imaging (MRI), electroencephalogram examination, and intelligence evaluation were performed to determine brain lesions and comorbid disorders. Results: All children exhibited different degrees of oral movement, dysphagia, and speech and language disorders. There was a significant difference between expressive and receptive language ability (P < 0.05). There were 10, 8, and 12 children who had an intellectual disability, limb disability, and epilepsy, respectively. In addition to the damage of the peri-tegmental cortex found in MRI, thalamus lesions occurred in 19 cases and white matter involvement in six cases. Interpretation: Children with acquired perisylvian syndrome caused by viral encephalitis are characterized by persistent pseudobulbar dysfunction, speech and language impairment, and orofacial diplegia. They have a high probability of secondary epilepsy and are prone to motor and cognitive impairment, which need systematic management.

Allostatic Load, Genetic Susceptibility, Incidence Risk, and All-cause Mortality of Colorectal Cancer.

BACKGROUND: Allostatic load (AL) reflects the cumulative burden of chronic stress throughout life, potentially influencing the onset and prognosis of cancer. However, the associations between AL, colorectal cancer (CRC) risk and all-cause mortality in patients with CRC remain unclear. METHODS: We analyzed the association between AL and CRC risk in 304,959 adults and all-cause mortality in 1,794 patients with CRC from the UK Biobank, using Cox proportional hazards regression models. RESULTS: Compared to the AL level in the first quartile, individuals in the second to fourth quartiles had a respective 20%, 29%, and 43% increased risk of CRC; 15%, 24%, and 42% increased risk for colon cancer; and 30%, 38%, and 45% increased risk for rectal cancer. We identified a positive dose-gradient association of AL score with CRC risk, including colon and rectal cancer. Additionally, the association between AL and increased risk of CRC was observed across different strata of genetic susceptibility for CRC. Eliminating AL exposures could prevent nearly 39.24% (95% CI: 36.16-42.32) of CRC incident cases. Meanwhile, a significant association between the AL and all-cause mortality in patients with CRC was found, with a HR of 1.71 (95% CI: 1.16-2.50) for the fourth quartile compared to the AL score in the first quartile, demonstrating a positive dose-response relationship. CONCLUSION: High AL was associated with increased CRC risk and all-cause mortality in CRC patients. Future research should prioritize the development of cognitive or behavioral intervention strategies to mitigate the adverse effects of AL on CRC incidence and prognosis.

Allostatic load increases the incidence and risk of adverse prognosis in inflammatory bowel disease.

BACKGROUND: Elevated allostatic load (AL) has been associated with the risk and poor prognosis of many chronic diseases. The association between AL and inflammatory bowel disease (IBD) is unknown. AIMS: The aim of this study is to investigate the associations between AL and the risk and prognosis of IBD. METHODS: We included 326,345 adults and 3767 patients with IBD from the UK Biobank. AL served as the exposure, estimated using the AL biomarker panel, with the primary outcomes including the risk and prognosis of IBD. We used Cox regression models to examine the associations. RESULTS: High AL biomarker panel was associated with a greater risk of IBD (hazard ratio: 1.19, 95% CI: 1.08-1.31), ulcerative colitis (1.17, 95%CI: 1.04-1.32), and Crohn's disease (1.25, 95%CI: 1.05-1.49). Risk of developing IBD increased by 12% in quartile 2, 20% in quartile 3, and 37% in quartile 4 as AL biomarker panel increased. The all-cause mortality risk in IBD compared with quartile 1 rose by 54% for quartile 2, 72% for quartile 3, and 82% for quartile 4, as AL biomarker panel increased. Similar effects were also observed for ulcerative colitis and Crohn's disease. An increase in AL biomarker panel count was associated with an elevated risk of intestinal resection and colorectal cancer in IBD. CONCLUSIONS: Increased AL is associated with IBD risk, as well as the risks of intestinal resection, colorectal cancer and mortality.

Multisystem health comorbidity networks of metabolic dysfunction-associated steatotic liver disease.

BACKGROUND: The global burden of metabolic dysfunction-associated steatotic liver disease (MASLD) is growing, but its subsequent health consequences have not been thoroughly examined. METHODS: A phenome-wide association study was conducted to map the associations of MASLD with 948 unique clinical outcomes among 361,021 Europeans in the UK Biobank. Disease trajectory and comorbidity analyses were applied to visualize the sequential patterns of multiple comorbidities related to the occurrence of MASLD. The associations jointly verified by observational and polygenic phenome-wide analyses were further replicated by two-sample Mendelian randomization analysis using data from the FinnGen study and international consortia. FINDINGS: The observational and polygenic phenome-wide association study revealed the associations of MASLD with 96 intrahepatic and extrahepatic diseases, including circulatory, metabolic, genitourinary, neurological, gastrointestinal, and hematologic diseases. Sequential patterns of MASLD-related extrahepatic comorbidities were primarily found in circulatory, metabolic, and inflammatory diseases. Mendelian randomization analyses supported the causal associations between MASLD and the risk of several intrahepatic disorders, metabolic diseases, cardio-cerebrovascular disease, and ascites but found no associations with neurological diseases. CONCLUSIONS: This study elucidated multisystem comorbidities and health consequences of MASLD, contributing to the development of combination interventions targeting distinct pathways for health promotion among patients with MASLD. FUNDING: X.L. was funded by the Natural Science Fund for Distinguished Young Scholars of Zhejiang Province (LR22H260001) and the National Nature Science Foundation of China (82204019) and Y.D. was funded by the Key Project of Traditional Chinese Medicine Science and Technology Plan of Zhejiang Province (GZY-ZJ-KJ-24077) and the National Natural Science Foundation of China (82001673 and 82272860).

How accurate is predicted root movement achieved in four first-premolar extraction cases with Invisalign?

OBJECTIVES: This study aims to compare the achieved and predicted root movements in adults after four first-premolar extractions and Invisalign treatment. MATERIALS AND METHODS: Thirty-three consecutive adults (22 Class I, 9 Cusp-to-cusp Class II and 2 Cusp-to-cusp Class III) from a single clinical division who completed the first series of aligners after premolar extractions were included in this retrospective study. A pretreatment cone-beam computed tomography model was registered onto the pretreatment surface-scanned dental model (SSDM) to locate the pretreatment root apices of the whole dentition. These were copied and transferred to the predicted and achieved post-treatment SSDMs to acquire the locations of the predicted and achieved post-treatment root apices. The differences between predicted and achieved root movements (DPARMs) were tested using the paired t-test or Wilcoxon signed rank test. RESULTS: In the anteroposterior direction, posterior root movements of maxillary and mandibular anterior teeth were poorly achieved (3.24-5.74 mm DPARMs, p < .05). In the vertical direction, roots of maxillary anterior teeth achieved greater intrusion (0.70-0.93 mm DPARMs, p < .05), while those of mandibular incisors achieved less intrusion (0.57-0.65 mm DPARMs, p < .05) than predicted. In the mediolateral direction, lateral incisor roots did not move distally (-0.65 to -0.96 mm DPARMs, p < .05), while those of canines did not move buccally, compared with the prediction (-0.75 mm DPARMs, p < .05). CONCLUSIONS: In the four first-premolar extraction treatments with Invisalign, root movements were not achieved as predicted, particularly for anterior teeth in the anteroposterior direction.

Dietary patterns in the progression of metabolic dysfunction-associated fatty liver disease to advanced liver disease: a prospective cohort study.

BACKGROUND: Metabolic dysfunction-associated fatty liver disease (MAFLD) is a significant health problem. Dietary intervention plays an important role in patients with MAFLD. OBJECTIVES: We aimed to provide a reference for dietary patterns in patients with MAFLD. METHODS: The presence of MAFLD was determined in the United Kingdom Biobank cohort. Nine dietary pattern scores were derived from the dietary records. Multivariable Cox regression models were used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs). The contrast test was employed to calculate the heterogeneity across MAFLD statuses. RESULTS: We identified 175,300 patients with MAFLD at baseline. Compared with non-MAFLD, MAFLD was significantly associated with chronic liver disease (CLD) (HR: 3.48; 95% CI: 3.15, 3.84), severe liver disease (SLD) (HR: 2.87; 95% CI: 2.63, 3.14), liver cancer (HR: 1.93; 95% CI: 1.67, 2.23), and liver-related death (LRD) (HR: 1.93; 95% CI: 1.67, 2.23). In the overall cohort, the alternate Mediterranean diet (aMED) (HRCLD: 0.53; 95% CI: 0.37, 0.76; HRSLD: 0.52; 95% CI: 0.37, 0.72), planetary health diet (PHD) (HRCLD: 0.62; 95% CI: 0.47, 0.81; HRSLD: 0.65; 95% CI: 0.51, 0.83), plant-based low-carbohydrate diet (pLCD) (HRCLD: 0.65; 95% CI: 0.49, 0.86; HRSLD: 0.66; 95% CI: 0.51, 0.85), and healthful plant-based diet index (hPDI) (HRCLD: 0.63; 95% CI: 0.47, 0.84; HRSLD: 0.61; 95% CI: 0.47, 0.78) were associated with a lower risk of CLD and SLD. Additionally, unhealthful plant-based diet index (uPDI) was associated with increased risk of CLD (HR: 1.42; 95% CI: 1.09,1.85), SLD (HR: 1.50; 95% CI: 1.19, 1.90), and LRD (HR: 1.88; 95% CI: 1.28-2.78). The aforementioned associations remained consistently strong within the MAFLD subgroup while exhibiting less pronounced in the non-MAFLD group. However, no significant heterogeneity was observed across different MAFLD statuses. CONCLUSIONS: These findings highlight the detrimental effects of MAFLD on the development of subsequent liver diseases and the importance of dietary patterns in managing MAFLD.

Refining a non-invasive prediction model for neurosyphilis diagnosis by using immunoassay to detect serum anti-TP0435 (TP17) and TP0574 (TP47) IgG antibodies: two-centre cross-sectional retrospective study in China.

OBJECTIVES: Invasive lumbar puncture is the conventional method for diagnosing neurosyphilis (NS). We investigated a non-invasive alternative method to detect serum Treponema pallidum-specific antibodies against highly immunogenic antigens TP0171 (TP15), TP0435 (TP17), and TP0574 (TP47) by using luciferase immunosorbent assay. METHODS: A total of 816 HIV-negative patients suspected of NS from the Beijing and Guangzhou cohorts were retrospectively selected and tested for serum anti-TP15, TP17, and TP47 IgG antibodies. Two diagnostic prediction models were developed using stepwise logistic regression in the Beijing cohort, and evaluated in the Guangzhou cohort for external validation. RESULTS: Serum antibodies against TP15, TP17, and TP47 showed moderate capability for NS diagnosis in the Beijing cohort and the corresponding area under the receiver operating characteristic curves (AUCs) were 0.722 [95% confidence interval (CI): 0.680-0.762)], 0.780 (95% CI: 0.741-0.817), and 0.774 (95% CI: 0.734-0.811), respectively. An expanded NS prediction model integrated with anti-TP17 and anti-TP47 antibodies showed better performance than the base NS diagnostic model without anti-TP17 and anti-TP47 antibodies with the AUC of 0.874 (95% CI: 0.841-0.906) vs. 0.845 (95% CI: 0.809-0.881) (p = 0.007) in the development cohort, and 0.934 (95% CI: 0.909-0.960) vs. 0.877 (95% CI: 0.840-0.914) (p < 0.001) in validation cohort, respectively. Decision curve analysis revealed that the net benefit of the expanded model exceeded that of the base model when the threshold probability was between 0.10 and 0.95 in both the development and external validation cohorts. DISCUSSION: Serum antibodies against TP17 and TP47 exhibited promising diagnostic capability for NS and significantly enhanced the predictive accuracy of model for NS diagnosis. Our study highlights the potential of serum treponemal antibody detection as a non-invasive method for NS diagnosis to substitute invasive lumbar puncture in NS diagnosis.

[NUT cancer of nasal cavity and sinuses: a case report and literature review].

NUT Carcinoma（NC） is a rare malignant tumor of unknown origin, which is highly aggressive. It is characterized by chromosome rearrangement accompanied by NUTM1 gene. The pathological manifestations were sudden and focal squamous in poorly differentiated or undifferentiated carcinoma. NUTM1gene rearrangement can be used to diagnose NC. The prognosis of NUT cancer is poor. Clinically, there is no established treatment plan. treatment options mainly comprise surgery, radiotherapy and chemotherapy. A 74-year-old patient with NC of the nasal cavity and sinuses was reported. Her clinical presentation was right nasal congestion with facial swelling. Sinus CT and MRI showed soft tissue density in the right nasal cavity and maxillary sinus with bone destruction. After admission, the patient underwent nasal endoscopic biopsy, and the postoperative pathological FISH staining showed BRD4/NUT fusion t（15, 19）. The tumor was significantly reduced after two courses of sequential chemoradiotherapy. Two months later, the patient underwent a partial maxillary resection due to the rapid regrowth of sinusoidal mass, invading the hard palate. The patient died 2 months after surgery due to multiple organ failure resulted from tumor metastasis, with a survival time of 11 months. The clinical characteristics, diagnosis and treatment of this case were reported and related literature was reviewed.

Temporal trends and projections in the global burden of neck pain: findings from the Global Burden of Disease Study 2019.

ABSTRACT: Data were obtained from the Global Burden of Disease study 2019. Joinpoint regression model was used to analyze the temporal trends from 1990 to 2019 of neck pain burden, focusing on age-standardized incidence rates, age-standardized prevalence rates, and age-standardized years lived with disability (YLDs) rates at the global, regional, and national levels. The age-period-cohort analysis was used to estimate the effects of age (5-99 years), period (1990-2019), and cohort (1893-2012) at the global, regional, and national levels. Future projections for the global burden of neck pain from 2020 to 2044 were estimated using the nordpred age-period-cohort model. From 1990 to 2019, the global incidence, prevalence cases, and YLDs counts of neck pain have increased by 71.89%, 98.21%, and 78.17%, respectively. The joinpoint analysis indicated significant shifts in the global trends of age-standardized neck pain burden, which varied across regions and nations. The age-period-cohort model indicated that the neck pain burden was predominantly concentrated in middle-aged and older age, with period and cohort effects showing minimal variation from 1990 to 2019. Compared with 2019, the incident cases, prevalent cases, and YLDs counts of neck pain were projected to increase by 134%, 142%, and 140% by 2044. The global burden of neck pain has persisted at a relatively elevated level from 1990 to 2019, with projections indicating a continuing upward trend. Future research is urgently needed to better understand the predictors and clinical course of neck pain and to enhance prevention and management strategies.

Mini Endoscopic Septoplasty for High Localized Nasal Septum Deviation: Surgical Technique, Outcomes, and Comparison With Regular Septoplasty.

OBJECTIVES: This prospective cohort study aimed to describe the technique of mini endoscopic septoplasty for patients with a high localized nasal septum deviation in front of the middle turbinate and chronic sinusitis or nasal sinus fungus ball. Our primary objective was to investigate the indications and outcomes of this procedure, and the secondary objective was to compare it with regular endoscopic septoplasty. METHODS: Patients with chronic sinusitis or nasal sinus fungus ball and high localized nasal septum deviation underwent mini endoscopic septoplasty, while those with a broad deviation of the nasal septum underwent regular endoscopic septoplasty. The study evaluated the procedure duration, blood loss, and complications associated with both methods. All patients were followed up for 3 months. RESULTS: Thirty patients underwent mini endoscopic septoplasty; another 30 underwent regular endoscopic septoplasty. Mini endoscopic septoplasty demonstrated a significantly shorter procedure duration and lower blood loss than regular endoscopic septoplasty. Neither group experienced operative complications, such as nasal septum perforation or hematoma. CONCLUSION: Mini endoscopic septoplasty is a safe, time-efficient, and effective technique indicated for highly localized nasal septum deviations in patients with chronic sinusitis or nasal sinus fungus ball. This procedure offers advantages in terms of the surgical approach and postoperative debridement. Future research could explore the broader clinical implications of these findings.

Impact of ambient air pollution on colorectal cancer risk and survival: insights from a prospective cohort and epigenetic Mendelian randomization study.

BACKGROUND: This study investigates the associations between air pollution and colorectal cancer (CRC) risk and survival from an epigenomic perspective. METHODS: Using a newly developed Air Pollutants Exposure Score (APES), we utilized a prospective cohort study (UK Biobank) to investigate the associations of individual and combined air pollution exposures with CRC incidence and survival, followed by an up-to-date systematic review with meta-analysis to verify the associations. In epigenetic two-sample Mendelian randomization analyses, we examine the associations between genetically predicted DNA methylation related to air pollution and CRC risk. Further genetic colocalization and gene-environment interaction analyses provided different insights to disentangle pathogenic effects of air pollution via epigenetic modification. FINDINGS: During a median 12.97-year follow-up, 5767 incident CRC cases among 428,632 participants free of baseline CRC and 533 deaths in 2401 patients with CRC were documented in the UK Biobank. A higher APES score was associated with an increased CRC risk (HR, 1.03, 95% CI = 1.01-1.06; P = 0.016) and poorer survival (HR, 1.13, 95% CI = 1.03-1.23; P = 0.010), particularly among participants with insufficient physical activity and ever smokers (Pinteraction > 0.05). A subsequent meta-analysis of seven observational studies, including UK Biobank data, corroborated the association between PM2.5 exposure (per 10 µg/m3 increment) and elevated CRC risk (RR,1.42, 95% CI = 1.12-1.79; P = 0.004; I2 = 90.8%). Genetically predicted methylation at PM2.5-related CpG site cg13835894 near TMBIM1/PNKD and cg16235962 near CXCR5, and NO2-related cg16947394 near TMEM110 were associated with an increased CRC risk. Gene-environment interaction analysis confirmed the epigenetic modification of aforementioned CpG sites with CRC risk and survival. INTERPRETATION: Our study suggests the association between air pollution and CRC incidence and survival, underscoring the possible modifying roles of epigenomic factors. Methylation may partly mediate pathogenic effects of air pollution on CRC, with annotation to epigenetic alterations in protein-coding genes TMBIM1/PNKD, CXCR5 and TMEM110. FUNDING: Xue Li is supported by the Natural Science Fund for Distinguished Young Scholars of Zhejiang Province (LR22H260001), the National Nature Science Foundation of China (No. 82204019) and Healthy Zhejiang One Million People Cohort (K-20230085). ET is supported by a Cancer Research UK Career Development Fellowship (C31250/A22804). MGD is supported by the MRC Human Genetics Unit Centre Grant (U127527198).

Systematic investigation of genetically determined plasma and urinary metabolites to discover potential interventional targets for colorectal cancer.

BACKGROUND: We aimed to identify plasma and urinary metabolites related to colorectal cancer (CRC) risk and elucidate their mediator role in the associations between modifiable risk factors and CRC. METHODS: Metabolite quantitative trait loci were derived from 2 published metabolomics genome-wide association studies, and summary-level data were extracted for 651 plasma metabolites and 208 urinary metabolites. Genetic associations with CRC were obtained from a large-scale genome-wide association study meta-analysis (100 204 cases, 154 587 controls) and the FinnGen cohort (4957 cases, 304 197 controls). Mendelian randomization and colocalization analyses were performed to evaluate the causal roles of metabolites in CRC. Druggability evaluation was employed to prioritize potential therapeutic targets. Multivariable Mendelian randomization and mediation estimation were conducted to elucidate the mediating effects of metabolites on the associations between modifiable risk factors and CRC. RESULTS: The study identified 30 plasma metabolites and 4 urinary metabolites for CRC. Plasma sphingomyelin and urinary lactose, which were positively associated with CRC risk, could be modulated by drug interventions (ie, olipudase alfa, tilactase). Thirteen modifiable risk factors were associated with 9 metabolites, and 8 of these modifiable risk factors were associated with CRC risk. These 9 metabolites mediated the effect of modifiable risk factors (Actinobacteria, body mass index, waist to hip ratio, fasting insulin, smoking initiation) on CRC. CONCLUSION: This study identified key metabolite biomarkers associated with CRC and elucidated their mediator roles in the associations between modifiable risk factors and CRC. These findings provide new insights into the etiology and potential therapeutic targets for CRC and the etiological pathways of modifiable environmental factors with CRC.

Evaluating the clinical utility of semi-quantitative luciferase immunosorbent assay using Treponema pallidum antigens in syphilis diagnosis and treatment monitoring.

To assess the clinical applicability of a semi-quantitative luciferase immunosorbent assay (LISA) for detecting antibodies against Treponema pallidum antigens TP0171 (TP15), TP0435 (TP17), and TP0574 (TP47) in diagnosing and monitoring syphilis. LISA for detection of anti-TP15, TP17, and TP47 antibodies were developed and evaluated for syphilis diagnosis using 261 serum samples (161 syphilis, 100 non-syphilis). Ninety serial serum samples from 6 syphilis rabbit models (3 treated, 3 untreated) and 110 paired serum samples from 55 syphilis patients were used to assess treatment effects by utilizing TRUST as a reference. Compared to TPPA, LISA-TP15, LISA-TP17, and LISA-TP47 showed a sensitivity of 91.9%, 96.9%, and 98.8%, specificity of 99%, 99%, and 98%, and AUC of 0.971, 0.992, and 0.995, respectively, in diagnosing syphilis. Strong correlations (rs = 0.89-0.93) with TPPA were observed. In serial serum samples from rabbit models, significant differences in the relative light unit (RLU) were observed between the treatment and control group for LISA-TP17 (days 31-51) and LISA-TP47 (day 41). In paired serum samples from syphilis patients, TRUST titres and the RLU of LISA-TP15, LISA-TP17, and LISA-TP47 decreased post-treatment (P < .001). When TRUST titres decreased by 0, 2, 4, or ≥8-folds, the RLU decreased by 17.53%, 31.34%, 48.62%, and 72.79% for LISA-TP15; 8.84%, 17.00%, 28.37%, and 50.57% for LISA-TP17; 22.25%, 29.79%, 51.75%, and 70.28% for LISA-TP47, respectively. Semi-quantitative LISA performs well for syphilis diagnosis while LISA-TP17 is more effective for monitoring syphilis treatment in rabbit models and clinical patients.

Nuclear KRT19 is a transcriptional corepressor promoting histone deacetylation and liver tumorigenesis.

BACKGROUND AND AIMS: Epigenetic reprogramming and escape from terminal differentiation are poorly understood enabling characteristics of liver cancer. Keratin 19 (KRT19), classically known to form the intermediate filament cytoskeleton, is a marker of stemness and worse prognosis in liver cancer. This study aimed to address the functional roles of KRT19 in liver tumorigenesis and to elucidate the underlying mechanisms. APPROACH AND RESULTS: Using multiplexed genome editing of hepatocytes in vivo, we demonstrated that KRT19 promoted liver tumorigenesis in mice. Cell fractionation revealed a previously unrecognized nuclear fraction of KRT19. Tandem affinity purification identified histone deacetylase 1 and REST corepressor 1, components of the corepressor of RE-1 silencing transcription factor (CoREST) complex as KRT19-interacting proteins. KRT19 knockout markedly enhanced histone acetylation levels. Mechanistically, KRT19 promotes CoREST complex formation by enhancing histone deacetylase 1 and REST corepressor 1 interaction, thus increasing the deacetylase activity. ChIP-seq revealed hepatocyte-specific genes, such as hepatocyte nuclear factor 4 alpha ( HNF4A ), as direct targets of KRT19-CoREST. In addition, we identified forkhead box P4 as a direct activator of aberrant KRT19 expression in liver cancer. Furthermore, treatment of primary liver tumors and patient-derived xenografts in mice suggest that KRT19 expression has the potential to predict response to histone deacetylase 1 inhibitors especially in combination with lenvatinib. CONCLUSIONS: Our data show that nuclear KRT19 acts as a transcriptional corepressor through promoting the deacetylase activity of the CoREST complex, resulting in dedifferentiation of liver cancer. These findings reveal a previously unrecognized function of KRT19 in directly shaping the epigenetic landscape in cancer.

Risk and incidence of cardiovascular disease associated with polycystic ovary syndrome.

AIMS: We aimed to evaluate the risk of cardiovascular disease (CVD) in women with polycystic ovary syndrome (PCOS) and estimate the global incidence of PCOS-associated CVD. METHODS AND RESULTS: We conducted a meta-analysis across five databases to evaluate the risk of CVD among women with PCOS. The global incidence of PCOS-associated CVD was calculated by a population attributable fraction modelling using the pooled risk ratio (RR), PCOS prevalence, CVD incidence number, and age-standardized rate (ASIR), from the Global Burden of Diseases 2019. An estimated annual percentage change (EAPC) was used to assess the temporal trend of PCOS-associated CVD. The risk of CVD was significantly increased in women with PCOS for an all-age group (pooled RR 1.51, 95% confidence interval 1.36-1.69) and 10- to 54-year-olds (1.37, 1.17-1.59). Globally, from 1990 to 2019, the PCOS-associated CVD cases in women across the all-age group has raised from 102 530 to 235 560. The most affected regions were East Asia and the Pacific (108 430, 66 090-166 150) in 2019. South Asia has the highest increase trend of PCOS-associated CVD ASIRs (EAPC 2.61%, 2.49-2.73). The annual increase in ASIR in PCOS-CVD incidence for the 10-54 age group (EAPC 0.49%, 0.41-0.56) is faster than that of the all-age group (0.34, 0.27-0.42). The middle- or low-middle sociodemographic index countries experienced higher increase trend of CVD due to PCOS in the past 30 years. CONCLUSION: Women with PCOS have a significantly increased risk of CVD. Efficient measures to enhance its prevention and treatment are important for regions with a high PCOS-associated CVD burden, especially premature CVD in women under 55 years.

Studies have reported that cardiovascular disease (CVD) is the leading cause of mortality for women. Meanwhile, women with polycystic ovary syndrome (PCOS) substantially elevate the risk of CVD. However, no studies have quantified the impact of PCOS on the overall CVD burden. This study performed a meta-analysis to assess the risk of CVD in an all-age group and 10- to 54-year-old women, living with PCOS with 17 articles, and estimated the burdens of PCOS-associated CVD burden globally, in 7 World Bank­defined regions, and in 204 countries, from 1990 to 2019, using population attributable fraction (PAF) modelling. Our study implicated that women in all-age group and 10 to 54 years old with PCOS face a 1.51-fold and 1.37-fold increased risk of CVD compared to those without, respectively. Globally, ∼0.85% of CVD new cases in 2019 were associated with PCOS, corresponding to a more than two-fold increase in PCOS-associated CVD cases from 1990. However, the burden of PCOS-associated CVD varies widely by region; for instance, nearly 1.49% of CVD new cases were attributed to PCOS in North America. Meanwhile, the East Asia and Pacific region had the highest PCOS-associated new CVD case, and South Asia experienced the highest increase in age-standardized incidence rates of CVD due to PCOS. Notably, we found higher worldwide PAFs and an annual increase in ASIR than that in all-age group women. This result suggests that premature CVDs in women with PCOS under 55 years deserve more attention.